Goal 1.

Describe the clinical characteristics of dystonia.

Goal 2.

Review the causes of hereditary dystonia.

Goal 3.

Provide an evaluation strategy to determine the etiology of hereditary dystonia in a proband.

Goal 4.

Review the differential diagnosis of hereditary dystonia (i.e., non-genetic causes of dystonia).

Goal 5.

Provide information regarding recurrence risk and evaluation of relatives of a proband with hereditary dystonia who are at risk.

Isolated Dystonias

DYT-TOR1A (early-onset generalized dystonia) typically first manifests in childhood (mean age 13 years, range 1-28 years) as twisting of an extremity. Symptoms tend to start in lower parts of the body, progressing to involve other limbs and the torso, but usually not the face or neck [Bressman et al 2000]. Penetrance is reduced; approximately 35% of persons heterozygous for a TOR1A pathogenic variant are affected. If manifestations are not evident in a person heterozygous for a TOR1A pathogenic variant by age 28 years, that individual will usually remain symptom-free for life. Expressivity varies with respect to age of onset, site of onset, and progression. Individuals with later onset or onset in the arms tend to be less severely affected. A specific TOR1A pathogenic variant, a three-base pair deletion (NM_000113.2:c.907_909delGAG) in the coding region, accounts for about 60% of generalized dystonia in the non-Jewish population and about 90% in the Ashkenazi Jewish population as a result of a founder effect [Ozelius et al 1997].

DYT-THAP1 (adolescent-onset segmental/generalized dystonia). Although some phenotypic overlap with DYT-TOR1A is observed, the onset of DYT-THAP1 is later (mean 19 years; range 5-38 years) and cranial involvement is more prominent especially in muscles of the tongue, larynx, and face, with dysphonia being a predominant feature. DYT-THAP1 was first identified in three Mennonite families who are related to a common ancestor [Fuchs et al 2009]. Currently more than 90 different pathogenic missense and truncating THAP1 variants have been reported – mainly in people from Europe but also from China and Brazil [Blanchard et al 2011]. Penetrance is estimated at 50%.

DYT-ANO3 (adult-onset focal or segmental dystonia). Pathogenic variants in ANO3 were initially reported in individuals with predominantly craniocervical dystonia with a widely variable age of onset [Charlesworth et al 2012]. Pathogenic variants were detected in about 1% of individuals with dystonia and shown to cosegregate with the disease phenotype in small family pedigrees. Notably, a large number of missense variants can be found in variant databases and in healthy individuals, however, the presence of a de novo variant in ANO3 supports pathogenicity of the variant [Zech et al 2017].

DYT-GNAL (adult-onset segmental dystonia) is characterized by cervical or cranial dystonia that often begins in the fourth decade (range 7-54 years) [Fuchs et al 2013]. About 30 different GNAL pathogenic variants, mostly in the heterozygous state, have been reported in individuals with dystonia and are spread over the entire gene. GNAL pathogenic variants appear to be highly but not fully penetrant [Vemula et al 2013].

DYT-KMT2B (early-onset, generalized dystonia with mild syndromic features) is characterized by early-onset, generalized dystonia, which may be clinically indistinguishable from DYT-TOR1A and may be the most common cause of early-onset generalized dystonia, at least outside the Askenazi Jewish population [Zech et al 2016, Meyer et al 2017].

As KMT2B has only very recently been described in conjunction with dystonia and mild syndromic features, it remains to be determined whether DYT-KMT2B falls under the "isolated" or "complex" category of inherited dystonias. Given the broad phenotypic overlap with DYT-TOR1A and only mild and inconsistent expression of microcephaly, intellectual disability, developmental delay, seizures, spasticity, eye movement abnormalities, and facial dysmorphism, it has been tentatively grouped in the "isolated dystonias" category.

