Etiology
The basal ganglia play an important role in the control of movements. The circuits between cortex-basal ganglia-thalamus-cortex establish the anatomic basis for the functions of the basal ganglia. Dystonia is characterized by an imbalance between the excitatory and inhibitory pathways in the circuits. The main neurotransmitters in these pathways are gamma-aminobutyric acid (GABA), glutamate, and dopamine.[11]
Dystonias are classified according to clinical characteristics (classification axis 1) and etiology (classification axis 2).[6][7] Classification along the clinical characteristics axis considers age at onset, body distribution, temporal pattern, and presence and type of associated features. Classification along the etiologic axis includes the presence or absence of neurodegeneration or static structural lesions, as well as the specific etiology, which may be acquired, inherited, or idiopathic.
The associated features element of the clinical axis can also help separate different etiologies of dystonia. Dystonia with or without tremor occurring in the absence of any other motor features is classified as isolated dystonia, while combined dystonia involves dystonia associated with other movement disorders. Complex dystonias are syndromes where dystonia is the predominant symptom among other neurologic or systemic features.
Where a specific genetic cause of dystonia is known, it can be named according to the type of disorder combined with the gene name: for instance, DYT-TOR1A.[12][13] It is important to consider that genetic or “inherited” dystonias, as named in the consensus classification, are often not familial. Patients with genetic dystonias may have “sporadic” disease with zero affected relatives due to recessive inheritance of the condition, de novo variants (i.e., a new change in the patient), or incomplete penetrance (a parent carries the disease variant without having symptoms).[2] Also, while genetic dystonias can be generally matched to patterns of dystonia and other neurologic involvement, it is important not to dismiss a possible genetic diagnosis in a patient who does not exactly match the “classic” pattern of that syndrome. Next-generation sequencing has revealed wide clinical variability where many patients with genetic dystonias have “atypical” phenotypes. Here we review some illustrative examples of dystonia syndromes in the context of the dystonia classification.
Infantile-onset inherited dystonia, nondegenerative
Several genetic causes are known for infantile-onset dystonia without evidence of significant neurodegeneration. However, not all genetic loci have been identified and the etiology may remain unknown in some patients, even those whose family history indicates inherited dystonia. In addition, transient dystonia of infancy and paroxysmal tonic upgaze of infancy are often idiopathic when no structural lesion can be identified.
Isolated dystonia without degeneration, previously classified as primary torsion dystonia, has several genetic causes, of which DYT-TOR1A can present in infancy.[14] DYT-TOR1A is an autosomal-dominant disorder with incomplete penetrance (30%) and variable expressivity, meaning it may be inherited from an unaffected or mildly affected parent. Almost all patients have a specific 3-base pair deletion in the coding region of TOR1A (DYT1), which has a dominant negative effect.[15] The TOR1A gene encodes the protein torsinA, which is highly expressed, especially in the dopaminergic neurons of the substantia nigra pars compacta, granule and pyramidal cells of the hippocampal formation, Purkinje and dentate nucleus neurons of the cerebellum, and cholinergic neurons of the neostriatum.[16] Its function is not clearly known.
Combined dystonia involving prominent myoclonus in an infant with nonprogressive focal arm or cervical dystonia, without neurodegeneration, suggests myoclonus-dystonia. DYT-SGCE, identified in about half of familial cases of myoclonus-dystonia, can have onset in infancy. This is an autosomal-dominant disorder caused by loss-of-function variants in the gene encoding epsilon-sarcoglycan, which normally binds to the transmembrane dystrophin-glycoprotein complex.[17] SGCE is maternally imprinted, so DYT-SGCE may appear to have an autosomal-recessive inheritance pattern due to very low penetrance of maternally inherited variants.[18] Dystonia with myoclonus also occurs in ADCY5-related dyskinesia.[19]
Paroxysmal dystonias can occur in infancy in several inherited dystonias.
