Introduction

Abnormal movements can refer to subtle physiological variants of normal development or can be caused by severe brain dysfunction. Furthermore, they are an almost constant feature in childhood encephalopathies whatever their origin might be. Inborn errors of metabolism (IEMs) frequently involve motor function not only because of the many anatomical regions that participate in this complex task, but also because they require perfect neurochemical interactions. The primary motor cortex (frontal lobe), and secondary motor cortices (e.g. parietal lobe) generate and transform neuronal impulses that control the execution of movement. The basal ganglia and cerebellum interact and regulate these signals that travel down the corticospinal tract through the spinal white matter to interact with interneurons and motor neurons in the spinal cord ventral horn. These ventral horn neurons send their axons through the ventral roots to individual muscle fibres. Each motor neuron in the spine is part of a functional unit called the motor unit. The motor unit is composed of the motor neuron, its axon, and the muscle fibres it innervates. Consequently, IEMs affecting motor cortex, basal ganglia, cerebellum, myelin, motor neurons, axons, muscle, or neuromuscular junctions or any of the interactions between them, can cause abnormal movements or disturbed locomotion. From a clinical point of view we can classify these motor abnormalities into movement disorders, spasticity, peripheral neuropathy, and muscle disorders. Because the last group corresponds to an extensive highly specialized field, it will not be considered in this review. As a rule, in IEMs, a combination of diverse motor signs will be present in most individual disorders (Table 1).

Table 1 Metabolic diseases with prominent motor disturbances
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Movement disorders

Our understanding of paediatric movement disorders is rapidly evolving stimulated by progress in the discovery of monogenic neurogenetic disorders and consecutively the development of structured diagnostic and therapeutic approaches. In neurometabolic disorders causing abnormal movements, investigations of specific metabolites can give important clues to diagnoses in addition to the clinical presentation. A logical series of investigations should be followed with the primary aim of early diagnosis of treatable conditions. In this part we will concentrate on the main causes of ataxia, dystonia, and other movement disorders.

IEMs and ataxia

Ataxia is defined as an inability to maintain normal posture and smoothness of movements while force and sensation are intact. There are many variations in the clinical phenotype, ranging from consequences of pure cerebellar dysfunction (Poretti et al. 2008) to mixed patterns of brain involvement (extrapyramidal pathways, brainstem, and/or cerebral cortical involvement). A wide range of molecular defects have been identified, all involving the spinocerebellar pathways and without metabolic abnormalities. IEMs present a less frequent cause of ataxias and can be clinically classified following a pragmatic approach based on the clinical evolution: intermittent or episodic, stable or progressive ataxias (Prasad et al. 2005). Figure 1 proposes a diagnostic algorithm.

Fig. 1
figure 1

Diagnostic approach for metabolic disorders with prominent ataxia

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Intermittent/episodic ataxias

If due to a neurometabolic disorder, these are mainly diseases of intermediary metabolism. Ataxia is a frequent sign during acute/subacute decompensations of amino acids (such as MSUD disease; Holmgren et al. 1980) and organic acid and urea cycle disorders. Usually, these disorders have other neurological or extraneurological markers. By contrast, defects of energy metabolism presenting with intermittent ataxia may involve exclusively the nervous system and may be more difficult to diagnose. This is the case of respiratory chain disorders, e.g. the NARP syndrome, pyruvate dehydrogenase deficiency, and biotinidase deficiency. In NARP syndrome, isolated mental retardation may precede the appearance of episodic ataxia by years. Furthermore, once ataxia appears it tends to remain constant, with worsening during episodes of decompensation. Carbohydrate- and fever-sensitive ataxia is a feature of mild pyruvate dehydrogenase deficiency (Robinson et al. 1996). Biotinidase deficiency may also give rise to intermittent ataxia. High plasma lactate and other characteristic biochemical features of these disorders may be present only intermittently.

GLUT1 deficiency can present with intermittent ataxia as the only finding, mimicking other episodic ataxias. In this disease ataxia usually worsens before meals. Some children improve greatly with frequent carbohydrate-rich snacks and may not even need a strict ketogenic diet (Wang et al. 2005). Intermittent ataxia can also be seen in Hartnup disease; additional symptoms are pellagra-like skin changes, photic dermatitis, and psychiatric symptoms (Kleta et al. 2004). Recently a new cause of intermittent ataxia and mental retardation due to urocanic aciduria in a patient with mutations in the urocanase gene has been described (Espinós et al. 2009).

