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DYT1 Early-Onset Primary Dystonia

Synonyms: Early-Onset Torsion Dystonia, Oppenheim's Dystonia

, PhD and , MD.

Author Information
, PhD
Departments of Genetics and Genomic Sciences and Neurology
Icahn School of Medicine at Mount Sinai
New York, New York
, MD
Department of Neurology
Beth Israel Medical Center
New York, New York

Initial Posting: ; Last Update: January 2, 2014.

Summary

Disease characteristics. DYT1 early-onset primary dystonia typically presents in childhood or adolescence and only on occasion in adulthood. Dystonic muscle contractions causing posturing of a foot, leg, or arm are the most common presenting findings. Dystonia is usually first apparent with specific actions such as writing or walking. Over time, the contractions frequently (but not invariably) become evident with less specific actions and spread to other body regions. No other neurologic abnormalities are present, except for postural arm tremor. Disease severity varies considerably even within the same family. Isolated writer's cramp may be the only sign.

Diagnosis/testing. DYT1 is diagnosed by molecular genetic testing of TOR1A revealing the three-base pair deletion c.907_909delGAG in most affected individuals.

Management. Treatment of manifestations: Oral medications, either alone or in combination, are usually tried first; these include anticholinergics, baclofen, benzodiazepines (particularly clonazepam) and others (levodopa, carbamazepine, and dopamine-depleting agents). Botulinum toxin injections for treatment of focal symptoms can be used in conjunction with oral medications. If oral medications and botulinum toxin injections do not provide sufficient control of symptoms, surgery enabling deep brain stimulation (DBS) of the globus pallidus interna (GPi) should be considered. Physical therapy and an appropriate exercise program may be of benefit.

Prevention of secondary complications: Aggressive medical and surgical intervention to prevent contractures of the joints and deformities of the spine.

Surveillance: Follow up with a neurologist specializing in movement disorders several times a year.

Genetic counseling. DYT1 is inherited in an autosomal dominant manner with reduced penetrance. Offspring of an affected individual or of an asymptomatic individual known to have a TOR1A disease-causing mutation have a 50% chance of inheriting the disease-causing mutation and a 30% to 40% chance of developing clinical findings. If the TOR1A c.907_909delGAG deletion has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for the disease/gene or custom prenatal testing.

Diagnosis

Clinical Diagnosis

DYT1 early-onset primary dystonia should be suspected in individuals with:

  • Primary dystonia, defined as involuntary sustained contraction of muscles that causes directional and repetitive movements often resulting in twisting of the involved body region with:
    • No other abnormalities on neurologic examination (except tremor);
    • Normal routine neuroimaging;
    • No history of known cause of acquired (secondary) dystonia (e.g., exposure to neuroleptic medications; cerebral trauma, infarct, infection).
  • Onset of dystonia before age 26 years (Note: Older age of onset may be seen among relatives of affected individuals; family members with later onset tend to have arm dystonia in the form of writer's cramp [Bressman et al 2000].)
  • Family history of early-onset dystonia (Note: Lack of a family history of early-onset dystonia does not preclude the diagnosis.)
  • Factors that are more specific to DYT1 early-onset primary dystonia, including:
    • Ashkenazi Jewish ancestry (though DYT1 dystonia can occur in individuals of any ethnicity);
    • Onset in a limb before age 24 years;
    • Two or more limbs affected limbs.

Molecular Genetic Testing

Gene. TOR1A, encoding the protein torsin-1A (torsinA), is the only gene in which mutations are known to be associated with DYT1 early-onset primary dystonia.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Early-Onset Primary Dystonia

Gene 1Test MethodMutations Detected 2 Mutation Detection Frequency by Test Method 3
TOR1ATargeted mutation analysisCommon mutation c.907_909delGAG >99% 4
Sequence analysisSequence variants 5Unknown 6

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Most individuals with DYT1, regardless of ethnic background, have the three base pair deletion c.907_909delGAG (sometimes referred to as 904_906delGAG) in TOR1A [Ozelius et al 1997, Warner & Jarman 1998].