ATP1A3-related autosomal-dominant disorders (including DYT/PARK-ATP1A3) can involve both paroxysmal and nonparoxysmal dystonias.[20][21] Patients with alternating hemiplegia of childhood typically have paroxysms involving asymmetric dystonia, which can generalize, is then followed by hemi- or quadriplegia, and resolved by sleep; patients also have eye movement abnormalities and developmental delay, with epilepsy in about 40%.[22] Another temporal pattern is abrupt fever-triggered onset of motor deficits (such as dystonia, generalized weakness, and/or ataxia) associated with encephalopathy, followed by persistent or slowly resolving deficits. This presentation occurs in patients with cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss (CAPOS) syndrome, as well as those with other ATP1A3 phenotypes variously referred to as atypical rapid-onset dystonia-parkinsonism, fever-induced paroxysmal weakness and encephalopathy, or relapsing encephalopathy with cerebellar ataxia.
ADCY5-related dyskinesia (CHOR/DYT-ADCY5), an autosomal-dominant disorder, involves a fluctuating and paroxysmal temporal pattern of mixed dyskinesias including dystonia, chorea, and myoclonus.[19] These dyskinesias typically involve the face as well as neck and limbs. Dyskinesias can occur during sleep, during arousals and drowsiness, and at other times of day or night. Variants with evidence suggesting both gain of function (with some missense variants) and loss of function (with a splice site variant) have been observed.
Paroxysmal movement disorder (PxMD)-PRRT2: the spectrum of autosomal-dominant disorders associated with PRRT2 includes paroxysmal kinesigenic dyskinesia (PKD), PKD/infantile convulsions, benign familial infantile epilepsy, episodic ataxia, and hemiplegic migraine.[23][24][25] Paroxysms are brief, triggered by movement or startle, and involve unilateral or bilateral dystonia and/or other dyskinesias. The disorder is caused by loss-of-function variants in PRRT2, including rare microdeletions involving the whole gene.
PxMD-PNKD, an autosomal-dominant disorder, accounts for some cases of familial paroxysmal nonkinesigenic dyskinesia (PNKD). Paroxysms typically involve chorea and dystonia affecting limbs, face, and trunk lasting 10 to 60 minutes. In addition to this clinical presentation, a pattern of features may help distinguish PNKD mutation-positive from mutation-negative patients: onset in infancy or early childhood, family history of affected relatives with caffeine- and alcohol-triggered attacks, normal neurologic exam between attacks, and response to benzodiazepines.[26]
PxMD-SLC2A1 is part of the spectrum of autosomal-dominant disorders associated with SLC2A1 (glucose transporter 1 [GLUT1]) variants.[27] SLC2A1 pathogenic variants can cause paroxysmal exercise-induced dyskinesias in the absence of other neurologic manifestations, or as part of GLUT1 deficiency syndrome with epileptic encephalopathy, spasticity, and other motor symptoms.
Infantile-onset inherited dystonia, due to disorders of neurotransmitters
Disorders of neurotransmitter metabolism or transport cause several combined and complex dystonias.
