Abstract
Movement disorders can present a diagnostic challenge, particularly those with onset at an early age as one component of a complex neurodevelopmental disorder. With advances in next-generation sequencing technologies, the number of genes associated with movement disorders has been rapidly increasing over the last few years. Some of these genes encode transport proteins or enzymes within well-characterized metabolic pathways and their abnormal function results in disorders defined as inborn errors of metabolism (IEMs). Although individually rare, IEMs have a collective estimated incidence of 1:800 to 1:2,500 live births [1]. Movement disorders are a common symptom in IEMs affecting the central nervous system [2]. In general, movement disorders are not the sole symptom of these disorders, but are more often part of complex phenotypes that include other neurological and systemic signs and symptoms. The ability to recognize IEMs is crucial for clinicians evaluating patients presenting with movement disorders, as some IEMs are amenable to therapy, including specific dietary therapies or supplementation with vitamins, minerals, or cofactors that can prevent intoxication or treat deficiencies [3].
Introduction
Movement disorders can present a diagnostic challenge, particularly those with onset at an early age as one component of a complex neurodevelopmental disorder. With advances in next-generation sequencing technologies, the number of genes associated with movement disorders has been rapidly increasing over the last few years. Some of these genes encode transport proteins or enzymes within well-characterized metabolic pathways and their abnormal function results in disorders defined as inborn errors of metabolism (IEMs). Although individually rare, IEMs have a collective estimated incidence of 1:800 to 1:2,500 live births [1]. Movement disorders are a common symptom in IEMs affecting the central nervous system [2]. In general, movement disorders are not the sole symptom of these disorders, but are more often part of complex phenotypes that include other neurological and systemic signs and symptoms. The ability to recognize IEMs is crucial for clinicians evaluating patients presenting with movement disorders, as some IEMs are amenable to therapy, including specific dietary therapies or supplementation with vitamins, minerals, or cofactors that can prevent intoxication or treat deficiencies [3]. The early recognition of IEMs and initiation of appropriate treatment, where available, thus has the potential to profoundly impact outcomes (Box 3.1). Furthermore, many IEMs require long-term surveillance and screening for complications and “harm avoidance” approaches (e.g. avoiding metabolic stressors and selected medications). The details of these important diagnoses and management issues will be dealt with in later chapters.
Box 3.1 Treatable IEMs not to miss: disorders in which appropriate treatment may prevent irreversible neurological injury or significantly improve neurological symptoms
Disorders of monoamine neurotransmission
Disorders of amino acid metabolism – e.g. glutaric aciduria type 1 (GA-1), organic acidurias, maple syrup urine disease, homocystinuria
Hypermanganesemia with dystonia
Wilson disease
Aceruluplasminemia
Glucose transporter type 1 (GLUT1) deficiency
Neuronal ceroid lipofuscinosis type 2 (CLN2/TPP1)
Ataxia with vitamin E deficiency
Niemann–Pick disease type C (NPC)
Cerebral creatine deficiency syndromes
Biotin–thiamine-responsive basal ganglia disease
Primary cerebral folate deficiency
Primary coenzyme Q10 deficiency
Biotinidase deficiency
Refsum disease
Pyruvate dehydrogenase (PDH) deficiency
This chapter will serve as a gateway to the subsequent chapters on “a phenomenology-based approach” and takes the perspective of a neurologist or movement disorder specialist who is confronted with two tasks when evaluating a patient with a movement disorder and suspected genetic or metabolic condition: (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 outlined below (Box 3.2). 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.
Box 3.2 General principles
1. Most IEMs are individually rare or even extraordinarily rare.
2. Most IEMs present in childhood but atypical cases with presentation in adulthood are recognized.
3. Most IEMs are multisystem diseases with neurological and non-neurological manifestations.
4. Most IEMs initially present with non-specific findings.
5. In most IEMs, phenotypes are variable and prototypical features are usually in the “worst-case scenario.”
6. In most IEMs, movement disorders are not the only or presenting symptom but their recognition can facilitate a diagnosis.
7. In most IEMs, movement disorders contribute substantially to the morbidity and can have a significant impact on quality of life.