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

6. The clinical utility of sequencing is limited. Despite extensive screening, only three other variations in TOR1A that change the amino acid sequence of torsinA have been found; none has been unequivocally associated with disease. These include c.966_983del18, c.934_937delAGAG, and c.646G>C (see Molecular Genetics for details).

Testing Strategy

To confirm/establish the diagnosis in a proband. Guidelines published by Bressman et al [2000] recommend genetic counseling and testing for symptomatic individuals who have at least one of the following:

  • Primary torsion dystonia (PTD) in any body region with onset before age 26 years
  • A family history of early-onset dystonia
  • Onset in a limb before the age of 30 years [Albanese et al 2011]

Targeted mutation analysis. Detection of the c.907_909delGAG deletion in TOR1A in a proband is diagnostic of DYT1.

Full gene sequencing. Because the c.907_909delGAG deletion is the only definitive DYT1 disease-causing mutation identified to date, sequence analysis is unlikely to provide additional diagnostic information in an individual who does not have the deletion. However, in very rare cases, other variants have been identified in single affected individuals, though it remains unknown whether these other rare variants are disease-causing mutations (see Molecular Genetics).

Clinical Description

Natural History

Dystonia is the involuntary sustained contraction of muscles that causes directional and repetitive movements often resulting in twisting and posturing of the involved body region. An updated definition and classification for dystonia can be found in Albanese et al [2013]. DYT1 dystonia is a form of early-onset primary dystonia; it is considered a primary dystonia because it is not associated with other neurologic abnormalities.

DYT1 dystonia usually starts in a leg (average age 9 years) or an arm (average age 15 years). Initially, dystonia is apparent with specific actions; typically there is a change in gait (foot inversion or eversion, abnormal flexion of the knee or hip) or problems writing. The small minority of individuals who do not have initial limb involvement have onset in the neck or a cranial muscle.

In most (not all) individuals who have onset in a leg, dystonia progresses over several years. The contractions become less action-specific and may even be present at rest. The dystonia can also spread to other body regions, frequently progressing over a period of months to years to "generalized dystonia" involving other limbs and the trunk. In individuals with onset in an arm, progression is more variable and dystonia generalizes in only approximately 50%. Those individuals with onset in the neck or cranial muscles also have variable progression. Overall, 60% to 70% of individuals have progression to generalized or multifocal dystonia involving at least a leg and arm, and often axial muscles.

The cranial muscles are involved in 11% to 18% of individuals [Muller et al 1998, Valente et al 1998, Bressman 2004]. Approximately 20% of DYT1 dystonia is restricted to a single body region, usually as writer's cramp. In one family, the only manifestation was early-onset brachial dystonia [Gasser et al 1998]. Unusual phenotypic expression of DYT1 dystonia includes isolated blepharospasm [Tuffery-Giraud et al 2001] and fluctuating unilateral myoclonic dystonia [Gatto et al 2003]. When a group of affected Korean individuals were compared to the typical northern European affected individuals, Asian individuals more commonly had segmental dystonia with more frequent axial onset of symptoms [Lee et al 2012].

Once they appear, dystonic movements usually persist through life.

Pain is not a prominent finding except in torticollis, which is uncommon in DYT1 dystonia.

An increased rate of recurrent major depression has been reported in individuals with a TOR1A mutation with or without dystonia [Heiman et al 2004].

The average age of onset of DYT1 dystonia is approximately 12 years; the median age is between nine and 11 years. Onset ranges at least from age four to 64 years [Opal et al 2002, Bressman 2004], with the vast majority beginning before age 26 years. Life span is not thought to be shortened.

Neuroimaging. Brain CT and routine MRI are normal.

Fluorodeoxyglucose (FDG) PET scan studies of individuals with a TOR1A mutation with and without dystonia show increased metabolism in the lentiform nucleus, cerebellum, and supplementary motor cortex. Individuals with a TOR1A mutation and dystonia have been found to have a distinct metabolic pattern characterized by relative metabolic increases in the pre-supplementary motor area (SMA) and parietal association cortices and decreases in the inferior cerebellum, brain stem, and ventral thalamus [Carbon & Eidelberg 2009].

