Clinical characteristics.

DYT1-TOR1A is an isolated dystonia with onset typically in childhood (median age of onset: 9 years; interquartile range: 7-12 years). About 5% of individuals have onset after age 30 years. Dystonia typically begins in a leg or arm. While onset can occur in axial, cervical, or cranial regions, these are far less common than onset in a limb. Pain is not a prominent finding. Initially, dystonia is typically triggered by specific actions, presenting as a change in gait (e.g., foot inversion or abnormal flexion of the knee or hip) or as writer's cramp, characterized by tightening and/or posturing of the hand or arm with writing. Over time, dystonic movements become less action specific and may be present at rest. Dystonia can also spread to other body regions, progressing over months to years to "generalized dystonia" involving other limbs and the trunk. In individuals with onset in a leg, progression of dystonia is common. In approximately 20% of individuals dystonia remains restricted to a single body region, most often as writer's cramp. Once dystonic movements appear, they usually persist lifelong. Status dystonicus, the most severe manifestation of dystonia that requires emergent hospitalization, can occur but is not common in DYT-TOR1A. Life span in DYT-TOR1A is not known to be shortened.

Diagnosis/testing.

The diagnosis of DYT-TOR1A is established in a proband with suggestive findings and a heterozygous pathogenic variant in TOR1A identified by molecular genetic testing. More than 98% of affected individuals have the 3-bp deletion c.907_909delGAG involving the highly conserved GAGGAG sequence in exon 5.

Management.

Treatment of manifestations: A movement disorder specialist should be involved at an early stage to discuss pharmacologic and/or surgical treatment options to relieve manifestations of dystonia. Timely medical intervention and appropriate referral for consideration of globus pallidus internus deep brain stimulation is recommended to optimally treat manifestations, minimize disability, and prevent long-term orthopedic complications such as joint contractures or spine deformities. Physiatry and physical therapy to tailor exercise programs to maintain function and prevent secondary orthopedic complications (e.g., joint contractures, hip dislocation, and/or kyphoscoliosis), provide adaptative aids, and support and maintain ambulation; occupational therapy to address fine motor skills (e.g., feeding, grooming, dressing, and writing); mental health specialist to address possible depression and/or anxiety concerning disease manifestations/progression.

Surveillance: Regularly scheduled follow up with treating clinicians to monitor existing manifestations, the individual's response to treatment and supportive care, and the emergence of new manifestations.

Agents/circumstances to avoid: Unless medically necessary, avoid immobilization with bracing or casting of the parts of the body affected by dystonia, which can worsen dystonia.

Genetic counseling.

DYT-TOR1A is inherited in an autosomal dominant manner. Most individuals diagnosed with DYT-TOR1A inherit a pathogenic variant from a parent. Each child of an individual with DYT-TOR1A has a 50% chance of inheriting the TOR1A pathogenic variant. The penetrance for the TOR1A c.907_909delGAG deletion is approximately 30%; thus, on average, 30% of individuals who inherit the TOR1A c.907_909delGAG deletion develop dystonia and 70% do not develop dystonia. DYT-TOR1A is associated with significant intrafamilial variability; thus, dystonia in an affected individual may be more or less severe than that of the parent from whom the TOR1A pathogenic variant was inherited. Once the TOR1A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for DYT-TOR1A are possible.

Suggestive Findings

DYT-TOR1A should be suspected in probands with the following clinical and supportive imaging findings and family history.

Clinical findings [Lange et al 2021]

• Onset is in childhood or adolescence (median age: 9 years; interquartile range: 7-12 years).
• Dystonia usually begins in a leg (average age: 9 years) or an arm (average age: 15 years).
• Initiation or worsening of dystonic movements and postures often follows voluntary movements.
• Absence of:
  • Other neurologic or systemic manifestations
  • A history of a known cause of acquired dystonia (See Differential Diagnosis.)

Imaging findings. Brain CT and routine MRI are normal.

Family history

• Consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.
• Because 70% of individuals who inherit the common c.907_909delGAG TOR1A deletion do not develop dystonia (see Penetrance) and intrafamilial variability of DYT-TOR1A is considerable, a proband with an inherited TOR1A pathogenic variant may appear to be the only affected family member.
• Affected individuals are often of Ashkenazi Jewish ancestry; however, DYT-TOR1A can occur in individuals of any ancestry [Lange et al 2021].