The so-called ‘episodic ataxias’ may be mistaken for metabolic disorders, although they belong to the channelopathies (Jen 2008). Correct diagnosis is important, as effective treatment exists. As a rule, metabolic parameters may be normal between bouts of ataxia in inborn errors of metabolism; testing is therefore mandatory when patients are symptomatic and usually involves CSF investigations. An important non-metabolic differential diagnosis for intermittent ataxia is intoxication, especially with benzodiazepines and other centrally acting drugs. Moreover, in a child with acute ataxia it is obviously mandatory to exclude more frequent aetiologies such as infectious diseases and opsoclonus-myoclonus syndrome.

Ataxias with progressive spinocerebellar dysfunction

The best example of this group is Friedreich’s ataxia. The main additional clinical symptoms are polyneuropathy and pyramidal tract lesions and cardiomyopathy. Vitamin E deficiency and abeta-/hypobetalipoproteinaemia can also result in retinopathy, neuropathy, ophthalmoplegia, progressive mental retardation, and cardiomyopathy. Ataxia with vitamin E deficiency (AVED; Mariotti et al. 2004; Marzouki et al. 2005) is caused by mutations in the gene for alpha-tocopherol transfer protein. Laboratory findings include low-to-absent serum vitamin E and high serum cholesterol, triglycerides, and beta-lipoprotein. High doses of vitamin E (400–1200 IU/day) improve the neurological function. Abetalipoproteinaemia is a rare disorder due to a dysfunction in the microsomal triglyceride transfer protein gene (MTP). Acanthocytosis on peripheral blood smears is a constant finding. Decreased serum LDL and VLDL and increased HDL cholesterol levels are present together with low triglyceride levels. High-dose supplementation of vitamin E has a beneficial effect on neurological symptoms (Homer et al. 2005). IOSCA (infantile-onset spinocerebellar ataxia) represents one of the most severe forms of recessive ataxias. It is characterized by progressive atrophy of the cerebellum, brainstem, and spinal cord and sensory axonal neuropathy (Table 1). It has been related to mitochondrial depletion syndromes (Hakonen et al. 2008). Cerebrotendinous xanthomatosis can also manifest as spinocerebellar ataxia (Siebner et al. 1996).

Ataxias with progressive neurological deterioration

Other disorders presenting with chronic (progressive) ataxia are Refsum disease, sphingolipidoses, l-2-hydroxyglutaric aciduria, cerebrotendinous xanthomatosis, and coenzyme Q10 deficiency. The degree of neurological deterioration depends on the disorder. In some cases the clinical picture may remain stable. Coenzyme Q10 deficiency may produce non-progressive ataxia as the only neurological manifestation. High-dose coenzyme Q10 supplementation is effective in some cases. Some phenotypes of GLUT-1 deficiency are characterized by chronic non-progressive ataxia, with intermittent fluctuations associated with fasting (Overweg-Plandsoen et al. 2003). The list of diseases to be included in this group is wide. Among them is also Niemann–Pick disease type C (NPC) and other neurodegenerative disorders; however, other signs of progressive neurological dysfunction as dementia usually become prominent.

Interestingly, in 4-hydroxybutyric aciduria and some forms of congenital disorders of glycosylation, ataxia may improve rather than deteriorate.

Ataxias with progressive myoclonic epilepsy

MERRF syndrome, Lafora disease, and neuronal ceroid lipofuscinoses are typical representatives of this group. Severe epilepsy is the clinical hallmark (Buccoliero et al. 2003). Ataxia and myoclonic epilepsy are also a feature of some lysosomal disorders such as the juvenile form of Gaucher disease (type 3), NPC, and sialidosis type 1.

IEMs and other movement disorders

Other than ataxia, movement disorders in children may be divided into rigid akinetic syndrome (‘parkinsonism’) and dyskinetic movements (dystonia, athetosis, tremor, chorea, myoclonus, tic, and stereotype) (Fernández-Alvarez 2001). Tics are very rarely related to IEMs. Important movement disorders in IEMs are dystonia, secondary parkinsonism, chorea, tremor, and myoclonus (see Fig. 2). Different movement disorders may coexist in the same patient with an IEM. In children with an IEM, movement disorders are often dystonic (Assmann et al. 2003). In general, diseases causing parkinsonism in adults, may present with dystonia in children. Some neurometabolic disorders require metabolic studies of CSF metabolites for diagnosis (Table 2; Hoffmann et al. 1998).