Dopa-responsive dystonia (Segawa syndrome, dystonia-parkinsonism with diurnal fluctuation) results from defects in metabolism of monoamine neurotransmitters (serotonin, dopamine, norepinephrine, and epinephrine).[28] It is characterized by excellent, sustained response to levodopa treatment. Most patients have diurnal fluctuation with worsening in the evening, and onset often involves the legs. The most frequent form, guanosine triphosphate cyclohydrolase I deficiency (DYT/PARK-GCH1), is an autosomal-dominant disorder with a more severe allelic autosomal-recessive phenotype. GCH1 encodes the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin (BH4), a required cofactor for phenylalanine, tyrosine, and tryptophan hydroxylase reactions during monoamine neurotransmitter biosynthesis.[29] A rarer autosomal-recessive form of dopa-responsive dystonia is tyrosine hydroxylase deficiency (DYT/PARK-TH). Tyrosine hydroxylase is the rate-limiting enzyme in the biosynthesis of the catecholamines dopamine, norepinephrine, and epinephrine.[30] Other forms of autosomal-recessive BH4 deficiency can also cause dystonia with some response to levodopa, such as 6-pyruvoyl-tetrahydropterin synthase (DYT/PARK-PTS), dihydropteridine reductase (DYT/PARK-QDPR), and sepiapterin reductase (DYT/PARK-SPR) deficiencies.[28]
Aromatic L-amino acid decarboxylase (AADC) deficiency (DYT-DDC), an autosomal-recessive disorder, also involves deficiencies of serotonin, dopamine, norepinephrine, and epinephrine because AADC is responsible for decarboxylation of dopa to dopamine and 5-hydroxytryptophan to serotonin. The phenotype includes limb and orofacial dystonia, which sometimes has diurnal fluctuation, as well as oculogyric crises, torticollis, choreoathetosis, myoclonus, parkinsonism, developmental delay, and autonomic manifestations.[28] A few patients improve with levodopa or dopamine agonists. Gene replacement therapy using viral vectors injected into the basal ganglia is in clinical development and has been approved for use in Europe.[31][32][33]
Dopamine transporter deficiency syndrome (DYT/PARK-SLC6A3, infantile parkinsonism-dystonia) is an autosomal-recessive complex dystonia that can involve dystonia, parkinsonism, and chorea.[34] Additional features include axial hypotonia, extraocular movement abnormalities such as saccade initiation failure and ocular flutter, eyelid myoclonus, developmental delay, and attention deficit hyperactivity disorder. Onset in every age group up to adulthood has been described, but the infantile-onset form typically starts within the first 6 months of life. Patients can have recurrent status dystonicus and oculogyric crises. The disorder results from biallelic loss-of-function variants in SLC6A3, which encodes a dopamine transporter expressed in neurons of the substantia nigra and ventral tegmental area. Decreased dopamine transporter activity results in impaired reuptake of dopamine from the synapse and depletion of dopamine in the presynaptic neuron.[34][35]
Dopamine-serotonin vesicular transport disease is an autosomal-recessive complex dystonia reported in a few consanguineous families due to homozygous missense variants in SLC18A2.[36][37][38] The motor phenotype includes dystonias (persistent, paroxysmal, and during walking) with oculogyric crises as well as parkinsonism, tremor, chorea, myoclonus, other eye movement abnormalities, and ataxia. Other manifestations can include hypotonia, hyporeflexia, developmental delay, epilepsy, and autonomic dysfunction. Symptoms worsen with levodopa but improve with pramipexole. SLC18A2 encodes vesicular monoamine transporter 2, which loads presynaptic vesicles with monoamine neurotransmitters and is required in monoaminergic neurons for dopamine, serotonin, and GABA signaling.
While not the primary feature of these disorders, dystonia can also be seen in cerebral folate deficiency, succinic semialdehyde dehydrogenase deficiency (a disorder of GABA metabolism), pyridoxine dependency, and pyridoxal phosphate dependency.[28]
Infantile-onset inherited dystonia, due to other metabolic disorders
Other inborn errors of metabolism can cause complex dystonias that often involve a combination of generalized dystonia, other movement disorders, neurologic manifestations such as encephalopathy and seizures, and systemic manifestations.[39] Neuroimaging may show basal ganglia lesions, and patients can have status dystonicus.
Organic acidemias with neurotoxic metabolites can cause both acute basal ganglia injury or “metabolic stroke” during encephalopathic crises and chronic, progressive injury. The organic acidemia most often associated with dystonia is glutaric aciduria type I. It is caused by the deficiency of glutaryl-CoA dehydrogenase activity, a mitochondrial matrix enzyme that functions in the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA in the degradation pathway for lysine, hydroxylysine, and tryptophan.[40] Dystonia can also be seen in: methylmalonic acidemia, propionic acidemia, and acute leucine encephalopathy due to maple syrup urine disease; and as a chronic symptom in disorders of intracellular cobalamin metabolism, such as cobalamin C deficiency, and degenerative disorders such as MEGDEL syndrome with 3-methylglutaconic aciduria.