Combined Dystonias

Complex Dystonias

Although complex dystonias share dystonia as a manifestation, atypical features and additional neurologic signs are often observed. These may include:

• Sustained dystonia at rest (whereas isolated or combined dystonia is usually action- or posture-dependent)
• Prominent tongue and perioral involvement leading to a risus sardonicus (i.e., fixed, exaggerated, or distorted smiling)
• Pyramidal or cerebellar signs
• Ataxia
• Oculomotor abnormalities
• Cognitive disturbances
• Hearing loss
• Intellectual disability / developmental delay
• Seizures

Although the list of complex dystonias is long and unwieldy, certain rules and patterns help to make an accurate diagnosis and tailor management. Grouping the complex dystonias into those that are hereditary neurodegenerative or metabolic disorders (see Table 4) and those that are acquired due to brain lesions, drugs, or psychological causes (see Table 5) has proven useful.

Neurodegenerative diseases

• Huntington disease. The cardinal movement disorder in Huntington disease is chorea, at least in adults. However, about 10% of individuals with Huntington disease have childhood onset (referred to as Westphal variant), which typically manifests as (1) focal or segmental dystonia (rather than chorea) that gradually becomes generalized and (2) parkinsonism [Bruyn & Went 1986]. Craniocervical dystonia including risus sardonicus is common and is often accompanied by speech and swallowing problems. Childhood-onset Huntington disease is more common when the pathogenic variant is paternally inherited. It is accompanied by a larger number of CAG repeats [Went et al 1984].
• Chorea-acanthocytosis is characterized by severe orolingual dystonia leading to chewing problems and sometimes mutilation of the lips, tongue, or cheeks (so called "eating dystonia") [Schneider et al 2007]. Other characteristic movement abnormalities include generalized chorea, motor and vocal tics, intermittent head drop, and sometimes parkinsonism.
• McLeod neuroacanthocytosis syndrome is defined as absent expression of the Kx erythrocyte antigen and weakened expression of Kell blood group antigens causing red blood cell acanthocytosis and compensated hemolysis. It is a multisystem disorder manifesting with sensorimotor axonopathy, muscle weakness, neuropsychiatric and cognitive disturbances, and movement disorders, particularly generalized chorea and orolingual dystonia.
• Rett syndrome. Asymmetric crural or generalized dystonia is common in Rett syndrome [Temudo et al 2008]. It occurs almost exclusively in girls because it is embryonic lethal in males. Following a near-normal early development affected girls develop autism, dementia, epilepsy, spastic paraparesis or tetraparesis, and characteristic stereotypies (hand clapping, knitting movements, or body rocking). After an initial rapid progression, symptoms usually stabilize, so that these individuals often survive into adulthood.

Disorders leading to brain calcification

• Primary familial brain calcification can present with dystonia in addition to cognitive and psychiatric symptoms. Vascular and brain parenchymal calcification, consisting primarily of calcium phosphate, is found in the basal ganglia and other brain areas including the cerebellum, thalamus, and brain stem.

Disorders of heavy metal metabolism

• Wilson disease, a disorder of copper metabolism, typically includes craniocervical dystonia that can be severe, early speech and swallowing problems, and other bulbar signs.
• Hypermanganesemia with dystonia, polycythemia, and cirrhosis resembles Wilson disease but is caused by disturbances of manganese metabolism. It is characterized by early-onset generalized dystonia and adult-onset parkinsonism. Serum manganese levels are elevated and brain MRI examination shows hyperintensities in the basal ganglia as well as in the subthalamic and dentate nuclei typical for hypermanganesemia.

Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterized by progressive iron storage in the brain and abnormal iron accumulation in the basal ganglia, which is evident as hypointense lesions predominantly (but not exclusively) in the globus pallidus and substantia nigra pars reticulata on T₂-weighted images. On T₁-weighted images, these regions are isointense. See NBIA Overview.