Fig. 2
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Diagnostic approach for metabolic disorders with prominent movement disorders (MD) other than ataxias

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Table 2 Clinical situations requiring CSF studies in patients presenting with predominant motor disturbances
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Rigid akinetic syndrome and IEMs

Metabolic disorders causing primarily a rigid-akinetic syndrome include: (1) neurotransmitter deficiencies (especially early-onset forms) such as tyrosine hydroxylase, aromatic l-amino acid decarboxylase, and sepiapterin reductase deficiencies, biopterin defects with or without hyperphenylalaninaemia (Hyland et al. 2009), and the recently described mutations in the dopamine transporter gene. Contrary to the former diseases, this last disorder produces an elevated level of homovanillic acid in the CSF (Kurian et al. 2009). (2) Early-onset disorders of energy metabolism such as pyruvate carboxylase deficiency (Garcia-Cazorla et al. 2006), or some mitochondrial DNA defects (Davidzon et al. 2006). (3) Wilson disease with neurological manifestations has only exceptionally been related to early childhood, but mild neurological and neuropsychiatric disturbances are not unusual in this period of life. However, as Wilson disease is a treatable disorder, copper studies are strongly recommended from early school age. (4) Early onset rigid-akinetic syndrome has been recently associated with PLAG6 mutations (Kurian et al. 2008).

Dystonia

Dystonia is a major symptom in many different metabolic diseases. In fact, almost all neurometabolic disorders can cause dystonia at some stage, but glutaric aciduria type I, Leigh syndrome, and other mitochondrial cytopathies are among the most frequent.

If dystonia is focal, progresses slowly, or remains isolated over time, the most likely IEMs to be considered are primary dopaminergic deficiencies such as autosomal dominantly inherited GTP cyclohydrolase deficiency (Segawa disease; Segawa et al. 2003) or late-onset forms of tyrosine hydroxylase deficiency. By contrast, if the dystonia appears abruptly, settles rapidly, is generalized and postural from the very first stages of the disease, different metabolic causes should be strongly considered. Organic acidurias such as propionic aciduria and methylmalonic aciduria can develop dystonia during acute periods of decompensation, although in general, movement disorders are not a prominent sign in these disorders (Deodato et al. 2006). In many cases, dystonia develops late in the course of the disease, with focal onset and progressive generalization, causing major disability and wheelchair dependency (e.g. homocystinuria, NPC, GAMT deficiency). In NPC, isolated dystonia may appear as the first symptom before visceral involvement takes place. Glutaric aciduria type I and late-onset forms of gangliosidoses types I and II may present as progressive dystonia also (Gouider-Khouja and Ben Youssef-Turki 2006). The distribution of dystonia may also be helpful to differentiate these disorders. For example, onset of dystonia in the lower limbs is frequent in primary dopaminergic deficiencies, whereas oromandibular dystonia is very characteristic of pantothenate kinase-associated neurodegeneration (PKAN). Dystonia is a typical sign in PKAN in children (usually starting at around 5–6 years of age and often preceded by psychomotor delay), whereas the adult form manifests as rigid-akinetic syndrome.

Although other signs of neurological dysfunction usually coexist, some metabolic diseases can initially present as isolated dystonia (IEM of dopamine, gangliosidoses, PKAN, Leigh syndrome, pyruvate dehydrogenase deficiency, juvenile form of metachromatic leukodystrophy). Recently, a new phenotype of GLUT1 deficiency consisting of paroxysmal exercise-induced dyskinesia has been described (Suls et al. 2008). Dystonic or choreoathetotic movements appear at a mean age of 8 years and are preceded by epileptic seizures in half of the patients. Paroxysmal exercise-induced dyskinesia is usually triggered by a prolonged walk and lasts from few seconds to a few hours. Sugar administration or rest may improve the dyskinesia. In opposition to the classical phenotype of GLUT1 deficiency described by De Vivo et al. (1991), these patients are neurologically normal between episodes and show higher only borderline low glucose CSF/plasma ratios (mean 0.52 compared with a mean of 0.33 in classical phenotypes). It is now considered the most frequent genetic disease responsible for paroxysmal exercise-induced dyskinesia. Haemolytic anaemia is another common laboratory finding in this condition. A recently described disorder that causes dystonia is hypermanganesaemia associated with hepatic cirrhosis and polycythaemia. Brain MRI is especially helpful, showing high intensity of basal ganglia in T1-weighted images, suggesting accumulation of manganese (Tuschl et al. 2008). Figure 2 is a diagnostic approach to movement disorders (other than ataxia) in IEMs.