Lesch-Nyhan syndrome (DYT/CHOR-HPRT) is an X-linked recessive disorder of purine metabolism with a motor phenotype characterized by self-injurious behavior and dyskinetic cerebral palsy with prominent dystonia.[41] Patients can also have choreoathetosis, ballismus, hypotonia with motor delay, dysarthria, dysphagia, and spasticity as well as systemic manifestations of hyperuricemia, crystalluria, renal calculi, urate nephropathy, and megaloblastic anemia. The disorder is caused by loss-of-function variants in HPRT (hypoxanthine-guanine phosphoribosyl transferase), which encodes a purine salvage enzyme needed to recover inosine or guanosine monophosphate nucleotides from, respectively, free hypoxanthine or guanine bases.
Among the mitochondrial encephalomyelopathies, Leigh syndrome is characterized by neuronal loss, gliosis, and overall bilateral and symmetric necrotizing lesions, preferentially localized to the basal ganglia, thalamus, and brainstem.[42] Additionally, relative sparing of cognitive function and lack of muscular and cardiac dysfunction, despite necrotic basal ganglia lesions, can be seen in childhood-onset dystonia and optic atrophy due to MECR pathogenic variants, an autosomal-recessive disorder affecting the last step of the mitochondrial de novo fatty acid synthesis pathway.[43]
Allan-Herndon-Dudley syndrome (AHDS, X-linked monocarboxylate transporter 8 deficiency) occurs in boys with pathogenic variants in the MCT8/SLC16A2 gene, who usually have hypotonia at birth with marked global developmental delay noted by 6 months and then dystonia and other dyskinesias.[44] Magnetic resonance imaging (MRI) shows delayed myelination. Diagnostic testing shows pathognomonic abnormal thyroid test results including elevated T3, decreased reverse T3, normal or occasionally mildly abnormal T4 and thyroid-stimulating hormone, and MCT8/SLC16A2 pathogenic variants.
Cerebral creatine deficiency syndromes present with global developmental delay, epilepsy, and hypotonia with some patients having dystonia, choreoathetosis, ataxia, and/or self-injurious behavior. Three such disorders are known due to loss of creatine biosynthesis enzymes (autosomal-recessive guanidinoacetate methyltransferase [GAMT] and arginine:glycine amidinotransferase [AGAT/GATM]) or the cerebral creatine transporter (X-linked SLC6A8); all three demonstrate depletion of cerebral creatine on magnetic resonance spectroscopy.[45]
Biotin-thiamine-responsive basal ganglia disease (BTBGD, DYT-SLC19A3), an autosomal-recessive disorder due to pathogenic variants in the gene encoding thiamine transporter 2, has a classic phenotype of acute or subacute encephalopathic episodes triggered by fever or other stressors, which involve dystonia, rigidity, spasticity, seizures, and in some cases cerebellar involvement.[46] MRI during the acute phase shows bilateral, symmetric basal ganglia lesions (with elevated lactate on magnetic resonance spectroscopy) with subsequent chronic atrophy. Other infantile presentations of this disorder are atypical infantile spasms and a Leigh-like syndrome with lactic acidosis.
Infantile-onset inherited dystonia, with complex phenotype
In neurodegenerative disorders, dystonia typically occurs as one of multiple progressive symptoms such as encephalopathy, epilepsy, spasticity, acquired microcephaly, or systemic manifestations.
