DiagnosisClinical DiagnosisEarly-onset primary dystonia (DYT1) is a form of primary dystonia; that is, aside from dystonia (involuntary sustained contraction of muscles that causes directional and repetitive movements often resulting in twisting of the involved body region) no abnormalities except tremor are evident on neurologic examination or routine neuroimaging.Age of onset of dystonia. Onset before age 26 years was the single diagnostic criterion with 100% sensitivity among 180 individuals with primary dystonia, including 89 with DYT1.Note: (1) Older ages of onset were also seen among relatives; (2) family members with later onset tended to have arm dystonia in the form of writer's cramp; and, (3) specificity for DYT1 increased, particularly in the case of Ashkenazi Jews, using the criterion of onset in a limb before age 24 years, or of having two or more limbs affected [Bressman et al 2000].Molecular Genetic TestingGene. TOR1A, encoding the protein torsin-1A (torsinA), is the only gene known to be associated with early-onset primary dystonia (DYT1).Clinical testingTargeted mutation analysis. 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].Sequence analysis. Despite extensive screening, only three other variations in TOR1A that change the amino acid sequence of torsin-1A have been found; none has been unequivocally associated with disease. Thus, the utility of sequence analysis for diagnosis is limited:An 18-base pair deletion (c.966_983del18) was identified in a family with individuals with dystonia and myoclonus who were subsequently found to have a mutation in SGCE, the gene that causes myoclonus-dystonia, casting doubt on the role of the 18-base pair deletion in causing symptoms [Leung et al 2001].A four-base pair deletion (c.934_937delAGAG) was found in an unaffected control blood donor who was not examined neurologically [Kabakci et al 2004].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.Table 1. Summary of Molecular Genetic Testing Used in Early-Onset Primary DystoniaView in own windowGene SymbolTest MethodMutations Detected Mutation Detection Frequency by Test Method ^{1Test AvailabilityTOR1ATargeted mutation analysisc.907_909delGAG>99%Clinical Sequence analysisSequence variants 2Unknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyEstablishing the diagnosis in a proband. Detection of the c.907_909delGAG deletion in TOR1A in a proband is diagnostic of DYT1.Note: 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.Guidelines published by Bressman et al [2000] recommend genetic counseling and testing for persons who have one or both of the following: Primary torsion dystonia (PTD) with onset before age 26 yearsA family history of early-onset dystoniaTesting of at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in TOR1A.}

Natural HistoryDystonia is the involuntary sustained contraction of muscles that causes directional and repetitive movements often resulting in twisting of the involved body region. Early-onset primary dystonia (DYT1) is considered a primary dystonia because it is not associated with other neurologic abnormalities.DYT1 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. Also, the dystonia spreads 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 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 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]. Dystonia that is restricted to an arm or the neck occurs in a minority of individuals with adult onset. Unusual phenotypic expression of DYT1 includes isolated blepharospasm [Tuffery-Giraud et al 2001] and fluctuating unilateral myoclonic dystonia [Gatto et al 2003].Once they appear, dystonic movements usually persist through life.Pain is not a prominent finding except in torticollis, which is rare in DYT1.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 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 additional movement-related hypermetabolism in the cerebellum, midbrain, and thalamus [Eidelberg et al 1998, Carbon et al 2004b].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.Other imaging abnormalities detected in individuals with a TOR1A mutation include decreased striatal D2 receptor binding [Asanuma et al 2005] and microstructural changes involving the subgyral white matter of the sensorimotor cortex [Carbon et al 2004a, Carbon et al 2004b], as well as pons in the region of the left superior cerebellar peduncle [Carbon et al 2008].Neuropathology. Very few brains of individuals with DYT1 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 CorrelationsAlthough the phenotype is highly variable, all affected individuals have the c.907_909delGAG deletion in the coding sequence of the gene. Thus, no genotype-phenotype correlations exist.

