Development and Developmental Disorders of the Forebrain

ten Donkelaar, Hans J.; Lammens, Martin; Cruysberg, Johannes R. M.; Ulzen, Karin Kamphuis-van; Hori, Akira; Shiota, Kohei

doi:10.1007/978-3-642-54687-7_9

Hans J. ten Donkelaar M.D., Ph.D.⁴,
Martin Lammens M.D., Ph.D.⁵,
Johannes R. M. Cruysberg M.D., Ph.D.⁶,
Karin Kamphuis-van Ulzen M.D.⁷,
Akira Hori M.D., Ph.D.^8,9 &
…
Kohei Shiota M.D., Ph.D.^10,11

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2 Citations

Abstract

Neurulation has been extensively studied in amphibian, avian and mammalian embryos and occurs in four stages: formation of the neural plate, shaping of the neural plate, bending of the neural plate and closure of the neural groove. The rostral part of the neural tube develops into the brain, whereas the caudal part becomes the spinal cord. This is the primary type of neurulation (Sect. 4.2). The most caudal part of the neural tube forms by aggregation of cells into a medullary cord which then cavitates and connects to the main neural tube. This process is called secondary neurulation (Sect. 4.3).

Neural tube defects (NTDs) are among the most common of human malformations with an incidence of 1-5 per 1,000 live births. Genetic mouse models for NTDs are discussed in Sect. 4.4, the aetiology of human NTDs in Sect. 4.5 and prenatal diagnosis and fetal therapy in Sect. 4.6. Cranial neural tube defects (anencephaly, encephaloceles and cranial meningoceles) are discussed in Sect. 4.7 and illustrated in several Clinical cases. In Sect. 4.8, spinal neural tube defects are discussed and again illustrated in several Clinical cases, followed by the Chiari malformations (Sect. 4.9) and caudal dysgenesis (Sect. 4.10).

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Neurulation and Neural Tube Defects

Embryology of Occult Spinal Dysraphisms

Development and Developmental Disorders of the Forebrain

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9.1 Introduction

The forebrain comprises those structures that are derived from the most rostral part of the neural plate, i.e. the primary prosencephalon. The primary prosencephalon divides into two major components, the (epichordal) caudal diencephalon and the rostral secondary prosencephalon. The secondary prosencephalon is the entire prechordal part of the neural tube, and includes the rostral diencephalon or hypothalamus, the optic vesicles, the preoptic region and the telencephalon. The derivatives of the forebrain are shown in MR images of human embryos (Fig. 9.1). The two major telencephalic subdivisions are the pallium (the roof) and the subpallium (the base). The pallium gives rise to the cerebral cortex, whereas the basal ganglia and most cortical interneurons derive from the subpallium. The amygdala has pallial as well as subpallial origins. Like the rest of the neural tube, the embryonic forebrain appears to be organized into transverse (prosomeres) and longitudinal subdivisions (alar and basal plates; Fig. 9.2). The caudal diencephalon arises from the prosomeres 1–3, whereas the rostral diencephalon was suggested to arise from the prosomeres 4–6 (Bergquist and Källén 1954; Puelles 1995; Rubinstein et al. 1998; Puelles et al. 2000). The relationship of these postulated segments to telencephalic subdivisions, however, remained controversial. More recently Puelles and Rubinstein (2003), revised their prosomeric subdivision of the forebrain by advocating a single, complex protosegment for the secondary prosencephalon, not further subdividable into prosomeres 4–6, but later again they distinguished two hypothalamic prosomeres and the acroterminal region as the most rostral part of the forebrain (Sect. 9.2). The theoretical framework of the prosomeric model has been extensively discussed by Puelles et al. (2012a).

Patterning of the forebrain involves the two general sets of mechanisms common to the neural plate, one along the anteroposterior axis and the other along the mediolateral axis (Chap. 2). An additional dorsal-ventral patterning mechanism is important for subdividing the telencephalon into dorsal, pallial and ventral, subpallial structures (Marín and Rubinstein 2002; Campbell 2003; Zaki et al. 2003; Sousa and Fishell 2010; Medina and Abellán 2012). Genetic engineering has produced a great variety of knockout mice and zebrafish, the study of which has greatly improved our knowledge of these patterning mechanisms (Schier 2001; Marín and Rubinstein 2002; Rallu et al. 2002b; Zaki et al. 2003; Tvrdik and Capecchi 2012). Defects in mediolateral patterning lead to the prosencephalies, a group of complex malformations of the forebrain, involving the hypothalamus, the eyes and the basal telencephalon. Holoprosencephaly (HPE) is the most common developmental malformation of the forebrain, ranging from 1 in 16,000 in live births to 1 in 250 in therapeutic abortions (Matsunaga and Shiota 1977; Shiota 1993; Muenke and Beachy 2001; Cohen and Shiota 2002; Shiota and Yamada 2010). Several developmental pathways such as those operating the Sonic hedgehog (SHH) and Nodal signalling factors are involved in the pathogenesis of HPE and laterality defects (Roessler and Muenke 2001, 2010; Cohen 2010; Sect. 9.7.2). In this chapter the development of the various derivatives of the embryonic forebrain and disorders that may appear during this development, HPE in particular, will be discussed. The further development of the cerebral cortex and its disorders will be discussed in Chap. 10.

9.2 Prosomeres and Pattern Formation of the Forebrain

Already during neurulation, the prosencephalon becomes subdivided into two transverse proneuromeric regions, known as the caudal, epichordal, proneuromere, giving rise to the caudal diencephalon, and the rostral, prechordal, proneuromere forming the secondary prosencephalon (Fig. 9.2). The secondary prosencephalon gives rise to the telencephalon, the eye vesicles and the hypothalamus or rostral diencephalon (Puelles 1995; Shimamura et al. 1995; Rubinstein et al. 1998; Puelles and Rubinstein 2003; Puelles et al. 2008, 2012a). The prosencephalic proneuromeres were subsequently subdivided into smaller transverse domains known as prosomeres (Puelles et al. 1987; Bulfone et al. 1993; Puelles 1995; Rubinstein et al. 1998; Puelles et al. 2000, 2008, 2013), which are composed of alar and basal components. Prosomeres P1–P3 form the diencephalon proper or caudal diencephalon: P1 is known as the synencephalon, P2 as the caudal parencephalon and P3 as the rostral parencephalon. The alar component of the synencephalon forms the pretectum, that of the caudal parencephalon the epithalamus and dorsal thalamus, and that of the rostral parencephalon the ventral thalamus or prethalamus. The basal components form the rostral part of the dopaminergic substantia nigra-ventral tegmental area of Tsai (VTA) complex and the interstitial nucleus of Cajal, some related nuclei and the fields of Forel, collectively the diencephalic or prerubral tegmentum. Molecular marker expression data in chicken and mouse embryos suggest the zona limitans intrathalamica (ZLI) or mid-diencephalic organizer as a bona fide compartment with local signalling function (Scholpp and Lumsden 2010; Kiecker and Lumsden 2012. The protosegment, previously described as the prosomeres P4–P6 gives rise to the secondary prosencephalon. From this prechordal part of the prosencephalon the hypothalamus or rostral diencephalon, the optic vesicles and the telencephalon arise (Puelles and Rubinstein 2003; Puelles et al. 2012a, 2013). Two hypothalamic prosomeres can be distinguished, a rostral (terminal) and a caudal (peduncular) one. The basal plate of the secondary prosencephalon gives rise to various subdivisions of the hypothalamus, as originally defined for human embryos by His (1893; Keyser 1972, 1979), and the subthalamic nucleus, whereas from the alar part the anterior hypothalamus, the supraoptic nucleus (SON) and paraventricular nucleus (PVN) and the entire telencephalon arise. From the most rostral part of the secondary prosencephalon, known as the acroterminal region, the commissural plate, the eye vesicles, the most rostral parts of the hypothalamus and the neurohypophysis arise (Fig. 9.3).

Fate mapping experiments suggest that the telencephalon derives from the anterolateral neural plate and the anterior neural ridge (Chap. 2). Ventral parts of the forebrain such as the hypothalamus and the eye vesicles arise from the medial part of the prosencephalic part of the neural plate. Pallial and subpallial parts of the telencephalon arise from the lateral parts of the prosencephalic neural plate. The lateral border of this part of the neural plate forms the dorsal, septal part of the telencephalon, whereas its rostral, median part gives rise to the commissural plate from which the anterior commissure, the corpus callosum and the hippocampal commissure arise. During the formation of the neural plate, anteroposterior patterning within the forebrain appears to be controlled by the anterior neural ridge at the rostral end of the neural plate (Shimamura and Rubinstein 1997; Houart et al. 1998, 2002; Marín and Rubinstein 2002; Rallu et al. 2002b). Its patterning properties may be mediated by FGF8. FGF8 signalling regulates the expression of Foxg1 (earlier known as brain factor 1 or BF1), a transcription factor that is required for normal telencephalic and cortical morphogenesis (Shimamura et al. 1995; Shimamura and Rubinstein 1997; Monuki and Walsh 2001). In all vertebrates studied, the forkhead transcription factor Foxg1, previously named BF-1, is one of the first transcription factors expressed in the neural plate telencephalic territory (Danesin and Houart 2012). It has been shown to be essential to many aspects of telencephalic development. Loss and gain of function mutations in the FOXG1 gene have been found to cause severe intellectual disability such as Rett syndrome, epilepsy and microcephaly (Chap. 10). In zebrafish and mice, Foxg1 orchestrates dorsoventral patterning of the telencephalon by integrating several signalling centres (Danesin et al. 2009): Foxg1-depleted telencephalic cells fail to adopt a ventral identity and transform into more dorsal fates. Early Wnt signalling appears to be required in formation of the pallium. Activation of the pathway is done by Wnt8b, secreted by the telencephalic dorsal signalling centre. Partition of the telencephalon in subpallial and pallial halves therefore depends upon Hh (secreted by the telencephalic floor) and Wnt (secreted by the roof plate) signalling. Foxg1 acts as an integrator of these two signalling activities in telencephalic progenitors.

Coordinate regulation and synergistic actions of BMP4, SHH and FGF8 in the rostral prosencephalon regulate morphogenesis of the telencephalic and optic vesicles (Hébert et al. 2002; Ohkubo et al. 2002). In mice, reduction in FGF8 expression in the anterior neural ridge leads to rostral midline defects in the forebrain (Shanmugalingam et al. 2000), similar to that described in mice lacking the Foxg1 gene (Xuan et al. 1995; Dou et al. 1999). Fibroblast growth factor (FGF) signalling is also required for olfactory bulb morphogenesis (Hébert et al. 2003). The olfactory bulb may be particularly susceptible to FGF signalling as observed in mouse embryos carrying a hypomorphic allele of Fgf8 (Meyers et al. 1998): they lack olfactory bulbs. Hébert et al. (2003) showed that the FGF receptor gene Fgfr1 is essential for the formation of the olfactory bulb. In Fgfr1 mutant mice, only small bulb-like protrusions are formed. Anteroposterior patterning of the rest of the telencephalon appears to be largely normal in Fgfr1 mutants.

Whereas anteroposterior patterning of the forebrain generates transverse subdivisions, i.e. the prosomeres, mediolateral patterning generates longitudinal subdivision of the neural plate into alar and basal plates (Fig. 9.4). Mediolateral patterning of the forebrain involves signals from the axial mesendoderm (the prechordal plate) and non-neural ectoderm (Rubinstein and Beachy 1998; Lee and Jessell 1999). Medial or ventral patterning of the prosencephalic part of the neural plate is primarily regulated by the prechordal plate through SHH signalling, whereas its lateral or dorsal patterning is mediated by members of the transforming growth factor β (TGFβ) superfamily such as bone morphogenetic proteins (BMPs) and growth differentiating factors, largely derived from the neural ridge and non-neural ectoderm flanking the anterior neural plate. Mouse embryos that lack SHH fail to form normal ventral brain structures and show markedly reduced expression of ventral markers (Chiang et al. 1996; Litingtung and Chiang 2000; Rallu et al. 2002a, b). In Drosophila, all hedgehog signalling is mediated through the cubitus interruptus (ci) gene (Aza-Blanc and Kornberg 1999). The mammalian homologues of ci, the Gli genes, have a similar function. Gli1 and Gli2 act as activators and Gli3 mainly as a repressor (Matise and Joyner 1999). In Gli3 mutant mice, ventral telencephalic markers expand dorsally into the cortex (Grove et al. 1998; Theil et al. 1999; Rallu et al. 2002a, b). The balance between Shh and Gli3 gene function appears to be crucial for the establishment of dorsoventral patterning within the telencephalon (Rallu et al. 2002b; Sousa and Fishell 2010). The SHH-GLI pathway may be deregulated in brain tumours (Dahmane et al. 2001; Biesecker 2008; Chap. 8).

9.3 Development of the Diencephalon

The diencephalon in its classic, columnar view (Herrick 1910; Droogleever Fortuyn 1912) was divided into four dorsoventrally arranged columns separated by ventricular sulci, i.e. the epithalamus, the dorsal thalamus, the ventral thalamus or subthalamus, and the hypothalamus (Fig. 9.5). Extensive embryological studies by the Swedish school of neuroembryologists (Bergquist and Källén 1954; Chap. 2) and a more recent Spanish school initiated by Luis Puelles made it clear that the thalamic ‘columns’ are derived from transversely oriented zones, the prosomeres. Currently, the diencephalon is subdivided into three segmental units (Puelles et al. 2008, 2012a, b, 2013; Figs. 9.3 and 9.6) which, from caudal to rostral, contain in their alar domains the pretectum (prosomere 1 or P1), the epithalamus and the thalamus (P2), and the prethalamus and the eminentia thalami (P3). The diencephalic basal plate contains the substantia nigra-VTA complex, the interstitial nucleus of Cajal and related nuclei and the fields of Forel, collectively the prerubral tegmentum (Fig. 9.6). The entire hypothalamus arises from the alar and basal components of the secondary prosencephalic protomere. The neurohypophysis appears to arise very rostrally from the acroterminal region (included in P6). Several genes show a diencephalic prosomere-related pattern, including Gbx2 (Bulfone et al. 1993; Miyashita-Lin et al. 1999), Otx1/Otx2 (Simeone et al. 1992, 1993; Larsen et al. 2001; Zeltser et al. 2001), Pax6 (Stoykova et al. 1996; Grindley et al. 1997), Dlx2 (Larsen et al. 2001; Zeltser et al. 2001), and Dlx5 and Math4a (González et al. 2002; Fig. 9.29). For more recent data, see the Allen Developing Mouse Brain Atlas (http://developingmouse.brain-map.org). Emx2 cooperates with Otx2 at the onset of its expression to generate the territory of the future diencephalon (Suda et al. 2001). The ZLI is established by the interaction between Fez and Otx genes (Scholpp and Lumsden 2010). The first step in generating neuronal diversity in the thalamus is the formation of spatial diversity of thalamic progenitor cells, which is controlled by locally expressed signalling molecules such as Shh, Wnt proteins and Fgf8 (Nakagawa and Shimogori 2012).

9.3.1 Development of the Thalamus

The development of the human thalamus has been rather extensively studied with classic staining techniques (Schwalbe 1880; Gilbert 1935; Cooper 1950; Dekaban 1954; Kuhlenbeck 1954; Yamadori 1965; Yakovlev 1969; Kostović 1990; Mojsilović and Zečević 1991). The thalamus is involved in central processing of sensory, motor and limbic functions. Early in development, the human diencephalon is thin-walled, but later the anlage of the thalamus expands enormously. Due to this expansion, the telencephalic-diencephalic boundary plane enlarges and changes its orientation from more or less transverse to almost rostrocaudal. Moreover, the lateral geniculate body becomes laterocaudally displaced.

The dorsal thalamus or, more appropriately, the thalamus is largely composed of nuclei, relaying sensory, motor and limbic information to the cerebral cortex and subpallial structures. The following groups are usually distinguished (Jones 1985; Hirai and Jones 1989; Armstrong 1990; Onye 1990; Morel et al. 1997; Voogd et al. 1998; Percheron 2004), partly separated by the internal medullary lamina (Fig. 9.7a):

1.
A lateral group, involved in somatosensory relay (nucleus ventralis posterior complex) and motor control (nuclei ventralis lateralis and ventralis anterior).
2.
A medial group, formed by the mediodorsal nucleus with extensive projections to the prefrontal cortex, and midline and intralaminar nuclei with projections to the striatum and to that part of the cerebral cortex that innervates the same part of the striatum.
3.
An anterior group, relaying information from the mammillary nuclei to the limbic cortex, the cingulate cortex in particular. The more posteriorly situated laterodorsal nucleus is often associated with the anterior group for its connections with the cingulate gyrus.
4.
A large posterior group is composed of the posterior complex, involved in pain transmission, the nucleus lateralis posterior and the pulvinar, involved in visual orientation, eye movements and accommodation, and the medial and lateral geniculate nuclei which relay auditory and visual information, respectively.

The thalamocortical and corticothalamic projections pass via the internal capsule (Chap. 10). The maturation of thalamic radiations between 34 and 41 weeks of gestation has been studied with DTI (Aeby et al. 2009). The cortical projection areas of the main thalamic nuclei in the adult human brain are shown in Fig. 9.7b, c.

The ventral thalamus is usually said to be composed of the ventral lateral geniculate or pregeniculate nucleus, the thalamic reticular nucleus and the zona incerta. Puelles and Rubinstein (2003) advocated the term prethalamus as an alternative. The thalamic reticular nucleus is a shell-like structure along the lateral border of the thalamus, and is situated between the external medullary lamina and the internal capsule (Fig. 9.7a). The human fetal reticular nucleus consists of four subdivisions, clearly visible in the sixth/seventh gestational month (Ulfig et al. 1998; Ulfig 2002b). The main portion and the perireticular nucleus are prominent structures. Both parts are dramatically reduced in size during further development. The perireticular nucleus is not even visible in the adult brain (Ulfig et al. 1998). In rats, the perireticular nucleus also disappears almost completely (Mitrofanis and Baker 1993; Earle and Mitrofanis 1996). These transient features can be correlated with the role of the reticular nucleus in guiding outgrowing thalamocortical axons and as an intermediate target for corticofugal fibres (Mitrofanis 1992; Mitrofanis and Baker 1993; Earle and Mitrofanis 1996).

The subthalamic nucleus is usually included in the basal ganglia, but is a dorsally migrated hypothalamic cell mass, which originated from the retromammillary area (Keyser 1972; Marchand et al. 1986; Skidmore et al. 2008). This migration can be easily verified in the Allen Atlas using the gene markers Pitx2 and Foxp1 (Puelles et al. 2012a). Therefore, the subthalamic nucleus must be classified as a hypothalamic nucleus.

In rodents, the birthdays of the thalamic nuclei have been extensively analysed in [³H]thymidine studies (Angevine 1970, 1978; Keyser 1972; McAllister and Das 1977; Altman and Bayer 1979a, b, c; Bayer and Altman 1995a, b). Most thalamic nuclei are born between E13 and E19 (Table 9.1). Spatiotemporal gradients were found in the time of origin of thalamic nuclei (Fig. 9.8), in general, caudorostrally, ventrodorsally and outside-in oriented. Cells of posterior thalamic nuclei are born before those of anterior nuclei. Ventral thalamic nuclei such as the reticular nucleus are generated slightly earlier than dorsal thalamic nuclei. Lateral nuclei are born before medial nuclei such as the mediodorsal nucleus. Bayer et al. (1995) estimated that in human embryos the reticular nucleus and the medial and lateral geniculate nuclei are generated from late in week 5 to week 6 of development, ventrobasal complex neurons from late in week 5 up to the middle of week 7 of development, and the anterior complex from weeks 7–11 (Table 9.1). Two thalamic nuclei in particular received much attention, the lateral geniculate nucleus (LGN) and the pulvinar.

Table 9.1 Time of neuron origin data of diencephalic nuclei in Chinese hamsters, rats and estimated data for the human brain

Full size table

The development of the LGN or corpus geniculatum laterale (CGL) has been extensively studied in rat (Brückner et al. 1976; Lund and Mustari 1977), cat (Shatz et al. 1990), ferret (Sur and Leamey 2001), rhesus monkey (Rakic 1977a, b) and human (Gilbert 1935; Cooper 1945, Dekaban 1954; Hitchcock and Hickey 1980; Hevner 2000) embryonic and fetal material. In the rhesus monkey, LGN neurons are generated during 8–9 days at the end of the first quarter of the 165-day gestational period. The first neurons are generated at E36, approximately 6 days after the first retinal ganglion cells are being born (Rakic 1977a, b). Several generations of neurons produced in a restricted area of the ventricular zone appear to migrate along a single cellular fascicle and accumulate in a column-shaped aggregate. Neurons are generated along an outside-in gradient (Fig. 9.9). Initially, the axis of this gradient is oriented lateromedially but later becomes oriented ventrodorsally, so that in the mature monkey, early generated neurons lie in the ventral magnocellular layers, whereas neurons generated later become part of the dorsal parvocellular layers. In the human brain, the CGL develops its characteristic six-layered structure from the 22nd until the 25th gestational week (Cooper 1945; Dekaban 1954; Hitchcock and Hickey 1980). Its cell layers are initially oriented parallel to the dorsoventral axis but, owing to rotation and differential growth of the thalamus, become oriented almost parallel to the mediolateral axis by the time of birth (Hevner 2000).

The pulvinar, the most prominent thalamic nucleus in the human brain, is not only generated in the diencephalic ventricular zone but, moreover, receives neurons from the ganglionic eminence of the telencephalon (Fig. 9.10). Rakić and Sidman (1969) showed that between the 16th and 34th week of gestation, cells pass from the medial ganglionic eminence into the lateral and posterior parts of the thalamus. Most of these neurons appear to migrate along a transient fetal structure, the gangliothalamic body. In a subsequent study of the fetal monkey brain, Ogren and Rakic (1981) were unable to demonstrate the presence of a gangliothalamic body, and suggested that this migration pathway is a unique feature of the developing human brain. Letinić and Kostović (1997) found the gangliothalamic body between 15 and 34 gestational weeks along the entire rostrocaudal thalamus, particularly at the level of the anterior nuclear complex, the mediodorsal nucleus, the pulvinar and the CGL, and suggested that, apart from the pulvinar, also the mediodorsal and anterior nuclei and the CGL are recipients of telencephalic neurons. Letinić and Rakic (2001) showed that these neurons are GABAergic and express Dlx1/Dlx2. A similar migratory pathway has not been found in non-human primates and rodents (Anderson et al. 1997a, 1999; Lavdas et al. 1999; Wichterle et al. 1999, 2001), supporting the idea that it may be a special feature of human thalamic development. GABAergic neurons are absent in many thalamic nuclei, except for the CGL (Harris and Hendrickson 1978; Ottersen and Storm-Mathisen 1984), but in the primate brain GABAergic cells form approximately 30 % of the neurons in every thalamic nucleus (Montero and Zempel 1986).

Thalamocortical projections arise rather early in development. Yamadori (1965) studied the development of thalamocortical projections in 5–130-mm-long human embryos. The first fibres were already recognized in the thalamus of a 5-mm embryo (approximately 3 weeks of development). Developing thalamocortical axons leave the thalamus ventrally and turn dorsolaterally at the telencephalic-diencephalic boundary. They advance below the ganglionic eminences and pause at the corticostriatal junction before entering the developing cerebral cortex. The earliest corticofugal projections, most of which originate from preplate neurons as shown in rodents, pause within the corticostriatal junction. In rodents, the corticostriatal junction has been characterized by lack of both Emx1 and Dlx1 gene expression and the presence of Pax6 expression (Smith-Fernández et al. 1998; Puelles et al. 2000; Zaki et al. 2003; Fig. 9.29, Table 9.2). Experiments in rodents indicate that the ganglionic eminence may be an intermediate target for corticofugal and thalamocortical axons (Métin and Godement 1996; Garel et al. 2002), and that the corticostriatal junction plays an active role in the further development of these connections (Molnár et al. 1998, 2012; Auladell et al. 2000; Molnár and Hannan 2000; Molnár and Butler 2002). It has become increasingly clear that several mechanisms are involved at different stages of thalamocortical development, and each contributes substantially to the eventual outcome (Molnár et al. 2012; Chap. 2). Subsequent to their interaction with cells at the corticostriatal junction, thalamocortical and corticofugal fibres proceed, intimately associated with each other, to their targets. They become ‘captured’ for a waiting period in the subplate before entering the cortical plate (Shatz et al. 1990).