Studies combining PET scanning and psychomotor testing in individuals with a TOR1A mutation without dystonia show subtle sequence-learning abnormalities in motor performance and recruitment of brain networks [Carbon et al 2002, Ghilardi et al 2003, Carbon et al 2008]. This PET evidence suggests the presence of abnormal brain processing in individuals with a TOR1A mutation regardless of the presence or absence of dystonia [Carbon et al 2011].

Diffusion tensor imaging (DTI) studies have shown microstructural changes involving the subgyral white matter of the sensorimotor cortex and the dorsal pons in manifesting and non-manifesting individuals with a mutation in TOR1A [Carbon et al 2004a, Carbon et al 2004b, Carbon et al 2008], with a greater degree of abnormality in the dorsal pons (in the region of the superior cerebellar peduncle) in the manifesting individuals [Carbon et al 2008], implicating abnormalities in the cerebello-thalamo-cortical pathways in the pathogenesis of dystonia.

Subsequent studies using DTI in conjunction with probabilistic tractography showed reduced integrity of cerebello-thalamo-cortical fiber tracts in both manifesting and non-manifesting individuals with a TOR1A mutation, and that reductions in cerebellothalamic connectivity correlated with increased motor activation responses, consistent with the hypothesis that abnormalities of cerebellar pathway development in dystonia are associated with loss of inhibition at the cortical level [Argyelan et al 2009].

Other imaging abnormalities detected in individuals with a TOR1A mutation include decreased striatal D2 receptor binding [Asanuma et al 2005].

Neuropathology. Very few brains of individuals with DYT1 dystonia have been examined. One study found that nigral dopaminergic neurons appeared larger [Rostasy et al 2003]; another study of four brains found perinuclear inclusion bodies in the midbrain reticular formation and periaqueductal gray matter [McNaught et al 2004].

Genotype-Phenotype Correlations

Although the phenotype is highly variable, most affected individuals have the c.907_909delGAG deletion in the coding sequence of the gene. Thus, no genotype-phenotype correlations exist.

Penetrance

The penetrance for a disease-causing mutation of TOR1A is approximately 30% overall. Thus, on average, 30% of individuals who inherit the disease-causing allele develop DYT1 dystonia and 70% do not.

Individuals who have an uncommon disease-modifying p.Asp216His variant in trans configuration with the c.907_909delGAG deletion (i.e., the variants are on different alleles) are largely protected from expression of the disease; disease penetrance is only 3% with the His216 variant, whereas it is 35% if the Asp216 variant occurs in trans configuration with the c.907_909delGAG deletion [Risch et al 2007]. In the study by Risch et al [2007], two of 119 symptomatic individuals with the c.907_909delGAG deletion had the His216 allele in trans configuration compared to 24 of 113 asymptomatic individuals. (All other chromosomes studied had the Asp216 amino acid variant.) While information regarding these disease-modifying variants may be useful, clinical genetic testing for these variants and determination of their chromosomal locations in relation to the disease-causing mutation is not clinically available.

The clinical variability of DYT1 is great; an affected individual may be more or less severely affected than the parent from whom the disease-causing allele was inherited. Clinical heterogeneity within a single family is exemplified by the report of a family with one individual with writer’s cramp and another with severe dystonic storm [Opal et al 2002].

Anticipation

There is no evidence for anticipation.

Nomenclature

Terms used for DYT1 primary dystonia in the past include the following:

  • Dystonia muscularum deformans
  • Primary torsion dystonia (PTD)

Prevalence

DYT1 dystonia is a common form of early-onset primary dystonia [Ozelius et al 1997].

DYT1 dystonia is estimated to account for approximately 16% to 53% of early-onset dystonia in non-Jews and approximately 80% to 90% in Ashkenazi Jews [Bressman et al 1994, Risch et al 1995, Valente et al 1998, Ikeuchi et al 1999, Slominsky et al 1999, Brassat et al 2000, Bressman et al 2000, Zorzi et al 2002]. Because a minority of primary dystonia is early onset, the rate of DYT1 dystonia as a percentage of all primary dystonia is low (i.e., adult-onset focal dystonia is far more common) [Grundmann et al 2003, Elia et al 2006, Lin et al 2006].

