Keywords

1 Introduction

Rare diseases are highly heterogeneous life-threatening or chronically debilitating diseases with a low prevalence and a high level of complexity. Most of them are the result of a genetic pathological mutation, a few result from environmental exposures during pregnancy or later in life, often in combination with genetic susceptibility, and the others being rare cancers, auto-immune diseases, congenital malformations, toxic, and infectious diseases. There is also a great diversity in the age at which the first symptoms occur, but half of rare diseases can appear at birth or during childhood.

Work over the last 25 years has resulted in the identification of genes responsible for ~50% of the estimated 7,000 rare monogenic diseases, and it is predicted that most of the remaining disease-causing genes will be identified by the year 2020. This acceleration in gene discovery is the result of the application of high-throughput next-generation sequencing technologies. We expect to rapidly move into a scenario where most families presenting with a rare disease may have a molecular diagnosis established, allowing adequate clinical follow-up and proper genetic counselling. Also, deciphering the genetic and molecular signatures underlying rare diseases will facilitate the design of new therapies that will hopefully interfere in an efficacious way in those pathogenic pathways.

There is a wide range of diseases that can be classified as neurodegenerative. Some are very rare, but all have a significant impact with a progressively increasing burden of management. Herein, we highlight the clinical and genetic features associated with those rare inherited forms of neurodegenerative diseases, including ataxias, multiple system atrophy, spastic paraplegias, Parkinson’s disease, dementias, motor neuron diseases, and rare metabolic disorders.

2 Cerebellar Ataxias

Cerebellar ataxias represent a heterogeneous group of disorders characterised by progressive degeneration of the cerebellum often accompanied by a variety of neurological and systemic symptoms. Two main categories are distinguished: sporadic and hereditary ataxias. Sporadic ataxias may be symptomatic or idiopathic. Symptomatic ataxias are due to structural lesions or malformations in the cerebellum, toxics (alcohol; antiepileptic drugs: benzodiazepines; antidepressants: lithium; antineoplastics: cyclosporine; and amiodarone, procainamide, isoniazid, metronidazole, nitrofurantoin, among others; heavy metals: lead and mercury; and chemicals: for instance solvents and pesticides), hypothyroidism, diabetes, malabsortion due to celiac disease, vitamin E or B12 deficiencies, abetalipoproteinemia, paraneoplastic syndromes, demyelinating disorders, Whipple disease and post-viral/immune-mediated ataxia. Symptomatic ataxias can be handled and diagnosed with a detailed medical history and common ancillary tests. Idiopathic ataxias include the so-called idiopathic late-onset cerebellar ataxia (ILOCA) and multiple system atrophy (MSA).

Hereditary ataxias can present with autosomal dominant (SCA), autosomal recessive, X-linked or mitochondrial inheritance. Overall, they comprise about 60–75% of ataxias. They are diagnosed on family history, physical examination, neuroimaging, and genetic testing. This section focuses on hereditary and idiopathic ataxias (ILOSCA and MSA).

2.1 Autosomal Dominant Ataxias

Forty-three different genetic subtypes of spinocerebellar ataxia (SCA) are now distinguished. They are conventionally referred as SCAs regardless of whether or not they present with spinal pathology. In addition, the complex form dentatorubral-pallidoluysian atrophy (DRPLA) and eight episodic ataxias (EA) are usually included (Table 25.1; modified from [16, 32]. Together with the autosomal recessive ataxias, the minimum prevalence rate in European descend populations would be 6–7 per 100,000 people, which is comparable to Huntington’s disease or motor neuron diseases [32].

Table 25.1 Genetics of dominantly inherited autosomal spinocerebellar ataxias
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2.1.1 SCAs

The prevalence of these diseases is not widely known and varies considerably among geographical areas due to founder effects. SCAs 1, 2, 3, 6 and 7 account up to 65% of all SCA worldwide cases [10], being SCA3 the most common subtype worldwide. The genotype still remains elusive in up to 40–50% of SCA families indicating a reservoir of yet to be characterised diseases.

Age of onset is quite variable usually presenting in adulthood, and the disease progresses over decades. Life span is shortened in SCAs 1, 2, 3 and 7 [16] Anticipation is observed in SCAs in which CAG repeat expansion occurs and it is a significant issue to be considered in the genetic counselling process.

Cerebellar dysfunction in SCAs is often associated with other clinical signs such as ophthalmoplegia, polyneuropathy, retinopathy, pyramidal and extrapyramidal features, dementia, chorea, seizures, and lower motor neuron signs. Despite the clinical overlap between different SCA genotypes some distinctive clinical features may help the clinician in pursuing direct genetic testing: marked slow saccades are associated with SCA2; ophthalmoplegia with SCA3; pyramidal signs with SCAs 1 and 3; polyneuropathy with SCAs 1, 4, 8, and 25; pigmentary retinopathy with SCA7; seizures with SCA10; cognitive impairment with SCAs 2, 12, 13, and 17; axial myoclonus with SCA14; chorea with SCA17; dysphonia and early calcification of dentate nucleus with SCA20; and lower motor neuron signs with SCAs 3 and 36 [8]. Conversely, the pure cerebellar phenotype has been mainly associated with SCAs 5, 6, 11, 14, 15/16, and 37 [39, 52].

SCAs are often subdivided into expanded exon-coding CAG repeat ataxias (SCAs 1, 2, 3, 6, 7, 17, and DRPLA); SCAs with mutations in non-coding regions (triplets and pentanucleotide repeat expansions: SCAs 8, 10, 12, 31, and 36); SCAs with conventional mutations in other identified genes, and SCAs with still unidentified loci.

This complex and expanded knowledge in SCAs has not yet led to find the ultimate common pathogenic mechanism. Basic scientific research has identified transcriptional dysregulation, protein aggregation and clearance, autophagy, alterations of calcium homeostasis, mitochondria defects, toxic RNA gain-of-function mechanisms and activation of pro-apoptotic routes, amongst others, as the main mechanisms leading to cerebellar Purkinje cell death [31, 33]. Thus, several identified potential targets open the way to find effective treatments that may act during the early stages of neurodegeneration in SCAs [31, 33, 46, 48].

However, regardless of several trials in cells and animals models, available human therapeutic trials in SCA are scarce and only recently, some positive output has emerged. Valproate, an antiepileptic drug acting as an histone deacetylation inhibitor, improved locomotor function in an open trial in SCA3 [24]; and riluzole, a small-conductance potassium KC2 channel activator showed symptomatic benefits in a double-blind 12-months trial in a few SCAs and FRDA [45]. Nevertheless, no approved treatment to modify neurodegeneration is available yet for these diseases. Piracetam for myoclonus; L-Dopa for dystonia; baclofen and botulin toxin for spasticity; beta-blockers, benzodiazepines and even thalamic stimulation for intention tremor; anticholinergic drugs for hypersalivation; clonazepam for muscle cramps in addition to physical therapy, are commonly used and recommended as symptomatic treatments.