8. Most IEMs present with more than one movement disorder.
9. Some IEMs that present with movement disorders are treatable and early diagnosis and treatment can improve outcomes.
10. All IEMs that present with movement disorders require interdisciplinary care and collaboration between pediatric neurologists, neurologists, geneticists, and experts in metabolism.
In this chapter, we provide a framework to patients presenting with a movement disorder and when to suspect an IEM, with an emphasis on treatable conditions. Such an approach begins by appropriately recognizing the phenomenology of the presenting movement disorder(s) and the IEMs potentially associated with the movement disorder phenotype. Next, phenotypic clues to specific IEMs may be sought through a careful evaluation for other neurological manifestations and involvement outside of the nervous system, along with defining the inheritance patterns within families. Accurately defining the phenotype in this manner may then guide the use of appropriate directed testing to identify the potentially causative IEM. A systematic approach to the diagnosis of IEMs presenting with movement disorders will lead to an early diagnosis and early therapeutic intervention that may reduce neurological and systemic morbidities.
Movement Disorder Phenomenology
Movement disorders are broadly classified into those presenting with an excess of involuntary movement – hyperkinetic movement disorders – and those characterized by a decrease in automatic and voluntary movement – hypokinetic disorders. Hyperkinetic movement disorders associated with IEMs include dystonia, ataxia, tremor, myoclonus, and chorea. The prototypical hypokinetic movement disorder is parkinsonism, often termed an akinetic–rigid syndrome. Usually, clinical suspicion for an underlying IEM should arise when a patient presents with various types of movement disorders (often a mixed phenotype) or movement disorders occurring in association with intercurrent illnesses or other stressors, in addition to other neurological or systemic manifestations. Signs and symptoms suggesting an underlying IEM etiology are listed in Table 3.1, based on the clinical history, family history, and physical examination features. In addition, patterns of neuroimaging abnormalities – particularly abnormal signal within the basal ganglia – may provide supportive evidence for an underlying IEM.
Table 3.1 Features suggestive of IEM disorders based on clinical history, family history, and physical examination features
| Features | Associated IEMs | |
|---|---|---|
| Clinical history | Recurrent encephalopathy triggered by intercurrent illness or stress | Mitochondrial disorders, disorders of amino acid metabolism |
| Failure to thrive or short stature | Disorders of monoamine neurotransmission, mitochondrial disorders, disorders of amino acid metabolism | |
| Protein aversion | Disorders of amino acid metabolism | |
| Developmental delay, developmental regression, or cognitive decline | Various | |
| Seizures | GLUT1 deficiency, mitochondrial disorders, Lafora disease, disorders of amino acid metabolism, lysosomal storage disorders, cerebral creatinine deficiency syndromes, disorders of monoamine neurotransmission, cerebral folate deficiency, biotin–thiamine-responsive basal ganglia disease, biotinidase deficiency, molybdenum cofactor deficiency, cerebrotendinous xanthomatosis, congenital disorders of glycosylation | |
| Hearing loss | Mitochondrial disorders, Refsum disease, biotinidase deficiency | |
| Progressive visual loss | Neuronal ceroid lipofuscinosis, mitochondrial disease, ataxia with vitamin E deficiency, abetalipoproteinemia, PKAN, aceruloplasminemia, Refsum disease | |
| Abnormal urine or body odour | Maple syrup urine disease, phenylketonuria | |
