Introduction

Inherited metabolic movement disorders are an important and evolving group of disorders that bridge two subspecialty areas: childhood-onset movement disorders and inborn errors of metabolism. Individually, many of these disorders are rare but in aggregate they represent a substantial clinical burden. It is in their complex nature that they require a multidisciplinary approach that includes pediatricians, neurologists, and geneticists among others. The amount of information and the pace at which new genetic techniques and therapeutic advances are evolving and shaping the definition of new and older disorders represent a significant challenge for physicians and investigators. Clinicians seeing patients with inherited metabolic movement disorders need to synthesize key concepts in neurology as well as biochemical and clinical genetics, and as we are approaching a molecular reclassification of many diseases, they need to have an increasing understanding of next-generation sequencing techniques in addition to traditional biochemical testing. The treatment of many of these disorders is evolving, too, and now bridges dietary approaches with pharmacotherapy and increasingly invasive treatments such as deep brain stimulation. This book intends to cover all these aspects in a clear, concise, and practical way by bringing the expertise in the various inherited metabolic movement disorders under one roof, from a clinical, biochemical, and genetic perspective.

Treatable Metabolic Movement Disorders

Since the description of alkaptonuria (or “black urine disease”) by Garrod in 1902 [1] and subsequently the first emergence of the term inborn error of metabolism (IEM) in 1908 [2], we have learned of several hundred single gene disorders that we classify as IEM today [3]. The classic IEMs stem from defects in enzymes that mediate the metabolism of amino acids, carbohydrates, and fatty acids, or mitochondrial and lysosomal function. The recent introduction of next-generation sequencing and other “omics” approaches has significantly expanded the spectrum of IEMs beyond traditional “enzymopathies” [4] and a broader definition is that of a deficiency in a metabolic pathway that results in an accumulation of a substrate or intermediate and/or a reduced ability to produce an essential compound [5]. It is the nature of IEMs that they are highly heterogeneous and often rare or even extraordinarily rare. In addition, most IEMs are multisystem diseases with neurological and non-neurological manifestations and initial clinical manifestations are often relatively non-specific. Therefore, IEMs call for an interdisciplinary approach requiring close collaboration of pediatric neurologists, neurologists, geneticists, and experts in metabolism.

Over the last decades, new treatment approaches have changed the scope of IEMs from a group of rare, untreatable, and often fatal disorders to an important cause of potentially treatable diseases. The recognition that early detection can improve outcomes for some IEMs has led to the development of advanced newborn screening efforts. In many cases, the diagnosis relies on clinical pattern recognition and biochemical testing but also, increasingly, next-generation sequencing. Here we present an approach to identifying the “top 10” treatable IEMs that present with movement disorders – diagnoses that should not be missed. Although the choice of our top 10 is certainly arbitrary, they illustrate important principles and herald the following chapters.

The Top 10 Treatable Metabolic Movement Disorders

The clinician is challenged with two tasks when evaluating a movement disorder of potential metabolic etiology: (1) identifying the correct movement disorder phenomenology; and (2) developing a differential diagnosis and rational approach to counseling and testing. The first task is similar to the general approach to any patient with a movement disorder but, in addition, is guided by the principles listed in the “key points” at the end of the chapter. The second task is challenged by the need to identify treatable conditions quickly in order to prevent irreversible complications and to reduce long-term morbidity and mortality. The following short presentation of the top 10 treatable metabolic movement disorders may help with this task.