• Mitochondrial membrane protein-associated neurodegeneration is characterized by dystonia that frequently involves limbs and occasionally becomes generalized [Hogarth et al 2013]. Associated features are parkinsonism with varying combinations of bradykinesia, rigidity, tremor and postural instability, cognitive decline progressing to dementia, prominent neuropsychiatric abnormalities, and motor neuronopathy. Brain MRI shows a distinctive pattern of brain iron accumulation with T₂-weighted/gradient echo hypointensities in the substantia nigra and globus pallidus, often with unique T₂-weighted hyperintense streaking between the hypointense internal and external globus pallidus.
• Fatty acid hydroxylase-associated neurodegeneration presents in childhood with spastic tetraparesis, ataxia, and often generalized dystonia, followed by episodic neurologic decline. Brain MRI typically demonstrates T₂-weighted hypointensity in the globus pallidus, confluent T₂-weighted white matter hyperintensities, and profound pontocerebellar atrophy [Kruer et al 2010].
• Neuroferritinopathy typically presents with progressive adult-onset chorea or dystonia and subtle cognitive deficits. The movement disorder involves additional limbs within five to ten years and becomes more generalized within 20 years. When present, asymmetry remains throughout the course of the disease. The majority of affected individuals develop a characteristic orofacial action-specific dystonia induced by speech leading to dysarthria and dysphonia. Frontalis overactivity, orolingual dyskinesia, and dysphagia are also common. Brain MRI often shows cystic lesions in the basal ganglia and bilateral pallidal necrosis, in addition to iron accumulation in the caudate, globus pallidus, putamen, substantia nigra, and red nuclei.
• Pantothenate kinase associated neurodegeneration (PKAN) accounts for approximately 50% of NBIA. In classic PKAN, onset is early, usually before age six years and progression is rapid. Affected children often present with dystonic gait, dysarthria, and limb rigidity. Corticospinal tract involvement causes spasticity. A central region of hyperintensity in the globus pallidus with surrounding hypointensity on T₂-weighted images ("eye-of-the-tiger sign") is pathognomonic for PKAN and is highly correlated with the presence of biallelic PANK2 pathogenic variants.
• PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features: classic infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (atypical NAD), and PLA2G6-related dystonia-parkinsonism. Progressive dystonia associated with dysarthria and behavioral abnormalities including hyperactivity and impulsivity is common in NAD (onset age ~4 years), but not in INAD. PLA2G6-related dystonia-parkinsonism is characterized by juvenile parkinsonism associated with pyramidal signs, dementia, psychiatric features, and cerebral and cerebellar atrophy without brain iron accumulation on MRI [Paisan-Ruiz et al 2009, Hayflick et al 2013].
• Beta-propeller protein-associated neurodegeneration is characterized by developmental delay with further regression in early adulthood and by progressive dystonia, parkinsonism, and dementia. Seizures, spasticity, and disordered sleep are also common. Although the parkinsonism is L-dopa responsive, nearly all affected individuals have early motor fluctuations and develop disabling dyskinesia. Brain MRI shows iron deposition in the substantia nigra and globus pallidus, with a characteristic "halo" of T₁-weighted hyperintense signal in the substantia nigra [Hayflick et al 2013].

Lipid storage disorders

• Niemann-Pick type C, juvenile variant, is a sphingomyelin storage disease with onset in preschool or early school years, characterized by splenomegaly, behavioral abnormalities, ataxia, and supranuclear gaze palsy. Progressive generalized dystonia typically involving the orofacial muscles is also common.

Mitochondrial disorders

• Leigh syndrome, a progressive neurodegenerative disorder, is characterized by developmental regression and signs of brain stem dysfunction including respiratory abnormalities and nystagmus. Other common manifestations include optic atrophy, ophthalmoparesis, failure to thrive, hypotonia, weakness, spasticity, ataxia, seizures, bulbar problems, and dystonia. The characteristic neuropathologic features are symmetric necrotic lesions in the basal ganglia, cerebellum, thalamus, brain stem, and optic nerves [Lera et al 1994].
• Leber hereditary optic neuropathy typically presents in young adults as painless subacute bilateral visual failure. Dystonia can be part of the clinical presentation [Wang et al 2009].
• Deafness-dystonia-optic neuronopathy syndrome (Mohr-Tranebjaerg syndrome) is characterized by profound sensorineural hearing loss in early childhood that precedes the onset of dystonia which ranges from the first to the sixth decades (peaking in the second and third decades). Dystonia tends to be focal, segmental, or multifocal in distribution at onset, with a predilection for the upper body, variably involving the head, neck, and upper limbs [Ha et al 2012]. In most affected males dystonia generalizes regardless of the onset age.