2.1.2 Episodic Ataxias (EA)

The episodic occurrence of symptoms differentiates EAs from SCAs [43]. Typically onset of EA occurs in childhood or early adulthood, however in E2, the most common form of EA, the onset may delay up to the fifth decade. Episodic ataxias can be provoked by exercise, emotional stress, startle or change of position. Tremor, muscle cramps, and stiffening may accompany the ataxia. Interictal and subclinical myokimia in face, arms, and legs may be seen in electromyography. Episodic ataxia 1 (EA1) presents with movement-induced attacks of ataxia that lasts less than 15 min and can appear up to 15 times a day. EA1 is caused by mutations in the potassium channel KCNA1 gene. In contrast, EA2 attacks may last for hours and days and they are often associated with nausea, migraine headache, and sometimes hemiparesis, dystonia and tinnitus; permanent cerebellar interictal signs may develop along the course of EA2, especially nystagmus, followed by a progressive cerebellar syndrome. Emotional and physical stress, caffeine, alcohol, exercise, intercurrent illness and phenytoin may trigger the attacks. EA2 is associated with point mutations in the CACNA1A gene whereas missense mutations in the same gene are associated with familial hemiplegic migraine, and CAG repeat expansions with SCA6. Evident clinical overlap exists with EA2, even within families [54]. Acetazolamide is an effective therapy for most patients with EA2 and half of the patients with EA1; phenytoin and carbamazepine are alternative therapies in EA1, whereas valproate, flunarizine, topiramate, and 4-aminopyridine may be an option in case acetazolamide fails in EA2. Episodic ataxias subtypes 3, 4, 5, 6, and 7 represent the minority of phenotypical variations in EA and few patients have been identified. EA5 shows an EA2 phenotype and EA6 additionally presents with seizures [43] (Table 25.1).

2.1.3 Other

Other rare autosomal dominant disorders like hereditary spastic ataxia and sensory motor neuropathy with ataxia may also present with ataxia.

2.2 Autosomal Recessive Ataxias

The autosomal recessive ataxias constitute a group of heterogeneous and rare disorders involving many genetic defects caused by a myriad of mechanisms of pathogenesis, which are mainly commonly caused by loss of function of the gene products (Tables 25.2 and 25.3).

Table 25.2 Autosomal recessive ataxias to be considered in adults
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Table 25.3 Autosomal recessive ataxias with exclusive or predominantly onset in childhood
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Friedreich ataxia (FRDA) is the most common recessively inherited ataxia with a prevalence of 1 in 50,000, followed by ataxia telangiectasia (AT) with a prevalence of 1 in 100,000 individuals [6]. Traditionally, neurologists take into account an age of onset of 25 years of age as a cut-off threshold to further screen these patients because only a minority of recessive and metabolic ataxias reveal an adult onset. In addition, all patients with a suspected recessive ataxia and negative screening should also be investigated for SCA.

2.2.1 FRDA

FRDA classically presents with ataxia, dysarthria, absent deep tendon reflexes, pyramidal signs, and an early-onset (<25 years). Cardiomyopathy, scoliosis, distal muscle atrophy, deafness, optic atrophy, and diabetes are common variable features. A milder phenotype with late-onset and a phenotype with spastic paraplegia without ataxia or polyneuropathy has also been reported. The underlying mutation consists of a GAA trinucleotide repeat expansion within the FXN gene (ranges: normal, 5–33 GAA repeats; mutable normal, 34–65 repeats; FRDA, 66–1,700). The expansion size accounts for less than 50% of the age of onset, and correlates more with the presence of diabetes and cardiomyopathy, particularly for larger alleles. Between 6 and 10% FRDA patients are compound heterozygotes for the GAA expansion. The FXN gene encodes for frataxin, a mitochondrial protein related to iron storage and sulphur-iron complexes biogenesis, thus being mitochondrial dysfunction a key feature underlying FRDA pathogenesis. Clinical trials with antioxidants [18, 22, 61], erythropoietin [29] and pioglitazone (ACTFRIE, unpublished data) have failed to prove any benefit.

2.2.2 Others

Once FRDA is excluded, an age-dependent screening for recessive ataxic syndromes and metabolic diseases is recommended (Table 25.2). It is important to note that some of these diseases are treatable [1]. Some clinical traits may help to direct the genetic test [6, 16]. Oculomotor apraxia is a common finding in ataxia telangiectasia (AT) and in ataxias presenting with oculomotor apraxia (AOA1, AOA2). Oculocutaneous telangiectases, choreoathetosis, dystonia, immunodeficiency, hypersensitivity to ionizing radiation, and predisposition to malignancy are also specific features for AT. Ataxia telangiectasia is due to mutations in the ATM gene, which encodes a protein related to DNA repair. The clinical disparity in AT is partly related to the relative preservation of ATM expression in some ATM mutations leading to milder phenotypes. As for AOAs 1 and 2, they both associate with polyneuropathy, and in addition AOA1 may show mild mental retardation. The aprataxin (APTX/AOA1) and the senataxin (SETX/AOA2) genes are both implicated in DNA repair pathways. Polyneuropathy is common in FRDA, vitamin E deficiency, abetalipoproteinemia, Refsum’s disease, and late-onset hexosaminidase A deficiency that may present as a FRDA-like phenotype. Retinitis pigmentosa with anosmia, polyneuropathy, cerebellar ataxia, deafness, and ichthyosis is typical of Refsum’s disease, while juvenile cataracts are a clinical hallmark of cerebrotendinous xantomatosis (CTX, sterol 27-hydroxylase deficiency) that will also present with tendon xanthomas, chronic diarrhea, ataxia, pyramidal signs, dementia, epilepsy, polyneuropathy, and white matter lesions on magnetic resonance imaging (MRI). In fact, MRI could also contribute to guide genetic testing [6]. White matter lesions are found in mitochondrial diseases and all leukodystrophies, such as the mentioned CTX, metachromatic leukodystrophy (arylsulfatase gene), and Krabbe disease (galactoceribrosidase deficiency).

A few other rare conditions may have an adult onset autosomal recessive ataxia such as Niemann-Pick C, a lipid storage disorder, often associated to dementia or psychiatric symptoms, and GM1 gangliosidosis that may associate with dystonia. Ataxia with a combination of migraine, epilepsy, myoclonus, late-onset ophthalmoplegia, and cognitive decline is presented in the autosomal recessive mitochondrial ataxic syndrome because of mutations in the POLG gene [13].

2.3 X-Linked Inherited Ataxias

Adult-onset adrenomyeloneuropathy is a mild form of adrenoleukodystrophy that typically presents in adult males (<50 year old) and is characterized by a progressive spastic paraparesia with sphincter and sexual dysfunction. Cerebellar ataxia may be present in up to 10% of these patients [6, 11]. White matter MRI lesions in the parietooccipital regions of the brain are commonly found. An increased level of very long chain fatty acids in plasma is diagnostic and the disease is due to mutations in the ABCD1 gene. Conversely, in >50 year old males with suspected X-linked ataxia, the fragile-X-associated tremor ataxia syndrome diagnostic should be considered. The syndrome combines progressive intention tremor, cerebellar ataxia, and white matter disease in the middle cerebellar peduncles. Additional features contributing to the diagnosis include executive function and memory deficits, parkinsonism, and additional MRI findings of global brain atrophy and white matter disease [14]. It has been reported in elderly male carriers of premutation allele (>200 CGG repeats) within the FMR1 gene, and the diagnostic should be considered in all males with onset of ataxia above 50 years because the carrier frequency is high (1:810 males).