The disease frequency in Ashkenazi Jews is estimated at 1:3000-1:9000; the prevalence of those having a TOR1A mutation is 1:1000-1:3000 [Risch et al 1995]. Among non-Jews, the prevalence is lower.

In one study from southeastern France that genotyped newborns, the heterozygote incidence was 1:12,000 [Frédéric et al 2007]; this is consistent with the approximately fivefold-increased frequency of early-onset dystonia in Ashkenazim compared to non-Jews proposed in studies prior to gene identification [Zeman & Dyken 1967].

The increased prevalence in Ashkenazim is the result of a founder mutation that appeared approximately 350 years ago [Risch et al 1995].

Differential Diagnosis

See Dystonia: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

In studies of individuals with different forms of dystonia (See Dystonia Overview) and unclassified movement disorders, a high proportion of those individuals with the typical phenotype (early-onset dystonia starting in limb and then generalizing) have the TOR1A c.907_909delGAG deletion [Kamm et al 1999, Klein et al 1999, Ozelius & Bressman 2011].

Dopa-responsive dystonia (GCH1), DYT6 (THAP1) dystonia, and DYT25 (GNAL) dystonia [Fuchs et al 2013] can cause clinical phenotypes similar to that of DYT1 dystonia.

Other, yet to be identified genetic forms of early-onset dystonia also exist [Valente et al 2001, Fasano et al 2006].

The following findings tend to exclude a diagnosis of DYT1 dystonia [Bressman et al 1997, Bressman & Greene 2000, Albanese et al 2006]:

  • Onset in adulthood (especially age >40 years)
  • Isolated focal or segmental cervical-cranial dystonia, including the following:
    • Spasmodic torticollis (cervical dystonia)
    • Spasmodic dysphonia (laryngeal dystonia resulting in either broken and strangled or breathy speech)
    • Blepharospasm (involuntary eye closure), which may also include contractions of other facial muscles
    • Oromandibular dystonia (the jaw is held open or shut)
      Note: Blepharospasm and oromandibular dystonia occurring together are called Meige or Brueghel syndrome.
  • Dramatic improvement with levodopa therapy suggests the diagnosis of dopa-responsive dystonia (DRD). DRD is an early-onset form of dystonia caused primarily by heterozygous mutation in GCH1, the gene encoding cyclohydrolase 1. Individuals with DRD have near-resolution of symptoms with low-dose levodopa. Another cause of early-onset dystonia that responds to levodopa is juvenile-onset Parkinson disease caused by mutations in PARK2, the gene encoding parkin (See Parkin Type of Juvenile Parkinson Disease).
  • Abnormal brain CT examination or MRI examination
  • Additional abnormalities on neurologic examination. Findings other than dystonia suggest that dystonia is not primary but caused by another disorder that may be genetic or acquired in etiology. Parkinsonism is a frequent associated finding. Genetic causes of disorders in which dystonia is frequently a prominent feature include: Wilson disease, Huntington disease, certain spinocerebellar ataxias (see Ataxia Overview), rapid-onset dystonia parkinsonism, and panthothenate kinase associated neurodegeneration, among others.
  • A history that suggests an acquired cause of dystonia, such as exposure to neuroleptics or other dopamine-blocking drugs (tardive dystonia), perinatal ischemia/injury, stroke, cerebral trauma, or encephalitis
  • Presence of inconsistent weakness, non-physiologic sensory findings, or incongruous movements that suggest a psychogenic basis. However, it is also important to note that dystonia can frequently be improperly diagnosed as "psychogenic," causing considerable distress in affected individuals.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with DYT1 early-onset primary dystonia, the following evaluations are recommended:

  • Thorough history, including family history
  • General physical examination
  • Neurologic examination. A useful tool to measure the clinical extent of dystonia is the Burke-Fahn-Marsden rating scale.
  • If evidence of psychiatric problems (especially depression) exists, consideration of psychiatric assessment
  • Medical genetics consultation

Treatment of Manifestations

Treatment is aimed at relieving symptoms [Adler 2000, Bressman & Greene 2000, Coubes et al 2000, Gross & Lozano 2000, Scott 2000, Goetz & Horn 2001].