| Psychiatric disturbance | Disorders of amino acid metabolism, Wilson disease, cerebrotendinous xanthomatosis, mitochondrial disorders, lysosomal storage disorders, cerebral creatinine deficiency syndromes, NBIA syndromes, neuroferritinopathy, aceruloplasminemia | |
| Movement disorders with sudden onset or paroxysmal course | GLUT1 deficiency, PDH deficiency, maple syrup urine disease, GA-1, biotin–thiamine-responsive basal ganglia disease, mitochondrial disorders, Hartnup disease | |
| Family history (extended three generation) | Including developmental delay, cognitive dysfunction, psychiatric disease, movement disorder, early death, repeated pregnancy losses, consanguinity | Will depend on inheritance pattern: autosomal-recessive, autosomal-dominant, X-linked, maternal |
| Physical examination and organ involvement | Dysmorphic features | Lysosomal storage disorders, molybdenum cofactor deficiency, PDH deficiency, congenital disorders of glycosylation, cerebral creatine deficiency syndromes |
| Macrocephaly or microcephaly |
| |
| Skeletal dysplasia | Lysosomal storage disorders, congenital disorders of glycosylation | |
| Skin abnormalities | Biotinidase deficiency, congenital disorders of glycosylation, Hartnup disease | |
| Ocular abnormalities | Lysosomal storage disorders, homocystinuria, molybdenum cofactor deficiency, Wilson disease, mitochondrial disorders, Refsum disease, PKAN, neuronal ceroid lipofuscinosis, cerebrotendinous xanthomatosis | |
| Hepatosplenomegaly or hepatic dysfunction | Lysosomal storage disorders, Wilson disease, mitochondrial disorders, congenital disorders of glycosylation, hypermanganesemia with dystonia, disorders of amino acid metabolism | |
| Cardiac involvement | Mitochondrial disorders, lysosomal storage disorders, Wilson disease, organic acidurias, Refsum disease, congenital disorders of glycosylation | |
| Myopathy | Mitochondrial disorders, cerebral creatine deficiency syndrome (GAMT) | |
| Renal involvement | Mitochondrial disorders, Wilson disease, Lesch–Nyhan disease, coenzyme Q10 deficiency, congenital disorders of glycosylation, Fabry disease, organic acidurias (renal failure especially in methylmalonic acidemia) | |
| Endocrine dysfunction | Mitochondrial disorders, aceruloplasminemia, Woodhouse–Sakati syndrome, congenital disorders of glycosylation |
Abbreviations: GA-1, glutaric aciduria type 1; GLUT1, glucose transporter type 1; PKAN, pantothenate kinase-associated neurodegeneration; NBIA, neurodegeneration with brain iron accumulation; PDH, pyruvate dehydrogenase; GAMT, guanidinoacetate methyltransferase deficiency.
The International Parkinson and Movement Disorder Society Task Force for Nomenclature of Genetic Movement Disorders recently published a review of the classification and nomenclature of genetically determined movement disorders, including IEM [4]. More than 30 genes associated with IEMs were included in this review and categorized, based on their prominent movement disorder(s). We refer the reader to this review article for a detailed discussion of movement disorder classification, but have summarized the IEMs associated with movement disorders based on the most prominent movement disorder phenomenology in Table 3.2.
Table 3.2 Clinical features of IEMs associated with movement disorders, classified by the most common/prominent movement disordera
| Disorder (gene) | Associated movement disorders | Other neurological features | Systemic features | Brain MRI patternb | Treatment |
|---|---|---|---|---|---|
| Dystonia | |||||
| Dystonia, parkinsonism | Pyramidal signs, spasticity | Normal | Levodopa | |
| Dystonia, parkinsonism, oculogyric crisis, tremor, myoclonus | Pyramidal signs, spasticity, hypotonia, ptosis, autonomic dysfunction, encephalopathy, global developmental delay | Normal or non-specific atrophy/WM changes | Levodopa | |
| Dystonia, oculogyric crisis, parkinsonism, chorea, tremor, myoclonus | Hypotonia, irritability, autonomic dysfunction, ptosis, sleep disturbance, seizures, global developmental delay | Normal or non-specific atrophy/WM changes | Pyridoxine, dopamine agonists, monoamine oxidase inhibitors | |