2.4 Mitochondrial Cerebellar Ataxia

Cerebellar ataxia is found in most subtypes of mitochondriopathies (MERFF, MELAS, NARP, Kearns-Sayre, Leigh and May-White syndromes). These are all multisystem disorders with involvement of peripheral and central nervous systems, heart, eyes, ears, guts, kidney and bone marrow as well as endocrine dysfunction.

2.5 Idiopathic Late-Onset Cerebellar Ataxia (ILOCA)

After exclusion of symptomatic cerebellar ataxia, a hereditary ataxia should be considered in patients younger than 50 even if the family history is negative. Recessive ataxias should be screened followed by SCAs. When all diagnostic tests are negative, the acronym ILOCA should be used.

2.6 Multiple System Atrophy (MSA)

MSA is the most common disease causing isolated late-onset cerebellar ataxia (30%) with a prevalence of 1.9–4.9 cases per 100,000 people. Clinical hallmarks include autonomic and urinary dysfunction, Parkinsonism, and cerebellar and corticospinal tract symptoms and signs. Diagnosis is considered possible, probable or definite according to established criteria [62]. It usually starts in the sixth decade with a mean survival of 6–9 years. Some patients show predominant Parkinsonism signs, some of them showing predominant cerebellar signs. MRI show olivopontocerebellar and putaminal atrophy, with hyperintensities of the pons and middle cerebellar peduncles in T2-weighted images. Pathologically, MSA is a α-synucleopathy with glial cytoplasmic inclusions. No effective treatment is available for MSA.

3 Hereditary Spastic Paraplegias

The hereditary spastic paraplegias (HSPs) were first identified by Seeligmüller, Strümpell and Lorrain as an autosomal dominant disease, characterised by progressive spasticity and weakness of the lower limbs, with moderate loss of vibratory sense and bladder dysfunction. At that time, the neuropathological hallmark of the disease was also described as the degeneration of the longest spinal pathways, corticospinal tracts, and medial dorsal columns. The classification of HSPs is difficult and, throughout the years, several proposals have been made based on phenotype, mode of inheritance, and mutated gene (SPGs). All modes of hereditary transmission are found: autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), and mitochondrial inheritance. Clinically, the HSPs have been subdivided into pure and complex forms, according to the presence or absence of other neurological and extra-neurological features.

3.1 Clinical Manifestations

The initial symptoms in HSP patients include a feeling of stiffness, muscle cramps, inability to walk rapidly and frequent falls. In early-onset cases the disease is often expressed as delayed gait acquisition. Age-at-onset is highly variable, particularly for pure forms, ranging from the first year of life to the 8th decade, tending to be later in autosomal dominant forms and earlier in recessive ones. At disease onset, spasticity is usually noticeable only while walking. Over time, especially in complex forms, pyramidal signs may affect the upper limbs, though many patients show only tendon hyperreflexia that may include a brisk jaw reflex; weakness or spasticity of the upper limbs is rare, particularly in pure forms. In some patients with complex forms, dysarthria and dysphagia may present as a pseudobulbar state. Other manifestations include cognitive impairment (mental retardation or deterioration), epilepsy, optic atrophy, amyotrophies, neuropathy (usually axonal), ataxia and dystonia [15].

Until now, 89 loci and 75 genes have been identified: 20 autosomal dominant, 57 autosomal recessive, five X-linked, one with mitochondrial inheritance, and 6 with both dominant and recessive transmission (Table 25.4). A recent study has identified HSP mutations in genes associated with Parkinson (ATP13A2/SPG78), neuronal ceroid lipofuscinosis (TPP1), and the hereditary motor and sensory neuropathy (DNMT1), highlighting the genetic, in addition to the clinical, heterogeneity of spastic paraplegia [17].

Table 25.4 Genetics of spastic paraplegias
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Table 25.5 Genetics of Parkinson disease
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Table 25.6 Genetics of inherited dementias
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Table 25.7 Molecular genetics of MNDs
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Table 25.8 Classification of the main neurometabolic disorders
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Table 25.9 Genes identified associated with the main neurometabolic conditions
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3.2 Prevalence

Prevalence of HSP varies widely among studies, probably due to a combination of factors, such as variable diagnostic criteria, epidemiological methodology, and population differences. Reported estimates vary from 0.1 to 9.6/100,000 in different series, 0.5–5.5/100,000 for dominant forms, and 0.0–5.3/100,000 for the recessive ones [9]. The most common dominant spastic paraplegia (SPG) in all series is SPG4, while SPG11 is the most frequent among the recessive HSPs.

3.3 Pathogenic Mechanisms

HSPs are among the most genetically heterogeneous diseases (Table 25.4). Many of the proteins involved act in the same cellular processes; nevertheless, the number of cellular mechanisms known to be affected continue growing and include: abnormal mitochondrial function, axonal transport dysfunction, alterations in lipid metabolism, abnormal DNA repair, alterations in membrane trafficking, organelle shaping and autophagy [12, 17]. Currently, no specific treatment exists to prevent, delay, or reverse progressive disability in patients with hereditary spastic paraplegia.

4 Inherited Parkinson’s Disease

Parkinson’s disease (PD) (OMIM 168600) is the second most common neurodegenerative disease after Alzheimer’s, albeit the inherited forms are considered rare presenting with a much lower prevalence [21, 25]. PD is characterized by instability, rigidity, bradykinesia, postural tremor, and positive response from Levodopa (30%). Its prevalence is higher than 1% in individuals over 50 years and about 3% in those older than 75. The physiopathology includes loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (LBs), except in a subtype of recessively inherited PD, PARK2, that courses without the typical ubiquitinated cell body inclusions. A direct relationship between several gene mutations and Parkinson’s disease presenting with an autosomal dominant, recessive, and X-linked modes of inheritance has been demonstrated (Table 25.5).

In many cases there is a confirmed genetic linkage between some loci and Parkinson disease, but the gene has not been isolated as of yet for the following cases: PARK3 (2p13) (602404), PARK10 (1p32) (606852), and PARK11 (2q36) (607688). The PARK12 locus is located on Xq21- q25 (300557) and was the first case presenting with an X-linked mode of inheritance. Two additional genes have been associated with PD: SNCAIP (Synphilin-1, 5q23.1–q23.3) (603779), which codifies for a protein that interacts with α-synuclein. An unique mutation p.R621C within the SNCAIP gene in two sporadic cases with PD were identified demonstrating the involvement of SNCAIP in PD [30]. In addition, a polymorphism within intron 6 of NR4A2 (Nuclear Receptor-related 1: NURR1) (2q22–q23) (601828) is present more frequently in affected patients than in healthy controls [64]. Two different mutations in Parkinson families, but not in sporadic cases [23], demonstrate the implication of NR4A2 in PD. However, other authors have not yet confirmed these findings.

4.1 Molecular Genetics Diagnosis

Traditionally the molecular genetics diagnosis in PD included the search for recurrent mutations within the genes implicated in Parkinson disease by DNA sequencing. If this approach was negative then, multiplex ligation-dependent probe amplification is used to look for gene dosage alterations in the SNCA gene. In the last years, implementation of next-generation sequencing enables the simultaneous analysis of a myriad of genes implicated in PD thus facilitating diagnosis (Table 25.5).