Table 9.2 Summary of mutant mice with altered early thalamocortical development

Full size table

Thalamocortical projections display two levels of topographic organization (Molnár 1998; López-Bendito and Molnár 2003; Marín 2003). First, specific thalamic nuclei, relaying distinct modalities of sensory (visual, somatosensory, auditory) or motor information, project to specific neocortical areas (interareal topography). In rodents, these thalamic nuclei are arranged following a more or less caudolateral to rostromedial gradient, whereas their corresponding cortical targets are found in caudorostral progression in the cortex. This interareal topography arises early in development and appears to be largely independent of functional activity within the thalamocortical radiation. The second level of topographic organization concerns the topic representation of different parts of the body, retina or inner ear in projections of thalamic nuclei to their cortical targets, resulting in somatotopic, retinotopic and tonotopic maps, respectively. This second level of topographic mapping appears later in development than interareal topography. It is redefined during the first postnatal weeks, partly through activity-dependent mechanisms (López-Bendito and Molnár 2003). Interareal topography may be explained by the expression of localized cues within the cortex, controlling the targeting of thalamic axons, or by the ‘handshake hypothesis’ (Blakemore and Molnár 1990; Molnár and Blakemore 1995; Molnár 1998; Fig. 9.11; Chap. 2). In this hypothesis it has been proposed that axons from the thalamus and from the early-born cortical preplate cells meet and intermingle in the basal telencephalon, so that thalamic axons grow over the scaffold of preplate axons. In mouse mutants (Table 9.2), often the disruption of thalamocortical and corticothalamic fibres is correlated (Cohen et al. 1997; Dahme et al. 1997; Kawano et al. 1999; Tuttle et al. 1999; Braisted et al. 2000; Mallamacci et al. 2000; Stoykova et al. 2000; Hevner et al. 2001, 2002; Jones et al. 2002; Molnár and Butler 2002; Molnár et al. 2012). Garel et al. (2002) showed that the establishment of topographic thalamocortical projections is not strictly determined by cortical cues, but instead is influenced by the relative position of thalamic axons inside the ventral telencephalon (Vanderhaeghen and Polleux 2004). It seems likely that the topographic organization that thalamic axons adopt in the cortex is already set upon their entry into the telencephalon, and that any alteration of their topography in this intermediate target results in a parallel perturbation of their topography in the cortex. Therefore, the development of interareal topography within the thalamocortical system occurs through the sorting out of thalamocortical axons in the ventral telencephalon. This sorting out is controlled by ephrins (Dufour et al. 2003; Seibt et al. 2003; Vanderhaeghen and Polleux 2004).

9.3.2 Development of the Hypothalamus

The hypothalamus is involved in a wide variety of functions in the brain. Alterations in hypothalamic nuclei are found in various endocrine diseases such as diabetes insipidus, Wolfram and Prader-Willi syndromes, and in various neurodegenerative diseases such as Alzheimer, Parkinson and Huntington diseases (reviewed in Swaab 1997, 2004). The hypothalamus is usually subdivided into four regions (Fig. 9.12), from caudal to rostral: (1) the mammillary region; (2) the tuberal region; (3) the anterior complex; and (4) the preoptic region (Braak and Braak 1987, 1992; Swaab et al. 1993; Swaab 1997, 2003; Voogd et al. 1998; Saper 2004), although the preoptic region is of subpallial origin. From a developmental point of view, however, three longitudinal subdivisions of the hypothalamus can be distinguished (Angevine 1970; Altman and Bayer 1986; Mai and Ashwell 2004) as originally proposed by Crosby and Woodburne (1940; Nauta and Haymaker 1969): a periventricular zone, an intermediate zone, and a lateral zone. The hypothalamus is now thought to arise from that part of the secondary prosencephalon that is known as the rostral diencephalon (Puelles and Rubinstein 2003).

The prosomeric approach to the development of the hypothalamus (Puelles et al. 2008, 2012a) revealed rostral (terminal) and caudal (peduncular) parts of the hypothalamus, earlier known as hypothalamic domains 2 and 1 and roughly comparable to Herrick’s ventral and dorsal hypothalamus, respectively (Figs. 9.3 and 9.6). The most rostral part, the acroterminal territory, is characterized by Six6 and Foxb1 gene expression (Conte et al. 2005; Zhao et al. 2008). Shimogori et al. (2010) identified over 1,000 genes expressed dynamically over the course of hypothalamic development. Only a handful of them have been analysed functionally in any detail. The scaffold of molecularly delimited major progenitor domains detected in the hypothalamus is formed by two alar and three basal domains in each of the two hypothalamic parts. The addition of the corresponding acroterminal areas makes a total of at least 15 distinct major histogenetic territories, some of which may be further subdivided (Puelles et al. 2012a). This emphasizes that the hypothalamus must be considered more complex than previously assumed.

Early steps in the development of the hypothalamus include the induction of hypothalamic identity and the migration of hypothalamic precursors. The prechordal plate provides the SHH protein necessary for the formation of the hypothalamus. In mice lacking the Shh gene, hypothalamic tissue is absent, whereas overexpression of SHH leads to ectopic expression of hypothalamic markers (Mathieu et al. 2002). Disturbance of the development of hypothalamic nuclei may be due to disruption of genes involved in neurogenesis (Otp), cell migration (Otp, SF-1), cell death (Brn2, Sim1, Arnt2) and differentiation (Nkx2.1). Brn4 knockout mice show a loss of the SON and PVN, and in mice with mutations in the gene encoding for the nuclear receptor SF-1 the ventromedial hypothalamic nucleus is absent (Martin and Camper 2001). These data suggest that similar defects may exist in human disease (Swaab 2003).

In rodents, in autoradiographic studies the hypothalamic nuclei were found to be generated mainly from E13 until E16, and preoptic nuclei over an even more protracted period, extending from E12 until E19 (Angevine 1970, 1978; Keyser 1972; Altman and Bayer 1978a, b; 1986; Bayer and Altman 1987a; Fig. 9.8, Table 9.1). The sexually dimorphic nucleus (SDN; Gorski et al. 1978) originates exceptionally late (E15-E19). Extrapolated to the human brain, hypothalamic nuclei would be generated between the fifth and the eighth week of development, and those from the preoptic region from weeks 4 to 11 of development (Bayer et al. 1995; Table 9.1). In the fetal human hypothalamus, Koutcherov et al. (2002); see also Mai and Ashwell 2004 found three waves of neurogenesis and migration as in the rodent brain (Altman and Bayer 1986). The first neurons generated migrate into the future lateral longitudinal zone of the hypothalamus where they form the lateral hypothalamic area, the posterior hypothalamus, the lateral tuberal nucleus and the perifornical nucleus. The second wave of postmitotic neurons form the nuclei of an intermediate longitudinal zone, including the medial preoptic nucleus, the anterior hypothalamic nucleus, the ventromedial and the dorsomedial nuclei, and the mammillary body. The last neurons to be generated differentiate in close proximity to the periventricular zone, and form the suprachiasmatic nucleus, the arcuate nucleus, the PVN and the SON. All nuclei are apparent early fetally.

In humans, the sexually dimorphic nucleus (SDN) is located between the SON and the PVN. In young adult males, this nucleus is twice as large as in adult women (Swaab and Fliers 1985; Swaab et al. 1993; Swaab 1997, 2003). At birth, only about 20 % of the SDN neurons are present and sexual dimorphism is not found in the human brain. From birth up to the age of 4 years, cell numbers increase equally rapid in both sexes. About the fourth year postnatally, the number of cells starts to decrease in girls (Swaab and Hofman 1988). The large neurosecretory cells of the supraoptic nucleus (SON) and paraventricular (PVN) nucleus produce the neuropeptides vasopressin and oxytocin, and innervate the neurohypophysis (Dierickx and Vandesande 1977). Vasopressin acts as antidiuretic hormone in the kidney and, in women, oxytocin is involved in labour and lactation. The infundibular nucleus contains, among many other neuropeptides and transmitters, gonadotropin-releasing hormone (GnRH) neurons, earlier known as luteinizing hormone-releasing hormone (LHRH) neurons (Muske 1993; Swaab 1997, 2003). GnRH neurons are found in the human fetal hypothalamus from the 9th week of development. The GnRH neurons are generated in the epithelium of the medial olfactory pit and migrate from the nose into the forebrain along branches of the terminal and vomeronasal nerves rich in the neural cell adhesion molecule NCAM (Schwanzel-Fukuda and Pfaff 1989; Schwanzel-Fukuda et al. 1989). No GnRH neurons were seen in the brain until a bridge of the terminal and vomeronasal nerves was formed between the nose and the forebrain. Observations in Kallmann syndrome (Sect. 9.7.4) suggested that GnRH neurons fail to migrate from the olfactory placode into the developing brain (Schwanzel-Fukuda et al. 1989). In human embryos, GnRH-immunoreactivity was first detected in the olfactory epithelium and in cells associated with the terminal and vomeronasal nerves at 42 days of gestation (Schwanzel-Fukuda et al. 1996). GnRH neurons appear to have multiple embryonic origins (Muske 1993; Northcutt and Muske 1994), however: the olfactory placode giving rise to the septo-preoptic system, and a second, non-placodal structure giving rise to the posterior GnRH neurons.

9.3.3 Development of the Pituitary Gland

The development of the human hypophysis cerebri or pituitary gland has been extensively studied (Atwell 1926; Conklin 1968; Andersen et al. 1971; Ikeda et al. 1988; O’Rahilly and Müller 2001). It consists of two main parts, the adenohypophysis and the neurohypophysis that form the sellar pituitary. The two components are in close contact from the beginning (Figs. 9.13, 9.14, and 9.15). The area of contact between Rathke’s pouch (Rathke 1838) and the forebrain gradually moves from rostral to caudal and, after 13 weeks of development, has a position similar to that found in the newborn (Ikeda et al. 1988).

The adenohypophysial primordium is induced by the adjacent floor of the rostral forebrain, from which the neurohypophysis develops (Sheng and Westphal 1999). In amphibian and avian embryos, the adenohypophysis originates from the anterior neural ridge (Eagleson et al. 1986; Couly and Le Douarin 1987; Chap. 2). In rats, it arises from a small area just anterior to the rostral end of the neural plate (Kouki et al. 2001). The neurohypophysis arises from the most rostral part of the secondary prosencephalon, the acroterminal region (Puelles and Rubinstein 2003; Puelles et al. 2012a). At the time Rathke’s pouch forms, the oral ectoderm is in direct contact with the neuroectoderm of the ventral forebrain (Fig. 9.13), without intervening mesoderm (Schwind 1928). In in vitro tissue recombination assays a dramatic effect of neuroectoderm on the growth and differentiation of Rathke’s pouch has been demonstrated (Daikoku et al. 1982; Watanabe 1982). The homeobox gene Nkx2.1, expressed in the ventral forebrain but not in the oral ectoderm or Rathke’s pouch (Lazzaro et al. 1991), may provide the inductive signal. In Nkx2.1 mutants, apart from severe defects in the development of the forebrain, the pituitary gland is ablated (Kimura et al. 1996). A two-step induction of Rathke’s pouch is required (Watkins-Chow and Camper 1998; Sheng and Westphal 1999; Dattani and Robinson 2000; Zhu and Rosenfeld 2004). Both a BMP4 signal and FGF8 activity from the ventral forebrain are required for the development of a definitive pouch. Initially, at E8.5, BMP4 induces the oral ectoderm to form a pouch placode. Formation of the definitive pouch requires the activation of two LIM homeobox factors (Lhx3 and Lhx4) in the rudiment. FGF8, expressed in the ventral forebrain at E9.25, provides the signal that initiates and maintains Lhx gene expression in the pouch (Sheng et al. 1997; Sheng and Westphal 1999; Zhu and Rosenfeld 2004). Hedgehog signalling is also required for pituitary gland development (Treier et al. 2001). In rats, by E12.5 pituitary-specific cell types are formed (Camper et al. 2002). Pitx1 and Pitx2 regulate precursor and cell-type specific proliferation (Szeto et al. 1999; Suh et al. 2002). Targeted disruption of the Pitx1 gene results in minor defects in later phases of pituitary development and defects in hindlimb and craniofacial morphogenesis (Kioussi et al. 2002), whereas Pitx2−/− mice display multiple developmental defects, including failure of body-wall closure, cardiac outflow tract abnormalities and defects in pituitary, eye and tooth development (Gage et al. 1999; Kitamura et al. 1999; Lin et al. 1999). Invagination of Rathke’s pouch and direct contact with the neuroepithelium occur normally, but the pituitary is developmentally arrested by E10.5. Hesx1 regulates pituitary proliferation indirectly through the interaction with Tle genes (Dasen et al. 2001). Deletion of Hesx1 results in either a complete lack of the pituitary gland (5 %) or multiple oral ectoderm invagination and/or cellular overproliferation of all pituitary cell types (Dattani et al. 1998; Martinez-Barbera et al. 2000; Dasen et al. 2001). Members of the Six homeodomain gene family (Six1, Six3, Six6) are required for tissue-specific precursor proliferation (Zhu and Rosenfeld 2004). Six1 and Eya modulate precursor cell proliferation in many organs, including the eyes, the pituitary, the auditory system, the kidneys and somites (Li et al. 2003).

In human embryos, the primordium of the adenohypophysis is situated immediately rostral to the oropharyngeal membrane at stage 11, and forms the adenohypophysial pouch. Between stages 14 and 17, the floor of the forebrain forms the neurohypophysial evagination, and by stages 20 and 21, the pouch loses its contact with the roof of the mouth (Figs. 9.14 and 9.15). The portion of the pouch that is in contact with the neurohypophysial evagination forms the pars intermedia of the hypophysis. Other parts of the adenohypophysis that surround the stalk of the neurohypophysis form the pars tuberalis, and the remaining part the pars distalis. The oropharyngeal part remains as the pharyngeal hypophysis throughout life (Boyd 1956). Rathke’s pouch migrates together with the pituitary cells, and remnants may be found in the sellar pituitary (Kjaer and Fischer-Hansen 1995; Hori et al. 1999b). Pituitary hormones are produced at the end of the embryonic period. In immunohistochemical studies of human embryonic and fetal pituitaries, adrenocorticotropic hormone and somatotropic hormone were demonstrated at gestational week 8, whereas thyrotropic hormone, follicle-stimulating hormone, luteinizing hormone and prolactin-releasing hormone were found at week 12 (Asa et al. 1986, 1988; Ikeda et al. 1988).

9.3.4 Developmental Disorders of the Hypothalamus and the Pituitary Gland

Developmental disorders of the hypothalamus are common in anencephaly and in HPE and related disorders. In anencephaly and in fetuses with HPE, adenohypophysial tissue was found not only in the sella turcica but also in the open craniopharyngeal canal (Nakano 1973; Kjaer and Fischer-Hansen 1995; Hori et al. 1999a, b). The intermediate part of the pituitary and the neurohypohysis are absent in most of the anencephalic cases studied (Nakano 1973; Visser and Swaab 1979). The adrenocorticotropic deficiency of the distal part of the pituitary is evident from the fact that the adrenal glands in anencephalics are invariably hypoplastic (Nakano 1973; Visser and Swaab 1979; Mazzitelli et al. 2002). At 17–18 weeks of gestation, the number and size of adrenocorticotropic hormone cells in the anencephalic pituitary gland are normal, but after 32 weeks their number and size are reduced (Pilavdzic et al. 1997). The involvement of the hypothalamus in HPE is discussed in Sect. 9.7.2.

Panhypopituitarism may also occur in transsphenoidal encephaloceles (Chong and Newton 1993; Brodsky et al. 1995; Morioka et al. 1995). These sporadic and rare anomalies are often associated with other midline anomalies such as cleft palate, hypertelorism, colobomata and agenesis of the corpus callosum. A 50 % reduction in the number of oxytocinergic PVN neurons was found in patients with Prader-Willi syndrome (Gabreëls et al. 1994, 1998; Gabreëls 1998), which is characterized by gross obesity and insatiable hunger. This syndrome is further characterized by diminished fetal motility, severe infantile hypotonia, intellectual disability, hypogonadism and hypogenitalism (Prader et al. 1956). Diabetes insipidus may have different hypothalamic causes. Apart from trauma, haemorrhage, inflammation and surgical manipulations, familial hypothalamic diabetes insipidus is found, owing to point mutations in the vasopressin-neurophysin-glycopeptide gene (Ito et al. 1991; Bahnsen et al. 1992; Nagasaki et al. 1995; Rittig et al. 1996). Available postmortem data suggest severe neuronal death in the SON and PVN in cases of familial hypothalamic diabetes insipidus associated with a loss of innervation of the posterior pituitary (Braverman et al. 1965; Nagai et al. 1984; Bergeron et al. 1991). Diabetes insipidus is also observed as part of midline developmental anomalies such as HPE and septo-optic dysplasia. The SON and PVN are also affected in Wolfram syndrome, an autosomal recessive disorder involving diabetes insipidus, diabetes mellitus, slowly progressive atrophy of the optic nerve and deafness (Wolfram 1938; Carson et al. 1977; Cremers et al. 1977). The PVN contains vasopressin neurons that cannot produce vasopressin by a precursor-processing deficiency.

Pituitary malformations include agenesis of the anterior pituitary gland (Brewer 1957; Larroche 1981), partial agenesis of anterior pituitary components (Miyai et al. 1971; Sato et al. 1975), a hidden pituitary gland (Paroder et al. 2013), duplication of the entire pituitary (Hori 1983; Hori et al. 1999b; Clinical Case 9.1) and ectopias (Decker 1985; Colohan et al. 1987; Ikeda et al. 1987). Developmental anomalies of the anterior pituitary include non-separation of the primary pituitary gland into sellar and pharyngeal components, a pharyngosellar pituitary (Hori et al. 1995; Clinical Case 9.2), and ectopic migration into the subarachnoid space. Invasion of basophil cells into the posterior lobe, the frequency and intensity of which increase in accordance with aging, is rather a physiological phenomenon (Hori et al. 1999a, b; Swaab 2004). Novel mutations in the homeobox gene Hesx1/HESX1 may play a role in undescended or ectopic posterior pituitary (Brickman et al. 2001). Pallister-Hall syndrome, a highly variable autosomal dominant disorder is due to mutations in the GLI3 gene (Kang et al. 1997; Biesecker 2008; Clinical Case 9.3).

Clinical Case 9.1 Duplication of the Pituitary Gland

Duplication of parts of the CNS has been observed occasionally. In a 26-day-old female baby, Hori (1983) described a brain with two complete pituitary glands, associated with malformations of ventral midline structures of the CNS and cranium (see Case Report). This rare condition of double hypophysis should be classified among the median cleft face syndrome (DeMyer 1967; Gorlin et al. 1977) in contrast to reported cases of double hypophysis in partial twinning (Ahlfeld 1880; Morton 1957; Warkany 1971). In the present case, the pituitary anlage, both of neurohypophysis and adenohypophysis, may have been divided during early development due to a median cleft. Subsequent histogenesis of each separate anlage may have caused duplication of the hypophysis.

Case Report. The child was born at term after an uncomplicated pregnancy and delivery, apart from an umbilical hernia operation on the 23-year-old mother early in her pregnancy. Apgar scores were 6/7/9 and asphyxia was evident, so the baby received assisted respiration for several days until her discharge. She was readmitted at the age of 26 days because of feeding difficulties. General examination revealed a V-shaped frontal hair line, hypertelorism, cleft palate, low-set ears, retrognathia, a wide prominent nasal root and a split on the top of the nose. Neurological and laboratory (chromosomal, amino acid and blood analyses) findings were normal. On X-ray examination no clear contour of the sella turcica was seen. The baby was in no distress at the time of admission. Shortly after feeding, she was found dead in bed the same evening. Hereditary diseases or malformations were not apparent in the family.

At autopsy, body weight was 2,750 g and length 54 cm. The head was not enlarged and the fontanelles were of normal size. After removal of the brain, the ‘sella’ appeared shallow and empty. Instead, two sellae were found situated on either side of the regular one, posterior to both optic canals (Fig. 9.16a). Both sellae contained a pituitary gland beneath the sellar diaphragm. Histologically, both hypophyses were completely normal. The distance between the optic canals was 2.3 cm (normal about 1.1 cm), and that between the cribriform plates 2 cm (normal about 0.8 cm). The very short clivus had a round midline defect, through which a stalk of connective tissue, extending from the leptomeninx of the pontine base, protruded into the nasal cavity. Histologically, the connective tissue consisted of collagen fibres and striated tissue with a small penetrating artery. The posterior fossa was of normal size. At the base of the brain (Fig. 9.16b), the olfactory bulbs and tracts were set widely apart, and the optic chiasm had a wide angle. A mass of hyperplastic tissue displaced the mammillary bodies laterally. The circle of Willis was abnormal with a very short basilar artery and elongated posterior communicating arteries. Between these communicating arteries and the vertebral arteries, two ectopic masses were found, measuring 2.5 mm × 4 mm and 3 mm × 5 mm, respectively. These contained neurons and myelinated fibres. In the forebrain, the corpus callosum, the anterior commissure and the posterior cingulate gyri were absent. The pineal gland had its normal position. Between the laterally displaced mammillary bodies, a mass of hypothalamic tissue formed the base of the third ventricle. This tissue contained magnocellular and medium-sized neurons without glial proliferation of any importance. Posterior to the chiasm, two hypophyseal stalks were present. Heterotopia were found in the tegmental raphe ventral to the aqueduct, in a slit-like deep floor of the rhomboid fossa of the medulla oblongata and in the dentate nuclei. The spinal cord showed a duplicated anterior median fissure at the cervico-thoracic level. In between, hyperplastic grey matter with myelinated fibers protruded from the central spinal grey matter. Posterior roots entered the cord not only medial but also lateral to the posterior horn. Immunohistochemical staining for anterior pituitary hormones, performed recently, revealed no abnormalities in the distribution of the hormone-producing cells in both of the pituitary glands. Since hedgehog signalling is required for both pituitary development (Sect. 9.3.3) and for the development of the ventral part of the spinal cord (Chap. 6), the presence of duplication of the pituitary gland and of part of the ventral spinal cord may be related to SHH signalling.

References

Ahlfeld F (1880) Die Mißbildungen des Menschen. Grunow, Leipzig

DeMyer W (1967) The median cleft face syndrome. Differential diagnosis of cranium bifidum occultum, hypertelorism, and median cleft nose, lip and palate. Neurology 17:961–971

Gorlin RJ, Červenka J, Cohen MM Jr (1977) “Newer” facial clefting syndromes. Birth defects, original article series 13:1–9

Hori A (1983) A brain with two hypophyses in median cleft face syndrome. Acta Neuropathol (Berl) 59:150–154

Morton WRM (1957) Duplication of the pituitary and stomatodaeal structures in a 38-week male infant. Arch Dis Child 32:135–141

Warkany J (1971) Congenital malformations. Year Book Med Publ, Chicago, p 419

Clinical Case 9.2 Pharyngosellar Pituitary

In pharyngosellar pituitary, the anterior part of the gland is continuous from the pharyngeal roof to the sella turcica. Hori et al. (1995) described this rare malformation in a 17-gestational-week-old male fetus with an encephalocele and amnion rupture sequence (see Case Report). The first description of this anomaly was made by Müller (1958). Later, this anomaly was found in several cases of trisomy 18 (Kjaer et al. 1998).