| Dystonia, oculogyric crisis, parkinsonism | Hypotonia, autonomic dysfunction, sleep disturbance | Normal or delayed myelination | Levodopa, 5-hydroxytryptophan | |
| Dystonia, oculogyric crisis, parkinsonism | Hypotonia, spasticity, seizures, global developmental delay | Normal | Levodopa, 5-hydroxytryptophan, tetrahydrobiopterin | |
| Dystonia, chorea, tremor | Hypotonia, seizures, bulbar dysfunction, hypersalivation, global developmental delay | Normal or non-specific WM changes, BG calcifications | Levodopa, 5-hydroxytryptophan, monoamine oxidase inhibitors, folinic acid | |
| Dystonia, parkinsonism, chorea | Pyramidal signs, spasticity, abnormal eye movements, dysarthria, peripheral neuropathy, seizures, optic atrophy, cognitive decline, behavior/psychiatric disturbance |
| T2 hypointentensity within BG, substantia nigra | Symptomatic (deferiprone and fosmetpantotenate currently in clinical trials for PKAN) |
| Parkinsonism, dystonia | Hypotonia, spasticity, psychomotor regression, seizures | Cherry-red spot, skeletal dysplasia, short stature, cardiomyopathy, hepatosplenomegaly, coarse facial features | WM, BG, cerebral/cerebellar atrophy | Symptomatic |
| Dystonia, chorea | Hypotonia, self-injurious behavior, dysarthria, dysphagia, pyramidal signs, spasticity, global developmental delay | Nephrolithiasis, gout | Normal or cerebral atrophy | Allopurinol |
| Dystonia, parkinsonism | Dysarthria, spasticity | Liver dysfunction, polycythemia | T1 hyperintensity within BG, BS, DN | Chelation therapy |
| Dystonia | Seizures, global developmental delay, psychiatric disturbance, cerebrovascular events | Ectopia lentis, high myopia, thromboembolism, marfanoid body habitus, hypopigmentation of skin/hair. | Normal or WM | Methionine-restricted diet, pyridoxine, folate, betaine, vitamin B12 |
| Dystonia, parkinsonism, chorea | Acute encephalopathic crises, spasticity | Macrocephaly | Frontotemporal atrophy, BG, WM, DN | Lysine-restricted diet, carnitine, emergency treatment protocol |
| Dystonia, ataxia, chorea | Hypotonia, spasticity, seizures, episodic encephalopathy, metabolic stroke, myopathy, optic atrophy, global developmental delay | Cardiomyopathy, acquired microcephaly, cytopenias, renal failure | WM, BG (including calcification), BS, cerebral/cerebellar atrophy | Dietary protein restriction, carnitine |
| Dystonia, parkinsonism | Seizures, encephalopathy, global developmental delay | Microcephaly, dysmorphic features, ectopia lentis | WM (including cystic changes), BG, cerebellum, cerebral/cerebellar atrophy | Cyclic pyranopterin monophosphate (if MOCS1) |
|
| Seizures, dysarthria, spasticity, global developmental delay | Acquired microcephaly | WM, DN, cerebellar atrophy | Ketogenic diet |
| Dystonia, tremor, parkinsonism, myoclonus | Myopathy, peripheral neuropathy, optic neuropathy, spasticity | Cardiac involvement | Normal or WM, cerebral atrophy | Symptomatic |
| Dystonia, ataxia, chorea, myoclonus | Encephalopathy with episodic deterioration, hypotonia, spasticity, seizures, eye movement abnormalities, weakness, bulbar dysfunction, peripheral neuropathy, optic atrophy, global developmental delay | Retinitis pigmentosa, cardiac involvement, liver involvement, renal involvement | BG, BS, cerebellum, WM, cerebral/cerebellar atrophy, lactate peak on magnetic resonance spectroscopy | Symptomatic |
| Tremor | |||||
| Tremor, dystonia, ataxia, parkinsonism, chorea | Dysarthria, dysphagia, drooling, psychiatric disturbance | Hepatic dysfunction, Kayser–Fleischer rings, hemolytic anemia, renal disease, cardiomyopathy, sunflower cataracts, arthritis | BG, BS (including “face of the giant panda” in the midbrain) | Copper chelation, zinc |