4.2 Autosomal Dominant Parkinson’s Disease

4.2.1 SNCA/PARK1-4

Mutations in the SNCA gene on 4q21–23 coding for alpha-synuclein (OMIM 163890) were the first genetic defects identified causing PD [41]. Nevertheless, mutations within SNCA are rare, and thus far, only three different missense mutations as well as duplications and triplications of the entire gene have been reported. The SNCA gene contains 6 exons and spans 117 kb. The protein localises in presynaptic terminals and interacts in vivo with synphilin-1 resulting in characteristic eosinophilic inclusions. Of the three missense mutations identified to date, p.A53T is by far the most frequent mutation reported. Penetrance of the missense mutations appears to be high, 85% for p.A53T. Increase of the dosage of the SNCA gene in familial PD is associated with PARK4 [53]. Other known allelic variants including p.A30P, p.E46K, and the presence of polymorphisms within the gene promoter associate with major susceptibility to develop Parkinson’s disease. These and other mutations are reported in the Parkinson’s Disease Mutation Database (PDMTD; www.thepi.org/parkinson-s-disease-mutation-database).

4.2.2 LRRK2/PARK8

Mutations in the LRRK2 gene are the most frequent cause of late-onset autosomal dominant and sporadic PD with a mutation frequency ranging from 2 to 40% [5, 36]. LRRK2 parkinsonism is clinically indistinguishable from idiopathic PD. LRRK2 codifies the leucine-rich repeat kinase 2 Dardarin, a protein with 2,482 amino acids containing a leucine-rich repeat, as well as kinase, Ras, and WD40 domains. The multidomain protein structure supports for a multifactorial role of LRRK2 in the neurodegenerative pathogenesis. The gene contains 51 exons and spans 144 kb. More than 20 mutations over the different protein motifs have been identified. The more prevalent mutations include G2019S, R1441G, and I2020T. To date, the mutations identified in LRRK2 are missense, two of them corresponding to intronic nucleotide changes (source: PDMTD).

4.3 Autosomal Recessive Parkinson’s Disease (ARPD)

4.3.1 PARKIN/PARK2

Parkin was the second identified PD gene and the first gene irrefutably causing an AR form of the disorder. Mutations in this gene trigger a disease onset usually in the third or fourth decade of the patients’ life, with slowly progression and an excellent response to dopaminergic treatment. However, some of Parkin-mutation carriers have an onset even in childhood, and homozygous mutations in Parkin are the most frequent cause of juvenile PD (age of onset ≤21 years). The clinical phenotype of Parkin-, PINK1-, and DJ-1-linked PD is indistinguishable. Reported post-mortem examinations indicate that the substantia nigra shows neuronal loss and gliosis, however, it frequently lacks Lewy bodies. A large number (>100) and wide spectrum of Parkin mutations have been identified, including alterations in all 12 exons, across various ethnic groups (PDMTD). Parkin is one of the largest genes in the human genome, spanning 1.38 Mb in 12 exons. The gene codifies for a protein involved in the protein degradation pathway by the ubiquitin–proteasome system [20].

4.3.2 PINK1/PARK6

Mutations in the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) gene are the second most common cause of AR early-onset PD (EOPD) after Parkin [58] and has been reported in sporadic cases as well. The frequency of PINK1 mutations is in the range of 1–9%, with considerable variation across different ethnic groups. The gene contains 8 exons and spans 1.8 kb. More than 40 punctual, insertions or deletion mutations have been reported (PDMTD). PINK1 is a 581 amino acid ubiquitously expressed protein kinase. It consists of an amino-terminal 34 amino acid mitochondrial targeting motif, a conserved serine–threonine kinase domain (amino acids 156–509; exons 2–8), and a carboxy-terminal autoregulatory domain. Two-thirds of the reported mutations in PINK1 are loss-of-function mutations affecting the kinase domain, demonstrating the importance of PINK1’s enzymatic activity in the pathogenesis of PD. Interestingly, recent studies provide evidence that PINK1 and Parkin function in a common pathway for sensing and selectively eliminating damaged mitochondria from the mitochondrial network. PINK1 is stabilized on mitochondria with lower membrane potential, and as such, it recruits Parkin from the cytosol. Once recruited to mitochondria, Parkin becomes enzymatically active and initiates autophagic clearance of mitochondria by lysosomes, i.e., mitophagy.

4.3.3 DJ-1/PARK7

DJ-1 is the third gene associated with AR PD, and it is mutated in about 1–2% of EOPD cases [4, 37]. Given that DJ-1-linked PD seems to be rare, very few patients have been reported in the literature. However, about 10 different point mutations and exonic deletions have been described mostly in the homozygous or compound-heterozygous state. The function of DJ-1 is not well known, yet it has been implicated as an oncogene and as a regulatory subunit of a RNA binding protein (RBP). The seven coding exons of the DJ-1 gene encode for a 189-amino acid-long protein that is ubiquitously expressed and functions as a cellular sensor of oxidative stress. The DJ-1 protein forms a dimeric structure under physiologic conditions, and it seems that most of the disease-causing mutants (p.L166P, p.E64D, p.M26I, and p.D149A) heterodimerise with wild-type DJ-1. In addition, the mutated proteins are frequently not properly folded, unstable, and promptly degraded by the proteasome. Thus, their neuroprotective function and antioxidant activity are reduced. There is a genetic and biochemical association between DJ-1 and PINK1. On this regard, an early-onset PD Chinese family presenting with a digenic inheritance of mutations in both genes was identified [57]. It is believed that digenic inheritance occurs because the proteins codified by both genes are functionally related to produce the specific PD phenotype by an epistasis effect. Up to date, more than 25 missense, deletions, frameshift or duplication mutations in DJ-1 have been reported (PDMTD).

4.3.4 ATP13A2/PARK9

Homozygous and compound-heterozygous mutations in ATP13A2 have been found to cause an AR atypical form of PD named Kufor-Rakeb syndrome [42]. This syndrome has juvenile onset with rapid disease progression, accompanied by dementia, supranuclear gaze palsy, and pyramidal signs. ATP13A2 is a large gene comprised of 29 exons coding for an 1,180-amino acid protein. The ATP13A2 protein is normally located in the lysosomal membrane and it contains ten transmembrane domains and an ATPase domain. About ten different pathogenic mutations have been identified in the homozygous or compound-heterozygous state, directly or indirectly affecting transmembrane domains. Most of the mutations produce truncated proteins that are unstable and are retained in the endoplasmic reticulum and subsequently degraded by the proteasome. No exonic deletions or deletions or multiplications of the entire gene have been found to date. Several single heterozygous missense mutations are known, but their role in PD pathogenicity is currently unclear.

4.4 Parkinsonism-Related Disorders

Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous disorder characterized by progressive iron accumulation in the basal ganglia and other regions of the brain, resulting in extrapyramidal movements including Parkinsonism and dystonia. Age at onset, severity, and cognitive involvement are highly variable. Associated genes identified include CP, FTL, C19ORF12, PLA2G6, PLAN, PANK2, WDR45, and COASY. Mutations in PANK2 account for most of the NBIA cases.