IEM and spasticity

Spasticity is a very common clinical situation in paediatric neurology. It results from damage to upper motor neurons or to the corticospinal tracts. Abnormal muscle contraction gives rise to muscle stiffness interfering with voluntary movements. Symptoms may vary from mild stiffness to severe muscle spasms and include hypertonia, brisk deep tendon reflexes, pathological reflexes, clonus, and weakness. In children, most events causing such motor damage occur during late pregnancy and delivery such as prematurity, neonatal asphyxia, birth trauma or infections. The resulting manifestations are usually grouped under the general term ‘cerebral palsy’. Spasticity is the most common motor symptom in IEMs, but at the same time the least specific. It is usually associated with additional neurological findings or systemic involvement. However, some disorders can start with isolated spastic paraparesis such as X-linked adrenoleukodystrophy, homocysteine remethylation defects, the hyperammonaemia-hyperornithinaemia-homocitrullinuria (HHH) syndrome, arginase deficiency, or Segawa disease. This possibility of an IEM should be considered in every child with the diagnosis of cerebral palsy but without history and MRI findings of perinatal or postnatal brain injury. In the diagnostic approach (Fig. 3) it is crucial to consider brain MRI findings. White-matter abnormalities and their main neuroradiological characteristics can be extremely helpful (Schiffmann and van der Knaap 2009) and allow diagnosis in certain cases, eliminating the need for much unnecessary metabolic and genetic testing. Other associated symptoms such as peripheral neuropathy also contribute to making a more specific differential diagnosis.

Fig. 3
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Diagnostic approach for metabolic disorders with prominent spasticity

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Treatable IEMs with diparesis/tetraparesis

Urea cycle disorders such as arginase deficiency can result in progressive spasticity, seizures, and mental retardation despite relatively mild hyperammonaemia. Sodium phenylbutyrate and dietary arginine restriction are effective therapeutic tools (Scaglia and Lee 2006). HHH syndrome is a disorder of ornithine transport between cytoplasm and mitochondria that causes progressive spastic diplegia and other signs of neurological dysfunction (Salvi et al. 2001). Therapeutic strategies include diet and ammonium-lowering agents.

Biotinidase deficiency may also cause progressive spastic paraparesis that improves with biotin administration (5–20 mg/day) (Ramaekers et al. 1993). Defects of homocysteine remethylation can cause demyelination of the pyramidal tracts and subacute combined degeneration of the spinal cord (Surtees 1998). It is important to measure plasma amino acids, total homocysteine and folate concentrations in every patient with isolated spasticity, as it may be the leading or only clinical sign for a long period. Patients treated with a combination of betaine (up to 10 g/day in 3 doses), folic acid (5–10 mg/day), and hydroxycobalamin (0.5–1 mg/day orally or 1 mg i.m. monthly) from the neonatal period may develop normally (Strauss et al. 2007), whereas late-treated patients show at most a partial recovery of the neurological signs together with an improvement of cerebral myelination on MRI (Surtees et al. 1991). This combination of betaine is not as effective as it is in resolving other neurological or psychiatric symptoms related to the defect. Untreated phenylketonuria and a recently described cerebral folate deficiency syndrome (Ramaekers et al. 2005), although the latter is still not clearly defined, are other examples of treatable IEMs that may exhibit progressive spasticity without treatment. Cerebrotendinous xanthomatosis may present with progressive spasticity from the second decade of life if appropriate treatment has not been initiated during early stages of the disease (Verrips et al. 2000).

Dopamine synthesis defects, especially autosomal dominant GTP cyclohydrolase I deficiency, may exhibit pyramidal tract signs. In some cases, lower limb dystonia can mimic spastic paraparesis. Therefore, CSF studies and a trial of levodopa, should be performed in all patients with unexplained spastic paraparesis or dystonic cerebral palsy (Hyland et al. 2009). In vitamin E deficiency, spasticity may appear together with ataxia, peripheral neuropathy, and retinitis pigmentosa.