| Tremor, parkinsonism | Cognitive impairment, psychiatric disturbance, spasticity, seizures | Musty odor, microcephaly, decreased skin/hair pigmentation | WM, cerebral atrophy | Phenylalanine-restricted diet, tetrahydrobiopterin trial |
| Palatal tremor, ataxia | Seizures, pyramidal signs, spasticity, hydrocephalus, cognitive decline, bulbar dysfunction | Macrocephaly |
| Symptomatic |
| Myoclonus | |||||
| Myoclonus, ataxia | Seizures, dysarthria, dementia | Normal or cerebral/cerebellar atrophy | Symptomatic | |
| Myoclonus, ataxia, parkinsonism | Seizures, psychomotor regression, pyramidal signs, spasticity, psychiatric/behavior disturbance, dysarthria | Vision loss, cardiac involvement (uncommon). | Cerebral/cerebellar atrophy. BG or WM in some forms | Intrathecal cerliponase alfa (if TPP1) |
| Myoclonus, ataxia, parkinsonism, retroflexion of neck | Eye movement abnormalities, horizontal supranuclear gaze palsy, spasticity, seizures, apnea, bulbar dysfunction, global developmental delay /dementia | Hepatosplenomegaly, cytopenias, pulmonary involvement | Normal | Enzyme-replacement therapy |
| Myoclonus, ataxia | Epilepsy, myopathy, peripheral neuropathy, pyramidal signs, dementia, ophthalmoparesis, pyramidal signs, optic atrophy, hearing loss | Retinitis pigmentosa, short stature, cardiac involvement | Cerebral/cerebellar atrophy, BG (including calcifications), BS, WM | Symptomatic |
| Myoclonus, ataxia | Seizures, visual loss | Cherry-red spot macula, cataracts, corneal opacities | Diffuse atrophy | Symptomatic |
| Chorea | |||||
| Chorea, dystonia, ataxia, parkinsonism, orofacial/orolingual dyskinesias, tremor | Dysarthria, dysphagia, abnormal eye movements, cognitive dysfunction, psychiatric disturbance |
| Symptomatic | |
| Parkinsonism | |||||
| Parkinsonism, dystonia, ataxia | Dementia, seizures, psychiatric disturbance | Calcifications in BG, DN/cerebellum, BS, subcortical WM | Symptomatic | |
| Ataxia | |||||
| Ataxia, dystonia, head tremor | Proprioceptive loss, areflexia, dysarthria, peripheral neuropathy, pyramidal signs | Retinitis pigmentosa | Cerebellar atrophy, WM | Vitamin E |
| Ataxia | Dysarthria, peripheral neuropathy, proprioceptive loss, areflexia | Steatorrhea, retinitis pigmentosa | Normal | Dietary fat restriction, vitamins E, D, K, and A |
| Ataxia, myoclonus, dystonia, chorea, parkinsonism | Hypotonia, pyramidal signs, spasticity, psychomotor regression, seizures, motor neuron disease, dysarthria | Cherry red spot, vision loss, macrocephaly, hepatosplenomegaly, skeletal dysplasia, doll-like facies | BG, WM, cerebral/cerebellar atrophy | Symptomatic |
| Ataxia, dystonia, myoclonus, tremor, chorea, parkinsonism | Vertical supranuclear gaze palsy, hypotonia, dysarthria, dysphagia, deafness, gelastic cataplexy, spasticity, seizures, cognitive decline/dementia, psychosis and other psychiatric symptoms | Hepatosplenomegaly, neonatal jaundice | Normal or cerebral/cerebellar atrophy, WM | Miglustat |
| Ataxia | Hypotonia, pyramidal signs, spasticity, peripheral neuropathy, dysarthria, seizures, cognitive decline, behavioral/psychiatric disturbance | Gallbladder involvement | WM (initially periventricular), cerebral/cerebellar atrophy | Hematopoietic stem-cell transplantation |
| Ataxia, dystonia, chorea, tremor, parkinsonism | Dysarthria, cognitive decline | Retinal degeneration, diabetes mellitus, anemia | T2 hypointensity within BG, substantia nigra, red nuclei, DN | Iron chelation |
| Ataxia, parkinsonism, dystonia | Dysarthria, pyramidal signs, spasticity, seizures, peripheral neuropathy, cognitive impairment/dementia, psychiatric disturbance | Chronic diarrhea, cataracts, tendon xanthomas | DN/cerebellum, WM, cerebral/cerebellar atrophy | Chenodeoxycholic acid |
| Ataxia, dystonia, chorea | Language delay, intellectual disability, seizures, spasticity, hypotonia, myopathy (GATM), behavioral/psychiatric disturbance | Microcephaly, dysmorphic features (SLC6A8). | Reduced creatine on MRS, BG | Creatine monohydrate; ornithine supplementation, arginine restriction (if GAMT); arginine, glycine (if SLC6A8) |