Lysosomal storage disorders associated with progressive neurologic dysfunction include Niemann-Pick disease type C, GM1 and GM2 gangliosidoses, and Gaucher disease.[47] Abnormal posturing, rigidity (either dystonia, or spasticity due to brainstem dysfunction), and athetosis can be seen late in the progression of early-onset acute neuronopathic (type 2) Gaucher disease, or in chronic neuronopathic (type 3) Gaucher disease.[48]
Neurodegeneration with brain iron accumulation (NBIA) includes a diverse group of disorders characterized by excessive brain iron deposition and overlapping phenotypes including progressive dystonia, choreoathetosis, parkinsonism, oculomotor abnormalities, pyramidal involvement, retinal degeneration, encephalopathy, and systemic manifestations. Many, but not all, patients with neurodegeneration associated with these genes have excessive iron deposition in the basal ganglia visible as T2 hypointensity on MRI.[49] MRI findings can vary between patients but recognition of patterns of involvement may aid diagnosis.[50]
Hypermanganesemia, with dystonia and parkinsonism due to neurotoxicity: two such autosomal-recessive disorders are known due to loss-of-function variants in genes encoding divalent cation transporters, SLC30A10 and SLC39A14.[51][52][53] In both disorders, patients generally have a progressive course starting with motor disturbances (hypotonia, loss of motor milestones, gait disturbance) then worsening dystonia, parkinsonism, spasticity, and other neurologic symptoms with relative sparing of cognition, and MRI findings characteristic of manganese deposition. Most patients with SLC30A10 pathogenic variants also have liver disease and polycythemia. Chelation therapy to reduce the systemic manganese load can lead to clinical improvement in both disorders.
Leukodystrophies/disorders with hypomyelination often present with hypotonia followed by spasticity. They include X-linked recessive Pelizaeus-Merzbacher disease and other autosomally inherited hypomyelinating leukodystrophies, such as GJC2 Pelizaeus-Merzbacher-like disease and TUBB4A-related hypomyelinating leukodystrophy. In hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), representing the severe childhood-onset end of the TUBB4A phenotypic spectrum, dystonia occurs in the context of other progressive movement disturbances, cerebellar signs, and pyramidal involvement.[54] Disorders of aminoacyl-tRNA synthetase genes can have somewhat similar presentations: for instance, biallelic pathogenic variants in AARS (nuclear-encoded alanyl-tRNA synthetase) cause epileptic encephalopathy with severely delayed myelination, peripheral neuropathy, and dyskinesias (limb dystonias, chorea, blepharospasm, orobuccal dyskinesia).[55] Pathogenic variants in BCAP31, involved in endoplasmic reticulum and Golgi transport, cause an X-linked recessive syndrome of dystonia with deafness and hypomyelination.[56]
Aicardi-Goutières syndrome (AGS) is a type I interferonopathy (monogenic disorder with abnormal upregulation of type I interferon signaling) resulting from pathogenic variants in any of several genes related to nucleotide metabolism and sensing.[57][58] Most patients have autosomal-recessive inheritance, but several types can involve dominant inheritance. The classic phenotype is acute/subacute onset of irritability, developmental regression, recurrent sterile pyrexia, chilblains, hepatosplenomegaly, and neurologic manifestations including dystonia, spasticity, axial hypotonia, seizures, and acquired microcephaly; the subsequent course may be static/nonprogressive.[59][60] Computed tomography or MRI of the brain show intracerebral calcifications, temporal lobe swelling followed by atrophy, and early global cerebral atrophy.[58][61][62][63] A confirmed genetic diagnosis is critical given the overlap of clinical features across several autoinflammatory disorders.[58] Mutations in the following disease-causing genes should be included in the genetic analyses: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1, LSM11, and RNU7-1.[58] Notably, patients with ADAR1 pathogenic variants (AGS6) can present with acute or subacute dystonia and MRI showing bilateral striatal necrosis.[57] Cerebrospinal fluid (CSF) analysis typically shows lymphocytosis.[58][63][64]
Other genes associated with phenotypes involving infantile developmental regression and dystonia include CYB5R3 (methemoglobinemia type II), TBCD, and VAC14. TBCD encodes a tubulin chaperone involved in microtubule assembly. Several groups have reported biallelic pathogenic variants in association with neonatal- or infantile-onset progressive encephalopathy with loss of milestones, hypotonia, subsequent spasticity and seizures, and acquired microcephaly with cerebral and cerebellar atrophy and hypomyelination. Some patients had severe dystonia.[65] VAC14 encodes part of a complex that regulates phosphatidylinositol 3,5-bisphosphate levels in endosomes; two patients with biallelic VAC14 pathogenic variants had rapid onset of dystonia (progressing from lower to upper extremities, jaw, neck, and back), hypertonia, loss of speech, and striatal abnormalities on MRI.[66]
In many neurodevelopmental disorders, dystonia is part of a complex phenotype along with other suggestive but nonspecific features, such as intellectual disability, microcephaly, cerebral atrophy, epilepsy, or cortical blindness.