Case Report. The pregnancy of a 27-year-old mother was unremarkable until at gestational week 17 the amnion was ruptured and the fetus was aborted spontaneously. The male fetus had a crown-heel length of 19 cm, a head circumference of 10 cm and weighed 190 g. Morphological examination of the fetus revealed a slight double cleft lip, left cleft palate, adhesive strangs at the nose, forehead and right hand, and short eye fissures with slight hypertelorism. A large encephalocele covered with skin was observed in the vertex of the microcephalic head, and an additional smaller encephalocele was found on the left forehead. After removing the covering of the head, a large round skull defect was found through which the larger encephalocele herniated. The skull base was hypoplastic: the anterior cranial fossa was narrow in transverse diameter, the middle fossa was shallow and the posterior fossa was normal in size. Anterior and posterior protuberances of the sella were absent. The pituitary gland was found in the ordinary position when observed from the cranial base. The encephalocele consisted of telencephalic tissue with molecular and neuronal cortical cell layers, white matter as well as basal ganglia-like structures. Part of the skull base, including the sella turcica, clivus and pharyngeal roof, was removed and divided through the midline (Fig. 9.17a); both blocks were embedded in paraffin without decalcification and sliced serially. Sections were stained by haematoxylin and eosin, periodic acid-Schiff (PAS) stain, and Gomori’s reticulin staining. Immunostaining for pituitary hormones was also performed.

The pituitary gland was found in the persistent craniopharyngeal canal as an elongated structure expanding from the pharyngeal roof to the sella turcica (Fig. 9.17b), forming a pharyngosellar pituitary. Reconstruction of the pharyngosellar pituitary from the histological sections revealed that the pituitary was composed of sellar and pharyngeal parts. The pituitary tissue was covered with a poorly ciliated epithelial layer at its pharyngeal end. The majority of the cell constituents of the pituitary gland were histologically chromophobic. The pituitary stalk and the posterior lobe were histologically normal. Immunohistochemical examination for anterior pituitary hormones showed that the distribution of hormone-producing cells in the malformed pituitary tissue was irregular: thyrotropic hormone (TSH) producing, follicle stimulating hormone (FSH) producing and luteinizing hormone (LH) producing cells were nearly absent in the sellar and middle sections of the pituitary but were found in small numbers mainly in the pharyngeal part of the pituitary. Somatotropic hormone (STH) producing, prolactin releasing hormone (PRL) producing, and adrenocorticotropic hormone (ACTH) producing cells were distributed diffusely. ACTH-producing cells were abundant in the pharyngeal part. Only few TSH-, FSH- and LH-producing cells were found in the sellar and middle sections. They were mostly found in the pharyngeal section.

References

Hori A, Schmidt D, Feyerabend B (1995) Pharyngosellar pituitary: a rare developmental anomaly of the pituitary gland. Acta Neuropathol (Berl) 89:459–463

Kjaer I, Kreeling JW, Reintoft I, Hjalgrim H, Nolting D, Hansen BF (1998) Pituitary gland and sella turcica in human trisomy 18 fetuses. Am J Med Genet 76:87–92

Müller W (1958) On the pharyngeal hypophysis. In: Currie AR (ed) Endocrine aspects of breast cancer. Proceedings of a conference held at the University of Glasgow, 8–10 July 1957. Livingstone, Edinburgh, pp 106–110

Clinical Case 9.3 Pallister-Hall Syndrome

Pallister-Hall syndrome is a developmental disorder consisting of hypothalamic hamartoma, pituitary dysfunction, polydactyly and visceral malformations. This syndrome was first reported in infants (Clarren et al. 1980; Hall et al. 1980). It consists of hamartoblastomas of the hypothalamus with primitive, undifferentiated neurons. The disorder is inherited as an autosomal dominant trait with incomplete penetration, variable expressivity or gonadal or somatic mosaicism (Penman Splitt et al. 1994) and has been mapped to chromosome 7p13. Most cases are sporadic (Kuo et al. 1999). Hamartoblastomas probably arise in the fifth week of pregnancy and seem to be part of a complex pleitrophic congenital syndrome that includes absence of the pituitary, craniofacial abnormalities, cleft palate, malformations of the epiglottis or the larynx, congenital heart defects, hypopituitarism, short-limb dwarfism with postaxial polydactyly, anorectal atresia, renal anomalies and abnormal lung lobulation and hypogenitalism (see Case Report).

Case report: Twins, born at the 35th week of gestation, both died shortly after birth. The first died on the second postnatal day with multiple malformations as the second child, but no autopsy was performed. The second child presented with multiple malformations such as facial dysmorphism, heptasyndactyly of the hands, hexadactyly of the feet and imperforate anus and died six days later due to anuria. At autopsy, other urogenital malformations were found including renal hypoplasia, ureter atresia and genital hypoplasia. Neuropathological examination revealed a large hamartoma of the hypothalamus and complete agenesis of the pituitary gland (Fig. 9.18). A diagnosis of Pallister-Hall syndrome was made. Histological examination showed ‘matrix cell’ aggregation and a few ganglion-like cells.

References

Clarren SK, Alvord EC Jr, Hall JC (1980) Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly – a new syndrome? Part 2: Neuropathologic considerations. Am J Med Genet 7:75–83

Hall JG, Pallister PD, Clarren SK, Beckwith JB, Wigglesworth FW, Fraser FC (1980) Ibid. Part 1: clinical, causal, and pathogenetic considerations. Am J Med Genet 7:47–74

Kuo J, Casey SO, Thompson L, Truwit CL (1999) Pallister-Hall syndrome: clinical and MR features. AJNR Am J Neuroradiol 20:1839–1841

Penman Splitt M, Wright C, Perry R, Burn J (1994) Autosomal dominant transmission of Pallister-Hall syndrome. Clin Dysmorphol 3:301–308

9.4 Development of the Visual System

9.4.1 Development of the Eye

The optic primordia are present very early in development (Mann 1928; O’Rahilly 1966; Hinrichsen 1990; Barishak 2001; O’Rahilly and Müller 2001; Sundin 2012). Presumably, a single eye field exists at the rostral end of the neural plate, the median part of which is suppressed under the influence of the prechordal plate, resulting in bilateral optic primordia (Li et al. 1997). In pioneering studies in Ambystoma, Adelmann (1929a, b, 1930, 1936a, b) showed that the vertebrate eye first develops as a single developmental field. Factors supplied by the prechordal plate are then required for its separation into two distinct eye structures. Any perturbation of this process may lead to cyclopia (Sect. 9.7.2). The lens arises from the surface ectoderm. In human embryos, the optic primordium becomes first visible as the optic sulcus appears in each neural fold at stage 10, i.e. at about 4 weeks of development. The right and left primordia are connected by a ridge that will become the optic chiasm. The optic sulcus deepens and forms an evagination at stage 11, leading to the formation of the optic vesicle at stage 12 (Figs. 9.19 and 9.20). By 4.5 weeks, the optic vesicle and the adjacent surface ectoderm thicken and form at stage 13 the retinal disc and the lens disc, respectively. The retinal disc becomes invaginated, resulting in a double-layered optic cup. This invagination extends partly onto the stalk of the optic cup to form the transient retinal fissure. A disturbance in the closure of the retinal fissure may lead to a coloboma (Fig. 9.21). The inverted layer of the optic cup is readily comparable to the wall of the developing forebrain. The walls of the optic cup form the optic part of the retina and the epithelium of the ciliary body and the iris. The lens disc becomes indented to form the lens pit at stage 14 which closes at stage 15 to form the lens vesicle. At the same time, retinal pigment appears in the external layer of the optic cup. The cells of the deep wall of the lens vesicle become elongated and form the primary lens fibres. Anterior cells of the lens form a simple epithelium from which the secondary lens fibres arise that form the bulk of the mature lens. Moreover, the primary vitreous body and the hyaloid artery develop. The hyaloid artery enters the vitreous cavity through the retinal fissure and supplies the thickened inner layer, the lens vesicle and the intervening mesenchyme. Later, the hyaloid artery disappears within the eye. Its stem forms the central retinal artery. The optic cup is anchored to the forebrain by the optic stalk that will form the optic nerve. Axons of retinal ganglion cells grow via the optic stalk to the brain. The lumen of the optic stalk is gradually obliterated as axons of ganglion cells accumulate in the inner layer of the optic stalk, resulting in the formation of the optic nerve between the sixth and eighth weeks of development. The optic vesicle becomes enveloped by a sheath of neural-crest-derived mesenchyme. This sheath forms the two coverings of the eye: the thin inner choroid and the fibrous outer sclera.

The development of the retina is shown in Fig. 9.22. The thinner outer layer of the optic cup becomes the pigmented layer of the retina. The inner layer can soon be divided into a thicker nine-layered posterior part, the pars optica retinae, which develops into the visual receptive part of the retina, and a thinner, one-layered part, the pars caeca retinae. The pars caeca does not develop photoreceptive cells and becomes subdivided into a posterior part, the pars ciliaris retinae, and an anterior part firmly fused with the outer pigmented layer to form the pars iridis retinae. The cavity of the optic vesicle is soon occluded by the apposition of its inner layer to the pigmented layer. The intraretinal space, separating the two layers, is obliterated as the retina develops, but the two layers never fuse firmly. The differentiation of the neural retina takes place between the sixth week and the eighth month (Mann 1928; Hinrichsen 1990; O’Rahilly and Müller 2001). By the fifth week the first of a series of shifts in nuclear arrangement occurs, resulting in the formation of an inner layer devoid of cells, and an outer nuclear layer. About the middle of the sixth week cells of the outer nuclear layer migrate centrally and form an inner cellular zone. Between the two layers the transient layer of Chievitz appears. In the third month the ganglion cells arise from the inner neuroblastic layer. As additional cells migrate from the outer neuroblastic layer to the inner zone, the layer of Chievitz disappears. Now, three nuclear zones can be distinguished separated by fibrous layers. From within outwards, these nuclear zones are the ganglion cell layer, the inner nuclear layer and the outer nuclear layer. The majority of the cells of the inner nuclear layer give rise to the bipolar neurons which relay impulses from the rods and cones to the ganglion cells. The cells in the outer layer form the rods and cones. Vascularization of the retina begins at about 15 weeks of development (Ashton 1970). Retinal cell diversity is achieved by the sequential production of cell types in a defined histogenetic order (Provis et al. 1985a; Young 1985; Dowling 1987; Fuhrmann et al. 2000; Marquardt and Gruss 2002). Retinal ganglion cells and horizontal cells differentiate first, followed in overlapping phases by cone photoreceptors, amacrine cells, rod photoreceptors, bipolar cells and, finally, Müller glia cells.

9.4.2 Congenital Malformations of the Eye

Genetic control of eye development has been extensively studied in the embryonic mouse brain (Macdonald and Wilson 1996; Graw 2000, 2003; Hirsch and Grainger 2000; Wawersik et al. 2000; Horsford et al. 2001; Pichaud and Desplan 2002; Sundin 2012). Mutations in at least ten human transcription factor genes have been shown to disrupt eye development. A large number of additional mouse transcription factor genes are also associated with developmental abnormalities of the eye (Hirsch and Grainger 2000; Graw 2000, 2003; Kerryson and Newman 2007; Sundin 2012). Human eye phenotypes can involve one or more ocular structures. Developmental anomalies that affect many parts of the eye are known as panocular defects, whereas other abnormalities may be restricted to the anterior segment, the posterior segment or the differentiation or maintenance of photoreceptors. Examples of such anomalies are shown in Clinical Cases 9.4 and 9.5. For a summary of prenatal imaging of the eye see Broaddus et al. (2012).

Panocular defects are broad phenotypes (Table 9.3) that arise by at least two different general mechanisms (Horsford et al. 2001; Graw 2003; Sachdeva and Traboulsi 2012). The first mechanism, shown for heterozygous mutations in the paired box gene PAX6, reflects the fact that the gene is expressed in and required for the normal development of all regions of the developing eye. The second mechanism by which panocular defects arise is due to mutations in genes such as CHX10 that are expressed in one region of the developing eye but, via secondary physiological processes, are essential for the normal development of other ocular structures. Pax6 is one of the nine members of the Pax gene family unified by the presence of a paired domain. The paired domain is a 128 aminoacid DNA-binding domain named after the prototypical Drosophila segment polarity gene paired. Haploinsufficiency for PAX6 function in humans leads to aniridia (Clinical Case 9.4), a heritable panocular disorder characterized by iris and foveal hypoplasia which can be accompanied by cataracts, corneal opacification, and progressive glaucoma (Glaser et al. 1995; Horsford et al. 2001; Sachdeva and Traboulsi 2012). Mutations in PAX6 have also been found in patients with Peters anomaly, congenital cataract, autosomal dominant keratopathy and isolated foveal hypoplasia (Prosser and van Heyningen 1998; van Heyningen and Williamson 2002, 2008; Sachdeva and Traboulsi 2012).

Table 9.3 Inherited eye diseases in man and mice due to mutations in transcription factor genes: panocular defects

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In mice, a naturally occurring mutation, Small eye (Sey), results from mutations in the Pax6 gene (Hill et al. 1991). Like human aniridia, Sey is inherited in a semidominant fashion, with Sey/+ heterozygotes showing corneal and lenticular abnormalities and Sey/Sey homozygotes lacking eyes entirely (Hogan et al. 1986). In Sey/Sey embryos, the lens and nasal placodes fail to develop, the optic vesicle fails to constrict and subsequently degenerates, and mesenchymal cells become interposed between the surface ectoderm and the optic vesicle (Hogan et al. 1988). Moreover, in Sey homozygotes, the anterior commissure, the corpus callosum and the olfactory bulbs are absent (Schmahl et al. 1993; Stoykova et al. 1996). In mice, the optic vesicle forms at E8.5 and comes into contact with the head and ectoderm at E9.0. Signals from the optic vesicle induce the lens placode to form by E9.5. At E10.0, the lens placode invaginates to form a lens pit, while the optic vesicle infolds and becomes the optic cup. The invagination of the lens pit is complete at E10.5, at which time the vesicle begins to separate from the overlying ectoderm. Normally, Pax6 is expressed in both the head ectoderm and the optic vesicle at E8.5, prior to lens induction (Walther and Gruss 1991; Grindley et al. 1995). At E9.5, prior to thickening of the head ectoderm to form the lens placode, the expression of Pax6 becomes restricted to the presumptive placodal region. In later stages, Pax6 is expressed in the optic cup as well as in the invaginated lens placode. The close similarities in phenotype and mode of inheritance between aniridia and Sey suggest that Pax6 functions in a similar way in human and mouse eye development (van Heyningen and Williamson 2002, 2008). Mild extraocular phenotypes are found in Sey, including olfactory bulb hypoplasia, axon guidance defects, cortical plate hypocellularity and decreased basal ganglia volume (Schmahl et al. 1993; Stoykova et al. 1996; Mastick et al. 1997). Using MRI and smell testing, Sisodiya et al. (2001) showed absence or hypoplasia of the anterior commissure and reduced olfaction in a large proportion of aniridia cases. Moreover, Ellison-Wright et al. (2004) found that individuals with aniridia have structural abnormalities of grey matter in the anterior cingulate cortex, the cerebellum and the medial temporal lobe as well as white matter deficits in the corpus callosum. Functional MRI demonstrated reduced activation of fronto-striato-thalamic systems during performance of, for instance, overt verbal fluency (Ellison-Wright et al. 2004). Therefore, PAX6 haploinsufficiency appears to cause more widespread malformations than previously thought.

CHX10, a paired-like homeodomain protein, regulates neuronal development, particularly the proliferation of interneurons. Homozygous putative null mutations of the CHX10 homeobox gene affect only the eye, resulting in blindness with microphthalmia and cataracts (Horsford et al. 2001). Its mouse equivalent, known as ocular retardation (or), is a recessive mutant with abnormal eye development. Homozygous or mice are blind with obvious microphthalmia, cataract, a poorly differentiated, thin retina, and no optic nerve (Truslove 1962; Theiler et al. 1976; Silver and Robb 1979). Burmeister et al. (1996) showed that the allele or ¹ has a premature stop codon in the homeobox of the Chx10 gene.

Anterior segment defects primarily affect the anterior chamber, iris, lens, cornea and trabecular network, and are phenotypically varied (Table 9.4). They result from mutations in a number of different transcription factor genes: the forkhead cluster FOXC1/FOXF2/FOXQ1, the paired-like/bicoid-like homeodomain genes PITX2 and PITX3, and the leucine zipper transcription factor MITF (Table 9.3). Similar phenotypes result from mutations at different loci, and there is a phenotypic overlap with some PAX6 missense mutations (Horsford et al. 2001; Smith and Traboulsi 2012). Genetic manipulations in murine embryos suggest that Pax6 regulates responsiveness of the head ectoderm to the inductive effect of the optic vesicle and Prox1 probably regulates signal reception from the retina in promoting lens fibre development. Sox2/Sox3 and Maf encoded proteins are probably the key factors of lens cell differentiation. Pax6 inhibits expression of genes for fibre characteristics in the epithelial cells, whereas Sox1 and c-Maf/L-Maf support fibre differentiation (Kondoh 1999; Hirsch and Grainger 2000; Smith and Traboulsi 2012). Autosomal dominant Waardenburg syndrome type 2A is associated with mutations in MITF (Tassabehji et al. 1994). MITF is expressed predominantly in developing pigment cells and neural crest cells. The mouse microphthalmia (mi) mutation, first described by Hertwig (1942), includes at least 17 mutant alleles at chromosome 6 (Steingrimsson et al. 1994). The affected gene encodes Mitf (microphthalmia-associated transcription factors).

Table 9.4 Inherited eye diseases in man and mice due to mutations in transcription factor genes: anterior segment defects

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Congenital aphakia (absence of the lens) in man occurs in primary and secondary forms (Vermeij-Keers 1975). Primary absence of the lens is characterized by the total absence of the lens or lens primordium, the iris and the anterior chamber, whereas secondary forms result from disturbances during lens development at a later stage by rubella infection and other factors affecting normal lens development. Several mouse mutants are known (Graw 2000).

Posterior segment defects, affecting only the retina and optic nerve, include optic nerve defects due to mutations in PAX2 and HESX1, and abnormalities in photoreceptor differentiation or maintenance due to mutations in CRX and NRL (Santos and Traboulsi 2012; Table 9.5). In 2012, more than 170 genes were known to cause retinal diseases (Retnet: http://www.sph.uth.tmc.edu/Retnet). In mouse embryos, Pax2 is expressed during the morphogenesis of the optic cup and stalk, and in the period of axogenesis (Nornes et al. 1990). In Pax2 null mutants (Torres et al. 1996) and in the Pax2 ^Neu mutation (Favor et al. 1996), the pigmented retina extends into the optic stalk, the optic fissure fails to close, leading to coloboma, no optic chiasm is formed, and some malformations of the inner ear are found. The mouse Pax2 ^Neu mutation is identical to a human PAX2 mutation in a family with renal-coloboma syndrome and results in developing defects of the brain, eye, ear and kidney (Favor et al. 1996). ‘Renal coloboma syndrome’ is more appropriately called papillorenal syndrome, because the dysplastic disks in papillorenal syndrome show no absence of ocular tissue owing to incomplete closure of the embryonic optic fissure, and consequently no characteristics of coloboma (Parsa et al. 2002). The paired-like homeobox gene HESX1 is mutated in cases of septo-optic dysplasia (Dattani et al. 1998, 1999; Brickman et al. 2001).

Table 9.5 Inherited eye diseases in man and mice due to mutations in transcription factor genes: posterior segment defects

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Mutations in two genes, CRX and NRL, result in abnormalities of photoreceptor differentiation or maintenance (Table 9.6). Leber congenital amaurosis is characterized by generalized rod and cone dystrophy and presents at birth or early in infancy (Aicardi 1998; Graw 2003; Koenekoop et al. 2012). It is responsible for 10–18 % of cases of congenital blindness. The disease may present only with ophthalmological features, but in some cases it is associated with intellectual disability, encephaloceles (Vaizey et al. 1977) and, especially, anomalies of the cerebellar vermis. Apart from CRX, various other genes contribute to this disorder (Fazzi et al. 2003; Graw 2003; Koenekoop et al. 2012). In the genetic subtype caused by mutations in RPE65, genetic replacement therapy has been found to be successful (Bainbridge et al. 2008; Maguire et al. 2008).

Table 9.6 Inherited eye diseases in man and mice due to mutations in transcription factor genes: abnormal photoreceptor differentiation/maintenance

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Retinitis pigmentosa is characterized by progressive visual field loss, night blindness and pigmentary deposition in the retina (Clinical Case 9.5). It is aetiologically very heterogeneous (Wang et al. 2001; Ferreyra and Heckenlively 2012). Mutations in at least 49 different identified genes can lead to non-syndromic forms. Retinitis pigmentosa is inherited through any of the known monogenic inheritance patterns (autosomal dominant, autosomal recessive and X-linked). Most forms of retinitis pigmentosa and related retinal degenerations affect only the eye, but in a minority of cases the retinal degeneration belongs to a syndrome that includes other systemic abnormalities such as deafness in Usher syndrome (Chap. 7).

In summary, mutations that lead to clinically relevant phenotypes highlight important steps in eye development (Graw 2003). Some affect genes that function at the top of the regulatory hierarchy and therefore at the initial stages of eye development. Mutations in such genes (PAX6, SOX2) lead to anophthalmia, microphthalmia and aniridia. Other genes (FKHL7, PITX3 and MAF) function downstream or later during development. Some mutants define genes that are important for only one particular tissue such as the crystalline-encoding genes in the development of the lens and PAX2 in the optic nerve.

Clinical Case 9.4 Aniridia

Aniridia is a bilateral congenital ocular disorder with absent or rudimentary iris. The disorder can be autosomal dominant or sporadic, and is caused by a defect in the PAX6 gene. Sporadic aniridia is associated with Wilms tumour (nephroblastoma) in one third of the cases.

Case Report. A newborn female was referred to the Ophthalmology Clinic because of congenital absence of the iris in both eyes. Ocular examination showed bilateral aniridia, microcornea (7–8 mm; normal 9–10 mm), mild posterior polar cataract, and small grey optic discs (Fig. 9.23). Systemic examination disclosed microcephaly (less than P3) and multiple ventricular septal defects (VSDs) with pulmonary hypertension. The patient was suspected to suffer from 11p-syndrome WAGR (Wilms tumour, aniridia, genitourinary malformations). The child died from pulmonary oedema and respiratory insufficiency at the age of 3 months. Postmortem examination confirmed the congenital heart defect, but no renal tumour or genitourinary abnormalities were found. Rao et al. (1992) described a 2-year-old female child with bilateral Wilms tumour along with multiple congenital anomalies like bilateral aniridia with congenital cataracts and nystagmus, microcephaly, mental retardation and ventricular septal defect. Karyotype analysis revealed 46 XX, del 11p13-14.1. Association of a VSD with the classic features of ‘Aniridia-Wilms tumour association’ is an unusual feature.

Reference

Rao SR, Athale UH, Kadam PR, Gladstone B, Nair CN, Pai SK, Kurkure PA, Advani SH (1992) Aniridia-Wilms’ tumour association: a case with 11p 13–14.1 deletion and ventricular septal defect. Indian J Cancer 29:117–121

Clinical Case 9.5 Retinitis Pigmentosa with CNS Malformations

Congenital disorders of glycosylation (CDGs) form a new group of autosomal recessive multisystem disorders characterized by defective glycoprotein biosynthesis. Disorders of nearly all organs and systems have been described (Jaeken and Carchon 2004; Chap. 3). Cerebral and ocular manifestations are common in the various biochemical CDG subtypes.