Progressive spasticity associated with additional neurologic signs, irritability, and global deterioration

This group of heterogeneous disorders usually results in complex neurological pictures, in which progressive spasticity is only one of the main features. Peripheral neuropathy and visual, auditory, and visceral involvement are frequently present. Brain MRI may reveal specific white-matter lesions (Fig. 3).

Lysosomal disorders and X-linked adrenoleukodystrophy share these characteristics and are well described elsewhere (Desnick and Schindler 2001; Moser 1997). Infantile neuroaxonal dystrophy (INAD) and related disorders are due to mutated PLA2G6, encoding a phospholipase. They manifest with progressive neurological regression and distended axons (spheroid bodies) in the nervous system and increased iron deposition in basal ganglia. Progressive spastic tetraparesis, extrapyramidal signs, dementia, retinitis pigmentosa, and optic atrophy are frequently present (Morgan et al. 2006). The first signs are nystagmus, hypotonia, and ataxia.

Pyramidal tract involvement is also frequent in mitochondrial disorders, but other signs and symptoms often guide the diagnostic approach (Table 1).

Some cerebral organic acidurias such as Canavan disease (high urine and brain MRS N-acetylaspartate) (Lyon et al. 2006) or l-2-hydroxyglutaric aciduria are examples of childhood leukodystrophies exhibiting different degrees of progressive spasticity and well-defined brain MRI patterns (Schiffmann and van der Knaap 2009).

Other signs

Other associated signs, especially cutaneous and ocular, can provide important clues to the diagnosis (Fig. 3).

IEMs presenting mainly as peripheral neuropathy

The peripheral nerves make up an intricate network that connects the brain and spinal cord to the muscles, skin, and internal organs. Peripheral neuropathies can be acute or chronic, involving large or small fibres, be demyelinating or axonal, the latter being differentiated by electrodiagnostic studies or nerve biopsy. In IEMs the peripheral nerves may affect the structure or function of myelin and axons due to metabolic pathway dysregulation or storage.

Acute polyneuropathies mimicking Guillain–Barré syndrome can be observed in acute attacks of porphyrias (Sedel et al. 2007), in patients with tyrosinaemia type I (Mitchell et al. 1990) and in pyruvate dehydrogenase deficiency (Debray et al. 2006).

Chronic axonal polyneuropathy is the most common form of peripheral neuropathy in IEMs. Many metabolic disorders may cause this form of neuropathy (Sedel et al. 2007). Treatable disorders are biotinidase deficiency, homocysteine remethylation defects, ornithine aminotransferase deficiency, vitamin E deficiency, serine deficiency, Wilson disease, and cerebrotendinous xanthomatosis (Sedel et al. 2007). Neuromyopathic forms of trifunctional protein deficiency can produce progressive polyneuropathy and limb girdle myopathy with recurrent episodes of rhabdomyolysis (Spiekerkoetter et al. 2004). Chronic sensorimotor polyneuropathy is the most common form of peripheral neuropathy associated with mitochondrial disorders. However, various other forms have been reported (Bouillot et al. 2002). NARP, SANDO (sensory ataxic neuropathy, dysarthria, and ophthalmoparesis), and MNGIE (myoneurogastrointestinal encephalopathy) are among the most common mitochondrial disorders that are associated with neuropathy. Long-chain fatty acid oxidation defects (LCHAD) present with peripheral sensorimotor polyneuropathy and pigmentary retinitis as late complications of the disease (Saudubray et al. 1999).

Chronic demyelinating polyneuropathy is a common feature in some lysosomal diseases involving myelin metabolism (such as metachromatic leukodystrophy and Krabbe disease), peroxisomal disorders (Wanders 2004), and some mitochondrial disorders such as MNGIE due to thymidine phosphorylase gene mutations (Needham et al. 2007).

In Fabry disease, painful acroparaesthesias with dysautonomic features is a sign of small-fibre peripheral neuropathy (Lacomis et al. 2005).

Lower motor neuron disease refers to any disease involving spinal or bulbar motor neurons. Muscle weakness and atrophy, cramps, and fasciculations are the main clinical features. In children, lower motor neuron disease has been described in peroxisomal biogenesis defects (Baumgartner et al. 1998) and mitochondrial depletion syndromes, especially thymidine kinase 2 deficiency (Oskoui et al. 2006; Pons et al. 1996). Anterior horn cell disease is also one of the features of infantile neuroaxonal dystrophy (INAD), recently related to PLAG6 mutations (Kurian et al. 2008).