ARX is associated with a spectrum of X-linked neurodevelopmental disorders encompassing severe brain malformation such as lissencephaly, early infantile epileptic encephalopathy without malformation, and syndromic and nonsyndromic intellectual disability.[67] Focal bilateral hand dystonia is a characteristic pattern seen with various other neurologic manifestations, such as intellectual disability (Partington syndrome) or early infantile epileptic encephalopathy (infantile-epileptic dyskinetic encephalopathy). Generalized onset and progression to involve limbs has also been observed.[68] More severe loss-of-function variants are associated with major brain malformation.[67]
DYT-KMT2B is an autosomal-dominant generalized, progressive dystonia.[69][70] Onset of dystonia is typically in childhood with initial lower limb involvement; a few patients have dystonia starting in infancy.[70] Some patients also have developmental delay/intellectual disability, microcephaly, dysmorphic features, and other systemic manifestations.[71] Motor symptoms respond to deep brain stimulation of the globus pallidus interna. KMT2B (MLL4) encodes a histone H3 lysine 4-specific lysine methyltransferase, which generates epigenetic marks associated with transcriptional activation.[71]
GNAO1 encephalopathy (neurodevelopmental disorder with involuntary movements [NEDIM]) is an autosomal-dominant disorder with a spectrum including both early infantile epileptic encephalopathy and hyperkinetic movement disorders with or without epilepsy.[72][73] The movement phenotype involves progressive generalized dystonia, choreoathetosis, and facial dyskinesias. Paroxysmal exacerbations with status dystonicus and severe chorea may need intensive care. Self-injurious behavior, stereotypies, and autonomic dysfunction are also seen. An underlying degenerative process has been proposed based on the progressive course and presence of structural lesions including global atrophy and periventricular gliosis.[72]
Other genes where mutations have been linked to brain malformation, epilepsy, and hyperkinetic movements include FOXG1 (dystonia, chorea, stereotypies) and GRIN1 (with hyperkinetic movements including apparent oculogyric crises).[74][75]
Acquired dystonia, due to drugs/toxins
In drug-related dystonia, most of the offending drugs are dopamine receptor antagonists. They may cause dystonia through dopamine receptors in the basal ganglia.
Acquired dystonia, other
In kernicterus, bilirubin causes selective neurotoxicity in the basal ganglia, especially globus pallidus and subthalamic nucleus, cerebellum, and brainstem nuclei by impairing intracellular calcium homeostasis. This triggers the release of cytochrome C from mitochondria resulting in the induction of apoptosis.[76]
Ischemic or hemorrhagic strokes, congenital or postpartum infections including with Zika virus, and autoimmune encephalitis are potential causes of dystonia in infants, as well as hypertonia in general.[7][77][78] Therefore, dystonia can occur as part of dyskinetic or spastic cerebral palsy, for which there are management guidelines based on expert opinion.[79] However, structural lesions in cerebral palsy do not rule out the possibility of an underlying genetic cause. The etiology should still be evaluated as appropriate, given that around 30% of children with cerebral palsy in one cohort were found to have a genetic diagnosis.[80]
Conditions that mimic dystonia
Various conditions mimic dystonia. In secondary infantile torticollis, caused by infection in the head and neck region, an inflammatory process irritates the cervical muscles, nerves, or vertebrae.[81]
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