Case Report. A 12-year-old girl was referred to the Ophthalmology Clinic with a history of early childhood strabismus and encephalopathy of unknown aetiology. Signs of general hypotonia and psychomotor retardation were established in the first year of life. Microcephaly, short stature and inverted nipples were apparent in infancy, followed by ataxia, dyspraxia, dysmetria and progressive polyneuropathy in the first decade. Neuroimaging showed severe cerebellar vermis hypoplasia. The eyes showed convergent strabismus with slight limitation of abduction. The ocular media were clear. Ophthalmoscopy showed retinitis pigmentosa of both eyes, with typical bony spicules in the retinal periphery and an indication of bull’s eye pattern maculopathy (Fig. 9.24). The electroretinogram was extinguished. At that time (1984) no systemic diagnosis could be made. At 18 years of age, the patient showed general signs of glycoprotein dysfunction, such as gonadal dysfunction and hypothyroidism. The diagnosis CDG syndrome type 1a was established by finding abnormal transferrin fractions with isoelectric focussing of serum. This type is the most common form in the group of CDGs. In the third decade, the retinitis pigmentosa was progressive and posterior subcapsular cataracts developed in both eyes.

Reference

Jaeken J, Carchon H (2004) Congenital disorders of glycosylation: a booming chapter of pediatrics. Curr Opin Pediatr 16:434–439

9.4.3 Development of the Visual Projections

The optic nerves of the two eyes converge to form the optic chiasm. Here the fibres from the nasal half of each retina cross to the opposite side and pass via the optic tract to the LGN (Fig. 9.25). Fibres from the temporal half of each retina pass to the LGN without crossing. LGN neurons relay the visual input via the optic radiation to the primary visual cortex. Each optic tract as well as the LGN and geniculocalcarine tract contain information from the contralateral visual hemifield. Axons from the two eyes terminate in different layers of the six-layered LGN (Hubel and Wiesel 1977; Hubel et al. 1977). Originally, two types visual pathways were distinguished: axons of M-type ganglion cells terminate in the two ventrally located magnocellular layers of the LGN, whereas axons of the smaller P cells terminate in the four dorsal parvocellular layers. This segregation continues in the optic radiation into the striate cortex and even beyond in the extrastriate visual areas (Livingstone and Hubel 1988; Merigan 1989; Gulyas et al. 1993; Zeki 1993). More recently, three retinal ganglion cell types have been linked with parallel pathways that remain segregated through the LGN and into the input layers and compartments of V1 (Dacey 2000; Hendry and Reid 2000; Kaplan 2004; Field and Chichilnisky 2007; Nassi and Callaway 2009).

Midget, parasol and bistratified ganglion cells form approximately 90 % of all ganglion cells found in the primate retina (Fig. 9.26). The midget ganglion cells (or P cells) give rise to the parvocellular pathway to the parvocellular layers of the LGN and form some 70 % of the total population of cells that project to the LGN (Dacey 2000). Parasol ganglion cells (or M cells) are the origin of the magnocellular pathway and project to the magnocellular layers of the LGN. They form some 10 % of the cells that innervate the LGN (Dacey 2000). Small and large bistratified ganglion cells make up at least part of the koniocellular pathway and together form some 8 % of the total population of cells that project to the LGN, which in turn projects to the cytochrome oxidase (CO) blobs of layers 2/3 in V1 (Hendry and Reid 2000). Lesion studies in primates have shown that magnocellular lesions result in a large decrease in luminance contrast sensitivity or motion discrimination (Merigan et al. 1991a, b). Parvocellular lesions cause an almost complete loss of colour vision (Dacey 2000; Kaplan 2004). Developmental dyslexia may be due to abnormalities of the magnocellular component of the visual system (Stein and Walsh 1997; Demb et al. 1998; Chap. 10).

The development of visual projections has been extensively studied in rat (Brückner et al. 1976; Lund and Mustari 1977; Blakemore and Molnár 1990), ferret (Sur and Leamey 2001), cat (Shatz 1983; Shatz and Luskin 1986; Shatz et al. 1990) and rhesus monkey (Rakic 1974, 1975, 1977a, b) embryonic and fetal brains, and more recently also in human fetuses (Hevner 2000). In the developing rat brain, neurons of the LGN are born between E12 and E14 (Brückner et al. 1976; Lund and Mustari 1977). Outgrowth of geniculocortical axons begins around E14-E15. By E16-E17, geniculocortical axons have reached the internal capsule and some already accumulate in the subplate below the primary visual cortex (Lund and Mustari 1977; Blakemore and Molnár 1990). In cats, Shatz and co-workers studied the development of retinogeniculate (Shatz 1983) and geniculocortical (Shatz and Luskin 1986; Shatz et al. 1990; Ghosh and Shatz 1992) projections. Axons from the LGN have entered the internal capsule by E30 (duration of gestation in cats 65 days). Axons reach the developing visual cortex by E36, and accumulate in the subplate over the following 3 weeks. Between E46 and E55, geniculocortical axons invade the marginal zone (layer 1), but an appreciable number of terminals in the cortical plate does not appear before E55. By birth, most axons have left the subplate and have established branches within layer 4 (Shatz and Luskin 1986; Shatz et al. 1990).

In rhesus monkeys for which the gestation period lasts about 165 days, Rakic (1977a) showed with the [³H]thymidine birthday labelling technique that the first retinal ganglion cells are generated about the 30th day of gestation (E30), whereas those for the LGN start to be born around E36 (Rakic 1977b). Neurogenesis of neurons of the primary visual cortex takes place between about E43 and E102 (Rakic 1974, 1975). Geniculocortical axons fan up towards the cortex in the optic radiation as early as midgestation (Rakic 1976, 1977a). They gather in the subplate below the occipital cortical plate and only penetrate the plate itself after a long waiting period (Smart et al. 2002). LGN axons are visible throughout the lower layers of the primary visual cortex 3 weeks before birth, and terminals are beginning to concentrate in the lower part of layer 4. Efferent connections from the visual cortex to the LGN, the pulvinar and the superior colliculus are established in a 1-month period, E63-E97 (Shatz and Rakic 1981), roughly in synchrony with the genesis of geniculocortical projections. Geniculocalcarine fibres segregate into columns postnatally according to ocular dominance (Hubel and Wiesel 1977; Hubel et al. 1977).

In the developing human brain, optic tract fibres reach the CGL by about seven gestational weeks (Gilbert 1935; Cooper 1945), and synapses between optic fibres and CGL neurons are formed by about 13–14 gestational weeks (Khan et al. 1993, 1994). The homogeneous CGL anlage becomes separated into its characteristic six layers at about 22 weeks of gestation (Cooper 1945; Dekaban 1954; Hitchcock and Hickey 1980). Each cellular layer receives retinal fibres from only one eye. Geniculocortical axons have reached the subplate below the visual cortex as early as 8.5 weeks of gestation (Kostović and Rakic 1990). After a long waiting period, geniculocortical synapses in the cortical plate are formed around 23–25 weeks of gestation (Kostović and Rakic 1990). In a 1,1′-dioctadecyl- 3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI) tracing study in fixed brains of human fetuses of 20–22 gestational weeks, Hevner (2000) showed that retinogeniculate projections were already segregated into eye-specific layers by 20 gestational weeks, preceding the cellular lamination of the CGL. Thalamocortical axons densely innervated the subplate, but hardly the cortical plate, consistent with observations on a waiting period in the human brain (Kostović and Rakic 1990). The human visual cortex attains its six-layered organization early during the third trimester (for data on the human visual cortices see Clarke and Miklossy 1990). The fetal human optic nerve shows overproduction and subsequent elimination of retinal ganglion cell axons. Provis et al. (1985b) found 1.9 million axons by about 10 weeks of development, 3.7 million at about 16 weeks, but only 1.1 million axons at about 27 weeks. The period of cell loss from the retinal ganglionic cell layer occurs after 30 weeks (Provis et al. 1985a), suggesting that many cells of the fetal ganglionic cell layer do not contribute axons to the optic nerve during the process between 20 and 30 weeks of development. Myelination of the optic nerve does not begin until about 32 weeks, and is largely complete by 7 months after birth (Magoon and Robb 1981). Myelination of the optic radiation begins at the CGL. For a DTI study of the optic radiation in premature neonates ranging from 29 to 41 weeks of gestational age, see Berman et al. (2009).

In albinism, retinofugal axons are misrouted in the optic chiasm so that some of the axons from the temporal retina, which normally stay ipsilaterally, cross to the other side. Abnormalities in the CGL of a human albino have been noted (Guillery et al. 1975). The opposite is found in isolated absence of the optic chiasm or non-decussating retinofugal fibre syndrome as first described by Apkarian et al. (1993, 1995) in two unrelated children, presenting with oculomotor instabilities. Comparable cases were described by Jansonius et al. (2001; Clinical Case 9.6) and Korff et al. (2003). In such cases, nasal retinal fibres project ipsilaterally, resulting in retinothalamic and thalamocortical misprojections and aberrant retinotopic cortical mapping. Optic nerve hypoplasia, a developmental defect in the number of optic nerve fibres, may be unilateral or bilateral (Aicardi 1998; Brooks and Traboulsi 2012). It may occur as an isolated defect or be associated with other CNS defects such as absence of the septum pellucidum in septo-optic dysplasia (Sect. 9.7.3). Zeki et al. (1992) found that optic nerve hypoplasia can be associated with partial or complete absence of the septum pellucidum (in 52 % of their cases), hydrocephalus (in 38 %), porencephaly (in 24 %), dilatation of the suprasellar and chiasmatic cisterns (in 19 %), partial or complete absence of the corpus callosum (in 14 %), or an intracranial cyst. Colobomas of the optic nerve may extend to involve the retina, the iris, the ciliary body and the choroid. Colobomas of the optic disc may be isolated, appearing as deep excavations with abnormal emergence of retinal vessels. They may be unilateral or bilateral and are often associated with agenesis of the corpus callosum, in isolation or as a component of the Aicardi syndrome (Chevrie and Aicardi 1986; Aicardi et al. 1987; Brooks and Traboulsi 2012).

Clinical Case 9.6 Isolated Absence of the Optic Chiasm

Isolated absence of the optic chiasm or non-decussating retinofugal syndrome is very rare (Apkarian et al. 1993, 1995; Jansonius et al. 2001; Korff et al. 2003). The four patients described so far presented with oculomotor instabilities (see Case Report). In this condition, nasal retinal fibres erroneously project ipsilaterally, resulting in aberrant retinothalamocortical mapping.

Case Report. An otherwise healthy 15-year-old girl with a congenital nystagmus was evaluated at a University Department of Ophthalmology using visual evoked potential recording and subsequent MRI examination. She appeared to have the unique inborn absence of the optic chiasm (Fig. 9.27). Unlike the cases described by Apkarian et al. (1993, 1995) she did not seem to display a seesaw nystagmus (Jansonius et al. 2001).

This case was kindly provided by Nomdo M. Jansonius (Department of Ophthalmology, Groningen University Medical Centre) and Ton van der Vliet (Groningen).

References

Apkarian P, Bour L, Barth PG (1993) A unique achiasmatic anomaly detected in non-albinos with misrouted retinal-fugal projections. Eur J Neurosci 6:501–507

Apkarian P, Bour L, Barth PG, Wenniger-Prick L, Verbeeten B Jr (1995) Non-decussating retinal-fugal fibre syndrome: an inborn achiasmatic malformation associated with visuotopic misrouting, visual evoked potential ipsilateral asymmetry and nystagmus. Brain 118:1195–1216

Jansonius NM, van der Vliet AM, Cornelissen FW, Pott JWR, Kooijman AC (2001) A girl without a chiasm: electrophysiologic and MRI evidence for the absence of crossing optic nerve fibers in a girl with a congenital nystagmus. J Neuro-Ophthalmol 21:26–29

Korff CM, Apkarian P, Bour LJ, Meuli R, Verrey J-D, Roulet Perez E (2003) Isolated absence of optic chiasm revealed by congenital nystagmus, MRI and VEPs. Neuropediatrics 34:219–221

9.5 Overview of the Development of the Telencephalon

Each developing cerebral hemisphere consists of a thick basal part, the subpallium, giving rise to the basal ganglia, the diagonal band and the preoptic area, and a thin part, the pallium that becomes the future cerebral cortex. The telencephalon medium or impar forms the non-evaginated part of the telencephalon. It surrounds the rostral part of the third ventricle and consists of the lamina terminalis and the preoptic region. The dorsal part of the lamina terminalis transforms into the commissural plate, from which the anterior commissure, the corpus callosum and the hippocampal commissure arise (Chap. 10). Dorsal and ventral domains of the developing telencephalon are distinguished by different patterns of gene expression, reflecting the initial acquisition of regional identity by progenitor populations (Puelles et al. 2000; Schuurmans and Guillemot 2002; Campbell 2003; Zaki et al. 2003; Sousa and Fishell 2012; Medina and Abellán 2012). The subpallium appears as medial and lateral elevations, known as the ganglionic (Ganglionhügel of His 1889) or ventricular eminences (Figs. 9.28 and 9.29). The derivatives of the ganglionic eminences are summarized in Table 9.7. The caudal part of the ventricular eminences or caudal ganglionic eminence (CGE) primarily gives rise to the subpallial parts of the amygdala. The medial ganglionic eminence (MGE) is involved in the formation of the globus pallidus and the basal nucleus of Meynert, the source of cholinergic input to the cerebral cortex. The lateral ganglionic eminence (LGE) gives rise to the caudate nucleus and the putamen. Both the LGE and the MGE are also involved in the formation of the cerebral cortex. The pyramidal cells of the cerebral cortex arise from the pallial ventricular zone, but its GABAergic interneurons arise from both ganglionic eminences, the medial eminence in particular (Anderson et al. 1997a, 2001; Parnavelas 2000; Marín and Rubinstein 2001, 2002; Chédotal and Rijli 2009). The caudal part of the human ganglionic eminence also gives rise to a contingent of GABAergic neurons for thalamic association nuclei such as the pulvinar through a transient fetal structure, the gangliothalamic body (Rakić and Sidman 1969; Letinić and Kostović 1997; Letinić and Rakic 2001). The ganglionic eminence of the human fetal brain plays an important role in prematurely born infants (Ulfig 2002a) and it is the most common site of intracranial haemorrhage, a frequent CNS complication in prematurely born infants (Chap. 3).

Table 9.7 Derivatives of the ganglionic eminences

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The pallium is usually divided into a medial pallium or archipallium, a dorsal pallium or neopallium, and a lateral pallium or paleopallium (Fig. 9.30). In mice, gene-expression studies led to redefining of the pallial-subpallial boundary and to a fourth component of the pallium, the ventral pallium (Puelles et al. 2000; Marín and Rubinstein 2002; Molnár and Butler 2002; Schuurmans and Guillemot 2002; Campbell 2003; Stenman et al. 2003). The medial pallium or archipallium forms the hippocampal cortex, the three-layered allocortex. Parts of the surrounding transitional cingulate and entorhinal cortex, the four-to-five-layered mesocortex, may have the same origin. The dorsal pallium or neopallium forms the six-layered isocortex or neocortex. The lateral pallium forms the olfactory cortex and the ventral pallium the claustro-amygdaloid complex. The development of the medial and the dorsal pallium and their malformations will be discussed in Chap. 10. The midline and paramedian areas of the telencephalon (the ‘cortical hem’) form specialized structures, and give rise to the commissural plate and the choroid plexus, respectively (Chap. 10).

The subpallium consists of three primary regions, the LGE, the MGE and the preoptic area. Among other structures such as cortical contributions the LGE gives rise to the striatum and the MGE to pallidal structures. The preoptic area is located close to the pallidal domain, and contains the preoptic area and the major fibre bundles to and from the telencephalon.

After induction of anterior neural character and specification of telencephalic character (Chap. 2), dorsoventral regionalization of the telencephalon occurs. Genetic analyses in mice have revealed that regionally restricted genes participate in the specification of the identity of the telencephalic territory in which they are expressed (Rubinstein et al. 1998; Smith-Fernández et al. 1998; Puelles et al. 2000; Marín and Rubinstein 2002; Zaki et al. 2003; Table 9.8). Emx1 and Emx2, and Dlx1 and Dlx2 are among the earliest expressed pallial and subpallial markers, respectively. Their expression delineates three main telencephalic subdivisions in vertebrates (Figs. 9.30 and 9.31): the pallial, intermediate or ventral pallial, and subpallial neuroepithelial domains. The ventral pallium uniquely expresses the homeobox gene Dbx1 (Yun et al. 2001) and is Emx1-negative (Puelles et al. 2000). The specific boundaries of the other pallial domains are less easily marked by discrete gene expression. Here, graded gene expression is more common. Emx1, Emx2 and Lhx2 all show high expression in the medial pallium with a progressive reduction in expression in more lateral regions (Gulisano et al. 1996; Pellegrini et al. 1996; Yoshida et al. 1997; Tole et al. 2000a; Mallamacci et al. 2000; Yun et al. 2001), whereas Pax6 and Tbr1 show an opposite profile with highest expression in the lateral and ventral pallium (Puelles et al. 2000; Toresson et al. 2000; Yun et al. 2001). Emx2 and Pax6 are involved in many aspects of cortical morphogenesis (Chap. 10). Nevertheless, in the absence of either Emx2 or Pax6, cerebral cortex does form. In Emx2−/−; Pax6 ^Sey/Sey double mutant mice, however, conversion of the cerebral cortex into basal ganglia occurs (Muzio et al. 2002). It seems likely that at least one fully functional allele of either Emx2 or Pax6 is necessary and sufficient for activating corticogenesis and to suppress competing subpallial morphogenetic programs.

Table 9.8 Some gene expression patterns during the development of the murine forebrain

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In the subpallium, many genes are expressed, more in particular the Dlx1, Dlx2, Dlx5 and Dlx6 genes (Eisenstat et al. 1999; Long et al. 2009a, b) as well as Gsh1 and Gsh2 (Toresson et al. 2000; Toresson and Campbell 2001; Yun et al. 2001) and Mash1 (Long et al. 2009a, b; Medina and Abellán 2012). The ventromedial telencephalon, including the MGE and the preoptic area, expresses Nkx2.1 (Shimamura et al. 1995; Sussel et al. 1999; Sousa and Fishell 2010). The preoptic area also expresses Isl1 (Marín and Rubinstein 2001). The CGE shares some molecular markers with both the LGE and the MGE (Xu et al. 2004; Flames et al. 2007; García-López et al. 2008). The CGE expresses Dlx2 and Ascl1 (formerly known as Mash1) at levels equivalent to those in the other ganglionic eminences. In contrast, Lhx6 is highly expressed in the MGE (Lavdas et al. 1999), hardly in the LGE and in only low levels in the CGE. The CGE is further characterized by a high level of cellular retinol binding protein 1 (Nery et al. 2002). The LGE can be subdivided into two major portions each with two domains (Flames et al. 2007). The dorsal LGE, characterized by Pax6 expression, appears to produce the GABAergic and dopaminergic interneurons of the olfactory bulb rostrally and caudally the lateral part of the central amygdala. The dorsal LGE also contributes cells to the caudate-putamen, the olfactory tubercle, the accumbens and the central extended amygdala. The ventral LGE, characterized by Isl1 expression, is the major source of projection neurons of the caudate-putamen and the accumbens and at caudal levels of the medial part of the central amygdala. The globus pallidus, the ventral pallidum and the extended amygdala are derived from the MGE (Xu et al. 2008; Long et al. 2009a, b). Most of the cortical GABAergic interneurons appear to arise in the MGE domain (Xu et al. 2008; Long et al. 2009a, b), which may contain five distinct progenitor domains (Flames et al. 2007). The embryonic preoptic area also contributes to the production of cortical interneurons (Gelman et al. 2009).

The pallial-subpallial or corticostriatal boundary does not lie at the boundary between the ventral pallial and LGE progenitor zones but is slightly more ventral in the dorsalmost part of the LGE. The early expression of the Pax6 and Gsh2 homeobox transcription factors overlaps in the dorsal part of the LGE. In Gsh2 mutants, the dorsal part of the LGE is respecified into a ventral pallium-like structure, whereas in Pax6 mutants the ventral pallium is respecified into a dorsal LGE-like structure (Stoykova et al. 1996, 2000; Toresson et al. 2000; Yun et al. 2001). Patterning defects caused by loss of Pax6 function result in multiple morphological abnormalities in the brain of Sey mutants such as dysgenesis of the piriform, insular and lateral cortices, and of the claustrum, failure in the differentiation of a subpopulation of cortical precursors, and absence of the olfactory bulbs. Tlx and Pax6 cooperate in the establishment of the pallial-subpallial boundary in the embryonic mouse telencephalon (Stenman et al. 2003). Tlx homozygous mutants show alterations in the development of this boundary similar, but less severe than those seen in Sey/Pax6 mutants. Malformations occur in the lateral and basolateral amygdala, both of which are derived from the ventral pallium. In human embryos, PAX6 is expressed early in the neural tube, just after its closure (Gérard et al. 1995). PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans (Sisodiya et al. 2001).

Like in the spinal cord, the roof plate (Fig. 9.4) may play an essential role in dorsal telencephalic or pallial patterning through BMP signalling. Explant studies support a role for BMPs in dorsal telencephalic development (Furuta et al. 1997) and in the expression of Lhx2 (Monuki et al. 2001). Receptor blocking studies, however, suggest that loss of BMP signalling in the dorsal telencephalon leads to a normal dorsal-ventral pattern but maldevelopment of the choroid plexus, suggesting only a local role for BMPs in the dorsal telencephalic midline (Hébert et al. 2002). Genetic ablation of the telencephalic roof plate leads to a severely reduced expression of Lhx2 and a severe reduction in cortical size (Monuki et al. 2001). Another transcription factor that is crucial in dorsal patterning is the zinc-finger gene Gli3 (Rallu et al. 2002b; Campbell 2003). Gli3 is required to antagonize the ventralizing signal SHH in the dorsal telencephalon (Rallu et al. 2002a). Loss of Gli3 function in Extra-toes mutants results in a loss of Emx gene expression as well as in the ectopic expression of certain genes characteristic of ventral telencephalic progenitors such as Gsh2 (Theil et al. 1999; Tole et al. 2000b; Rallu et al. 2002a). Extra-toes mutant mice also lack the telencephalic choroid plexus and olfactory bulbs (Franz 1994). Gli3 mutations are also responsible for the abnormalities in the arhinencephalic Pdn/Pdn (homozygote of Polydactyly Nagoya mouse, Pdn) mice (Naruse and Keino 1995). In man, GLI3 mutations lead to Greig’s (Greig 1926) cephalopolysyndactyly syndrome (Vortkamp et al. 1992), characterized by the presence of hypertelorism and polysyndactyly, and Pallister-Hall syndrome (Kang et al. 1997).

The secreted glycoprotein SHH is required for ventral telencephalic or subpallial patterning as shown in Shh-null mice (Chiang et al. 1996; Litingtung and Chiang 2000). Although these mutants lack any sign of MGE development such as expression of the Nkx2.1 homeodomain protein, many of them express genes normally found in both the MGE and the LGE such as Gsh2 and Dlx2 (Rallu et al. 2002a, b); therefore, SHH is required for ventromedial telencephalic development. A mutation in Nkx2.1 results in the acquisition of striatal-like properties by the presumptive pallidum, suggesting that Nkx2.1 both specifies an MGE fate and inhibits LGE phenotypes (Sussel et al. 1999; Butt et al. 2008; Flandin et al. 2010). Nodal signalling is also required for induction of Nkx2.1 expression as shown in zebrafish (Rohr et al. 2001). In Pax6 (Sey) mutants, MGE markers expand into the LGE, leading to an overall reduction in size of the striatum and expression of MGE-derived structures (Stoykova et al. 2000); therefore, Pax6 and Nkx2.1 both operate at the LGE-MGE border, maintaining LGE and MGE identity, respectively. Gsh1 and Gsh2 also encode homeodomain proteins and are important for ventral telencephalic specification. In Gsh2 single and Gsh1/Gsh2 double mutants, dorsal markers cross the LGE-pallial boundary into the LGE and ventral markers are suppressed (Corbin et al. 2000; Toresson et al. 2000; Toresson and Campbell 2001). Probably, Gsh2 maintains dorsal LGE identity without directly regulating ventral marker expression (Toresson et al. 2000), whereas expression of ventral genes in the ventral part of the LGE involves a more direct role of Gsh1 and/or Gsh2 (Toresson and Campbell 2001; Yun et al. 2001; Waclaw et al. 2009). Sousa and Fishell (2010) suggested that ventral telencephalic patterning is largely mediated by two sequential periods of competence, designated as C1 and C2. The SHH-mediated induction of Nkx2.1 expression provides the hallmark of the initiation of MGE development and correspondingly the C1 period. This is followed by the C2 competence period, during which SHH signalling induces the LGE/CGE. Both structures induced during C1 (MGE) and C2 (LGE/CGE) are characterized by early production of projection neurons from their ventral aspects and late production of interneurons from their dorsal domains. In the human brain, cortical interneurons are also produced in the dorsal subventricular zone (Chap. 10).