Organic acidurias

• Glutaric aciduria type 1 (OMIM 231670) caused by glutaryl-CoA-dehydrogenase deficiency is associated with gliosis and neuronal loss in the basal ganglia resulting in dystonia [Harting et al 2009]. The classic clinical scenario is acute encephalopathy triggered by infection or immunization with rapid onset of chorea and hypotonia, followed in months and years by the gradual development of severe generalized dystonia. Dystonia at rest with action-induced exacerbation, which profoundly interferes with any voluntary movement, is often incapacitating. Dysarthria and dysphagia are also common, whereas cognitive functions can be preserved. Early diagnosis and special diet can prevent encephalopathic crises and thus improve the prognosis considerably.

Disorders of thiamine metabolism

• Biotin-thiamine-responsive basal ganglia disease typically presents in childhood with subacute episodes of encephalopathy triggered by febrile illness and characterized by confusion, dysarthria, dysphagia, and external ophthalmoplegia. The disease is progressive and leads to persistent severe dystonia, quadriparesis, or coma and death if untreated. Symptoms resolve within a few days following administration of high doses of biotin and thiamine. The precise mechanism by which biotin and thiamine improve symptoms is unclear. Brain MRI typically shows symmetric and bilateral lesions in the caudate nucleus and putamen, infra- and supratentorial brain cortex, and brain stem [Tabarki et al 2013].

Non-DNA Testing

Non-DNA-based clinical tests for the following are available (also see Table 4):

• Dopa-responsive dystonia (DYT-GCH1, DYT-TH, and DYT-SPR). Trial of L-dopa, abnormal phenylalanine loading test, measurement of the concentration of total biopterin (BP) (most of which exists as BH4) and neopterin (NP) (the by-product of the GTPCH1 reaction) in CSF is useful for the diagnosis of GTPCH1-deficient DRD. In GTPCH1-deficient dopa-responsive dystonia, the concentrations of BP and NP in CSF are low, whereas in TH-deficient dopa-responsive dystonia, the concentrations of both BP and NP in CSF are normal.
• Primary familial brain calcification (bilateral striatopallidodentate calcinosis). Brain calcification is best detected using CT scanning [Manyam et al 1992].
• Neurodegeneration with brain iron accumulation. Iron deposition is detected on brain MRI.
• Chorea-acanthocytosis. Peripheral blood films show acanthocytosis; serum creatine kinase concentration may be elevated.
• McLeod neuroacanthocytosis syndrome. Expression of Kell antigens is weak.
• Diagnostic workup in persons with dystonia and cerebellar signs – even when cerebellar signs are subtle – should include testing for spinocerebellar ataxia if family history suggests autosomal dominant inheritance.

Molecular Genetic Testing

Molecular genetic testing approaches can include a multigene panel, comprehensive genomic sequencing, and single-gene testing.

Mode of Inheritance

Genetic counseling. While hereditary, isolated, and combined dystonias are usually inherited in an autosomal dominant manner, complex dystonias are often inherited in an autosomal recessive or mitochondrial manner. In general, X-linked forms are rare but should be considered. Genetic counseling and risk assessment depend on determination of the specific cause of an inherited dystonia in an individual.

Importantly, most dominant forms of dystonia are characterized by reduced penetrance, which can be lower than 50%. For two hereditary dystonias, mechanisms affecting penetrance have been identified:

• DYT-SGCE only manifests when SGCE pathogenic variants are paternally inherited due to maternal imprinting of this gene [Müller et al 2002].
• Penetrance of the GAG deletion in TOR1A, is reduced from about 35% to 3% in individuals who also have a heterozygous NM_000113.2:646G>C ( p.Asp216His) variant in TOR1A on the other allele [Risch et al 2007].

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Individuals with an autosomal dominant dystonia inherit the pathogenic variant from one parent or have the disorder as the result of a de novo pathogenic variant.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant may include molecular genetic testing or clinical evaluation if molecular genetic testing is not available.
• The family history may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing and/or clinical evaluation have been performed.
• Note: Due to reduced penetrance, there may be asymptomatic family members or several generations of individuals with the pathogenic variant who remain symptom free.

Sibs of a proband

• The risk to sibs depends on the genetic status of the proband's parents: if one of the proband's parents has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Because many of the inherited dystonias demonstrate incomplete penetrance, not all individuals who inherit the pathogenic variant will develop dystonia.