4.5 Mitochondrial Inheritance

Pathogenic mitochondrial DNA (mtDNA) mutations are also associated with PD. MtDNA is a 16,569 base pair length genome that encodes 13 genes for subunit components of the oxidative phosphorylation subunits (OXPHOS) and its own tRNAs and rRNAs. As hundreds to thousands copies of mtDNA reside in virtually each mammalian cell, a state of heteroplasmy arises when different mtDNA genotypes, such as wild type and mutant forms, co-exist within the same cell. Substantia nigra neurons from autopsies of normal aged people and PD patients harbour high levels of mutated mtDNA with large-scale deletions causing mitochondrial dysfunction. Furthermore, mitochondrial disease patients with mutations in polymerase γ, the polymerase responsible for mtDNA replication, excessively accumulate mtDNA mutations and also have an increased risk of developing PD. The many links between mitochondrial dysfunction and the pathogenesis of PD has stimulated interest in the roles of PINK1 and Parkin on mitophagy.

4.6 Multifactorial Inheritance

Vaughan et al. [59] proposed that nigral degeneration with the presence of Lewy bodies leading to the several clinical symptoms might represent a common final outcome of a multifactorial process of the disease due to genetic as well as environmental agents [59]. In these regard, it has been observed that the Mendelian inheritance has a major role in PD cases where the disease onset appears in the third or fourth decade of life whereas a polygenic model with a higher environmental participation would account for adult late-onset Parkinson’s disease. In this later scenario several genes and their respective polymorphic variations would provide a priori risk contribution. This risk would be posteriorly modulated by acquired environmental circumstances.

5 Inherited Dementias

The term dementia encompasses a group of cognitive, psychological, and memory problems which ultimately render an individual unable to carry-out daily functions involving social interactions, assessment of the environment and consequences of events, reasoning, and problem solving. There are 47.5 million people with dementia worldwide, and 8 million new cases diagnosed every year according to the most recent data published by the World Health Organization [63]. Genetics per se contributes to a small proportion of all dementia cases and thus familiar forms are considered rare. Alzheimer’s disease (AD) is the most common cause of dementia accounting for 60–80% of all cases, followed by vascular dementia responsible for 25%, Lewy Body dementia (LBD) for 15%, and frontotemporal dementia lobar degeneration forms by less than 5%. Other genetically linked dementia include Niemann-Pick, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler disease (GSD), and Huntington’s disease [26]. Most individuals with dementia present the late-onset form starting after the age of 65 making up 90–95% of all cases. Although there are greater numbers of individuals with familial history of early-onset dementia, 95% of all cases are of unknown aetiology. Early-onset AD is 5–10% of all cases of which only 10% is familial [7]. Therefore, most recent efforts in dementia research have focused on finding the genetic factors causing Mendelian inheritance of dementia or can be one of the contributing factors to genetically complex diseases of which dementia forms part of the symptoms (Table 25.6).

5.1 Alzheimer’s Disease (AD)

The most common symptoms of Alzheimer’s disease include difficulty remembering recent events and conversations, often accompanied with apathy and depression followed by poor judgement, personality changes, disorientation, impaired communication, difficulty speaking, swallowing, and walking. AD is currently considered a disease of slow progression starting well before the presentation of symptoms. The major neuropathological hallmarks are the beta-amyloid protein fragment plaques and the tau protein tangles in addition to neuronal damage and loss. Some of the affected individuals express a mutation in one of three genes: the amyloid precursor protein gene (APP) and two presenilin genes (PSEN1 and PSEN2). These mutations show dominant inheritance with low prevalence (1 in 1,000 people) and result in early-onset dementia (EOD) with presentation of symptoms as early as the third decade of life. On the other hand, AD presenting after the age of 65 is considered late-onset (LOAD), which is more common than EOAD and exhibits a complex inheritance. No specific gene has been identified to cause LOAD but rather a number of genes increasing the risk. The best known of such risk genes and the one with the highest effect is apolipoprotein E (APOE), found on chromosome 19. Specifically, one of its isoforms, APOE ε4 is present in about 25% of the total population and is associated with the highest risk for developing AD. Less than 2% of the population carry two copies of the APOE ε4 which increases their chances tenfold for developing AD, although it does not predict whether they will have AD symptoms in their lifetime. Some of the functions of the proteins encoded by the mutated genes associated with EOAD have been described. APP is known to function as a receptor on the surface of neurons to regulate neurite growth, neuronal adhesion, and axonogenesis. A buildup of amyloid-beta APP fragment has been linked to AD although not exclusively, since elderly people with identified build-up did not exhibit AD symptoms. Both PSEN1 and PSEN2 appear to function as catalytic subunits of gamma-secretase complex responsible for the intramembrane cleavage of the receptors NOTCH and APP. The specific roles of the mutation effects and the risk factors on the pathogenesis are still unclear.

5.2 Vascular Dementia

Vascular dementia is the most frequent EOD, being the second most common form of dementia in the general population and younger people [35]. It often results following many small strokes that restrict blood flow to the brain. It is a progressive condition affecting speech, memory, language, and learning. Recent studies support a role for APOE ε4 as a risk factor for vascular dementia, but with much less impact than in AD. Other known risk factors include high cholesterol levels, high blood pressure, and diabetes. In general, genes appear to play a much lesser role in the common forms of vascular dementia compared to familial Alzheimer. However, a rare form of vascular dementia known as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is found to be caused by the dominant inheritance of mutations in the notch homolog protein 3 gene (NOTCH3). Affected individuals experience migraines and temporary loss of vision and numbness followed by progressive cognitive problems around the age of 50. The NOTCH3 gene encodes a receptor for membrane-bound ligands, and is mostly expressed in vascular smooth muscle cells regulating cell fate during development. The mutation is thought to alter its ligand-binding site resulting in dysfunction of the vascular muscle.

5.3 Dementia with Lewy Bodies (DLB)

Ten percent of individuals with dementia with early-onset have dementia with Lewy body (DLB) also known as Lewy body disease. Some of the clinical symptoms are generally common to other dementias such as difficulty with attention, spatial awareness and memory. In addition, some individuals suffer with hallucinations and movement problems resembling Parkinson’s disease (PD). DLB is the second more prevalent form of age related dementia affecting approximately 5% of people over age 85. The hallmark neuropathological finding of the DLB affected individuals is the presence of diffuse Lewy bodies in the cortical and subcortical regions. Genetic analysis identified a mutation in the alpha-synuclein gene (SNCA) that co-segregated with the disease phenotype and two different heterozygous mutations in the beta-synuclein gene (SNCB) in unrelated individuals [34]. It has been proposed that the mutations may alter the ability of beta-synuclein to inhibit the toxic alpha-synuclein fibril formation. Moreover, the expression of synuclein specific isoforms are differentially altered in brains of patients with DLB compared to PD [3]. Heterozygous mutations in the glucosylceramidase gene (GBA) have also been identified and shown to enhanced susceptibility to the disease. GBA is a lysosomal enzyme involved in glycolipid metabolism. Mutations result in the accumulation of glucocerebrosides in the lysosome leading to cell damage.