Number 10: Niemann–Pick Disease Type C

Niemann–Pick disease type C (NPC, OMIM 257220 and 601015) is an autosomal-recessive lysosomal storage disease with significant clinical heterogeneity ranging from severe forms with neonatal onset to delayed presentations in adulthood [6, 7]. The disorder is caused by bi-allelic variants in NPC1 (~95%) [8] or NPC2 (~5%) [9] leading to the accumulation of unesterified cholesterol in lysosomes in several tissues including the central nervous system. Broadly speaking, there are two neurological presentations: (1) an early-onset and often rapidly progressive form with significant developmental delay starting in early childhood, followed by cerebellar dysfunction with ataxia and dysarthria, spasticity, dystonia, vertical supranuclear gaze palsy, gelastic cataplexy, seizures, and cognitive decline; and (2) a delayed form with onset in adolescence or adulthood with intellectual disability, ataxia, vertical supranuclear gaze palsy, and psychiatric symptoms. Movement disorders are common across the spectrum of NPC and sometimes a presenting symptom [10, 11], particularly in adult patients [12]. The most prevalent movement disorder in NPC is cerebellar ataxia with prominent involvement of the trunk and limbs, which is present in over 70% of patients [6, 7, 12, 13]. Hence, NPC should be evaluated for in all patients with onset of ataxia before the age of 40 years. The diagnostic yield is high particularly when ataxia is present in combination with abnormal vertical saccades, cognitive decline, or neuropsychiatric symptoms [14–16]. Dystonia is a second important movement disorder in NPC, occurring in up to 40% of patients [12], and can present initially as dystonic tremor of the head and neck and often progresses to generalized dystonia [10, 11, 13]. Facial involvement, particularly of perioral muscles is common. Myoclonus has been reported in a few cases [10, 12, 13, 17], sometimes as the presenting symptom [13], and can be quite impairing. Chorea appears to be rare overall [10, 12]. Vertical supranuclear gaze or saccade palsy is an important diagnostic clue. Other manifestations are hepatosplenomegaly, hepatic dysfunction, dysphagia, dysarthria, seizures, gelastic cataplexy, acute psychosis, depression, obsessive-compulsive disorder, and other neuropsychiatric symptoms. Brain MRI findings are variable. Cerebral (particularly frontal lobe) and cerebellar atrophy, elevated T2 signals in the periventricular white matter, and deep grey matter and hippocampal atrophy have been described but are non-specific. Normal brain MRI does not exclude NPC [14]. Owing to the clinical heterogeneity, the diagnosis of NPC is often significantly delayed (on average by ~4 years); hence, there is a great need to improve recognition [18]. New biomarker profiling (i.e. with oxysterols and bile acids) and genetic analysis technologies are now recommended as first-line diagnostic tests for NPC [14]. Miglustat is currently the only approved therapy for patients with neurological manifestations (approved by the European Medicines Agency) [19]. Several promising therapies are being investigated in clinical trials, i.e. 2-hydroxypropyl-beta-cyclodextrin, which has shown positive results in open-label phase I/II trials (see Table 1.1, which provides a summary of all treatable IEMs, at the end of the chapter) [20]. The development of these treatments has a high chance of turning NPC into a treatable disorder and it is anticipated that early diagnosis and treatment will lead to superior outcomes. The approach to NPC in the context of ataxia is discussed in Chapter 7 by Stelten and van de Warrenburg.

Number 9: Manganese Transporter Defects

Inborn errors of manganese transport are important treatable disorders that present with prominent movement disorders (see Table 1.1). Bi-allelic mutations in SLC30A10 [21, 22] lead to a syndrome of dystonia and parkinsonism, hepatic cirrhosis, polycythemia, and hypermanganesemia (OMIM 613280) [23–25]. Symptoms start in early childhood with truncal hypotonia, impaired gait, dystonia, and impaired fine motor skills [21, 26]. Early-onset limb dystonia is almost universal and in most cases progresses to generalized dystonia. Adult-onset, akinetic–rigid parkinsonism has been reported in older individuals [22] and is usually poorly responsive to levodopa therapy. Intellectual development and cognitive function are relatively preserved. Variable expressivity has been noted within families [27]. Blood and urine manganese levels are markedly elevated, iron stores are usually depleted, transaminases and unconjugated bilirubin are elevated, and there is polycythemia [21, 26]. Brain MRI can facilitate a diagnosis as it shows a pattern of bilateral, symmetrical T1 signal hyperintensity of the globus pallidus, putamen, caudate, subthalamic and dentate nuclei, consistent with manganese deposition [21]. Abdominal imaging often reveals hepatomegaly and cirrhotic changes. Bi-allelic mutations in another manganese transporter gene, SLC39A14 [28] were more recently described in a syndrome of childhood-onset dystonia with hypermanganesemia (OMIM 617013) [28–31]. Onset is in infancy or early childhood with developmental delay, dystonia, and bulbar dysfunction [28, 32]. The course is progressive and most children develop generalized dystonia, spasticity, contractures, and severe scoliosis within the first 10 years of life [28]. Akinetic–rigid parkinsonism may develop as well. Just like with SLC3A10-associated hypermanganesemia, intellect and cognition seem to remain relatively preserved. Interestingly, while manganese blood levels are high and T1 hyperintensity in the basal ganglia is seen, similar to patients with SLC3A10 mutations, polycythemia is typically not present and liver involvement has not been reported [28]. Chelation therapy with disodium calcium ethylenediaminetetraacetic acid (EDTA) combined with iron supplementation can lower blood manganese levels in both SLC3A10– and SLC39A14-related hypermanganesemia, halt disease progression, and improve the movement disorder [21–23, 28, 32–36]. Penicillamine and DMSA have been suggested as alternative chelating agents (see Table 1.1) [27, 37]. A detailed review by the disorders of manganese metabolism and their movement disorders is provided in Chapter 17 by Tuschl and Clayton, who discovered these fascinating disorders.