Offspring of a proband

• Each child of an individual with autosomal dominant dystonia has a 50% chance of inheriting the pathogenic variant.
• Because many of the inherited dystonias demonstrate incomplete penetrance, not all individuals who inherit the pathogenic variant will develop dystonia.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the dystonia-related pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one dystonia-related pathogenic variant).
• Heterozygotes are asymptomatic.

Sibs of a proband

• At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes are asymptomatic.

Offspring of a proband. All offspring are obligate heterozygotes (carriers) for a pathogenic variant in a dystonia-related gene.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a dystonia-related pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the dystonia-related pathogenic variants in the family.

Mitochondrial Inheritance – Risk to Family Members

Parents of a proband

• Single mtDNA deletions
  • Mitochondrial DNA (mtDNA) deletions generally occur de novo and thus affect only one family member.
  • When single mtDNA deletions are transmitted, inheritance is from the mother.
  • The predisposition to form multiple mtDNA deletions can be inherited as an autosomal dominant or an autosomal recessive trait.
• Mitochondrial DNA single-nucleotide variants and duplications
  • Mitochondrial DNA single-nucleotide variants and duplications may be transmitted through the maternal line.
  • The father of a proband is not at risk of having the mtDNA pathogenic variant.
  • The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have symptoms.

Sibs of a proband

• The risk to the sibs depends on the genetic status of the mother: if the mother has the mtDNA pathogenic variant, all sibs are at risk of inheriting it.
• When a proband has a single mtDNA deletion, the current best estimate of the recurrence risk to sibs is 1/24 [Chinnery et al 2004].

Offspring of a proband

• Offspring of males with a mtDNA pathogenic variant will not inherit the variant.
• All offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant.
• A female harboring a heteroplasmic mtDNA single-nucleotide variant may transmit a variable amount of mutated mtDNA to her offspring, resulting in considerable clinical variability among sibs within the same nuclear family [Poulton & Turnbull 2000].

Other family members. The risk to other family members depends on the genetic status of the proband's mother: if she has a mtDNA pathogenic variant, her sibs and mother are also at risk.

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor will he be hemizygous for the dystonia-related pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the dystonia-related pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a de novo pathogenic variant, in which case the mother is not a carrier.

Sibs of a male proband. The risk to sibs depends on the genetic status of the proband's mother:

• If the mother of the proband has the dystonia-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be heterozygotes (carriers) and will not typically be affected.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the dystonia-related pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism.

Offspring of a proband. Affected males will transmit the pathogenic variant to all of their daughters and none of their sons.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending on their sex, may be at risk of being carriers or of being affected.

Heterozygote (carrier) detection. Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the dystonia-related pathogenic variant has been identified in the proband.

Related Genetic Counseling Issues

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative genetic alteration/s are unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Mutation of nuclear DNA. Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for dystonia are possible.

Mutation of mitochondrial DNA (mtDNA). Prenatal molecular genetic testing and interpretation for mtDNA disorders is difficult because of mtDNA heteroplasmy. The percentage level of mutated mtDNA in a chorionic villus sampling (CVS) biopsy may not reflect the percentage level of mutated mtDNA in other fetal tissues, and the percentage level may change during development and throughout life [Hellebrekers et al 2012].

Author History

Christine Klein, MD (2014-present)
Katja Lohmann, PhD (2017-present)
Connie Marras, MD, PhD (2014-present)
Alexander Münchau, MD (2014-present)
Andrea H Nemeth, MRCP, DPhil; Churchill Hospital and Institute of Molecular Medicine (2003-2014)

Revision History

• 22 June 2017 (sw) Comprehensive update posted live
• 1 May 2014 (me) Comprehensive update posted live
• 23 January 2006 (me) Comprehensive update posted live
• 27 May 2005 (cd) Revision: information on neuroferritinopathy
• 21 December 2004 (cd) Revision: information on Mcleod neuroacanthocytosis syndrome
• 3 June 2004 (cd) Revision: change in test availability
• 5 February 2004 (cd) Revision: change in test availability
• 28 October 2003 (me) Review posted live
• 8 April 2003 (an) Original submission

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