Differential DiagnosisIn 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, de Carvalho Aguiar & Ozelius 2002]. However, there are clearly other, rarer genetic causes of early-onset primary dystonia (DTY1) that have yet to be identified [Bressman et al 1994, Valente et al 2001, Fasano et al 2006, Saunders-Pullman et al 2007].The following findings tend to exclude a diagnosis of DYT1 [Bressman et al 1997, Bressman & Greene 2000, Albanese et al 2006]:Onset in adulthood (especially after age 40 years)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 musclesOromandibular 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, suggesting dopa-responsive dystonia (DRD). DRD is an early-onset form of dystonia caused primarily by heterozygous mutations in GTP, 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 examinationAdditional abnormalities on neurologic examination. Findings other than dystonia suggest that dystonia is not primary but caused by another disorder that may be inherited, complex, or acquired in etiology. Parkinsonism is a frequent associated finding. Inherited causes of dystonia include: Wilson disease, Huntington disease, spinocerebellar ataxias (see Ataxia Overview), rapid-onset dystonia parkinsonism, and panthothenate kinase associated neurodegeneration (formerly Hallervorden-Spatz syndrome), among others.A history that suggests an acquired cause of dystonia such as exposure to neuroleptics and other dopamine-blocking drugs (tardive dystonia), perinatal ischemia/injury, head or peripheral trauma, encephalitis, toxins, or strokePresence of inconsistent weakness, non-physiologic sensory findings, or incongruous movements that suggest a psychogenic basis. However, it is also important to note that often dystonia is 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with early-onset primary dystonia (DYT1), the following evaluations are recommended:Thorough history, including family historyPhysical examinationNeurologic 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 assessmentTreatment of ManifestationsTreatment 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 (moderately effective for ~40%-50% of individuals)Baclofen (Lioresal^®)Other medications tried alone or in combination: levodopa, clonazepam and other benzodiazepines, carbamazepine, and dopamine depleting agents (reserpine, tetrabenazine)If oral medications fail:Surgery to enable deep-brain stimulation of the globus pallidus interna (GPi) is a treatment option that has been effective in randomized controlled studies [Vidailhet et al 2005, Kupsch et al 2006, Vidailhet et al 2007] particularly for intractable generalized primary dystonia, including DYT1 dystonia [Cif et al 2003, Kupsch et al 2003, Coubes et al 2004, Krause et al 2004].Intrathecal baclofen may be considered, though efficacy rates for primary dystonia have not been well established [van Hilten et al 2000, Walker et al 2000, Albright et al 2001].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 be helpful.Physical therapy and an appropriate exercise program may be of benefit.Prevention of Secondary ComplicationsAggressive medical and surgical intervention, including regular follow-up for adjustment of medicines and orthopedic surgery when necessary, has been advocated to prevent contractures of the joints and deformities of the spine. However, little systematic data support or negate the use of this approach.SurveillanceFollow-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 data regarding the benefit of this approach are available.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Dystonia, Early-Onset Primary (DYT1): Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTOR1A9q34​.11Torsin-1ATOR1A homepage - Mendelian genesTOR1AData 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 Dystonia, Early-Onset Primary (DYT1) (View All in OMIM) View in own window 128100DYSTONIA 1, TORSION, AUTOSOMAL DOMINANT; DYT1 605204TORSIN 1A; TOR1ANormal allelic variants. The normal gene comprises five exons. Exon 5 includes a GAGGAG sequence that is highly conserved.Pathologic 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).Table 2. Selected TOR1A Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesDisease modifierc.646G>Cp.Asp216HisNM_000113​.2
NP_000104​.1Unknown clinical significance 1c.934_937delAGAG ^{2p.Arg312Phefs*14c.966_983del18p.Phe323_Tyr328delPathologicc.907_909delGAGp.Glu303delSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variations that change the amino acid sequence; neither has been unequivocally associated with disease (see Molecular Genetic Testing).2. 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) but also to neurite varicosities and vesicles, and along neuronal processes [Ferrari-Toninelli et al 2004]. In addition, torsin-1A has been shown to interact with the kinesin light chain 1 (KLC1) [Kamm et al 2004] and with vimentin (VIM) [Hewett et al 2006], as well as to regulate the cellular trafficking of the dopamine transporter and other membrane-bound proteins [Torres et al 2004]. These and other findings suggest a chaperone function for torsin-1A [Bragg et al 2004].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 DYT1 brain samples [Bragg et al 2004].Knockin, knockout, and knockdown mouse models as well as cellular studies support a loss of function mechanism in DYT1, which is presumed to result from a dominant-negative effect [Goodchild & Dauer 2004, Goodchild et al 2005]. 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 2005]. 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.}