Number 8: Cerebrotendinous Xanthomatosis

An important metabolic movement disorder, often diagnosed late, is cerebrotendinous xanthomatosis (CTX, OMIM 213700), an autosomal-recessive lipid storage disease caused by defective bile acid synthesis due to mutations in the cytochrome P450 gene CYP27A1 [38]. The onset of symptoms is mostly in young adulthood and the disease is progressive. Spasticity is the leading movement disorder; signs of corticospinal tract dysfunction are the predominant neurological features [39, 40]. Cognitive decline, seizures, psychiatric symptoms, peripheral neuropathy, and atypical parkinsonism are seen later in the disease course [39]. In addition to ataxia that is present in the majority of patients, dystonia and myoclonus [41] have been reported in a subset of patients. Parkinsonism in older patients (average age ~40 years) is often asymmetrical and most patients will present with walking difficulties and balance impairment including early falls [42]. The response to levodopa is often limited [42]. Non-neurological manifestations are often key to a diagnosis. A history of neonatal cholestatic jaundice, bilateral childhood-onset cataracts, or chronic diarrhea may represent the earliest clinical manifestation of CTX and should raise suspicion for this disorder. Xanthomas are pathognomonic but often only appear in the second or third decade of life. The average diagnostic delay for CTX is estimated to 15–20 years, highlighting the need to improve clinical recognition [34]. Brain MRI shows cortical and cerebellar atrophy, white matter signal alterations, and symmetrical hyperintensities in the dentate nuclei [43]. Plasma cholestanol levels are elevated and together with low levels of bile alcohols in plasma or urine are usually diagnostic. Confirmation is obtained by sequencing of CYP27A1. While treatment with chenodeoxycholic acid can lower cholestanol levels and can prevent progression, the effect on existing symptoms is variable (see Table 1.1) [42, 44]. In Chapter 10, Tochen and Pearson discuss CTX in the differential diagnosis of metabolic movement disorders that present with spasticity and Chapter 26 by Mochel and Roze reviews all aspects of CTX in detail.

Number 7: Glutaric Aciduria Type 1

The most common among the organic acidurias, glutaric aciduria type 1 (GA-1, OMIM 231670), is an important metabolic movement disorder (see Table 1.1). GA-1 is caused by bi-allelic variants in the glutaryl-coenzyme A dehydrogenase (GCDH) gene [45] leading to accumulation of neurotoxic metabolites, 3-hydroxyglutaric and glutaric acids [46]. The classic presentation of GA-1 is that of early progressive macrocephaly, hypotonia, and developmental delay followed by acute encephalopathic crises in the setting of an intercurrent illness or other catabolic state [47]. These metabolic crises often occur early with a sepsis-like clinical picture during infancy, and irreversibly damage the basal ganglia (putamen and caudate nuclei), leading to a sudden onset of movement disorders, usually in early childhood [47, 48]. A combination of axial hypotonia and dystonia with movement is typical and as the disease progresses, a fixed, generalized dystonia with intermittent tonic posturing develops [48]. Early orofacial involvement, with dystonia and dyskinesias, has been described and can lead to swallowing dysfunction and dysphagia [48]. Dystonia occurs most often after at least one metabolic crisis but a subset of patients shows a more insidious-onset dystonia [47]. Akinetic–rigid parkinsonism or choreoathetoid movements are also common, leading to a mixed movement disorder in the majority of patients [48]. A late-onset form in a small subset of patients can present with non-specific neurological signs such as polyneuropathy, headaches, early-onset cognitive decline, or tremor [49]. Non-neurological manifestations are rare but an increased risk for adult-onset renal impairment has been reported [50]. Brain imaging classically shows a widened operculum with dilatation of the subarachnoid spaces surrounding underdeveloped frontotemporal lobes, subdural fluid collections, diffuse white matter changes, and abnormal signal intensity of the caudate and putamen. Encephalopathic crises lead to major changes in the putamen, globus pallidus, and caudate nucleus [51]. Given its treatable nature, GA-1 has been included in routine mass-spectrometry-based newborn screening in many countries. Metabolic crises carry a high morbidity and can be life-threatening. Immediate and adequate emergency treatment is imperative [52–54]. Early diagnosis and consequent metabolic treatment (low lysine diet, carnitine supplementation, and intensified emergency treatment during periods of catabolism) can prevent metabolic crises and subsequent dystonia (see Table 1.1). The movement disorders associated with GA-1 are discussed by Kölker in Chapter 12.