Dlx1, Dlx2, Dlx5 and Dlx6 are expressed in overlapping sets of cells in the developing forebrain and single mutants have mild phenotypes, suggesting redundancy of function (Bulfone et al. 1993; Anderson et al. 1997b; Liu et al. 1997; Eisenstat et al. 1999; Panganiban and Rubinstein 2002). Dlx2 is expressed before Dlx1, which is expressed before Dlx5 and Dlx6. In the basal forebrain, the Dlx-positive cells differentiate into striatal and pallidal projection neurons as well as into interneurons for the cerebral cortex and olfactory bulb. Dlx2 mutants have reduced numbers of dopaminergic neurons in the olfactory bulb (Acampora et al. 1999; Eisenstat et al. 1999). In Dlx1/Dlx2 double mutants, neurogenesis in the subpallium is disturbed, in particular the subventricular zone fails to mature (Anderson et al. 1997b; Marín et al. 2000). Cortical interneuron development appears to be dependent on Dlx dosage: one wild type Dlx2 allele in a Dlx1 null background is sufficient to rescue tangential migration to the cortex, though not subsequent radial migration into the cortical plate (Cobos et al. 2007). Dlx function is tightly labelled to the development of neurons derived from the basal telencephalon that produce GABA, acetylcholine and dopamine (Marín and Rubinstein 2002; Panganiban and Rubinstein 2002). Ectopic expression of Dlx2 and Dlx5 genes induces the expression of glutamic decarboxylase (GAD), the enzyme that synthesizes GABA (Stühmer et al. 2002). Moreover, Dlx5 regulates the development of peripheral and central components of the olfactory system (Long et al. 2003). Ascl1, formerly known as Mash1, a basic helix-loop-helix transcription factor, regulates neurogenesis in the ventral telencephalon (Casarosa et al. 1999). Mash1 mutant mice show severe loss of progenitors, particularly of neuronal precursors in the subventricular zone of the MGE. Discrete neuronal populations of the basal ganglia and cerebral cortex are subsequently missing. Loss of Mash1 function also causes widespread defects in the primary olfactory pathway (Murray et al. 2003). Cells that migrate tangentially from the subpallium to the pallium express Dlx1/Dlx2, Arx and/or Lhx6. Lack of both Dlx1 and Dlx2, or Arx, or Lhx6 in mice is correlated with a dramatic decline in the number of GABAergic interneurons in the cerebral cortex (Anderson et al. 1997b, 2001; Cobos et al. 2005a, b, 2007). The decline of specific subtypes of GABAergic interneurons in the cerebral cortex due to mutations in Dlx1 or Arx has been correlated with epileptic activity in mice and with epilepsy, lissencephaly and intellectual disability in humans (Kitamura et al. 2002; Colombo et al. 2004, 2007; Cobos et al. 2005b; Kato and Dobyns 2005; Marsh et al. 2009; Price et al. 2009; Chap. 10).

In the forebrain two main modes of migration can be recognized: radial and tangential (Fig. 9.32). The coexistence of these two different methods of cell migration has been well established for the developing cerebral cortex (Chap. 10). Lineage analysis studies showed that radially and tangentially migrating cells in the developing cortex arise from different progenitors (Mione et al. 1997; Tan et al. 1998). Moreover, the presence of Dlx2-positive neurons in the developing cortex suggested that cells of subpallial origin might have migrated tangentially into the pallium (Porteus et al. 1994). It is now clear that most cortical GABAergic neurons are born in the subpallium as already suggested by van Eden et al. (1989), and reach the developing cortex in several tangentially migrating streams (de Carlos et al. 1996; Anderson et al. 1997a; Tamamaki et al. 1997).

After these first studies on the origin of GABAergic neurons from the subpallium, a variety of experimental studies showed that GABAergic neurons for the entire cerebral cortex, including the neocortex, the piriform cortex and the hippocampus arise subpallially (Lavdas et al. 1999; Wichterle et al. 1999, 2001; Corbin et al. 2001; Marín and Rubinstein 2001; Nery et al. 2002; Brazel et al. 2003; Kriegstein and Noctor 2004). The three ganglionic eminences contribute different types of cells to different brain structures, and a similar pattern is likely to be present in man. The MGE appeared to be the main source of cortical interneurons (Lavdas et al. 1999; Wichterle et al. 1999, 2001). These cells express the LIM homeobox gene Lhx6 and reach to the cerebral cortex via dorsal and lateral cortical streams (Fig. 9.33). The MGE also contributes cells to the globus pallidus and the cholinergic basal nucleus of Meynert. LGE cells migrate ventrally and anteriorly, and give rise to the GABAergic medium spiny neurons in the striatum, nucleus accumbens and olfactory tubercle, and to granule and periglomerular cells of the olfactory bulb. The striatal and olfactory bulb cells arise from two distinct progenitor populations in the LGE (Stenman et al. 2003). Progenitor cells in the subventricular zone of the LGE generate granule and periglomerular cells for the olfactory bulb (Hinds 1968a, b; Altman 1969; Bayer 1983; Kishi 1987). In neonatal and adult rodents and primates, these cells reach their final position via a rostral migratory stream (Luskin 1993; Lois and Alvarez-Buylla 1994; Kornack and Rakic 2001). The CGE contributes to the posterior neocortex, the hippocampus, the amygdala and posterior parts of the striatum and globus pallidus (Nery et al. 2002).

9.6 Development of the Rhinencephalon

The mammalian rhinencephalon, i.e. the part of the telencephalon involved in the processing of chemosensory information, is composed of the main olfactory system, the accessory olfactory or vomeronasal system and the terminal nerve (Stephan 1975; Voogd et al. 1998). Olfactory fibres originate in the olfactory epithelium and pass as fila olfactoria through the cribriform plate of the ethmoid to contact the olfactory bulb. The central part of the main olfactory system comprises the olfactory bulb and the targets of its projections within the telencephalon, i.e. the retrobulbar region or anterior olfactory nucleus, the olfactory tubercle, the prepiriform, periamygdaloid and entorhinal cortices, and the cortical and medial nuclei of the amygdaloid complex (Lohman and Lammers 1967; Price 1990; Shipley et al. 1995; Fig. 9.34). The accessory olfactory system, also known as the vomeronasal system, comprises the vomeronasal organ of Jacobson, the accessory olfactory bulb and some nuclei of the amygdaloid complex (Halpern 1987; Shipley et al. 1995). The accessory olfactory system is primarily involved in the regulation of reproductive behaviour, elicited by pheromones, chemical messengers from other members of the same species (Dulac and Torello 2003). In humans, the vomeronasal system is established during embryonic development and regresses in the fetal period (Ortmann 1989; Kjaer and Fischer-Hansen 1996), although as many as 850 cells may be present by 4 months after birth (Oelschläger et al. 1987). The human vomeronasal organ of Jacobson, a pocket lying in the nasal septum, opens into the vomeronasal pit, about 1 cm dorsal to the columella and 1–2 mm above the floor of the nose. In some 40 % of adults, this opening can be seen macroscopically (Moran et al. 1991), and even in 73 % of the population using endoscopy (Trottier et al. 2000).

The olfactory bulb arises as an evagination of the rostral telencephalon (Fig. 9.35) and receives primary olfactory afferent fibres from neurons in the olfactory epithelium. The primary olfactory fibres synapse on the dendrites of glutaminergic projection neurons (the mitral and tufted cells) found in specialized structures called glomeruli, forming the glomerular layer. Many thousands of olfactory receptor cells synapse with the dendritic branches of one or only a few mitral cells within a glomerulus, resulting in a high degree of convergence of olfactory receptors onto mitral cells (Shepherd and Greer 1990). A large number of inhibitory, GABAergic interneurons are present in the olfactory bulb, the most common of which are the granule and periglomerular cells. Most of the periglomerular cells are GABAergic as well as dopaminergic. The following layers can be recognized in the olfactory bulb: (1) the outer fibre layer, consisting of the incoming olfactory fibres; (2) the glomerular layer, consisting of several rows of glomeruli surrounded by periglomerular cells; (3) the external plexiform layer, containing the dendritic branches of mitral cells and granule cells; (4) the mitral cell layer, not well-defined in man; (5) an ill-defined internal plexiform layer, largely composed of axons of mitral and tufted cells; (6) the granular layer, with the granule cells; and (7) a periventricular layer, composed of the subventricular zone, a reservoir of progenitor cells that produces new granule and periglomerular cells in the adult brain, and ependymal cells, remnants of the epithelial layer of the olfactory ventricle.

Development of the olfactory bulb begins with its induction and evagination from the rostral telencephalon. FGF signalling through FGFR1 is required for olfactory bulb morphogenesis (Hébert et al. 2003). Signalling from the olfactory placode may contribute to patterning the anlage of the olfactory bulb (Graziadei and Monti-Graziadei 1992; de Carlos et al. 1995; LaMantia et al. 2000). The mitral and tufted neurons have a pallial origin and are regulated by cortical transcription factors such as Tbr1 (Bulfone et al. 1998), whereas the granule and periglomerular cells have a subpallial origin and are regulated by subpallial transcription factors such as Dlx1 and Dlx2 (Qiu et al. 1995; Bulfone et al. 1998). The Dlx family of homeobox genes is expressed in the olfactory bulb as well as in the olfactory epithelium (Acampora et al. 1999; Depew et al. 1999; Long et al. 2003). In particular, Dlx5 is expressed in the olfactory placode, the olfactory epithelium and local circuit neurons of the olfactory bulb. In Dlx5−/− mutants, the size of the olfactory epithelium is reduced and the few olfactory neurons formed fail to generate axons that innervate the olfactory bulb (Long et al. 2003). Despite this lack of innervation, the olfactory bulb forms, and neurogenesis of projection and local circuit neurons proceeds. Widespread defects in the primary olfactory pathway are caused by loss of Ascl1 (formerly Mash1) function (Murray et al. 2003). This homologue of the Drosophila proneural genes achaete and scute is normally expressed by neuronal progenitors in the developing peripheral nervous system and CNS, including the olfactory epithelium and the olfactory bulb and ganglionic eminences (Guillemot et al. 1993; Cau et al. 2002). Neurogenin 1, related to the Drosophila proneural gene atonal, is necessary for the differentiation of olfactory sensory neuron progenitors (Cau et al. 2002). In human cases of arhinencephaly as found in HPE and in Kallmann syndrome, both olfactory receptor cells and olfactory nerves are present (Braddock et al. 1995), also suggesting that the initial development of the olfactory nerves is independent of the formation of the olfactory bulb. Bilaterally enlarged olfactory bulbs with abnormal laminar structures were described as olfactory bulb dysplasia in a case of Pena-Shokeir phenotype (Yamanouchi et al. 1999). Loss of smell (anosmia) is rather common and the frequency increases with age. A much smaller group have no memory of ever being able to smell and are classified as having isolated congenital anosmia (Karstensen and Tommerup 2012). Families are rare and tend to present in a dominant inheritance pattern. Anosmia is part of the clinical spectrum in various diseases such as Kallmann syndrome, various ciliopathies and congenital insensitivity to pain.

Pearson (1941b, 1942) described the development of the human olfactory bulb (Fig. 9.35). At the end of the first gestational month (stage 13), the olfactory placodes can be distinguished as epithelial thickenings on either side of the head. Subsequently, the olfactory placodes are overgrown by the nasal folds, resulting in the formation of the olfactory pits (Chap. 5). The first bipolar cells appear in the olfactory placode at stage 14. At stage 16, olfactory fibres enter the wall of the telencephalon when still no olfactory bulb can be identified (Lemire et al. 1975; Bossy 1980; Pyatkina 1982; Müller and O’Rahilly 1989a, 2004). Soon afterwards, the olfactory bulb begins as a slight bulge (stage 17), and by stage 20 it consists of a slight protrusion. By stage 22 all layers of the olfactory bulb are represented (Humphrey 1967; Lemire et al. 1975; Bossy 1980; Müller and O’Rahilly 1989b, 2004). Occasionally, a remnant olfactory ventricle may be observed (Clinical Case 9.7).

The vomeronasal organ of Jacobson first appears as a groove in the nasal septum at stage 18 (Humphrey 1940). Nerve fibres from this region may be traced into the vomeronasal and terminal nerves. The vomeronasal nerve arises from cells found in the medial border of the olfactory placode and is difficult to separate from the terminal nerve which arises in the same area at the same time (Pearson 1941a, 1942; Fig. 9.36). Vomeronasal fibres pass dorsomedially along the developing olfactory bulb to enter the accessory olfactory bulb around stage 18 (Humphrey 1940). The accessory olfactory bulb moves from its original dorsomedial position to a dorsolateral position. It begins to regress at the beginning of the third gestational month and is vestigial by the end of the third gestational month (Humphrey 1940; Lemire et al. 1975; Meisami and Bhatnagar 1998; Meredith 2001; Savic et al. 2001). The development of the vomeronasal nerve and accessory olfactory bulb parallels the development and regression of the vomeronasal organ in the human embryo. The terminal nerve is characterized by ganglion cells along its course and has been described in adults (Crosby and Humphrey 1941). At stages 16 and 17, the terminal nerve arises from cells in the medial part of the olfactory placode and is closely associated with the vomeronasal nerve (Pearson 1941a). GnRH neurons migrate along the vomeronasal and terminal nerves to the forebrain (Schwanzel-Fukuda and Pfaff 1989; Schwanzel-Fukuda et al. 1989; Boehm et al. 1994; Berliner et al. 1996). GnRH neurons can be detected in the olfactory epithelium as early as 5.5 weeks of development (Fig. 9.55a, b). These cells migrate along the developing vomeronasal and terminal nerves shortly afterwards (Verney et al. 1996).

The development of human primary and secondary olfactory areas is shown in basal views of the brain (Fig. 9.37). At first olfactory regions of the brain occupy a large part of the basal aspect of the brain. Later in development, the olfactory regions become restricted to a small part of the basal frontal lobe and the rostromedial part of the temporal lobe (Macchi 1951; Gastaut and Lammers 1961; Kahle 1969; Stephan 1975).

Extensive birthdating studies on the olfactory system have been carried out in rodents. Data are available for the olfactory bulb (Hinds 1968a, b; Bayer 1983, 1986a, b), the olfactory tubercle (ten Donkelaar and Dederen 1979; Bayer 1985a; Bayer and Altman 1987b) and the primary olfactory cortex (Bayer 1985b; Bayer and Altman 1987b). In rats, mitral cells in the olfactory bulb are born on E14-E16, and granule cells from E20 onwards, continuing in the adult brain. Several neurogenetic gradients in all structures receiving olfactory input were found. Bayer (1986b) suggested a relationship between these gradients in the olfactory target structures and their connections with the olfactory bulb. Bayer et al. (1995) estimated the time of neuron origin of human mitral cells between 5 and 8 weeks of development. Human granule cells are formed from the 19th week of development onwards.

The development of olfactory bulb projections has been studied in rats (Schwob and Price 1984; López-Mascaraque et al. 1996; Hongo et al. 2000). Using the fluorescent carbocyanine tracer DiI, the first olfactory projections can already be detected at E13 (López-Mascaraque et al. 1996). Pioneering fibres begin to grow through the ventral part of the telencephalon. At E14 and E15, these fibres have reached distant parts in the basal and lateral parts of the telencephalic vesicle, and establish the first contacts with the future amygdaloid area and the primary olfactory cortex. At E16, fibres from the olfactory bulb run caudally in a fan-like fashion, the lateral olfactory tract increases considerably and some fibres course along the anterior commissure. At E17, the major fibre systems appear already established, providing the substrate of the adult pattern. The further development of axonal connections in the central olfactory system has been studied by Schwob and Price (1984). In genetic arhinencephaly mouse embryos (Pdn/Pdn), the olfactory bulb is not formed, and olfactory fibers do not enter the CNS. They form a tangled mass under the cerebral hemisphere at E16 (Hongo et al. 2000). Pdn/Pdn mice exhibit preaxial polydactyly in both the forelimbs and hindlimbs (Naruse and Keino 1995). Newborns do not suckle milk and die within 1 day after birth. They also exhibit various brain malformations, including absence of the olfactory bulbs and corpus callosum. Apoptosis of precursor mitral cells in the anlage of the olfactory bulb may be induced by non-innervation of olfactory neurons, and sequential apoptosis of precursor neurons in the pyriform cortex may be induced by non-innervation due to death of mitral cells (Naruse and Keino 1995).

Clinical Case 9.7 A Remnant Olfactory Ventricle

An olfactory ventricle is an embryonic structure which appears in connection with the development of the olfactory nerve. It regresses after the formation of the olfactory bulb, but in certain pathological conditions, a remnant olfactory ventricle persists (see Case Report).

Case Report. A newborn male baby without any familial history died of a connatal infection shortly after birth. No gross malformations were observed. At autopsy, only agenesis of the olfactory nerves was observed (Fig. 9.38a). On the right side of the brain, there was a small protrusion, suggesting a rudimentary olfactory structure in which histologically a remnant olfactory ventricle was found (Fig. 9.38b). An olfactory ventricle is seen in embryonic stages (Fig. 9.38c). The persistence of such an embryonic structure may indicate a developmental disturbance.

9.7 The Prosencephalies

Prosencephalic malformations may be the result of defects in mediolateral patterning of the rostral part of the embryonic neural plate. Since this anlage gives rise to the forebrain with the eye vesicles and the hypothalamus/neurohypophysis, prosencephalic defects are usually accompanied by anomalies of the eyes and the pituitary gland. These disorders are sometimes described as midline field defects (Opitz 1993; Opitz et al. 1997; Roessler and Muenke 2001) but from an embryological point of view they are quite heterogeneous and a real midline field does not exist (O’Rahilly and Müller 2001). The general term prosencephalies (Probst 1979) includes a scala of malformations, ranging from aprosencephaly to partial or lobar HPE (Sergi and Schmitt 2000; Kakita et al. 2001; Table 9.9). The most severe forms of developmental malformations of the forebrain are complete absence of the forebrain (aprosencephaly) or of the telencephalon (atelencephaly). The most frequent prosencephalies are the various forms of HPE. Related disorders are septo-optic dysplasia (de Morsier syndrome) and isolated arhinencephaly as found in disorders such as Kallmann syndrome.

Table 9.9 Subdivision of the prosencephalies

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9.7.1 Aprosencephaly

Aprosencephaly and atelencephaly are extremely rare CNS defects. Several cases were studied neuropathologically (Garcia and Duncan 1977; Siebert et al. 1986, 1987; Lurie et al. 1979, 1980; Towfighi et al. 1987; Kim et al. 1990; Harris et al. 1994; Ippel et al. 1998; Sergi and Schmitt 2000; Kakita et al. 2001; Clinical Case 9.8). In aprosencephaly, the forebrain structures derived from the telencephalon (the cerebral cortex, the basal ganglia and the hypothalamus) and the diencephalon (the eyes and the thalamus) are absent or rudimentary. In atelencephaly, the thalami are developed and some residual hemispheres may be found. The aetiology of aprosencephaly and atelencephaly remains controversial. Some cases may be due to a destructive, encephaloclastic process (Norman et al. 1995), but could also be primary malformations (Leech and Shuman 1986; Sergi and Schmitt 2000). Sergi and Schmitt (2000) described two cases of a vesicular forebrain (pseudo-aprosencephaly), a possible missing link in the teratogenic spectrum of defective forebrain anlage (Table 9.9). Which genes are involved is unknown, but OTX2 is apparently not involved (Florell et al. 1996). The case of aprosencephaly described by Kakita et al. (2001) did not show evidence of destruction. In their case, a male fetus of 20 weeks of gestation, the prosencephalon was extremely small and was replaced by a solid, cylindrical mass without hemispheric cleavage or a ventricle. The most rostral part of the CNS penetrated through a midsagittal ectopic canal in the sphenoid bone, comparable to a case of cyclopia (Kakita et al. 1997).

Clinical Case 9.8 Aprosencephaly

Aprosencephaly is an extremely rare fetal CNS defect in which the forebrain structures derived from both the telencephalon and the diencephalon are absent or rudimentary (Kakita et al. 2001; see Case Reports). Sergi and Schmitt (2000) reported a case in which the forebrain was missing but remnants of a forebrain bleb were observed (pseudo-aprosencephaly).

Case Reports. In the first case, on ultrasound examination of the fourth pregnancy of a 32-year-old mother with severe diabetes mellitus type 1, the fetus was suspected for anencephaly; therefore, delivery was induced at 20 gestational weeks. The immature female fetus showed multiple congenital malformations (Fig. 9.39a– c), including: (1) aprosencephaly, characterized by the absence of the diencephalon and the telencephalon with absence of the olfactory bulbs and a malformed optic chiasm; (2) low brain weight (6.8 g instead of the 40 g normal for 20 gestational weeks); (3) skull malformations with a strongly flattened skull cap, a malformed skull base with absence of the crista galli and one frontal bone, and absence of fonticuli; (4) lateral cheilognathopalataschisis on the right; (5) low-positioned, malformed ears; (6) short neck with slight webbing; (7) skeletal malformations (immature skeleton, fusion of some ribs, open spine at the Th11 level. Chromosomal analysis showed a normal 46XX karyotype. The rostral end of the mesencephalon was nodular and rounded (Fig. 9.39d). Microscopically, disorganized neuronal tissue was present without recognizable structures.

In the second case, amniotic band constriction of the fetus was diagnosed in a primigravida during routine examination at the 16th week of gestation. Abortion was induced and at autopsy no amniotic strang was found but a dysmorphic face with asymmetrical eyes and a hare lip extending through the nose to the forehead (Fig. 9.40a). The small head was partially covered by membranous tissue in the frontal area with a defective calvarium. The prosencephalon was absent when the cranial vault was opened but the cerebellum was grossly identified and the pituitary gland existed. The anterior cranial fossa was narrow and the roof of the orbita elevated (Fig. 9.40b). A small tissue fragment from the cranial base appeared as leptomeninx and was histologically shown hypervascularized, suggesting an area cerebrovasculosa (Fig. 9.40c). The desmocranium showed ossification and a heterotopic subcutaneous cartilaginous fragment (Fig. 9.40d). The structure of the cerebellum and pons was histoloically normal (Fig. 9.40e). This case of aprosencephaly may be caused by a destructive process given the area cerebrovasculosa-like tissue fragments and the clinical diagnosis of amniotic band constriction.

The first case was kindly provided by Gerard van Noort (Laboratory for Pathology East-Netherlands, Enschede, The Netherlands) and the second case by Akira Hori (Toyohashi).

References

Kakita A, Hayashi S, Arakawa M, Takahashi H (2001) Aprosencephaly: histopathologic features of the rudimentary forebrain and retina. Acta Neuropathol (Berl) 102:110–116

Sergi C, Schmitt HP (2000) The vesicular forebrain (pseudo-aprosencephaly): a missing link in the teratogenic spectrum of the defective brain anlage and its discrimination from aprosencephaly. Acta Neuropathol (Berl) 99:277–284

9.7.2 Holoprosencephaly

Holoprosencephaly (HPE) is usually described as a developmental field defect of impaired midline cleavage of the embryonic forebrain (DeMyer and Zeman 1963; Probst 1979; DeMyer 1987; Cohen 1989a, b; Siebert et al. 1990; Cohen and Sulik 1992; Norman et al. 1995; Golden 1998; Muenke and Beachy 2000, 2001; Roessler and Muenke 2001; Sarnat and Flores-Sarnat 2001; Cohen and Shiota 2002). HPE is frequently associated with specific craniofacial anomalies, including midline facial defects, cyclopia and nasal malformations (Chap. 5), and a broad range of ophthalmological anomalies (Pineda-Alvarez et al. 2011. Its incidence in live-born children with normal chromosomes has been estimated to be 0.48–0.88 per 10,000. In contrast, the rate among therapeutic abortuses was estimated at 40 per 10,000, indicating a very high rate of embryonic and fetal loss (Matsunaga and Shiota 1977; Shiota 1993; Shiota and Yamada 2010). In a large epidemiologic study in a Californian population, Croen et al. (1996) observed an overall prevalence of 1.2 per 10,000 live births and fetal deaths, whereas the prevalence for live births was 0.88 per 10,000.