5.4 Frontotemporal Dementias (FTD)

Frontotemporal dementia (FTD) is a group of neurological disorders caused by damage to the cells of the frontal and temporal lobes of the brain. These disorders are also referred to, by the pathological finding, frontotemporal lobar degeneration diseases (FTLD). The frontal lobe controls the emotions, behaviour, and personality, and is required for language. Most cases occur at ages between 45 and 65 with almost half of the affected individuals having a family history and being caused by a mutation in a single gene [2]. Several subtypes of FTD have been classified by the most prominent clinical symptoms which differ depending on the region of the frontal and temporal lobes affected and mostly restricted by the presence of pathologic inclusions [19]. Clinical symptoms include obsessive, and aggressive behaviours, loss of inhibitions and/or speech difficulties. The FTD subtypes include the behavioural variant (bvFTD), and the language variants primary progressive aphasia (PPA), which include the progressive non-fluent aphasia (PNFA), semantic dementia (SD) and logopenic progressive aphasia (LPA). The most common form is bvFTD. It is characterized by progressive atrophy of the frontal and anterior region of the brain resulting in deficits in complex thinking and planning, and changes in behaviour and personality mostly stemming from behavioural disinhibition, apathy, loss of empathy, and compulsive behaviours. In contrast, the clinical features of PPA include difficulty speaking, word errors, and loss of word retrieval in PNFA, SD, and LPA subtypes respectively. Unlike other types of dementia, memory and executive functions are not affected in the early stages, many times causing patients to become frustrated and depressed as they become aware of their deficits.

The frontotemporal lobar degenerations diseases (FTLD) have been classically grouped by the neuropathological findings after post-mortem examination, mainly the presence of tau-positive inclusions (FTLD-tau) or those with ubiquitin-positive inclusions most of which are also TAR-DNA-binding protein 43 (TDP-43) positive (FTDLD-TDP43) [28]. Other neuropathological subtypes include those with positive inclusions for the RNA-binding protein FUS or for ubiquitinated proteasome system components [55]. Most recently, the identification of genetic mutations associated with the inheritance of these conditions is helping to link both the pathology and clinical features of these disorders. The most common mutations involve genes encoding for the proteins tau (MAPT), progranulin (GRN), and a gene called chromosome 9 open reading frame 72 (C9orf72). Less frequent associated mutations include chromatin-modifying protein 2b (CHMPB2), TAR-DNA-binding protein (TARDBP), the valosin-containing protein (VCP) genes, coiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10), sequestosome 1 (SQSTM1), tank-binding kinase 1 (TBK1), and fused in sarcoma (FUS) genes (Tables 25.6 and 25.7).

The most common clinical subtype bvFTD, with or without motor symptoms resembling Parkinson’s disease (PD), is associated with mutations in the tau gene (MAPT). More than 50 mutations in tau have been identified associated with hereditary FTD. These mutations can disrupt the function of tau in the maintenance of the neuronal structure and the axonal transport and result in the accumulation and clumping of this protein within neurons. Neuropathological post-mortem findings in these individuals show FTLD-tau positive inclusions. The mutations in the progranulin (GRN) gene are responsible for 5–10% of all cases of FTLD and 13–25% of familial cases. GRN mutations are associated with bvFTD, PNFA, and rarely with amyotrophic lateral sclerosis (ALS). The missense mutations in GRN result in reduced progranulin levels and the formation of TDP-43 and ubiquitin positive inclusions. Likewise, mutations in the TARDBP gene encoding the TDP-43 protein have been identified in individuals with sporadic and familial ALS lead to accumulation of ubiquitin and TDP-43 inclusions. Progranulin is involved in cell growth, TDP-43 regulates the protein expression, and ubiquitin helps to clear out the cellular waste products particularly damaged proteins. Mutations in the C9orf72 gene consisting of a hexanucleotide repeat expansion (GGGGCC) are present in approximately 60% of hereditary FTD with ALS (FTDALS1). Affected individuals show TDP-43 positive inclusions. The protein encoded from the C9orf72 gene is enriched in neurons and appears to function in membrane trafficking and in the nucleus in RNA homeostasis. The most recent model proposes a role for both, an arginine-rich protein and a repeat-containing RNA in the C9orf72 mutation induced pathogenesis. Mutations in the VCP gene has shown a 100% association with an autosomal dominant condition called inclusion body myopathy associated with Paget disease of bone (PDB) and/or FTD (IBMPFD). VCP mutations potentially disrupting the proteins role in the ubiquitin pathway cause the accumulation of inclusions made of ubiquitin rarely TDP-43 or VCP, but not tau. Mutations in the CHMP2B gene have only been detected in a single Danish family and lead to ubiquitin, but not TDP-43 positive inclusions in the brain. The protein encoded by the CHMP2B gene is involved in the recycling or destroying cell surface proteins or receptors. Because of low casuistic, genetic diagnosis based on mutations in TARDBP and CHMP2B genes is mostly done on a research basis only. Mutations in CHCHD10 underlie FTD with ALS (FTDALS2). The CHCHD10 gene encodes a small mitochondrial protein proposed to be involved in maintaining the morphology of the mitochondrial cristae and in oxidative phosphorylation. Expression of the CHCHD10 mutations in cells result in mitochondria fragmentation and dysfunction. The SQSTM1 gene underlying FTDALS3 encodes a scaffolding protein involved in NFKB signalling and ubiquitin-mediated autophagy. Mutations in the TBK1 gene are associated with FTDALS4, which encodes a serine/threonine kinase involved in inflammatory responses. The FUS gene encodes a nuclear protein involved in DNA and RNA metabolism including repair, transport, as well as transcription. Mutations in this gene are associated in ALS6 with or without FTD.

5.5 Progressive Supranuclear Palsy (PSP) and Corticobasal Syndrome (CBS)

Two movement disorders, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), are also related to FTD and they share some common symptoms. PSP is the second most frequent cause of degenerative Parkinsonism and results in progressive damage to the neurons controlling eye movement. In addition to supranuclear gaze palsy, the clinical symptoms include early postural instability and cognitive decline. The most prominent neuropathological feature is the abundance of neurofibrillary tangles in both neurons and glia in subcortical regions while in Alzheimer’s disease these are prominent in the cortex and detected in neurons. Several mutations in the MAPT gene, some of which appear to increase tau expression, have been associated with PSP. These mutations often result in particular difficulty with spelling, writing, or math skills. CBS is characterized by progressive neurodegeneration of the cerebral cortex and the basal ganglia beginning in people from 50 to 70 years of age. The prominent symptoms include Parkinsonism, Alien hand syndrome, apraxia, aphasia and cognitive dysfunction. Some individuals are particularly difficult to diagnose since they also experience behavioural and other symptoms resembling Alzheimer’s or Parkinson’s disease. Recently, two new loss-of-function mutations in the GRN gene have been differentially associated with CBS, but not with FTLD diagnosed individuals [56].

5.6 Niemann-Pick Disease

Niemann-Pick disease encompasses a group of metabolic disorders characterised by the accumulation of sphingomyelin within lysosomes. Most of the affected individuals are children (70%) and the remainder of individuals having a disease onset during early adolescence (30%). The disease course could be severe, fatal during early childhood or milder resulting in a somewhat normal life span. The most pronounced symptoms result from the organs with the most abnormal accumulation of sphingomyelin such as in the liver, spleen, bone marrow or the nervous system. The later results in ataxia, dysarthria, dysphagia and dystonia, and seizures and dementia. The symptoms may first present while in early adulthood, at which time the psychiatric illness may appear as schizophrenia or bipolar disorder. Mutations in the SMPD1 gene produce deficient sphingomyelinase activity and underlie Niemann–Pick disease types A and B (NPCA and NPCB). Mutations in the NPC1 and NPC2 encoding proteins intracellular cholesterol transporter proteins 1 and 2, involved in lipid transport cause Niemann–Pick disease type C (NPC). Type D delineates a common ancestry from Nova Scotia with NPC.