Number 6: Cerebral Creatine Deficiency

A group of three disorders, cerebral creatine deficiencies are important treatable IEMs. Movement disorders are relatively common in guanidinoacetate N-methyltransferase (GAMT) deficiency (OMIM 612736), which is an autosomal-recessive condition, and creatine transporter (CRTR) deficiency (OMIM 300352), which is X-linked [55, 56]. Dystonia and ataxia are the most common movement disorders in GAMT deficiency and are found in about a third of patients [55, 57]. Often, the movement disorder is a mixed picture of ataxia, dystonia, tremors, and choreoathetosis, superimposed on developmental delay, intellectual disability, seizures, and behavioral problems. While the onset of symptoms, including movement disorders, is usually during childhood, delayed presentations are possible [58]. In the largest cohort of males with CRTR deficiency published to date, motor dysfunction was reported in about two-thirds of patients [59]. Hypotonia was most common, followed by spasticity in about 30% and dystonia or athetosis in about 10% of cases. The latter included athetoid hand movements, intermittent dystonic posturing of the hands or wrists, choreoathetoid movements, or facial dystonia [59]. Early recognition and testing for creatine deficiency syndromes is crucial as disease-specific treatments can improve neurodevelopmental outcomes and can ameliorate movement disorders. A diagnosis can be achieved through a combination of biochemical tests (plasma or urine guanidinoacetate level, urine creatine to creatinine ratio) and magnetic reonance spectroscopy (see Table 1.1). Molecular testing can further support a diagnosis. GAMT deficiency is treated with a combination of creatine and ornithine supplementation as well as a protein- or arginine-restricted diet, while CRTR deficiency is treated with creatine, arginine, and glycine supplementation. Mercimek-Andrews discusses the latest knowledge about cerebral creatine deficiency in Chapter 28.

Number 5: Biotin–Thiamine-Responsive Basal Ganglia Disease

In 1998, Ozand and colleagues described a peculiar biotin-responsive basal ganglia disease in ten patients from consanguineous families [60]. Seven years later, bi-allelic mutations in SLC19A3 [61], encoding the human thiamine transporter-2, were discovered as the cause of what is now referred to as biotin–thiamine-responsive basal ganglia disease (BTBGD, OMIM 607483). Mutations in SLC19A3 leading to thiamine transporter-2 deficiency cause a spectrum of disease manifestations including at least two allelic diseases: BTBGD and Wernicke’s-like encephalopathy [62]. Although thiamine transporter-2 deficiency is rare, a correct diagnosis is important because of the therapeutic benefit resulting from high doses of biotin [60, 63] and/or thiamine [64, 65]. BTBGD usually presents acutely in childhood with encephalopathy, dysarthria, dysphagia, dystonia, external ophthalmoplegia, ataxia, and seizures; often in the setting of a minor febrile illness [66, 67]. Progression to severe cogwheel rigidity, dystonia, parkinsonism, quadriplegia, epilepsy, and, eventually, death is seen in individuals who are left untreated [66, 67]. Dystonia is the most common and important movement disorder occurring in nearly all patients [60, 63–66]. Like dystonia, ataxia is often part of the initial acute presentation [66]. Cogwheel rigidity is a classic feature and parkinsonism may develop in untreated individuals [66]. Brain imaging is often diagnostic and shows a “Leigh syndrome-like” pattern with central bilateral necrosis in the head of the caudate and putamen nuclei [66, 67]. Vasogenic edema is seen during the acute presentation while atrophy and gliosis in the affected regions are seen in chronic disease [67]. A dramatic response to thiamine or high-dose biotin corroborates the diagnosis and sequencing of SLC19A3 confirms it (see Table 1.1). Misko and Eichler discuss their approach to BTBGD in Chapter 25.