Oral medications are usually tried first:

  • Anticholinergics such as trihexyphenidyl (moderately effective for ~40%-50% of individuals).
    • Trihexyphenidyl can be titrated to high doses (in the range of 100mg/day) in younger individuals.
    • Anticholinergic side effects, particularly cognitive effects, must be monitored closely.
  • Baclofen (Lioresal®)
  • Benzodiazepines, especially clonazepam
  • Other medications tried alone or in combination with the above categories: levodopa, carbamazepine, and dopamine depleting agents (reserpine, tetrabenazine)
  • Botulinum toxin injections directly into dystonic muscles are generally the treatment of choice for adult-onset focal dystonias. For individuals with more widespread dystonia in whom specific muscle groups produce disabling symptoms, such injections may also be helpful, and are often used in combination with oral medications.

If medications fail:

  • Surgery to enable deep-brain stimulation (DBS) of the globus pallidus interna (GPi) has been shown to be an effective treatment for medically refractory primary generalized dystonia in randomized controlled studies [Vidailhet et al 2005, Kupsch et al 2006, Vidailhet et al 2007], including in individuals with DYT1 early-onset dystonia.
    • GPi DBS has become a well-established and important treatment option for individuals with medically-refractory DYT1 early-onset dystonia. Overall, individuals with DYT1 early-onset dystonia tend to have good outcomes after GPi DBS, with some showing dramatic improvement.
    • Some, though not all, studies have found that the presence of aTOR1A mutation is a positive predictive factor of good outcome of GPi DBS surgery [Isaias et al 2008, Andrews et al 2010, Borggraefe et al 2010, Air et al 2011].
    • Clinical effect has been found to be well-sustained at follow up of up to 10 years [Alcindor et al 2010, Cif et al 2010, Panov et al 2013].
  • Note: Intrathecal baclofen therapy has been used for treatment of generalized dystonia of various etiologies in the past [van Hilten et al 2000, Walker et al 2000, Albright et al 2001], however, GPi DBS surgery has become the preferred surgical treatment for severe, medically-refractory DYT1 early-onset dystonia because of the good treatment outcomes.
  • Physical therapy and an appropriate exercise program may be of benefit.

Prevention of Secondary Complications

Aggressive medical and surgical intervention, including regular follow-up for adjustment of medicines and timely referral for GPi DBS surgery when indicated is appropriate in order to prevent long-term orthopedic complications such as joint contractures or spine deformities. However, little systematic data support or negate the use of this approach.

Surveillance

Follow up several times a year with a neurologist specializing in movement disorders is recommended (especially if there is progression) to prevent secondary complications, although little information regarding the benefit of this approach is available.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Data on the use of the oral medications typically used for treatment of dystonia during pregnancy are limited. Isolated case reports of treatment with trihexyphenidyl or carbidopa/levodopa for various conditions (including certain forms of dystonia) during pregnancy have not found adverse effects on either the affected mother or the fetus [Watanabe et al 2009, Mendhekar & Andrade 2011, Robottom & Reich 2011, Serikawa et al 2011, Watanabe & Matsubara 2012, Dostal et al 2013].

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

DYT1 early-onset primary dystonia (DYT1 dystonia) is inherited in an autosomal dominant manner with reduced penetrance and broad clinical variability.

Risk to Family Members

Parents of a proband

Note: Although most individuals diagnosed with DYT1 dystonia have a parent who has the c.907_909delGAG deletion in TOR1A, many parents are unaffected because the penetrance is low (~30%). The family history may also appear to be negative because of failure to recognize the disorder, particularly in family members affected with writer's cramp only.