HPE is aetiologically very heterogeneous. It can be associated with chromosomal abnormalities, single gene mutations, polygenic mechanisms, and environmental factors such as diabetes mellitus and alcohol (Warkany 1971; Cohen 1989a; Cohen and Sulik 1992; Norman et al. 1995; Kelley et al. 1996; Muenke and Beachy 2001; Cohen and Shiota 2002; Edison and Muenke 2003). Cytogenetic studies of HPE patients suggest at least 13 different autosomal dominant loci (Roessler and Muenke 1998, 2010; Nanni et al. 2000; Bendavid et al. 2010; Cohen 2010; Table 9.10), giving rise to about 15–20 % of all cases of HPE (Cohen and Shiota 2002). Several HPE genes have been identified: SHH (also known as HPE3: Belloni et al. 1996; Roessler et al. 1996; Nanni et al. 1999), SIX3 (HPE2: Wallis et al. 1999; Domené et al. 2008), ZIC2 (HPE5: Brown et al. 1998; Roessler et al. 2009), TGIF (HPE4: Gripp et al. 1998; El-Jaick et al. 2007), Patched/PTCH (Ming and Muenke 1998; Ming et al. 2002), GLI2 (HPE9: Roessler et al. 2003) and NODAL (Roessler et al. 2008). Their possible interactions with normal signalling pathways and cholesterol biosynthesis is shown in Fig. 9.41. SHH mutations account for about 17 % of familial cases, and 3.7 % of all HPE cases (Cohen and Shiota 2002). Clinical manifestations of HPE are quite variable among patients and even among family members who carry a defined type of gene mutation (Ming and Muenke 2002; Edison and Muenke 2003).

Table 9.10 Causative genes of human holoprosencephaly

Full size table

HPE is a developmental malformation sequence in which impaired midline cleavage of the forebrain up to no cleavage (a holosphere) is the basic feature. The more severe forms can be diagnosed prenatally by ultrasound (Blaas et al. 2002; Pooh 2009; Volpe et al. 2009; Clinical Case 9.9).

In a majority of cases, this non-cleavage involves the basal ganglia, thalamus and hypothalamus. Diabetes insipidus occurs in about 67 % of children with HPE (Sarnat and Flores-Sarnat 2001), but other endocrine disorders involving the anterior pituitary occur less common and usually in addition to diabetes insipidus. The hypothalamus shows the highest incidence of non-cleavage of subcortical structures in HPE (Simon et al. 2000). The involvement of the basal ganglia may lead to generalized chorea (Louis et al. 1995). The most severe, complete or alobar type, and the incomplete forms, including the semilobar type and the least severe lobar type, represent degrees of severity rather than clearly distinguishable forms of this disorder. Together with the associated craniofacial malformations they constitute the HPE sequence (Cohen and Sulik 1992). The craniofacial malformations also vary in extent from the most severe being cyclopia with a single proboscis located above the midline eye to mild facial abnormalities. In general, the “face predicts the brain” (DeMyer et al. 1964; Fig. 9.42). It should be emphasized, however, that in 10–20 % of the holoprosencephalies no or only minor craniofacial abnormalities are present (Chap. 5), and that severe HPE may be present in the absence of obvious facial anomalies. The severity of the malformations has an anterior-to-posterior gradient, with the anterior portions being the least well formed (Cohen 1989b; Norman et al. 1995; Golden 1998; Simon et al. 2000). The gyral pattern of the posterior cerebrum more closely resembles the normal gyral pattern than that of the anterior cerebrum (Barkovich et al. 2002). Most HPE patients have normal cortical thickness (Barkovich et al. 2002). Sylvian fissures were displaced further rostrally and medially as HPE became more severe, until in the most severe cases, no Sylvian fissures could be identified at all. These data corroborate Yakovlev’s (1959) cytoarchitectonic analysis of the cerebral cortex of alobar and semilobar cases of HPE. The typical motor cortex was found in the cortex of the anterior midline. The arterial pattern in HPE brains varies (van Overbeeke 1991; van Overbeeke et al. 1994). The rostral part of the circle of Willis is usually absent. In two cases with incomplete HPE, both internal carotid arteries contributed to the vascularization of the cerebral cortex. In six other specimens with incomplete and complete forms of HPE, one of the internal carotids supplied the largest part of the brain.

Cyclopia has been known since ancient times through the figure of the cyclopean shepherd Polyphemos in Homer’s Odyssey (around 800 BC). Modern knowledge of cyclopia and prosencephalies originates from the three-volume treatise on teratology by Geoffroy Saint-Hilaire (1832–1837) who introduced the terms ethmocephaly and cebocephaly. Kundrat (1882) extended these observations and distinguished six types of forebrain malformations as arhinencephaly. Much of our present knowledge on HPE dates back to the work of DeMyer and Zeman (DeMyer and Zeman 1963; DeMyer et al. 1964; DeMyer 1987), whose practical subdivision into alobar, semilobar and lobar types is commonly used. In the alobar form, only one single ventricle (a holosphere) of variable size is present without interhemispheric diversion. Posteriorly, a membrane usually closes the holosphere. This membrane is actually the posterior roof of the single ventricle (Golden 1998) and may bulge dorsally to form a fluid-filled ‘dorsal sac’ or cyst (Fig. 9.43a). The dorsal cyst may originate as a dilatated suprapineal recess of the third ventricle (Sarnat and Flores-Sarnat 2001; Simon et al. 2001; Marcorelles and Laquerrière 2010). Probst (1979) based his subdivision of prosencephalies on the presence and extent of the dorsal sac (Table 9.9). Siebert et al. (1990) proposed a simpler subdivision of the holoprosencephalies into complete and incomplete forms. The thalami and corpora striata are undivided. The olfactory bulbs and tracts and the corpus callosum are always absent. In the semilobar type, rudimentary cerebral lobes with an interhemispheric posterior fissure and a rudimentary corpus callosum may be present. The olfactory bulbs and tracts are absent or hypoplastic. In the least severe, lobar type, a distinct interhemispheric fissure is present with some midline continuity. The olfactory bulbs and tracts may vary from normal to absent. Midline separation of the thalami and corpora striata may be incomplete. Fertuzinhos et al. (2009) showed selective depletion of molecularly defined cortical interneurons in human holoprosencephaly with severe striatal hypoplasia (Chap. 10). More recently, five types of HPE are distinguished (Hahn and Barnes 2010; Solomon et al. 2010; Table 9.11). Some examples of MR imaging of HPE are shown in Figs. 9.44 and 9.45. Two rare HPE cases, one with hypertrophic olfactory nerves, the other with a unique traversed coronal sulcus, are shown in Clinical Cases 9.10 and 9.11, respectively.

Table 9.11 Types of holoprosencephaly

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An additional form is known as the middle interhemispheric variant or syntelencephaly (Barkovich and Quint 1993; Lewis et al. 2002; Simon et al. 2002; Pulitzer et al. 2004; Marcorelles and Laquerrière 2010; Clinical Case 9.12). In this variant, the posterior and anterior portions of the falx cerebri are present, but its midportion is absent near the frontoparietal convexity. Here, the cerebral hemispheres ‘fuse’ in the midline, mainly in the posterior frontal lobes. The middle part of the corpus callosum may be misformed, the septum pellucidum is absent and the olfactory bulbs and tracts may show variable deficiency. This anomaly may best be explained by a focal paucity of the primitive dorsal meninx leading to failure of induction within this small area (Barkovich 2000). Recently, a mild subtype of HPE, septopreoptic HPE has been distinguished (Hahn et al. 2010), in which midline fusion is restricted to the septal region or preoptic region of the telencephalon.

Part of the phenotypic variability in human HPE as found in the Kyoto Embryological Collection is illustrated in Fig. 9.46 (Yamada et al. 2004). Other embryological cases were described by Mall (1917), Vermeij-Keers (1987; Chap. 5) and Müller and O’Rahilly (1989c). Embryos after Carnegie stage 18 were classified into complete (true) cyclopia (Fig. 9.47), synophthalmia (partially fused eyes in a single eye fissure), closely apposed eyes (possible forerunners of ethmocephaly and cebocephaly) and milder forms of HPE with median cleft lip (premaxillary agenesis). At Carnegie stages 13–17, when facial morphogenesis is not completed, HPE embryos showed some facial characteristics which are specific to these stages and different from those in older HPE embryos. The midline structures of the brain, including the pituitary gland, were lacking or seriously hypoplastic. Complete cyclopia was found in two cases after CS18 but none at earlier stages.

The eye field begins as a single structure that spans the midline (Adelmann 1936a, b; Li et al. 1997; Chap. 5). Under the influence of signals from the prechordal plate, the vertebrate eye field splits into discrete left and right eyes (Marlow et al. 1998; Varga et al. 1999). In zebrafish, this process has been directly studied under time-lapse photography (England et al. 2006). The division of the eye fields is an active process involving directed cellular movements and the critical orientation of the midline prechordal plate signalling centre beneath the telencephalon. If these developmental stages are not completed correctly the default result is cyclopia (Roessler and Muenke 2010). For example, when the prechordal plate is surgically removed, such animals consistently develop cyclopia (Shih and Fraser 1996; Feldman et al. 1998). Hedgehog signalling is also required: reduced hedgehog signalling results in hypotelorism, whereas no hedgehog leads to cyclopia (Cordero et al. 2004).

Clinical Case 9.9 Prenatal Diagnosis of Holoprosencephaly

The holoprosencephalies are usually classified into three variations: (1) the alobar type, a single-sphered cerebral structure with a single common ventricle, a posterior large cyst of the third ventricle (a dorsal sac), absence of the olfactory bulbs and tracts and a single optic nerve; (2) the semilobar type with formation of a posterior portion of the interhemispheric fissure; and (3) the lobar type with formation of the interhemispheric fissure anteriorly and posteriorly but not in the midhemispheric region; fusion of the fornices is seen. Associated anomalies include: (1) facial abnormalities such as cyclopia, ethmocephaly, cebocephaly, a flat nose, a cleft lip and palate are invariably associated with HPE; (2) extracerebral abnormalities are also invariably associated and include: renal cysts/dysplasia, omphalocele, cardiac disease or myelomeningocele. HPE can be diagnosed prenatally (Pooh 2009). Two cases are shown in Figs. 9.48 and 9.49.

Data for this case were kindly provided by Ritsuko Pooh (Osaka, Japan).

Reference

Pooh R (2009) Neuroscan of congenital brain abnormality. In: Pooh R, Kurjak A (eds) Fetal neurology. Jaypee, St Louis, pp 59–139

Clinical Case 9.10 Holoprosencephaly with Hypertrophic Olfactory Nerves

Holoprosencephaly (HPE) has a wide spectrum of morphological features, ranging from alobar through semilobar to lobar types. The term arhinencephaly was once used as a synonym for HPE, although in fact it is a misnomer since not all rhinencephalic structures are lacking in HPE. Agenesis of the olfactory nerves does not define arhinencephaly. In his series of HPE cases, Akira Hori found olfactory nerves in 24 % of the cases and two fetal HPE cases with hypertrophic olfactory nerves (see Case Report).

Case Report. Following spontaneous abortion at the 22nd gestational week, a male fetus came to autopsy with a body length of 30.3 cm and body weight of 525 g. General pathology revealed open ductus venosus Arantii, foramen ovale and dusctus arteriosus Botalli. Neuropathological examination revealed a plain cranial base without laminae cribrosae. No longitudinal interhemispheric fissure was formed and the cerebral surface was lissencephalic. The olfactory nerves protruded from a hypertrophic grey substance in the middle part of the frontal lobe base (Fig. 9.50a). In the infratentorial structures no malformations were observed. Macroscopically, the atypical cut surface of the hypertrophic substance with protrusion showed grey substance corresponding to the olfactory nerve (Fig. 9.50b). Histologically, a mass of matrix cells were recognized in the hypertrophic grey matter including primitive neuroblasts (Fig. 9.50c). Apoptotic rates were extremely low (TUNEL method; Fig. 9.50d) and apoptosis inhibition was demonstrated by Bcl-2 immunohistochemistry (Fig. 9.50e). In conclusion, in this case HPE with hypertrophic olfactory nerves was found, a rare morphological variation of HPE.

Clinical Case 9.11 Semilobar Holoprosencephaly with a Unique Traversed Coronal Sulcus

Holoprosencephaly (HPE) is a developmental disorder in which the forebrain fails to divide into two separate hemispheres. Although at least 13 different chromosomal loci contributing to HPE have been reported, mutations of the four most common genes (SHH, ZIC2, SIX3 and TGIF) have been identified in HPE patients (Roessler and Muenke 2010; Solomon et al. 2010a, b). With regard to genotype-phenotype correlation, structural brain anomalies were most commonly observed in individuals with the ZIC2 mutation. Itoh et al. (2011) presented an HPE case with a ZIC2 deletion, showing a unique coronal sulcus which divided the brain into rostral and caudal parts (see Case Report).

Case Report. Fetal ultrasonography at the 18th week of gestation showed HPE with a normal facial appearance in a male fetus (Fig. 9.51a–c). A normal karyotype 46XY was demonstrated by G-band chromosome analysis and no increased number of the chromosome 13 was discerned by conventional FISH analysis of amniotic fluid. The fetus was stillborn at the 20th week of gestation. His face appeared normal and no external anomalies were found (Fig. 9.51d, e). At autopsy, the external appearance of the cerebral hemispheres was unique in that a deep coronal sulcus traversed from one side to the other across the midline when viewed dorsally, and it was partially separated by the interhemispheric fissure at the fronto-orbital and occipital areas (Fig. 9.51f). Knotted olfactory bulbs, extending medially and then rostrally, appearing immature for the gestational age, but other structures, such as the optic chiasm, infundibulum and pituitary gland, were formed normally. The brain stem appeared normal but the posterior part of the cerebellum was not well developed. The cut surface of the brain showed a single ventricle with a partial separation in the orbital and occipital areas by the interhemispheric wall (Fig. 9.51g). The separated fronto-orbital ventricles were fused in the dorsal part and communicated with a large single ventricle by a narrow canal. The caudal ventricle was separated again by the interhemispheric wall. The fornix and the corpus callosum were not identifiable. The basal ganglia, the thalamus and the hypothalamus were separated into right and left parts with a normally formed third ventricle in between.

Comparative genomic hybridization microarray revealed a copy number loss at the regio spanning chromosome 13q32.3 to 13q33.3, including the ZIC2 gene, which indicated a deletion of ZIC2. Solomon et al. (2010b) reviewed 16 cases with a ZIC2 deletion, including 5 with alobar HPE, 3 with semilobar HPE and 1 with lobar HPE. It is tempting to speculate that the semilobar type of HPE with a traversed coronal sulcus, may be one of the distinct phenotypes of HPE, accompanied by the loss of function due to a ZIC2 deletion (Roessler et al. 2009).

References

Itoh K, Ogi H, Yaoi T, Yoshifugi K, Pooh R, Yamasaki M, Fushiki S (2011) Semilobar holoprosencephaly with a unique traversed sylvian sulcus. Neuropathol Appl Neurobiol 37:685–688

Roessler E, Lacbawan F, Dubourg C, Paulussen A, Herbergs J, Hehr U et al (2009) The full spectrum of holoprosencephaly-associated mutations within the ZIC2 gene in humans predicts loss-of-function as the predominant disease mechanism. Hum Mut 39:E541-E554

Roessler E, Muenke M (2010) The molecular genetics of holoprosencephaly. Am J Med Genet Part C 154C:52–61

Solomon BD, Mercier S, Vélez JI, Pineda-Alvarez DE, Wyllie A, Zhou N et al (2010a) Analysis of genotype-phenotype correlations in human prosencephaly. Am J Med Genet Part C 154C:133–141

Solomon BD, Lacbawan F, Mercier S, Clegg NJ, Delgado MR, Rosenbaum K et al (2010b) Mutations in ZIC2 in human prosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals. J Med Genet 47:513–524

Clinical Case 9.12 Middle Interhemispheric Variant of Holoprosencephaly

The middle interhemispheric variant of holoprosencephaly (MIH) is a rare malformation in which the cerebral hemispheres fail to divide in the posterior frontal and parietal regions (Barkovich and Quint 1993; Simon et al. 2002). Autopsy was done in only a few cases (Pulitzer et al. 2004; see Case Report).

Case Report. The patient was born at 42 weeks of gestation as the fourth child of a 36-year-old healthy mother, who had already three healthy children. There were no previous obstetrical problems. Some intrauterine growth retardation was apparent. Birth was normal with Apgar scores of 9/10. Birth weight was 3,345 g and crown-heel length 49 cm. There were microcephaly, a midface hypoplasia, bilateral cheilognathopalatoschisis (Fig. 9.52a) and panhypopituitarism. Colobomas were found in both eyes. Ultrasound examination of the head suggested holoprosencephaly. A falx was only apparent in the frontal part of the head. MRI could not be performed anymore due to the rapid deterioration of the child. The child died at day 8 owing to necrotizing enterocolitis with sepsis.

At autopsy, the necrotizing enterocolitis and a complicating acute respiratory distress syndrome were found. Brain weight was 300 g (normal range: 420 ± 33 g). The brain showed a gyral pattern that was somewhat less-developed than normal with underdeveloped frontal lobes. From above, the presence of two hemispheres separated over their whole length was suggested (Fig. 9.52b). The olfactory bulbs and the pituitary gland were absent. The optic nerves were smaller than normal. In frontal sections (Fig. 9.52c–e), there was no subdivision of the cerebrum into two hemispheres in the rostral half of the brain. A gyrus in the depth of a midsagittal sulcus crossing from left to right gave the false impression of two hemispheres rostrally. Two hemispheres were evident from the level of the globus pallidus caudalwards. At that level a corpus callosum could be seen as well as a small third ventricle. In the posterior half of the brain the two hemispheres looked quite normal. There were no structural abnormalities in the brain stem and cerebellum, except for some hypoplasia of the pyramids.

References

Barkovich AJ, Quint DJ (1993) Middle interhemispheric fusion: an unusual variant of holoprosencephaly. AJNR Am J Neuroradiol 14:431–440

Pulitzer SB, Simon EM, Crombleholme TM, Golden JA (2004) Prenatal MR findings of the middle interhemispheric variant of holoprosencephaly. AJNR Am J Neuroradiol 25:1034–1036

Simon EM, Hevner RF, Pinter JD, Clegg NJ, Delgado M, Kinsman SL et al (2002) The middle interhemispheric variant of holoprosencephaly. AJNR Am J Neuroradiol 23:151–155.

9.7.3 Septo-optic Dysplasia

Primary absence of the septum pellucidum is rarely an isolated finding (Fig. 9.53) and frequently associated with other malformations such as HPE, agenesis of the corpus callosum and septo-optic dysplasia (Bruyn 1977; Friede 1989). It may be secondary to head trauma (Corsellis et al. 1973). De Morsier (1956) emphasized the combination of optic atrophy and defects of the septum pellucidum. The cases described as septo-optic dysplasia (de Morsier syndrome) form a rather heterogeneous group of disorders (Roessmann et al. 1987; Barkovich and Norman 1989; Barkovich et al. 1989; Friede 1989; Norman et al. 1995; Clinical Case 9.13). The clinical manifestations include a characteristic triad (Morishima and Aranoff 1986; Willnow et al. 1996; Hellström et al. 2000; Miller et al. 2000): (1) hypopituitarism, ranging from panhypopituitarism to insufficiency of isolated hormones; (2) aplasia of the optic disks that present with amblyopia or hemianopia; and (3) absence of the septum pellucidum. Aetiological factors may be viral infections, gestational diabetes, vascular disruption, drug toxicity and fetal alcohol syndrome (Hellström et al. 2000; Miller et al. 2000). The homeobox gene HESX1 is implicated in a familial form of septo-optic dysplasia (Dattani et al. 1998, 1999; Brickman et al. 2001; Thomas et al. 2001).

Clinical Case 9.13 Septo-optic Dysplasia

Septo-optic dysplasia is a developmental disorder of midline structures characterized by uni- or bilateral hypoplasia of the optic nerves, tracts and chiasm, and by the absence of the septum pellucidum, first described by de Morsier (1956). The syndrome is not rare and highly variable (Morishima and Aranoff 1986; Roessmann et al. 1987; Miller et al. 2000; see Case Report).

Case Report. The infant was born after an uncomplicated pregnancy of her 33-year-old mother. Multiple malformations were noted at birth, including bilateral cleft lips and palate, ulnar deviation of the hands, polydactyly and frontal synostosis. The infant was septic from the second day of life. She died at the age of 1 week. The cause of death appeared to be peritonitis due to perforated colonic ulcers and bilateral bronchopneumonia. The fixed brain weighed 287 g. The olfactory nerves were absent. The right eye and optic nerve were smaller than the left eye and optic nerve and both optic tracts were hypoplastic. The cerebellum was small. Coronal sections revealed an abnormal mass in the region of the genu of the corpus callosum that extended down to the third ventricle (Fig. 9.54). The walls of the third ventricle were fused at the base. Microscopic examination revealed marked retinal dysplasia. The lateral geniculate nuclei were reduced in size and showed no lamination. The tumour-like mass in the place of the corpus callosum consisted of a mixture of immature grey and white matter. Bundles of fibres, likely fornix fibers, was seen dorsal and ventral to the corpus callosum. Pronounced glial heterotopia were present at the base of the brain. The medullary pyramids were small, the pyramidal crossing was incomplete, and corticospinal fibres in the spinal cord were found predominantly in the anterior column.

References

de Morsier G (1956) Etudes sur les dysraphies crânio-encéphaliques. III. Agénésie du septum pellucidum avec malformation du tractus optique. La dysplasie septo-optique. Schweiz Arch Neurol Psychiatr 77:267–292

Miller SP, Shevell MI, Patenaude Y, Poulin C, O’Gorman AM (2000) Septo-optic dysplasia plus: a spectrum of malformations of cortical development. Neurology 54:1701–1703

Morishima A, Aranoff GS (1986) Syndrome of septo-optic dysplasia: the clinical spectrum. Brain Dev 8:233–239

Roesmann U, Velasco ME, Small EJ, Hori A (1987) Neuropathology of “septo-optic dysplasia” (de Morsier syndrome) with immunohistochemical studies of the hypothalamus and pituitary gland. J Neuropathol Exp Neurol 46:597–608

9.7.4 Isolated Arhinencephaly

Olfactory hypoplasia and isolated absence of the olfactory bulbs may occur without other cerebral malformations as an accidental finding at autopsy (Norman et al. 1995). In 1856, Maestre de San Juan first observed the association of hypogonadism with olfactory system abnormalities. Isolated absence of the olfactory bulb and tract can be transmitted as a single gene defect, especially in Kallmann syndrome. Kallmann syndrome (hypogonadotropic hypogonadism; Kallmann et al. 1944) is inherited in various ways, as an autosomal dominant trait (KAL2) with variable penetrance, and less commonly as an autosomal recessive (KAL3) or X-linked (KAL1) disorder (Cohen 1989a; Ballabio and Rugarli 2001; Oliveira et al. 2001). So far, six causative genes (KAL1, FGFR1, FGF8, CHD7, PROK2 and PROKR2) have been documented in Kallmann syndrome, explaining about 305 of all cases (Dodé et al. 2006; Hardelin and Dodé 2008; Karstensen and Tommerup 2012). It is the most common form of isolated gonadotropin deficiency due to a migration disorder. Olfactory cells (Fig. 9.55) and GnRH-producing cells in the hypothalamus fail to migrate along their normal pathway from the developing olfactory placode (Schwanzel-Fukuda and Pfaff 1989; Schwanzel-Fukuda et al. 1989, 1996; Wray et al. 1989a, b). The gene responsible for the X-linked form (KAL1) encodes an extracellular matrix protein (anosmin-1) that is expressed in the olfactory bulb (Franco et al. 1991; Legouis et al. 1991; Rugarli et al. 1993; Izumi et al. 1999, 2001). It has been suggested that anosmin-1 is involved in terminal stages of olfactory axon guidance to the bulb and that olfactory bulb hypoplasia or aplasia in Kallmann syndrome is secondary to lack of innervation (Hardelin et al. 1999; Rugarli 1999; Ballabio and Rugarli 2001; Hardelin 2001; Hardelin and Dodé 2008). The most pertinent findings in Kallmann syndrome are abnormalities of the olfactory system such as hypoplasia or aplasia of the olfactory bulbs, and hypoplasia of the anterior aspect of the olfactory sulci (Truwit et al. 1993; Quinton et al. 1996). More recently, the KAL2 gene was identified (Dodé et al. 2003). Mutations in the FGFR1 gene appear to be responsible for the autosomal dominant trait of Kallmann syndrome. The CHD7 gene is frequently found mutated in patients with CHARGE syndrome (Kim et al. 2008). CHARGE patients have aplasia or hypoplasia of the olfactory bulb and hypogonadotroph hypogonadism (Pinto et al. 2005; Asakura et al. 2008). CBD7 is expressed during development of the olfactory bulb and the olfactory epithelium, consistent with the associated anosmia (Sanlaville et al. 2006).

