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Early-Onset Primary Dystonia (DYT1)

[Oppenheim's Dystonia, Early-Onset Torsion Dystonia]

Summary

Disease characteristics.  Early-onset primary dystonia (DYT1) typically presents in childhood or adolescence (early-onset); adult onset occurs in a minority of individuals with DYT1. Dystonic muscle contractions causing posturing of a foot, leg, or arm are the most common presenting symptom. Dystonia is usually first apparent with specific actions, e.g., 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. DYT1 is one of the more common early-onset primary dystonias.

Diagnosis/testing.  DYT1 is diagnosed by molecular genetic testing of the TOR1A gene revealing a 3-base pair GAG deletion in most affected individuals.

Genetic counseling.  DYT1 is inherited in an autosomal dominant manner with reduced penetrance. Offspring of an affected individual or an asymptomatic individual known to have a TOR1A disease-causing mutation have a 50% chance of inheriting the disease-causing mutation and a 30-40% chance of developing clinical findings. Prenatal testing and preimplantation genetic diagnosis are available.

Diagnosis

Clinical Diagnosis

Age of onset of dystonia (repetitive twisting, or directional movements and postures).  Before age 26 years was a single criterion with 100% sensitivity in a sample of 176 clinically diagnosed individuals from 92 families 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. (3) Specificity for DYT1 increased, particularly in the case of Ashkenazi Jews, for onset in a limb (leg > arm) before age 24 years and for two or more limbs affected [Bressman et al 2000].

DYT1 is a form of primary dystonia; i.e., no abnormalities except tremor are evident on neurologic examination or neuroimaging.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

Gene.   The TOR1A gene, which encodes the torsin A protein, is the only gene known to be associated with early-onset primary dystonia (DYT1).

Molecular genetic testing: Clinical uses

• Diagnostic testing
• Testing at-risk asymptomatic adult family members
• Prenatal diagnosis

Molecular genetic testing: Clinical method

• Targeted mutation analysis.  Most individuals with DYT1, regardless of ethnic background, have a deletion of the 3-base pair GAG sequence in the TOR1A gene [Ozelius et al 1997 , Warner & Jarman 1998].

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic  Testing Used in Early-Onset Primary Dystonia Test Method Mutation Detected Mutation Detection Rate Test Availability Targeted mutation analysis TOR1A GAG deletion >99% Clinical Sequence analysis  1 TOR1A sequence variations Unknown

1. One individual with dystonia and myoclonus had an 18-base pair deletion in TOR1A; however, this individual also had a mutation in SGCE, the gene that causes myoclonus-dystonia . Thus, the role of the 18-base pair deletion in causing symptoms in this individual is unclear [Leung et al 2001].

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutations in TOR1A.

Clinical Description

Natural History

Dystonia is the simultaneous, involuntary sustained contraction of opposing muscles that may cause repetitive movements and twisting of the involved body region into an unnatural position. DYT1 is considered a primary dystonia because it is not associated with other neurologic abnormalities.

DYT1 usually starts in a leg (average age nine years) or an arm (average age 15 years). Initially, dystonia is apparent with specific actions, and typically there is a change in gait (foot inversion or eversion, abnormal flexion of the knee or hip) or problems writing. The 5% of individuals who do not have initial limb involvement have onset in the neck or a cranial muscle.

In most but 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 only about 50% generalize. Those with onset in the neck or cranial muscles have variable progression. Overall, 60-70% 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 11-18% of individuals [Bressman et al 1994 , Muller et al 1998 , Valente et al 1998 , Bressman 2004]. About 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 about 12 years, and the median age is between nine and 11 years. Onset ranges from age four to 64 years [Opal et al 2002 , Bressman 2004] with the vast majority beginning before age 26 years. Lifespan is not thought to be shortened.

Neuroimaging.  Brain CT and MRI are normal. 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 2004].

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 2002]. This PET evidence suggests the presence of abnormal brain processing in individuals with a TOR1A mutation regardless of the presence or absence of dystonia.