Sibs of a proband

  • The risk to the sibs of an affected person depends on the genetic status of the proband's parents.
  • If a parent has the c.907_909delGAG deletion in TOR1A, the risk to sibs of inheriting the mutation is 50%. The penetrance for a disease-causing mutation of TOR1A is approximately 30%. Thus, on average, 30% of individuals who inherit the mutant allele develop dystonia and 70% do not develop dystonia. The clinical variability is great, and an affected individual may be more or less severely affected than the parent who transmitted the disease-causing allele. One study indicated that a sib who has the His216 disease-modifying variant (p.Asp216His) in trans configuration with the c.907_909delGAG deletion is unlikely to develop dystonia (see Penetrance).
  • When molecular genetic testing does not reveal the c.907_909delGAG deletion in TOR1A in either parent, the risk to the sibs of a proband appears to be low. No instances of germline mosaicism have been reported, although it remains a possibility.

Offspring of a proband

  • A proband with the c.907_909delGAG deletion in TOR1A has a 50% risk of transmitting it to each offspring whether the proband is symptomatic or not.
  • The penetrance for the disease-causing mutation of TOR1A is 30%. Thus, on average, 30% of offspring who inherit the mutant allele develop DYT1 and 70% do not. One study indicated that an individual who had the His216 disease-modifying variant (p.Asp216His) in trans configuration with the c.907_909delGAG deletion is unlikely to develop dystonia (see Penetrance).
  • The clinical variability is great, and an affected child may be more severely or less severely affected than the parent who transmitted the disease-causing allele.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent has a disease-causing mutation, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Testing of at-risk asymptomatic adults for DYT1 dystonia is available using the techniques described in Molecular Genetic Testing. It is appropriate to offer molecular genetic testing to asymptomatic at-risk adult relatives for genetic counseling purposes.

Note: Asymptomatic adults rarely develop symptoms, particularly after age 26 years, and those with mild symptoms are unlikely to progress significantly if at all. Thus, while there is a reduced age-related risk for adults, the term "predictive testing" may not be appropriate for DYT1 dystonia.

Testing of asymptomatic at-risk adult family members usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of DYT1 dystonia, the possible impact of positive and negative test results for the individual and for family members, and neurologic status are assessed. An in-depth discussion of reduced age-related penetrance and variable symptom severity (also age-related) is a critical part of genetic counseling. Affected individuals should also be apprised of possible problems that they may encounter as a result of genetic testing with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. The primary reasons for testing asymptomatic at-risk adults are to facilitate decision making regarding reproduction and to better assess the risk to children. Another motivation for testing may be simply a "need to know." After proper counseling, a positive TOR1A c.907_909delGAG deletion test result in an asymptomatic adult is unlikely to affect financial decisions or career planning. When testing at-risk individuals for DYT1 dystonia, an affected family member should be tested first to confirm the molecular diagnosis in the family.

Molecular genetic testing of asymptomatic individuals younger than age 18 years at risk for DYT1 dystonia is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

Genetic testing in affected or symptomatic individuals is indicated in a family with established DYT1 regardless of age. See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the TOR1A c.907_909delGAG deletion has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for the disease/gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) for the c.907_909delGAG deletion in TOR1A has also been reported [Rechitsky et al 2004]. PGD may be an option for families in which the disease-causing mutation has been identified. The presence of the TOR1A mutation detected by PGD does not predict whether individuals will be symptomatic, or, if they are, what the age of onset or severity of the disorder will be.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Dystonia Medical Research Foundation
    One East Wacker Drive
    Suite 2810
    Chicago IL 60601-1905
    Phone: 800-377-3978 (toll-free); 312-755-0198
    Fax: 312-803-0138
    Email: dystonia@dystonia-foundation.org
  • Dystonia Society
    89 Albert Embankment
    3rd Floor
    London SE1 7TP
    United Kingdom
    Phone: 0845 458 6211; 0845 458 6322 (Helpline)
    Fax: 0845 458 6311
    Email: support@dystonia.org.uk
  • Chicago Center for Jewish Genetic Disorders
    Ben Gurion Way
    30 South Wells Street
    Chicago IL 60606
    Phone: 312-357-4718
    Email: jewishgeneticsctr@juf.org
  • Dystonia International Patient Registry (DIPR)
    Email: contact@dipregistry.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. DYT1 Early-Onset Primary Dystonia: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
TOR1A9q34​.11Torsin-1ATOR1A homepage - Mendelian genesTOR1A