9.8 Development and Developmental Disorders of the Basal Ganglia and the Amygdala

9.8.1 Development of the Basal Ganglia

The basal ganglia are a group of closely connected cell masses, forming a continuum, extending from the telencephalon to the midbrain tegmentum. This complex comprises the striatum (the nucleus caudatus and the putamen, largely separated by the internal capsule), the globus pallidus, the subthalamic nucleus and the substantia nigra. The output of the basal ganglia is aimed at the ventral anterior and ventral lateral thalamic nuclei (parts of the motor thalamus), the centromedian thalamic nucleus, the habenula, the pedunculopontine tegmental nucleus and the superior colliculus (ten Donkelaar et al. 2011). In most non-primate mammals, the nucleus caudatus and the putamen are not clearly separated by an internal capsule and are known as the caudate-putamen complex. In primates, the globus pallidus consists of external or lateral and internal or medial parts. In other mammals, the homologue of the internal segment is formed by the entopeduncular nucleus. The caudate nucleus, the putamen and the globus pallidus form the dorsal part of the striatal complex. Heimer and co-workers (Heimer 1976; Heimer et al. 1982, 1991, 1997; Alheid et al. 1990) introduced the terms ventral striatum and ventral pallidum to include the limbic system into the basal ganglia. The nucleus accumbens, both cytoarchitectonically and histochemically closely resembling the caudate nucleus and the putamen, and the greater part of the olfactory tubercle form the ventral striatum (Fig. 9.56). The rostral part of the substantia innominata forms a ventral extension of the globus pallidus. The substantia innominata also contains the widely spread cholinergic basal nucleus of Meynert, the main source of cholinergic input to the cerebral cortex. The globus pallidus, the ventral pallidum and the substantia nigra are iron-rich areas of the brain as shown with Perl’s diaminobenzidine method (Switzer et al. 1982; Hill and Switzer 1984) and high-resolution MRI (Drayer et al. 1986).

The cerebral cortex, including its sensory and motor fields, has extensive connections with the striatum that, via the globus pallidus and ventral thalamic nuclei, projects to the motor, premotor and prefrontal areas of the cortex. This cortico-striato-pallido-thalamocortical circuit is known as the principal striatal circuit or loop and is involved in initiating motor activities stemming from cognitive activities (Figs. 9.57, 9.65a). The ventral striatum and pallidum are included in a limbic striatal loop, involving the allocortex, the nucleus accumbens, the ventral pallidum, the mediodorsal thalamic nucleus, and prefrontal and limbic cortices. The ventral striatopallidum is involved in initiating movements in response to emotionally or motivationally powerful stimuli (Heimer et al. 1991, 1997; Nieuwenhuys 1996). Nearly all cortical areas in primates participate in a strip-like patterned corticostriatal projection (Kemp and Powell 1970). Input from the somatosensory and motor cortices is extensive, whereas that from the visual cortex is minimal. In the rhesus monkey, Künzle (1975) showed that the motor cortex projects almost exclusively, organized in patches and in a somatotopical pattern, to the putamen. A comparable pattern of termination was found for the primate somatosensory cortex (Künzle 1977). In contrast, associative areas of the prefrontal, temporal, parietal and anterior cingulate cortices appear to project almost exclusively to the monkey caudate nucleus (Kemp and Powell 1970; Goldman and Nauta 1977; Künzle 1978; Van Hoesen et al. 1981). The various areas of the association cortex in monkeys project to longitudinal territories that occupy restricted mediolateral domains of the striatum (Selemon and Goldman-Rakic 1985). Limbic regions, particularly the basolateral part of the amygdala, and allocortical (entorhinal, piriform and hippocampal) structures, project to the striosomes of the ventromedial part of the caudate nucleus and to the ventral striatum (Graybiel 1986; McGeorge and Faull 1989). These findings suggest that the caudate nucleus in primates is more closely related to complex and associative types of behaviour, whereas the putamen appears more directly involved in sensorimotor control. The segregation of influences from the association and sensorimotor cortices that exist in the caudate nucleus and the putamen, respectively, is not only preserved at pallidal levels, but is also maintained at nigral and thalamic levels (DeLong and Georgopoulos 1981; Alexander et al. 1986; Gerfen and Wilson 1996). The current model of basal ganglia circuitry, introduced by Albin et al. (1989) and elaborated by DeLong and collaborators (Alexander and Crutcher 1990; DeLong 1990), involves two major striatal efferent pathways, known as the direct and indirect pathways, the first to facilitate or induce movements and the second to ‘brake’ movements. Although challenged by the increasing complexity brought about by anatomical, physiological and clinical observations (see ten Donkelaar et al. 2011 for review), this model still serves as a basis to explain pathophysiological mechanisms underlying motor disorders (Sect. 9.8.2). Psychic disorders such as obsessive-compulsive behaviour are observed in patients with lesions affecting various parts of the basal ganglia circuitry (Graybiel and Rauch 2000; Heimer 2000). This may also be true for mood disorders (Price and Drevets 2011). The ventral parts of the basal ganglia are intimately related to the basal nucleus of Meynert and the extended amygdala. These interdigitating and partly overlapping anatomical systems are involved in some of the most devastating neuropsychiatric disorders such as schizophrenia and Alzheimer disease (Alheid and Heimer 1988; Heimer et al. 1991, 1997; Heimer 2000).

Compartmental organization of the mammalian striatum has been demonstrated with histochemistry (acetylcholinesterase staining) and immunohistochemistry (staining for tyrosine hydroxylase, an enzyme necessary for dopamine biosynthesis, dopamine, enkephalins and other neuropeptides). Clustering of striatal neurons is obvious particularly in the developing mammalian striatum (Goldman-Rakic 1981, 1982; Graybiel 1984). The dopaminergic innervation of the striatum of young animals is organized in patches (‘dopamine islands’) as first shown with formaldehyde-induced catecholamine fluorescence (Olson et al. 1972; Tennyson et al. 1972), spatially corresponding with acetylcholinesterase-rich patches (Graybiel et al. 1981). In adult animals, the distribution of tyrosine hydroxylase or dopamine immunoreactivity does not show such prominent local inhomogeneities except in the ventral striatum – accumbens region (Graybiel et al. 1981; Graybiel 1984). With acetylcholinesterase staining, Graybiel and Ragsdale (1978) showed that within the otherwise acetylcholinesterase-rich striatal tissue (the striatal matrix) a mosaic of small zones of low acetylcholinesterase activity was present and called them ‘striosomes’ (Fig. 9.58). In cats, during development the dopamine islands first correspond with acetylcholinesterase-rich patches of the immature striatum, but later in development with the acetylcholinesterase-poor striosomes (Graybiel 1984). A similar patchy arrangement of the striatum was shown in the developing human brain (Kostović 1986; Holt et al. 1997). Letinić and Kostović (1996) showed that patches rich in calbindin-immunoreactive neuropil correspond to acetylcholinesterase-rich patches of prenatal brains. Ulfig et al. (2001) showed that the expression of AKAP79, a kinase-anchoring protein enriched in postsynaptic densities, in the striatal compartments of the fetal human brain correlates with the dopaminergic innervation of the striatum (Fig. 9.59). These data provided the basis for heterogeneity in the arrangement of striatal fibre connections (Graybiel 1990; Parent and Hazrati 1995; Parent et al. 1995; Gerfen and Wilson 1996; Haber and Gdowski 2004).

The basal ganglia and the amygdala arise from the ganglionic eminences (Fig. 9.60) as already suggested in early studies on the developing human forebrain (His 1889; Hochstetter 1919; Macchi 1951; Hewitt 1958, 1961; Humphrey 1968, 1972; for data in rhesus monkey see Gribnau and Geysberts 1985). The olfactory tubercle and the nucleus accumbens arise from the rostral part of the LGE, the nucleus caudatus and putamen from its intermediate part, and the subpallial part of the amygdala from the caudal eminence (Table 9.7). The MGE gives rise to the globus pallidus, the basal nucleus of Meynert and the bed nucleus of the stria terminalis. The nucleus basalis complex develops the earliest acetylcholinesterase activity in the human telencephalon (Kostović 1986) and sends widely distributed fibres to the anlage of the neocortex and limbic cortex by the end of the second trimester of gestation (Fig. 9.61). The development of the cortical layer innervation coincides with the appearance of an ‘adult’ pattern of topographic relationships. The LIM homeobox gene L3/Lhx8 is necessary for proper development of basal forebrain cholinergic neurons (Mori et al. 2004).

In rodents, the time of neuron origin has been determined in the basal ganglia and related basal forebrain (ten Donkelaar and Dederen 1979; Fentress et al. 1981; Bayer 1984; Marchand and Lajoie 1986; Marchand et al. 1986; Bayer and Altman 1987b; Van der Kooy et al. 1987). Large-celled structures such as the globus pallidus, the nucleus of the horizontal limb of the diagonal band of Broca as well as large cells in the rostral part of the substantia innominata, the caudate-putamen-complex and the olfactory tubercle arise early, whereas medium-sized and small cells in the basal forebrain have a persistent origin over a much longer period. Neuron formation in the basal forebrain persists decrementally until P4. A clear caudorostral spatiotemporal gradient as well as a distinct ‘outside-in’ gradient have been found in the caudate-putamen complex. The time span for neurogenesis in the nucleus accumbens is essentially the same as for the medial part of the caudate-putamen complex. Medium-sized neurons in the neostriatum and the nucleus accumbens, generated simultaneously, are usually arranged in scattered clusters. The neurons of the two striatal compartments are generated during largely non-overlapping developmental periods (Marchand et al. 1986; Van der Kooy et al. 1987). Most of the earliest-born neurons form the patch compartment, and later-born cells make up the matrix compartment. Cell counts indicate that in rats there may be as many as 2,000,000 neurons in the striatum on each side at P4, but that that number is reduced by apoptosis to the adult figure of approximately 690,000 at P8 (Fentress et al. 1981), suggesting extensive programmed cell death in the striatum. About 97 % are medium-sized neurons and about 3 % are large cells. Itoh et al. (2001) studied the presence of programmed cell death in the human striatum and globus pallidus of fetuses and newborns (gestational age ranging from 12 to 40 weeks) with the transferase-mediated dUTP-biotin nick end-labelling (TUNEL) technique. In the caudate and putamen, TUNEL-labelled cells were observed from the 12th week of gestation onwards. The numerical density of the total number of neurons was significantly decreased, whereas the labelling index of apoptotic cells was significantly increased with advancing gestational age. In the globus pallidus, comparable data were obtained.

The GABAergic striatal projection neurons are derived from the LGE (Deacon et al. 1994; Olsson et al. 1995, 1998; Anderson et al. 1997b; Flames et al. 2007; Sect. 9.5) and Dlx1,2,5,6, Gsh2 and Mash1 are involved in their specification and differentiation (Porteus et al. 1994; Anderson et al. 1997b; Casarosa et al. 1999; Eisenstat et al. 1999; Toresson and Campbell 2001). Most striatal interneurons appear to migrate tangentially from the MGE or the adjacent preoptic/anterior entopeduncular area, and express the NKX2.1 homeodomain protein (Marín et al. 2000). Nkx2.1 mutants are defective in striatal interneurons (Sussel et al. 1999), whereas the number of striatal interneurons is reduced in Mash1 and Dlx1/Dlx2 mutants (Casarosa et al. 1999; Eisenstat et al. 1999). Mash1 mutants primarily have a reduction of early-born striatal interneurons, whereas Dlx1/Dlx2 mutants primarily have reduced numbers of late-born striatal interneurons.

SHH and FGF8 are essential for the formation of the dopaminergic neurons of the substantia nigra and the ventral tegmental area (VTA; Ye et al. 1998; Wurst and Bally-Cuif 2001; Holzschuh et al. 2003; Chap. 7). Several early ventral midbrain markers contribute to their specification, including En1/En2, Lmx1b, Pax2/Pax5 and Wnt1 (Hynes and Rosenthal 1999; Smidt et al. 2000), before expression of dopamine-specific markers. In mice, TH is present at E11.5, shortly after expression of the orphan nuclear receptor Nurr1 (Zetterstrom et al. 1996, 1997) and the homeobox gene Pitx3 (Smidt et al. 1997; van den Munckhof et al. 2003). Nurr1 mutants fail to induce TH in the mesencephalic dopaminergic progenitor neurons and die soon after birth (Zetterstrom et al. 1997). Pitx3 expression is maintained throughout life in both mice and men (Smidt et al. 1997). Pitx3 is also expressed in the developing lens (Semina et al. 1997). PITX3 mutations were found in two families with inherited forms of cataract and anterior segment dysgenesis (Semina et al. 1998). Abnormal lens development is also found in a naturally occurring mouse mutant, the aphakia mouse, which has two deletions in the Pitx3 gene (Rieger et al. 2001). Van den Munckhof et al. (2003) showed that Pitx3 is expressed only in the ventral tier of the substantia nigra pars compacta and in about half of the VTA neurons. In aphakia mice, Pitx3 was not detectable, and selective degeneration of dopaminergic neurons was found, leading to a more than 90 % decrease in striatal dopamine levels and marked reduction in spontaneous locomotor activity.

Most of the neurons of the substantia nigra are generated between E13 and E15, according to a gradient from rostral/dorsolateral to caudal/ventromedial (Hanaway et al. 1971; Altman and Bayer 1981; Marchand and Poirier 1983). This gradient extends to the VTA: neurons of the VTA are born later (E14-E16) than those of the substantia nigra (Altman and Bayer 1981; Marchand and Poirier 1983). It should be emphasized that the classic unitary SN/VTA is in fact a plurisegmental series of very similar units from the floor plate and the contiguous basal plate found across prosomeres 1–3, mesomeres 1 and 2 and the isthmic rhombomere (Puelles and Verney 1998; Verney et al. 2001a; Fig. 9.62).

The neurogenetic gradients in both the substantia nigra (Altman and Bayer 1981) and the caudate-putamen complex (ten Donkelaar and Dederen 1979; Fentress et al. 1981; Bayer 1984) in rodents can be correlated with the topographic principles in the nigrostriatal projections. The axonal projections are arranged so that the oldest nigral neurons are located in the dorsolateral part (generated before E15), whereas the younger neurons (born after E15) are located in the ventromedial part. In the rhesus monkey, substantia nigra neurons are generated between E36 and E43 with a peak around E38-E40 and without an appreciable spatiotemporal gradient (Levitt and Rakic 1982). All neurons in the caudate nucleus and putamen are generated within the first half of gestation (Brand and Rakic 1979). Dopaminergic axons are present in the putamen around E60 (Brand and Rakic 1984). The first morphologically defined synapses appear in the putamen at E60 and in the head of the caudate at E65 (Brand and Rakic 1984). During this period the neostriatum receives its first corticostriatal input (Goldman-Rakic 1981), preceding its cytoarchitectonic differentiation into separate island and matrix cellular components (Goldman-Rakic 1982). A similar putamen-to-caudate gradient of synaptogenesis has been observed in the developing human neostriatum (Zečević and Kostović 1980).

Data on the development of the human substantia nigra are limited. Cooper (1946) first delineated the substantia nigra at the end of the embryonic period (stages 20–21), but (by extrapolating rhesus monkey data) its cells are presumably generated between stages 18 and 21. Ontogeny of human mesencephalic dopaminergic cells was studied with histofluorescence (Nobin and Björklund 1973; Olson et al. 1973) and TH immunohistochemistry (Pearson et al. 1980; Pickel et al. 1980; Freeman et al. 1991; Verney et al. 1991, 2001a, b; Zecevic and Verney 1995; Almqvist et al. 1996; Puelles and Verney 1998). Evidence of TH-immunoreactive substantia nigra neurons as found as early as stages 15–16, i.e. at 4.5 weeks of development (Puelles and Verney 1998; Verney et al. 2001a). DiI labelling suggests that dopaminergic neurons innervate the striatum as early as week 10 of fetal life (Sailaja and Gopinath 1994). Binding studies for dopaminergic markers suggest that dopaminoceptive neurons in the striatum expressing the dopamine receptors D1R or D2R are present in the human fetal striatum at least from week 16 of life (Brana et al. 1995, 1996) and from week 12 in the substantia nigra and VTA (Aubert et al. 1997).

The development of the striatal dopaminergic innervation in rats has been studied with histofluorescence techniques (Olson and Seiger 1972; Seiger and Olson 1973) and immunohistochemical techniques using antibodies against TH (Specht et al. 1981a, b) and dopamine (Voorn et al. 1988). At E14, the first dopaminergic, nigrostriatal fibres reach the striatal anlage. This projection rapidly increases in size. The developmental pattern of the dopaminergic innervation of the striatum and the nucleus accumbens and the pattern of their neurogenesis are closely related. The first dopaminergic fibres arrive in the two striatal subdivisions well before their peaks in neurogenesis. In the immature caudate-putamen complex the dopaminergic innervation is organized as a system of patches called ‘dopamine islands’ (Olson et al. 1972). These islands express high TH-like immunoreactivity and are also rich in acetylcholinesterase activity. In rats, at E19 the first signs of this inhomogeneous distribution of dopaminergic fibres can be observed in the dorsolateral part of the striatum. In the following prenatal and postnatal days these dopaminergic patches, i.e. the first sign of structural compartments in the developing striatum, also appear more medially. By the third postnatal week, however, most of the patches are no longer detectable and only the most dorsolaterally located (the first arising) remain visible through the adult stage (Voorn et al. 1988). Data on the development of the human nigrostriatal projection indicate that already in the early fetal period the neostriatum receives dopaminergic terminals. The putamen becomes innervated somewhat earlier than the caudate nucleus (Olson et al. 1973). Nobin and Björklund (1973) studied 3–4-month-old fetuses (10–15-cm crown-rump length). At this stage of development, catecholaminergic cell groups and nigrostriatal pathways are already richly developed and innervate abundantly the basal ganglia and olfactory region (Fig. 9.63). TH studies in 9–10-week-old fetuses (about 50-mm crown-rump length) show that loose clusters of TH-immunoreactive neurons are present in the pars compacta of the substantia nigra and the VTA. In these early fetal stages, the TH-immunoreactive neurons in the substantia nigra already have well-established processes which are richly distributed in the pars reticulata and in the basal ganglia. These data strongly suggest that also in primates including man the generation of neurons in the substantia nigra and the VTA as well as the ingrowth of nigrostriatal fibres takes place in the last part of the embryonic period, i.e. between stages 17 and 23, comparable to E14-E17 in rat (Table 9.12). In rat and human embryos, the penetration of dopaminergic fibres in the cerebral cortex occurs at similar developmental stages in each species (Verney et al. 1982, 1993, 2001b; Kalsbeek et al. 1988; Zecevic and Verney 1995).

Table 9.12 Development of dopaminergic cell groups in the mesencephalon and their innervation of the basal ganglia and prefrontal cortex in rats, rhesus monkeys, and man

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9.8.2 Congenital and Acquired Disorders of the Basal Ganglia

Developmental malformations of the basal ganglia are rare, and are usually associated with malformations of other areas of the CNS (Lemire et al. 1975; Friede 1989). Sarnat (2000) reported a case of congenital absence of the basal ganglia (Fig. 9.64). Acquired disorders of the basal ganglia are much more common, especially in the perinatal period. From a clinical point of view disorders of movement due to abnormal functioning of the basal ganglia can be divided into two broad groups (Fig. 9.65): (1) the hypokinetic-rigid syndromes, the fundamental disturbances of which consist of hypokinesia and/or bradykinesia, i.e. difficulty and/or slowness in initiating and completing movements, generally associated with rigidity; and (2) the dyskinesias, including tremor, chorea and ballismus, dystonia and athetosis, tics, and myoclonus (Fernández-Alvarez and Aicardi 2001; Hoon et al. 2003; Sanger 2003). Disorders with a hypokinetic-rigid syndrome in childhood include early-onset Parkinson disease, juvenile Huntington disease, Wilson disease, juvenile GM2 gangliosidosis, multiple-system atrophies, Hallervorden-Spatz disease and many other rare disorders (Fernández-Alvarez and Aicardi 2001; Clinical Case 9.14; Table 9.13). Many patients with Hallervorden-Spatz disease have mutations in the gene encoding pantothenate kinase 2 (PANK2), resulting in pantothenate kinase associated neurodegeneration (Hayflick et al. 2003). The ‘eye-of-the-tiger sign’ is typical on MRI examination. The medial part of the globus pallidus appears to be especially sensitive to deficiency of PANK2.

Table 9.13 Involvement of the basal ganglia in some childhood motor impairment syndromes

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A selective vulnerability of the basal ganglia is found in many acquired lesions such as subependymal haemorrhages affecting the ganglionic eminence, status marmoratus, subacute necrotizing encephalopathy (Leigh syndrome; Clinical Case 9.16 and kernicterus. The basal ganglia are susceptible to injury because they are metabolically very active in the immature brain (Chugani and Phelps 1986) and possess a high concentration of excitatory receptors (Mitchell et al. 1999). Subependymal or germinal matrix haemorrhages are very common in premature infants (see Norman et al. 1995; Squier 2002). Status marmoratus (marbled state or état marbré) is characterized by the presence of myelinated fibres in aggregations of a density abnormal for a given site (Norman 1947). Typically, such aggregations are associated with abnormal collections of glial fibres. Status marmoratus is usually restricted to the striatum, but may involve the globus pallidus, red nucleus and cerebral cortex. It is usually associated with the athetoid form of cerebral palsy (Malamud 1950). Severe intellectual disability, spasticity and epileptic seizures are common. Kernicterus may result as a complication of infantile hyperbilirubinaemia from any cause, and may lead to necrosis of selective brain stem, basal ganglia and cerebellar neurons (Kinney and Armstrong 1997). In the term infant, the common sites of the gross lesions with a bright yellow colour are the globus pallidus, subthalamus and Ammon’s horn. Kernicterus is now rare in regions where hyperbilirubinaemia can be anticipated, treated or prevented.