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 2004].

Genotype-Phenotype Correlations

Although the phenotype is highly variable, all affected individuals have the 3-bp deletion in the coding sequence of the gene. Thus, no genotype-phenotype correlations exist.

Prevalence

DYT1 is one of the most common forms of early-onset primary dystonia [Ozelius et al 1997]. It is estimated to account for about 30-60% of early-onset dystonia in non-Jews and about 90% in Ashkenazi Jews [Bressman et al 1994 ; Risch et al 1995 ; Raymond 1999, unpublished data]. Because a minority of primary dystonia is early onset, the rate of DYT1 as a percentage of all primary dystonia is low [Grundmann et al 2003].

The disease frequency in Ashkenazi Jews is estimated at 1/3000-1/9000, with the prevalence of those with a TOR1A mutation of 1/1000-1/3000 [Risch et al 1995]. Among non-Jews the prevalence is lower, about 1/10,000 to 1/30,000 [Nutt & Risch, personal communication].

The increased prevalence in Ashkenazim is the result of a founder mutation that appeared about 250 years ago [Risch et al 1995].

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

In studies of individuals with different forms of dystonia (see Dystonia Overview) and unclassified movement disorders a high proportion (60-75%) of those with the typical phenotype (early-onset dystonia starting in limb and then generalizing) have the TOR1A GAG deletion [Kamm et al 1999 , Klein et al 1999 , de Carvalho et al 2002].

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

• Onset in adulthood (especially after the age of 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 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, suggesting dopa-responsive dystonia (DRD). DRD is an early-onset form of dystonia caused primarily by heterozygous mutations in GTP, the gene encoding cyclohydrolase1. 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 the Parkin gene (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 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 parkinonism, 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 stroke
• Presence 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.

Management

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 (moderately effective for about 40-50% of individuals)
  • Baclofen (trade name "Lioresal")
  • Other medications tried alone or in combination are levo-dopa, 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 successful treatment option, 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 affected individuals in whom specific muscle groups produce disabling symptoms, such injections may be helpful.
• Physical therapy and an appropriate exercise program may be of benefit.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

Mode of Inheritance

DYT1 is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Many individuals diagnosed with DYT1 have a parent who has the mutant TOR1A allele.
• About 70% of individuals who have the disease-causing allele have no symptoms.
• It is appropriate to offer molecular genetic testing to both parents of an affected individual to determine if either has the GAG deletion in the TOR1A gene.
• A proband with DYT1 may also have the disorder as the result of a de novo gene mutation. While de novo mutations are probably rare [Ozelius, unpublished], two cases have been reported [Klein et al 1998 , Hjermind et al 2002].

Note: Although most individuals diagnosed with DYT1 have a parent who has the GAG deletion in the TOR1A gene, 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 parent.
• If a parent has the GAG deletion in the TOR1A gene, the risk of inheriting the mutation is 50% for each sib. The penetrance for a disease-causing mutation of the TOR1A gene is about 30%. Thus, on average, 30% of individuals who inherit the mutant allele will develop DYT1 and 70% will not develop DYT1. The clinical variability is great and an affected individual may be more or less severely affected than the parent who has the disease-causing allele.
• When molecular genetic testing does not reveal the GAG deletion in the TOR1A gene in either parent, the risk to the sibs of a proband appears to be low. No instances of germline mosaicism have been reported, although this remains a possibility.

Offspring of a proband

• A proband with the GAG deletion in the TOR1A gene 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 the TOR1A gene is 30%. Thus, on average, 30% of offspring who inherit the mutant allele will develop DYT1 and 70% will not.
• The clinical variability is great and an affected child may be more severely or less severely affected than the parent who has the disease-causing allele.

Other family members of a proband.  The risk to other family members depends upon the status of the proband's parents. If a parent is found to have a gene 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 nonmedical explanations including alternate paternity 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. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.

Testing of at-risk asymptomatic adults for DYT1 is available using the same 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, 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.