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for DYT1 Early-Onset Primary Dystonia (View All in OMIM)

128100DYSTONIA 1, TORSION, AUTOSOMAL DOMINANT; DYT1
605204TORSIN 1A; TOR1A

Gene structure. TOR1A comprises five exons. Exon 5 includes a GAGGAG sequence that is highly conserved.

Pathogenic allelic variants. The majority of affected individuals have a 3-bp deletion c.907_909delGAG involving the highly conserved GAGGAG sequence in exon 5 [Ozelius et al 1997] (for more information, see Table A and Table 2).

Two deletions that change the amino acid sequence of torsin-1A have been reported; neither has been unequivocally associated with disease (Table 2).

In addition, three other novel changes, each identified in a single affected individual, have been reported.

  • A missense variant (c.863G>A; p.Arg288Gln) in a patient with facial palsy and severe fixed dystonia starting in infancy [Zirn et al 2008]
  • A missense variant (c.613T>A; p.Phe205Ile) in a man with orobulbar dystonia beginning in his forties [Calakos et al 2010]
  • A 6-bp deletion (c.40_45delGCGCCG; p.Ala14_Pro15del) in a female with cervical dystonia with onset at age 31 followed by dystonic head and hand tremor later in life [Graf et al 2012]

Finally, a disease-modifying variant p.Asp216His encodes aspartic acid in 88% and histidine in 12% of alleles in control populations [Ozelius et al 1997] and modifies DYT1 penetrance [Kock et al 2006b, Risch et al 2007]. Thus, sequence analysis or testing for this variant could potentially be used to refine risk estimates for asymptomatic individuals with the c.907_909delGAG deletion (see Penetrance).

Table 2. TOR1A Variants Discussed in This GeneReview

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
Disease modifierc.646G>Cp.Asp216HisNM_000113​.2
NP_000104​.1
Unknown clinical significance 2c.40_45delGCGCCG 3p.Ala14_Pro15del
c.613T>A 3p.Phe205Ile
c.863G>A 3p.Arg288Gln
c.934_937delAGAG 4p.Arg312PhefsTer14
c.966_983del18p.Phe323_Tyr328del
Pathogenicc.907_909delGAG
(904_906delGAG)
p.Glu302del

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Variations that change the amino acid sequence; none has been unequivocally associated with disease (see Molecular Genetic Testing).

3. Each identified in a single affected individual (see Pathogenic allelic variants). When the missense variants are over-expressed in cells, they show a similar cellular phenotype (i.e., inclusions) to that seen in the deletion mutant. However, how/if this cellular phenotype is related to the disease is not known.

4. Mutation identified in an unaffected control blood donor who was not examined neurologically [Kabakci et al 2004]; see Molecular Genetic Testing.

Normal gene product. The protein torsin-1A comprises 332 amino acids. It has an ATP-binding domain and a putative N-terminal leader sequence. It is a member of a superfamily of ATPases, with particular homology to heat shock proteins, and is ubiquitous, with particularly intense expression in the substantia nigra, dopamine neurons, cerebellar Purkinje cells, thalamus, globus pallidus, hippocampal formation, and cerebral cortex [Augood et al 1998, Augood et al 2003]. Torsin-1A is expressed in at least four brain regions beginning between age four and eight weeks [Siegert et al 2005]. In vitro and in vivo studies have localized torsin-1A primarily to the lumen of the endoplasmic reticulum (ER) where it shuttles between the ER and the nuclear envelope (NE) [Goodchild & Dauer 2004, Naismith et al 2004, Hewett et al 2006]. In the ER, it plays a role in endoplasmic reticulum-associated degradation (ERAD) making cells less sensitive to ER stress [Nery et al 2011]. TorsinA also localized to neurite varicosities and vesicles, and along neuronal processes [Ferrari-Toninelli et al 2004]. It has been implicated in synaptic vesicle recycling, including dopamine release [Torres et al 2004, Misbahuddin et al 2005, Esapa et al 2007, Granata et al 2008], tyrosine hydroxylase activity [O’Farrell et al 2009] and dopamine metabolism [Wakabayashi-Ito et al 2011]. TorsinA has recently been found in large ribonucleoprotein granules, where it is thought to play a role in delivering messenger RNAs to synapses [Jokhi et al 2013]. In addition, torsinA is involved in cytoskeletal dynamics that may be important for neurite extensions during brain development [Kamm et al 2004, Hewett et al 2006, Hewett et al 2007, Nery et al 2008, Naismith et al 2009].