Number 4: Ataxia with Vitamin E Deficiency

Ataxia with vitamin E deficiency (AVED, OMIM 277460) is a rare but important treatable condition caused by autosomal-recessive mutations in the alpha-tocopherol transfer protein (TTPA) gene [68]. AVED patients present in late childhood or adolescence with a slowly progressive spinocerebellar ataxia that often mimics Friedreich ataxia [69, 70]. Manifestations shared with the latter include a progressive ataxia, dysarthria, areflexia, loss of proprioception and sensory disturbance, as well as upper motor neuron signs. Cardiomyopathy, however, is usually not a prominent feature in AVED. Head titubation or tremor and dystonia seem more common to AVED and atypical presentations with dystonia preceding ataxia have been reported [71, 72]. The phenotype varies greatly between families and sometimes even within a given family. The mechanism of neurological dysfunction in AVED is unknown. Brain imaging shows cerebellar atrophy in the majority of patients [73]. Post-mortem studies show a loss of cerebellar Purkinje cells, posterior column degeneration, and lipofuscin accumulation [74]. The diagnosis is suspected when a very low plasma vitamin E concentration is detected (with a normal lipid and lipoprotein profile) and confirmed by a pathogenic bi-allelic TTPA variant. Early diagnosis is imperative as treatment with high doses of vitamin E [75] can halt disease progression or even reverse some manifestations (see Table 1.1) [70, 73, 76]. Primary prevention is possible and treatment should be continued lifelong. Plasma vitamin E levels should be monitored in regular intervals. Chapter 24 by Johansen and Aasly examines AVED in the context of the ataxias.

Number 3: GLUT1 Deficiency Syndrome

The phenotypic spectrum of glucose transporter type 1 (GLUT1) deficiency (OMIM 606777) forms a fascinating continuum from the classic syndrome of infantile-onset seizures, developmental delay, acquired microcephaly, and complex movement disorders [77] to several paroxysmal movement disorders including paroxysmal exercise-induced dyskinesia [78]. The underlying genetic defects are heterozygous variants in the glucose transporter gene, SLC2A1 [79], leading to impaired glucose uptake through the blood–brain barrier. The majority of patients with GLUT1 deficiency have seizures that usually develop in infancy and are often resistant to treatment with conventional antiseizure drugs [80]. Motor symptoms in GLUT1 deficiency syndrome consist of both persistent (ataxia, dystonia, spasticity, chorea, myoclonus) and episodic paroxysmal dyskinesias of various forms [81]. The predominant movement disorders are ataxia (often as an ataxic-spastic gait), chorea (often mild and distal), and dystonia (more often limb then axial) in the classic form [81]. A peculiar paroxysmal eye–head movement disorder has recently been described in infants with GLUT1 deficiency syndrome and can be an important early manifestation [82]. Presentations with predominant ataxia and dystonia but without seizures have been reported [83]. Paroxysmal exercise (or exertion)-induced dyskinesia (PED, OMIM 612126) with or without epilepsy is a well-described phenotype in GLUT1 deficiency [79, 84]. PED is characterized by episodes of involuntary movements that typically last between 5 minutes and 30 minutes and are clearly triggered by sustained exercise. Other triggering or precipitating factors include stress, prolonged fasting, anxiety, and sleep deprivation. A classic presentation is that of lower limb dystonia brought on by running or exercising for a few minutes, but other, often more complex, movement disorders involving chorea, dystonic movements, or myoclonus are also observed. First attacks typically occur in childhood or early adolescence. Most patients with PED have a normal interictal examination but learning disabilities or developmental delay is reported in some 30% of individuals. Other less common presentations of GLUT1 deficiency with a predominant movement disorder include cases presenting with choreoathetosis [85, 86], stereotypies [81], alternating hemiplegia of childhood [87], overlap syndromes between hemiplegic migraine and alternating hemiplegia [88], and writer’s cramp [89]. In general, patients with GLUT1 deficiency syndrome show a variety of episodic symptoms [81]; hence, the presence of non-epileptic paroxysmal symptoms should raise suspicion for this disease. Recognizing the broad range of neurological phenotypes associated with GLUT1 deficiency is key to diagnosing this treatable IEM. A reduced cerebrospinal fluid (CSF) glucose concentration in the setting of a normal blood glucose level (often meeting a ratio of less than 0.4) is the classic laboratory abnormality. Brain imaging is usually normal [90]. Identification of a heterozygous pathogenic variant in SLC2A1 confirms the diagnosis. Early and prompt treatment with a ketogenic [81] or related diet such as the modified Atkins diet [91] can mitigate symptoms, as nicely illustrated in the original description of the syndrome [77] and confirmed in many subsequent studies (see Table 1.1). Supplementation with L-carnitine and alpha-lipoic acid is often recommended. Several medications including phenobarbital, valproic acid, and carbonic anhydrase inhibitors should be avoided. Written by experts, Pons, Pearson, and De Vivo, Chapter 13 reviews the fascinating spectrum of movement disorders in GLUT1 deficiency syndrome.