5.7 Inherited Prion Diseases

The Creutzfeldt-Jakob disease (CJD) is the most common human form of the rare fatal brain disorders called prion diseases affecting both people and several other mammals. The incidence of all forms of CJD is 0.5–1.5 per million per year of which 15% are familial cases. Unlike the familial CJD, the variant CJD commonly referred to as “mad cow disease” occurs in cattle, and has been transmitted to people mostly through consumption of affected tissue. Likewise, the Gerstmann-Straussler disease (GSD), also known as PRNP-related cerebral amyloid angiopathy, is a prion disease with an autosomal inheritance. GSD is associated with mutations in the prion protein gene (PRNP). It is characterized by memory loss, dementia, ataxia, and pathologic deposition of amyloid-like plaques in the brain. This disease first presents with truncal ataxia, dysarthria, and cognitive decline in the third and fourth decade of life. The fatal familial insomnia (FFI) disorder is another familial disease caused by mutations in the PRNP gene. The pathological changes appear localized to the anterior and dorsomedial thalamus. The Asp-178->Asn mutation in the PRNP gene (D178N) when the amino acid at position 129 is a methionine, is the only mutation associated with FFI described to date. However, the D178N mutation accompanied by the M129 V mutation in the PRNP gene has been shown associated with CJD. GSD is distinguished from CJD and FFI in that it normally has a longer disease course and shows prominent cerebellar ataxia.

5.8 Huntington’s Disease (HD) and Other Choreas

Huntington’s disease (HD), also known as Huntington’s chorea, is an inherited autosomal dominant neurodegenerative disease characterised by motor, psychiatric, and cognitive dysfunction. Most commonly, the symptoms first present from the third to the fifth decade. Early symptoms include loss of short-term memory and their planning and organisational skills. The classic signs of the disorder are progressive chorea, rigidity, and dementia accompanied by caudate nucleus atrophy. The clinical features develop progressively with severe increase in choreic movements and dementia. HD is one of the most common dementia. However, because it can sometimes present without chorea it is difficult to recognize particularly in young patients with dementia. Early onset or juvenile Huntington’s disease, typically beginning by 20 years of age, is approximately less than 10% of all HD cases. The genetic cause of HD is an abnormal expansion of a CAG repeat in the HTT gene encoding a polyglutamine tract in the N- terminus of huntingtin [27]. The juvenile form is associated with very large number of CAG repeats (more than 60) in the HTT gene. It is usually transmitted through an affected father due to the genetic phenomenon of anticipation and male transmission bias. Huntingtin is a ubiquitously expressed protein, which can translocate to the nucleus where it has been shown to regulate transcription. It also has roles in the cytoplasm where its functions include axonal transport [50]. The toxicity of the expanded repeat protein appears to be increased upon cleavage by enhancing the altered conformation and aberrant protein interactions of the mutant protein fragments [47, 49]. A toxic gain-of-function of the mutant protein rather than a loss-of-function mutation has been proposed to be responsible for the pathogenesis in HD.

Some individuals with similar symptoms to HD negative for the HTT mutation were further investigated for distinguishing clinical features and potential alternate genetic causes. This led to the description of three Huntington disease-like (HDL1-3) disorders and the categorisation of SCA17 as HDL4. HDL1 presents with chorea, cognitive decline, dementia, ataxia, rigidity, cell loss and gliosis in the basal ganglia, kuru and multicentric plaques in the cerebellar cortex. It is an autosomal dominant disease caused by insertion of 8 additional octapeptide repeats in the prion protein gene (PRNP). It distinguishes from other prion disorders by the prominence of psychiatric symptoms and the long progression of the disease course. Huntington disease-like 2 (HDL2) presents chorea and also dementia. It is associated with a heterozygous expanded CAG/CTG repeat in the junctophilin-3 gene (JPH3). While normal alleles contain 6–28 repeats, the pathogenic alleles contain over 41 repeats. JPH3 protein mediates the interaction between the endoplasmic reticulum and the plasma membrane thereby mediating the regulation between the cell surface and the intracellular ion channels. It has been proposed that a toxic RNA gain-of-function effect underlies the pathogenesis caused by this mutation since expression of the RNA is sufficient to cause toxicity in cells. Unlike HLD1 and HDL2, HDL3 shows autosomal recessive inheritance which was described in children (onset age 3–4 years old) presenting with Huntington disease-like prominent seizures, rapid course, speech disturbances such as mutism. The identification of the associated mutation is still in progress.

Choreoacanthocytosis (CHAC) and McLeod neuroacantocitosis syndrome are rare movement disorders characterized by progressive basal ganglia neurodegeneration with red cell acanthocytosis, showing variable age of onset typically in the third to fifth decade of life. These are caused by mutations in the VSP13A and XK genes respectively. The VSP13A gene encodes chorein protein while the XK gene encodes the membrane transport protein XK, both membrane-bound proteins.

6 Motor Neuron Diseases (MND)

Motor neuron diseases (MND) are classified according to whether they are inherited or sporadic, these being the most common, and to whether degeneration affects upper motor neurons (UMNs), lower motor neurons (LMNs), or both. In adults, the most common MND is amyotrophic lateral sclerosis (ALS or Lou Gehri disease), characterised by progressive skeletal muscle weakness, amyotrophy, spasticity, and fasciculations as a result of degeneration of the upper and lower motor neurons, culminating in respiratory paralysis. It has inherited and sporadic forms and can affect the arms, legs, or facial muscles. Most ALS cases are sporadic, and only 5–10% of cases are considered to be familial. Mutations in the C9orf72 gene are responsible for 30–40% of familial ALS cases in the United States and Europe. Worldwide, approximately 20% of cases of familial ALS are due to a mutation in the Cu/Zn superoxide dismutase–1 gene (SOD1). Western Pacific ALS occurs on the islands of Guam (Guam ALS), on the Kii peninsula of Japan, and in Western New Guinea. It is now clear that a subset of ALS cases shows features of frontotemporal lobar degeneration (FTLD) (ie, FTLD-MND/ALS) (Tables 25.6 and 25.7).

Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder that primarily involves the UMNs, resulting in progressive spinobulbar spasticity. Because substantial numbers of cases initially diagnosed as PLS would be reclassified as ALS as the disease progresses, a disease duration of at least 3 years is required to render this diagnosis clinically. There is still debate regarding whether PLS is a distinct pathologic entity or whether it represents one end of a clinical spectrum of ALS.