Abnormal gene product. The common c.907_909delGAG deletion results in the loss of one of a pair of glutamic acid residues in a conserved region of the torsin-1A protein. In cell cultures, over-expressed mutant torsin-1A forms spheroid inclusions usually flanking the nucleus and deriving from ER or nuclear membrane. The significance of these inclusions is unclear because they have not been found in postmortem brain samples of individuals with DYT1 [Bragg et al 2004].

Knock-in, knockout, and knockdown mouse models, a drosophila knockout model, as well as cellular studies support a loss-of-function mechanism in DYT1 dystonia, which is presumed to result from a dominant-negative effect [Goodchild & Dauer 2004, Goodchild et al 2005a, Wakabayashi-Ito et al 2011, Zhao et al 2013]. Both knockin and knockout mice homozygous for the c.907_909delGAG deletion die at birth with seemingly normal morphology, but showing postmigratory neurons with abnormal nuclear membranes [Goodchild et al 2005b]. RNA interference (RNAi) has been used in cell culture systems overexpressing the mutant torsin protein to block aggregate formation and restore normal distribution of wild type torsin-1A (torsinA) [Kock et al 2006a], suggesting a possible future role for RNAi in DYT1 therapy. Mutant torsinA appears to destabilize the wild-type protein, causing premature degradation through not only the macroautophagy pathway but also by the proteasome [Giles et al 2008, Giles et al 2009].

References

Published Guidelines/Consensus Statements

  1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 12-29-13. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. National Society of Genetic Counselors. Genetic testing of minors for adult-onset conditions. Available online. 2012. Accessed 12-29-13.

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Suggested Reading

  1. Bressman SB, Ozelius L. DYT1, an inherited dystonia. In: Waxman SG, ed. Molecular Neurology. London, UK: Elsevier; 2007:295-306.
  2. Kamm C. Early onset torsion dystonia (Oppenheim's dystonia). Orphanet J Rare Dis. 2006;1:48. [PMC free article: PMC1693547] [PubMed: 17129379]
  3. Walker RH, Shashidharan P. Developments in the molecular biology of DYT1 dystonia. Mov Disord. 2003;18:1102–7. [PubMed: 14534912]

Chapter Notes

Author History

Susan B Bressman, MD; Albert Einstein College of Medicine (1999-2014)
Deborah de Leon, MS; Beth Israel Medical Center (1999-2005)
Naomi Lubarr, MD (2014-present)
Laurie Ozelius, PhD (2014-present)
Deborah Raymond, MS; Beth Israel Medical Center (2005-2014)

Revision History

  • 2 January 2014 (me) Comprehensive update posted live
  • 23 November 2010 (cd) Revision: corrected mutation nomenclature: c.904_906delGAG → c.907_909delGAG
  • 1 July 2008 (me) Comprehensive update posted live
  • 31 August 2006 (cd) Revision: TOR1A mutations other than 3-bp deletion may cause DYT1; clinical testing available for such mutations
  • 5 April 2005 (me) Comprehensive update posted to live Web site
  • 21 January 2003 (me) Comprehensive update posted to live Web site
  • 14 April 1999 (pb) Review posted to live Web site
  • 2 December 1998 (ddl) Original submission
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