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, 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 at-risk, asymptomatic adults are in order make decisions regarding reproduction and to better assess the risk to children. Another motivation for testing may be a simple "need to know." After proper counseling, a positive TOR1A GAG deletion test result in an adult is unlikely to affect financial decisions or career planning. When testing at-risk individuals for DYT1 an affected family member should be tested first to confirm that the disorder in the family is actually DYT1.

Testing of at-risk individuals during childhood.  Consensus holds that individuals younger than 18 years who are at risk for adult-onset disorders should not have testing in the absence of symptoms. The principal arguments against testing asymptomatic individuals during childhood are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications [Bloch & Hayden 1990 , Harper & Clarke 1990]. Furthermore, no preventive treatment for DYT1 is available. Children who are symptomatic usually benefit from having a specific diagnosis established. (See also the resolution of the National Society of Genetic Counselors on genetic testing of children 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.  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. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Prenatal testing for pregnancies at 50% risk for DYT1 is possible by analysis of DNA extracted from fetal cells obtained through chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or amniocentesis usually performed at about 15-18 weeks' gestation. The disease-causing allele must be identified in an affected family member before prenatal testing or PGD can be performed. The presence of the TOR1A mutation detected by prenatal testing or PGD does not predict whether individuals will be symptomatic, or if they are, the age of onset or progression of the disorder.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) for the GAG deletion in TOR1A has also been reported [Rechitsky et al 2004]. PGD may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see .

Molecular Genetics

Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.

Normal allelic variants: The normal gene comprises five exons. Exon 5 includes a GAGGAG sequence that is highly conserved.

Pathologic allelic variants: Most affected individuals have a 3-bp deletion that results in the deletion of a GAG sequence within a highly conserved GAGGAG sequence in exon 5 [Ozelius et al 1997]. (For more information, see Genomic Databases table above.)

Normal gene product: The protein torsin A comprises 332 amino acids. It has an ATP-binding domain and a putative N-terminal leader sequence. It has similarities to a heat shock protein and has high expression in substantia nigra pars compacta [Augood et al 1998]. Immunoreactivity studies have localized torsin A primarily to the lumen of the endoplasmic reticulum (ER) where it may function as a chaperone protein [Bragg et al 2004].

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

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

References

Published Statements and Policies Regarding Genetic Testing

• American Society of Human Genetics and American College of Medical Genetics (1995) Points to consider : ethical, legal, and psychosocial implications of genetic testing in children and adolescents
• National Society of Genetic Counselors (1995) Resolution on prenatal and childhood testing for adult-onset disorders

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• Valente EM, Warner TT, Jarman PR, Mathen D, Fletcher NA, Marsden CD, Bhatia KP, Wood NW (1998) The role of DYT1 in primary torsion dystonia in Europe. Brain 121 [Part 12]:2335-9 [Medline]
  
  
• van Hilten BJ, van de Beek WJ, Hoff JI, Voormolen JH, Delhaas EM (2000) Intrathecal baclofen for the treatment of dystonia in patients with reflex sympathetic dystrophy. N Engl J Med 343:625-30 [Medline]
  
  
• Walker RH, Danisi FO, Swope DM, Goodman RR, Germano IM, Brin MF (2000) Intrathecal baclofen for dystonia: benefits and complications during six years of experience. Mov Disord 15:1242-7 [Medline]
  
  
• Warner TT and Jarman P (1998) The molecular genetics of the dystonias [editorial]. J Neurol Neurosurg Psychiatry 64:427-9 [Medline]
  
  

Suggested Readings

• Berardelli A, Rothwell JC, Hallett M, Thompson PD, Manfredi M, Marsden CD (1998) The pathophysiology of primary dystonia. Brain 121 [Part 7]:1195-212 [Medline]
  
  
• Walker RH and Shashidharan P (2003) Developments in the molecular biology of DYT1 dystonia. Mov Disord 18:1102-7 [Medline]
  
  

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