Chorea is a relatively infrequent movement disorder in children but at least 150 causes of chorea have been described (Padberg and Bruyn 1986). Primary (idiopathic) and secondary forms of dystonia are found. Secondary dystonias can be classified into structural, metabolic, degenerative and miscellaneous disorders. Dystonia is a frequent symptom in the course of many inborn errors of metabolism such as glutaric aciduria type 1, an autosomal recessive metabolic disorder, which is characterized by severe reduction or total absence of glutarylcoenzyme A dehydrogenase (GCDH) activity (Goodman et al. 1977; Goodman and Frerman 2001). Its prevalence has been estimated to be 1 in 30,000 (Kyllerman and Steen 1980). At least 100 disease-causing mutations have been described (Goodman et al. 1998; Zschocke et al. 2000). GCDH deficiency leads to an accumulation of the marker metabolites 3-hydroxyglutaric acid, glutaric acid and glutaryl carnitine. If untreated, the disease is complicated by acute encephalopathic crises, resulting in neurodegeneration of vulnerable brain regions, especially the putamen. 3-Hydroxyglutaric acid is the major neurotoxin in this disease (Kölker et al. 2003). Clinical manifestations generally appear between 5 and 14 months of age, but mild symptoms such as slight motor delay and hypotonia can be observed earlier (Hoffmann et al. 1996; Fernández-Alvarez and Aicardi 2001). Macrocephaly at birth or somewhat later in infancy is present in about 70 % of cases (Hoffmann et al. 1996). In about two thirds of cases, the disease starts abruptly, on average at 12 months of age, with focal seizures or generalized convulsions and vomiting, usually following an infectious disease. Psychomotor regression and dystonic or choreoathetotic movements then appear (Fernández-Alvarez and Aicardi 2001). Autopsy studies have shown rather minimal changes in severely affected patients who died at 1 year of age but changes much more marked in patients who died at more than 2 years of age (Goodman et al. 1977; Leibel et al. 1980; Chow et al. 1988; Soffer et al. 1992; Kimura et al. 1994; Clinical Case 9.15). These findings are remarkably similar to those in ‘familial holotopistic striatal necrosis’ (Miyoshi et al. 1969) or ‘familial striatal degeneration’ (Roessmann and Schwarz 1973). These cases may have been unrecognized forms of glutaric aciduria.

In subacute necrotizing encephalopathy or Leigh syndrome (Leigh 1951), movement disorders of any type, including hypokinetic-rigid syndrome, chorea, myoclonus or dystonia, may be the most obvious clinical features. Leigh syndrome is characterized by multifocal, bilateral areas of subtotal necrosis in the basal ganglia, the brain stem tegmentum, the cerebellum and to some extent the spinal cord. The lesions may involve the white matter, especially the posterior columns, the corticospinal tracts, the optic nerves and the superior cerebellar peduncles (Lemire et al. 1975). This syndrome usually presents in infancy with feeding difficulties, psychomotor retardation, ophthalmoplegia, ataxia and weakness. Leigh syndrome is a heterogeneous mitochondrial disorder among children that may be associated with deficiency of pyruvate dehydrogenase and of enzymes of the respiratory chain, especially complex I and complex IV (Zeviani et al. 1996; Darin et al. 2001; Tulinius et al. 2003; Clinical Case 9.16).

MRI studies have shown bilateral lesions of the thalamus and the basal ganglia in children with severe birth asphyxia, leading to dyskinetic and spastic types of cerebral palsy (Yokochi et al. 1991; Rutherford et al. 1992; Krägeloh-Mann et al. 1995; Rademakers et al. 1995; Rutherford 2002). In addition to hyperintensity (T2-weighed images) in the ventrolateral thalamus and the posterior part of the nucleus lentiformis, lesions of the perirolandic region and of the hippocampus were found in some patients. Bilateral lesions of the thalamus and the basal ganglia have also been found in term neonates as a consequence of severe birth asphyxia (Voit et al. 1987; Pasternak et al. 1991; Baenziger et al. 1993; Rutherford et al. 1995; Sie et al. 2000; Rutherford 2002). Krägeloh-Mann et al. (2002) defined three different patterns of MRI lesions in children with bilateral lesions of the thalamus and basal ganglia due to birth asphyxia, neonatal shock or late prenatal compromise: (1) a mild pattern with involvement of the lentiform nucleus and ventrolateral thalamus only; (2) an intermediate pattern with involvement of the lentiform nucleus, the ventrolateral thalamus and pericentral regions; and (3) a severe pattern with additional involvement of the entire thalamus and of the hippocampus. This grading of MRI findings corresponded rather well with the severity of cognitive and motor impairment and the type of cerebral palsy. Normal cognitive development and mild motor delay was only seen with the mild pattern. All children developed cerebral palsy: purely dyskinetic cerebral palsy was only found with the mild pattern, the dyskinetic-spastic or spastic forms were found in all three groups, with dyskinetic-spastic cerebral palsy more related to the moderate pattern, and purely spastic cerebral palsy more related to the severe pattern.

Clinical Case 9.14 Selective Vulnerability of the Basal Ganglia

A selective vulnerability of the basal ganglia is found in many acquired lesions such as subependymal haemorrhages affecting the ganglionic eminence, status marmoratus, subacute necrotizing encephalopathy (Leigh syndrome; see Clinical case 9.16) and kernicterus. The basal ganglia are susceptible to injury because they are metabolically very active in the immature brain and possess a high concentration of excitatory receptors (Mitchell et al. 1999). Moreover, many disorders of movement due to abnormal functioning of the basal ganglia occur (Fernández-Alvarez and Aicardi 2001). Some examples are shown as Case Reports.

Case Report 1: In methyl-malonic acidemia (MMA), a severe, classic organic aciduria, the globus pallidus is selectively involved. In a seven-year-old girl with MMA, an MRI showed bilateral destruction of the globus pallidus (Fig. 9.66a, b). She presented in the first week of life with an acute encephalopathy with coma and seizures. Laboratory investigation revealed a severe metabolic acidosis and hypoglycaemia. Despite appropriate treatment in the acute phase and interventions during follow-up, such as a special diet and prevention of a catabolic state during intercurrent illnesses, she became severely disabled with profound mental retardation, spasticity and dystonia.

Case Report 2: In infantile bilateral striatal necrosis, patients present with progressive motor disturbances. A previously healthy boy with a so far normal development presented with such symptoms at the age of five years. Neurological examination showed generalized, symmetrical dystonia and chorea. An MRI resembled the images as reported in infantile bilateral striatal necrosis (Fig. 9.66c). Laboratory investigations did not show any arguments in favour of an underlying mitochondrial or other metabolic disorder, poststreptococcal chorea or other causative disease processes. Molecular analysis of the only gene known to be responsible for infantile bilateral striatal necrosis (nup62) was negative.

Case Report 3: In kernicterus, hyperbilirubinaemia leads to bilateral damage of the globus pallidus (Fig. 9.66d–g). In a female neonate, postnatal development was complicated by hyperbilirubinaemia, despite phototherapy and transfusions. At the age of one week, MR images showed bilateral signal abnormalities in the globus pallidus, prominent on T1-weighted images but hardly visible on T2. At the age of three months, the T1-weighted images have become almost fully normal, including the globus pallidus. On these T1-weighted images, the stripes with increased signal intensity reflect the normal pattern of myelination of the posterior limb of the internal capsule at this age; these areas show normal low signals on T2-weighted images. Three months later, however, on T2-weighted images, strong signal intensities of the globus pallidus are now clearly visible. These images illustrate the transition of signal changes depending on the stage (acute versus chronic) of the disorder and the selective vulnerability of the globus pallidus in bilirubin encephalopathy.

References

Fernández-Alvarez E, Aicardi J (2001) Movement disorders in children. MacKeith, London

Mitchell IJ, Cooper AJ, Griffiths MR (1999) The selective vulnerability of striatopallidal neurons. Prog Neurobiol 59:691–719

Clinical Case 9.15 Familial Striatal Degeneration (Glutaric Aciduria Type 1)

Glutaric aciduria type 1 (GA-1) is an autosomal recessive metabolic disorder which is characterized by severe reduction or total absence of glutarylcoenzyme A dehydrogenase (GCDH) activity (Goodman et al. 1977; Kimura et al. 1994; Hoffmann et al. 1996). The neuropathological findings in a 15-year-old Turkish male adolescent will be discussed as the Case Report.

Case Report. Rapidly progressive neurological symptoms were evident from birth in this 15-year-old male adolescent whose parents were consanguineous to the third degree. Hypertonia began at the left side, became generalized later and ended with episodes of generalized epilepsy. His monozygous twin brother and two sisters were neurologically and developmentally normal, but a younger brother also had GA-1. They both displayed the so-far unreported mutation M801 (240 G → C) in exon 3 of the GCDH gene.

His first episode occurred at 7 months of age when, 2 weeks after gastroenteric dehydration, he had paroxysmal hypertonia of the left arm which progressed to status epilepticus with subcoma. The idiopathic relapsing fever was labelled as acute encephalopathy without any obvious metabolic cause. The second episode occurred 11 months later, again in the form of gastroenteric dehydration and encephalopathy. A peak of urinary glutaric acid (GA) and the presence of 3-OH-GA suggested the diagnosis of glutaric aciduria type 1. Blood tests were normal, but the patient’s CSF revealed a raised acetic acid level. The finding of normal GCDH activity in hepatocytes and fibroblasts, however, led to the erroneous dismissal of the GA-1 diagnosis. Constant episodes of laryngeal dyspnoea when he was 4 years old led to retesting of organic acid levels. They were found to be normal and so GA-1 was completely dismissed. The patient had now severe psychomotor retardation. He suffered from dyskinetic dystonia with compulsive nuchal torsion dystonia to the right side. Additional manifestations included hip adduction hypertonia, hyperextension and torsion of the spine. Although no fixed contractures were found, there was total loss of voluntary movements, except for visual expression and eye motility. The patient had hypotonia alternating with periods of opisthotonus and an overall dystrophic expression of the body until he died at the age of 15 years from bronchopneumonia. The diagnosis of GA-1 could only be confirmed after postmortem gene analysis.

At autopsy, the spleen and liver were found to be normal, making the diagnosis of a storage disease unlikely. The brain weighed 1,275 g. Macroscopically, there were widened lateral ventricles and loss of gyral convolutions. Frontal atrophy and a small caudate nucleus and putamen were also evident (Fig. 9.67a). The white matter appeared grossly normal. Microscopically, the striatum showed obvious neuron loss, with small neurons being more affected than large cells (Fig. 9.67b). This was marked in the putamen, moderate in the caudate nucleus and only mild in the globus pallidus. This neuronal loss was associated with marked astrocytic gliosis. Interestingly, on close examination of the striatum we noted that the neuronal loss and astrogliosis were non-continuous in nature. In fact, such changes were confined to areas within the sections which bore great resemblance to the patch-matrix compartments of the striatum.

References

Goodman SI, Norenberg MD, Shikes RH, Brelick DJ, Moe PG (1977) Glutaric aciduria: biochemical and morphological considerations. J Pediatr 90:746–750

Hoffmann GF, Athanassopoulos S, Burlina AB, Duran M, de Klerck JBC, Lehnert W et al (1996) Clinical course, early diagnosis, treatment and prevention of disease in glutaryl-CoA dehydrogenase deficiency. Neuropediatrics 27:115–123

Kimura S, Hara M, Nezu A, Osaka H. Yamazaki S (1994) Two cases of glutaric aciduria type 1: clinical and neuropathological findings. J Neurol Sci 123:38–43

Clinical Case 9.16 Leigh Syndrome

Leigh syndrome (Leigh 1951) or subacute necrotizing encephalomyopathy is a progressive subcortical disorder, characterized by multifocal, bilateral areas of subtotal necrosis in the basal ganglia, the brain stem tegmentum, the cerebellum, and to some extent the spinal cord (see Case Report). It is the prototype of a large group of mitochondrial encephalomyopathies, currently known as defects of oxidative phosphorylation (OXPHOS defects; Chap. 3).

Case Report. A boy was born after an uncomplicated pregnancy as the second child of non-consanguineous parents. His mother and grandmother were known with retinitis pigmentosa. As a baby, head balance was poor and the boy was very quiet. Marked developmental delay and subsequently progressive loss of motor and social skills became evident at the age of 8 months. Cerebral MRI showed marked cerebral atrophy and abnormal signs in the basal ganglia (Fig. 9.68), suggesting Leigh syndrome. Blood lactate levels were between 1.8 and 9.4 mmol/l (normally below 2.0 mmol/l), and CSF lactate was also elevated to 4.8 mmol/l (normally 1.2–2.0 mmol/l). At the age of 11 months, respiratory failure due to pneumonia necessitated artificial ventilation. At that time a muscle biopsy was taken. Histological examination of the tissue showed no structural abnormalities of the muscle fibres. Biochemical analysis demonstrated defective respiratory chain functions. Mutation analysis finally confirmed the diagnosis Leigh syndrome by demonstration of the 8993 T > G mutation in mitochondrial DNA. Although he initially recovered, the boy died at the age of 14 months due to aspiration and subsequent respiratory failure.

At autopsy, brain weight was 830 g. Macroscopical inspection revealed bilateral slightly asymmetric, dark grey to light brown lesions in the thalamus, hypothalamus, mesencephalic tegmentum, periaqueductal grey matter and hindbrain nuclei (Fig. 9.69a–c). The putamen and the pulvinar were bilaterally pseudocystically degenerated. All these lesions were characterized by spongiosis of the neuropil, reactive astrocytes and important capillary proliferation and endothelial swelling (Fig. 9.69d). In the less severe lesions such as in the periaqueductal grey matter, neurons were still well recognizable. In the more severely affected regions such as the putamen, almost all neurons had disappeared, leading to pseudocystic lesions. These are the classic signs found in Leigh syndrome. Large parts of the cerebral cortex, including frontal, insular and temporobasal cortex, were atrophic, and showed gliosis in the molecular layer and spongiosis and neuronal loss in layer II. Such lesions are reminiscent of Alpers disease. Moreover, in the occipital cortex an ischaemic lesion at the borderzone between the territories of the anterior and middle cerebral arteries was found with pseudolaminar necrosis of the complete cortex. There was also important cell loss and spongiosis in areas CA1 and CA3 of the hippocampus. Probably, these lesions resulted from generalized circulatory failure.

Reference

Leigh D (1951) Subacute necrotizing encephalomyopathy in an infant. J Neuro Neurosurg Psychiatr 14:216–221

9.8.3 Development of the Amygdala

The amygdala is composed of pallial and subpallial parts (Lammers 1972; Stephan and Andy 1977; Amaral 1987; de Olmos 1990, 2004; Heimer et al. 1991). The basolateral parts and the associated cortical amygdala form the pallial part, whereas the central and medial amygdaloid nuclei form the subpallial part (Fig. 9.70). The centromedial amygdala forms a continuum with the bed nucleus of the stria terminalis, known as the extended amygdala (Alheid and Heimer 1988; Alheid et al. 1995; Heimer et al. 1997; de Olmos 2004). Time of neuron origin data in rodents indicate a rostrocaudal gradient within the amygdaloid complex (ten Donkelaar et al. 1979; Bayer 1980; McConnell and Angevine 1983) and strongly support a subdivision of the amygdala into two groups: a group of early-arising (E13-E15/E17) structures (central, medial and anterior cortical nuclei) and a group of later-born (E14/E15-E16/E17) nuclei (lateral, basolateral, basomedial and posterior cortical nuclei). This distinction between two groups of nuclei in the amygdaloid complex is comparable with the subdivision of Stephan and Andy (1977). Molecular genetic data have been reviewed by Medina and Abellán (2012). In rhesus monkeys, neurogenesis in the amygdaloid nuclear complex starts at E33, peaks between E38 and E48 and ceases between E50 and E56 (Kordower et al. 1992).

Developmental studies on the human amygdala are few (Macchi 1951; Humphrey 1968, 1972; Kahle 1969; Ulfig 2002b; Ulfig et al. 2003a, b; Müller and O’Rahilly 2006). The primordial amygdala is recognized as a thickening in the ventrocaudal wall of the interventricular foramen as soon as the cerebral hemisphere has evaginated (stages 14–16). Apparently, slightly later, the medial nucleus develops first, followed by the basolateral complex later at stage 20. Most of the amygdaloid nuclei arise from the medial ganglionic eminence (Müller and O’Rahilly 2006). All amygdaloid nuclei are present by stages 21–22. Kahle (1969) and Ulfig and co-workers (Ulfig 2002b; Ulfig et al. 2003a, b) studied the fetal development of the human amygdala (Fig. 9.71). In the fifth and six gestational month, the inferior part of the amygdala reveals cell-dense columns merging with the caudal part of the ganglionic eminence. These columns contain vimentin-positive glial fibres which provide a scaffold for migrating neurons. In the seventh and eighth month, distinct reorganization of the cytoarchitecture of the amygdala occurs, accompanied by a rearrangement and disappearance of vimentin-positive fibres, leading to a high degree of maturity in the eighth month.

The amygdala may be involved in Ammon’s horn sclerosis and in schizophrenia and other neurobehavioural disorders such as the autism spectrum disorder (Chap. 10). Postmortem and MRI studies have highlighted the frontal lobes, the amygdala and the cerebellum as pathological in autism (Amaral et al. 2008; Chap. 10). The amygdala in boys with autism appears to undergo an abnormal developmental time course that includes a period of precocious enlargement that persists through late childhood (Sparks et al. 2002; Schumann et al. 2004). Sparks et al. (2002) found a 13–16 % abnormal enlargement of the amygdala in young children with autism (36–56 months of age). Amygdala enlargement may be associated with severe anxiety (Juranek et al. 2006) and worse social and communication skills (Munson et al. 2006). Schumann et al. (2004) found that the amygdala was enlarged by 15 % in 8- to 12-year-old boys with autism relative to typically developing controls, but did not differ in 13- to 18-year-old boys. Kemper and Baumann (1993) were the first to report abnormalities in the microscopic organization of the amygdala. Quantitative observations in six postmortem cases of autism between 9 and 29 years of age (five with intellectual disability, four with seizures) indicated that neurons in certain nuclei of the amygdala in autism cases appeared unusually small and more densely-packed than in age-matched controls. Schumann and Amaral (2006) compared nine autism cases 10–44 years of age without seizures with ten typically developing age-matched male controls. The autism group had significantly fewer neurons in the total amygdala and in the lateral nucleus than the controls. The amygdala is selectively involved in Urbach-Wiethe disease, a rare autosomal recessive neurocutaneous disorder (Clinical Case 9.17).

Clinical Case 9.17 Urbach-Wiethe Disease

Urbach-Wiethe disease, also known as lipoid proteinosis, is a rare autosomal recessive neurocutaneous disorder caused by mutations in the extracellular matrix protein 1 gene (ECM1; Hamada et al. 2003). ECM1 is thought to contribute to protein binding of collagens and glycosaminoglycans. Hoarseness, due to laryngeal deposition of hyaline material, is generally the first manifestation of the disease. The CNS gradually becomes affected with characteristic calcifications of the amygdala leading to temporal lobe epilepsy and neuropsychiatric manifestations. Histologically, the skin disorder is characterized by periodic acid-Schiff (PAS)-positive basement membrane thickening and accumulation of hyaline material. Based on the clinical observations of three patients, Adolphs et al. (1995, 1999) suggested that the amygdala is involved in a broad spectrum of social attributions.

Case report. A 15-year-old girl was referred to the Department of Pediatric Neurology after she was diagnosed with Urbach-Wiethe disease due to a homozygous nonsense mutation in the ECM1 gene by a dermatologist. From infancy onwards, the girl was known with remarkable hoarseness and typical skin abnormalities. Her motor and language development were fully normal and her school performance was excellent. From the age of 11 years onwards, she had suffered from unexplained paroxysms with strange abdominal sensations, followed by a short period with confusion but without motor signs. Neurological examination and routine electroencephalography were completely normal. Cerebral CT showed bilateral calcifications of the globus pallidus and amygdala (Fig. 9.72). The paroxyms were considered partial epileptic seizures, caused by cerebral involvement in Urbach-Wiethe disease. During follow-up, her epilepsy appeared drug-resistant and she developed memory problems as well as a panic disorder.

This case was kindly provided by Michèl Willemsen (Department of Pediatric Neurology, Radboud University Nijmegen Medical Centre, Nijmegen).

References

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935 Departments of Neurology, Radboud University Nijmegen Medical Centre, 9101, 6500 HB, Nijmegen, The Netherlands
Hans J. ten Donkelaar M.D., Ph.D.
Department of Pathology, University Hospital Antwerpen, Wilrijkstraat 10, B-2650, Edegem, Belgium
Martin Lammens M.D., Ph.D.
Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Johannes R. M. Cruysberg M.D., Ph.D.
766 Department of Radiology, Radboud University Nijmegen MC, 9101, 6500 HB, Nijmegen, The Netherlands
Karin Kamphuis-van Ulzen M.D.
Institute of Pathology, Medizinische Hochschule, Hannover, Germany
Akira Hori M.D., Ph.D.
Research Institute for Longevity Medicine, Fukushimura Hospital, Noyori-Yamanaka 19-14, Toyohashi, 441-8124, Japan
Akira Hori M.D., Ph.D.
Congenital Anomaly Research Center, Kyoto University Gradute School of Medicine, Kyoto, 606-8501, Japan
Kohei Shiota M.D., Ph.D.
Shiga University of Medical Sciences, Otsu, Shiga, 520-2192, Japan
Kohei Shiota M.D., Ph.D.

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Hans J. ten Donkelaar M.D., Ph.D.
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Martin Lammens M.D., Ph.D.
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ten Donkelaar, H.J., Lammens, M., Cruysberg, J.R.M., Ulzen, K.Kv., Hori, A., Shiota, K. (2014). Development and Developmental Disorders of the Forebrain. In: Clinical Neuroembryology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-54687-7_9

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DOI: https://doi.org/10.1007/978-3-642-54687-7_9
Published: 19 April 2014
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-54686-0
Online ISBN: 978-3-642-54687-7
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Development and Developmental Disorders of the Forebrain

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Development and Developmental Disorders of the Forebrain

Keywords

9.1 Introduction

9.2 Prosomeres and Pattern Formation of the Forebrain

9.3 Development of the Diencephalon

9.3.1 Development of the Thalamus

9.3.2 Development of the Hypothalamus

9.3.3 Development of the Pituitary Gland

9.3.4 Developmental Disorders of the Hypothalamus and the Pituitary Gland

Clinical Case 9.1 Duplication of the Pituitary Gland

Clinical Case 9.2 Pharyngosellar Pituitary

Clinical Case 9.3 Pallister-Hall Syndrome

9.4 Development of the Visual System

9.4.1 Development of the Eye

9.4.2 Congenital Malformations of the Eye

Clinical Case 9.4 Aniridia

Clinical Case 9.5 Retinitis Pigmentosa with CNS Malformations

9.4.3 Development of the Visual Projections

Clinical Case 9.6 Isolated Absence of the Optic Chiasm

9.5 Overview of the Development of the Telencephalon

9.6 Development of the Rhinencephalon

Clinical Case 9.7 A Remnant Olfactory Ventricle

9.7 The Prosencephalies

9.7.1 Aprosencephaly

Clinical Case 9.8 Aprosencephaly

9.7.2 Holoprosencephaly

Clinical Case 9.9 Prenatal Diagnosis of Holoprosencephaly

Clinical Case 9.10 Holoprosencephaly with Hypertrophic Olfactory Nerves

Clinical Case 9.11 Semilobar Holoprosencephaly with a Unique Traversed Coronal Sulcus

Clinical Case 9.12 Middle Interhemispheric Variant of Holoprosencephaly

9.7.3 Septo-optic Dysplasia

Clinical Case 9.13 Septo-optic Dysplasia

9.7.4 Isolated Arhinencephaly

9.8 Development and Developmental Disorders of the Basal Ganglia and the Amygdala

9.8.1 Development of the Basal Ganglia

9.8.2 Congenital and Acquired Disorders of the Basal Ganglia

Clinical Case 9.14 Selective Vulnerability of the Basal Ganglia

Clinical Case 9.15 Familial Striatal Degeneration (Glutaric Aciduria Type 1)

Clinical Case 9.16 Leigh Syndrome

9.8.3 Development of the Amygdala

Clinical Case 9.17 Urbach-Wiethe Disease

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