| Ataxia, dystonia, rigidity | Subacute encephalopathy, seizures, pyramidal signs, dysarthria, dysphagia, eye movement abnormalities, facial palsy | BG, BS, cerebral/cerebellar atrophy | Biotin, thiamine | |
| Ataxia, chorea, tremor | Seizures, global developmental delay | Microcephaly, megaloblastic anemia, diarrhea, oral ulcers, immunodeficiency (SLC46A1) | WM, cerebral/cerebellar atrophy; intracranial calcifications (SLC46A1) | Folinic acid |
| Ataxia, dystonia, tremor, spasticity, parkinsonism, myoclonus | Encephalopathy, seizures, hypotonia, peripheral neuropathy, myopathy, stroke-like episodes, optic atrophy, global developmental delay | Cardiac involvement, nephrotic syndrome, retinopathy | Cerebral/cerebellar atrophy, BG, cortex | Coenzyme Q10 |
| Ataxia, dystonia, tremor; may be paroxysmal | Psychiatric disturbance | Dermatitis | Normal or diffuse atrophy | Nicotinamide |
| Ataxia, dystonia | Seizures, pyramidal signs, spasticity, hypotonia, global developmental delay, brain tumors | Macrocephaly | Subcortical WM, BG, DN, cerebral/cerebellar atrophy | Dietary protein restriction, carnitine, riboflavin |
| Ataxia, dystonia, tremor, chorea, parkinsonism. May be paroxysmal | Episodic encephalopathy, spasticity, cognitive impairment, psychiatric disturbance | Maple syrup odor, anorexia, vomiting. | Diffusion restriction in WM, BG, BS, dentate/cerebellum. | Leucine-restricted diet |
| Ataxia | Seizures, hypotonia, myelopathy, spasticity, hearing loss, optic neuropathy, global developmental delay | Rash, alopecia | Normal or cerebral/cerebellar atrophy, BG | Biotin |
| Ataxia, chorea | Hypotonia, seizures, global developmental delay, behavior disturbance | Normal or BG, WM, BS, DN, cerebellum | Symptomatic | |
| Ataxia | Peripheral neuropathy, hearing loss | Retinitis pigmentosa, anosmia, icthyosis, cardiac involvement | Normal or cerebral atrophy | Phytanic acid-restricted diet |
| Ataxia | Hypotonia, seizures, peripheral neuropathy, myopathy, abnormal eye movements, stroke-like events, global developmental delay | Eye abnormalities, dysmorphic features, skin abnormalities, liver involvement, heart involvement, skeletal abnormalities, endocrine dysfunction, renal involvement, immune dysfunction | Cerebellar hypoplasia/atrophy | Symptomatic |
| Ataxia, dystonia, chorea (may be paroxysmal) | Hypotonia, seizures, encephalopathy, spasticity, peripheral neuropathy, global developmental delay | Microcephaly, dysmorphic features | BG, BS, cerebellum, corpus callosum, cerebral atrophy | Ketogenic diet, thiamine, dichloroacetate |
| Ataxia, chorea, myoclonus, parkinsonism | Hypotonia, encephalopathy, seizures, peripheral neuropathy, progressive external ophthalmoplegia, myopathy, hearing loss, global developmental delay, psychiatric disturbance | Liver involvement, endocrine dysfunction, cardiac involvement, retinopathy. | Cerebral/cerebellar atrophy, DN/cerebellum, WM, BG, BS. | Symptomatic |
| Ataxia | Peripheral neuropathy, seizures, optic atrophy, learning difficulties | Retinitis pigmentosa. | Cerebral/cerebellar atrophy, BG, WM | Symptomatic |
a Abbreviations: BG = basal ganglia/thalamus; BS = brainstem; DN = dentate nucleus; WM = white matter.
Related posts:
Chapter 1 – Treatable Metabolic Movement Disorders: The Top 10
Chapter 7 – A Phenomenology-Based Approach to Inborn Errors of Metabolism with Ataxia
Chapter 9 – A Phenomenology-Based Approach to Inborn Errors of Metabolism with Parkinsonism
Chapter 13 – Disorders of Energy Metabolism: GLUT1 Deficiency Syndrome and Movement Disorders
Chapter 21 – Neurotransmitter Disorders: Disorders of Dopamine Metabolism and Movement Disorders
Chapter 27 – Purine Metabolism Defects: The Movement Disorder of Lesch–Nyhan Disease
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