Progressive bulbar palsy (PBP) is a progressive degenerative disorder of the motor nuclei in the medulla specifically involving the glossopharyngeal, vagus, and hypoglossal nerves, that produces atrophy and fasciculations of the lingual muscles, dysarthria, and dysphagia. In adults, because most of the cases presenting with these pure bulbar symptoms represent so-called bulbar-onset ALS and eventually develop widespread symptoms typically seen in ALS, some authors consider this disorder to be a subset of ALS. Infantile PBP is a rare disorder that occurs in children and presents as the following two phenotypically associated forms: Brown-Vialetto-Van Laere syndrome (pontobulbar palsy with deafness) and Fazio-Londe disease. Brown-Vialetto-Van Laere syndrome is characterised by bilateral sensorineural deafness that is followed by CNs VII, IX, and XII palsies, whereas Fazio-Londe disease causes progressive bulbar palsy without deafness. Both disorders are genetically heterogeneous (Table 25.7).

7 Rare Metabolic Neurodegenerative Diseases

Inborn errors of metabolism can be defined as genetic disorders that interfere with chemical reactions that the body uses to maintain life, including energy production. They are an important cause of neurodegenerative processes, and in a recent epidemiological study, they represent up to 60% of progressive neurological deterioration cases, being the most frequent, mitochondrial disorders, mucopolysaccharidosis, and neuronal ceroid lipofuscinosis (NCL) [60]. In this clinical context, they must be considered early in the diagnosis algorithm, as many of them are treatable disorders while in turn a specific diagnosis is crucial for genetic counselling, prenatal diagnosis and assessment of family members.

7.1 Classification of Rare Metabolic Neurodegenerative Diseases

According to the mechanisms responsible for their pathophysiology, Saudubray proposed three main groups of metabolic diseases (Table 25.8) [51]:

Group I including those diseases associated with the accumulation of toxic substances because of the defect in the function of an enzyme or transport protein. The main examples are disorders of protein metabolism including aminoacidopathies, organic acidemias and urea cycle disorders. These disorders usually present as an acute encephalopathy and start at young age or even in the neonatal period.

Group II includes diseases where a defect of energy production is implicated in the deficient cellular functioning. The major disorders included in this group are respiratory chain diseases (OXPHOS), beta-oxidation, glycogen storage, and creatine metabolism disorders. They present with either a slowly progressive course and/or intermittent metabolic crises precipitated by stress.

Group III comprises disorders of cellular organelles in which there are storage of large molecules causing progressive dysfunction. Lysosomal storage diseases, peroxisomal disorders, and congenital disorders of glycosylation (CDG) are included among others.

7.2 Main Clinical Symptoms

Metabolic diseases are usually multiorganic, albeit in many cases there are predominant features [40]. Global developmental delay can be the main symptom in adenylosuccinate lyase deficiency, lysosomal storage disorders, CDG, but also in urea cycle disorders, creatine metabolism diseases, mild forms of non-ketotic hyperglycinemia (NKH), homocystinuria, and cerebrotendinous xanthomatosis. Refractory epilepsy starting in the neonatal period or infancy should raise suspicion of possible pyridoxine-dependent seizures, pyridoxamine-5′-phosphate oxidase (PNPO) deficiency, GLUT-1 deficiency syndrome, serine or folate deficiencies, creatine disorders or NKH. Instead, the progressive appearance of pyramidal signs associated sometimes with cognitive decline, movement disorders or ataxia is characteristic of leukodystrophies. Dystonia can be seen in mitochondrial diseases, Segawa disease, late-onset tyrosine hydroxylase deficiency, and in organic acidurias (OAs) like glutaric aciduria type I following episodes of acute decompensation, whereas late forms of GLUT-1 deficiency syndromes can manifest as paroxysmal exercise-induced dyskinesia that improves with rest or administration of sugar. Intermittent ataxia is a main feature in disorders of protein metabolism and mitochondrial disorders, while chronic ataxia appears in mitochondrial disorders (Leigh syndrome, Kearns-Sayre, CoQ10 deficiency), vitamin E deficiency, Refsum disease, CDG, GM2 and Niemann-Pick type C. Finally, autism can be a predominant manifestation of Smith-Lemli-Opitz syndrome, mitochondrial disorders or creatine, folate or biotinidase deficiencies.

7.3 Diagnosis

A family history of consanguinity, unexplained hydrops foetalis, sibling deaths or developmental delay must raise the suspicion of a metabolic disease. Similarly, the presence of cerebral palsy of unknown origin or coexistence of neurological and non-neurological features should always raise suspicion of a metabolic disorder. At the neurological level, to differentiate whether the predominant involvement is in the white matter (hypotonia or spasticity and visual impairment) or grey matter (dementia, personality changes, seizures) can be helpful to guide complementary exams. Another important point is to consider treatable disorders first and the most frequent according to the age of onset of symptoms.

Most of neurometabolic disorders are autosomal recessive (Table 25.9), whereas maternal transmission might suggest an X-linked or mitochondrial mode of inheritance. Sporadic cases with de novo mutations are frequent.

In acute metabolic decompensations, studies including lactate/pyruvate ratio, NH3, blood gases, plasma amino acids, urine organic acids, and acylcarnitines are recommended. However, in slowly progressive processes testing for urine glycosaminoglycans, white cell enzymes activity, studies in muscle biopsy, transferrin isoelectric focusing, VLCFA, and 7-dehydrocholesterol may be needed. In other cases, CSF studies may be undertaken in order to demonstrate high lactate levels in mitochondrial disorders, low glucose CSF/plasma ratio in GLUT1 deficiency and for neurotransmitter analysis [44]. Magnetic resonance imaging (MRI) is important to detect white matter abnormalities, which can have a very characteristic pattern in some leukodystrophy patients, but also signs of cortical or cerebellar atrophy or basal ganglia abnormalities. MR spectroscopy may uncover a low creatine/phosphocreatine ratio, a high lactate peak in mitochondrial disorders, or elevated concentration of N-acetylaspartate in Canavan disease [38].

In recent years, newborn screening (NBS) has been implemented in many countries, allowing early detection of several metabolic disorders before clinical manifestations appear. On the other hand, performance of next generation sequencing (NGS) studies can help in confirmation of molecular basis and guide genetic counselling.

7.4 Treatment

In acute metabolic encephalopathies, emergency treatment based on glucose infusions to reverse catabolism and medications or haemofiltration to remove toxins is crucial in order to avoid irreversible brain damage.

In some metabolic disorders there are specific treatment options: enzyme replacement treatment (ERT) have been developed for some lysosomal storage diseases including Gaucher, MPS type I, II, IV, VI, VII, Pompe and Fabry disease; substrate reduction with miglustat has been used in Gaucher disease type 1 and to delay Niemann-Pick C (NPC) progression; ketogenic diet in patients with GLUT1 deficiency syndromes or with refractory epilepsy; and early haematopoietic stem cell transplantation for X-linked adrenoleukodystrophy, Hurler syndrome (MPS I), Maroteaux Lamy (MPS VI) and Sly (MPS VII) syndromes. For most mitochondrial disorders there is no specific treatment, with the exception of coenzyme Q10 and riboflavin responsive complex I deficiency, although some antioxidant molecules have also been used. Creatine deficiency syndromes caused by L-arginine:glycine amidinotransferase (AGAT) or guanidinoacetate methyltransferase (GAMT) enzymatic defects can be successfully treated by creatine and arginine supplements. In the last years, therapy with small molecules chaperones is being investigated in some lysosomal disorders such as Fabry disease, whereas there has been significant progress in the development of gene therapy for several diseases, with currently ongoing clinical trials on Pompe’s disease, MLD, and MPS IIIA.