Establishing the Diagnosis

The diagnosis of DYT-TOR1A is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in TOR1A identified by molecular genetic testing (see Table 1). Note: More than 98% of affected individuals have the 3-bp deletion c.907_909delGAG involving the highly conserved GAGGAG sequence in exon 5 [Lange et al 2021].

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. Identification of a heterozygous TOR1A variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Note: Single-gene testing (sequence analysis of TOR1A, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

Clinical Description

DYT1-TOR1A is an early-onset isolated dystonia with a median age of onset of nine years (interquartile range: 7-12 years); approximately 5% of individuals have onset after age 30 years [Lange et al 2021]. Onset is typically in an arm or a leg; however, when dystonia becomes generalized, axial and cervical involvement are common. Craniofacial or laryngeal involvement is uncommon.

Presentation. Onset is usually in a leg (average age: 9 years) or an arm (average age: 15 years). Initially, dystonia is apparent with specific actions such as a change in gait (foot inversion or eversion, abnormal flexion of the knee or hip) or writer's cramp (dystonia of the upper extremity that is task specific to writing caused by tightening and/or posturing of the upper extremity).

Onset in axial, cervical, or cranial regions can occur but is far less common than onset in a limb. Pain is not a prominent finding except in cervical dystonia, which is an uncommon presentation.

In approximately 20% of individuals dystonia is restricted to a single body region, most often as writer's cramp.

Dystonic tremor is common.

Rare findings reported include the following:

• Isolated blepharospasm [Tuffery-Giraud et al 2001]
• Fluctuating unilateral myoclonic dystonia [Gatto et al 2003]
• Abrupt onset of craniocervical dystonia [Pavelekova et al 2021]

Once dystonic movements appear, they usually persist throughout life.

Progression. In individuals who have onset in a leg, progression of dystonia is common, occurring over months to years. Over time, dystonic movements become less action specific and may be present at rest. Dystonia can also spread to other body regions, 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. Most individuals have spread to other body regions, with dystonia becoming generalized in 50% of individuals; however, a significant proportion, about 25%, have dystonia that remains restricted to the arm. The vast majority of individuals with DYT1-TOR1A will have dystonia involving an arm regardless of where it began.

Overall, 60%-70% of individuals have progression to generalized or multifocal dystonia involving at least a leg and an arm, and often axial muscles. Although spread to craniofacial muscles can occur, it is much less common.

Individuals with onset in the neck or cranial muscles also have variable progression.

Status dystonicus (also called dystonic storm or dystonic crisis), the most severe manifestation of dystonia, is an emergency characterized by increasingly severe and frequent episodes of generalized dystonia requiring urgent hospital admission as there is significant risk of mortality if dystonia progresses to bulbar dysfunction and respiratory failure [Lumsden et al 2023]. Although status dystonicus can occur in individuals with DYT-TOR1A, it is not common. Triggers for status dystonicus can include infection/fever, pain, adjustment or inadvertent withdrawal of medication, and abrupt battery failure or dysfunction of deep brain stimulation (DBS) hardware [Ben-Haim et al 2016, Termsarasab & Frucht 2017].

Depression. An increased incidence of recurrent major depression has been reported in individuals who have a TOR1A pathogenic variant with clinical manifestations or without dystonia due to reduced penetrance [Heiman et al 2004].

Cognition is largely normal, with some evidence of isolated executive dysfunction, while other domains of cognitive function are intact [Jahanshahi & Torkamani 2017].

Intrafamilial variability of DYT-TOR1A is considerable. The dystonia in an affected individual may be more or less severe than that of the parent from whom the TOR1A disease-causing variant was inherited. An example is a family with one individual with writer's cramp and another with severe status dystonicus [Opal et al 2002].

Age of onset within families is also highly variable. Once a proband with the typical findings of early-onset dystonia is identified, other family members with later onset and a milder phenotype such as isolated writer's cramp may be identified [Bressman et al 2000].

Life span is not known to be shortened.

Neuroimaging. For additional information about positron emission tomography scan studies and diffusion tensor imaging studies in DYT-TOR1A, click here.

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been identified.

Penetrance

The penetrance of the common c.907_909delGAG TOR1A deletion is approximately 30% [Bressman et al 1989, Lange et al 2021]. Thus, on average, 30% of individuals who inherit this variant will develop DYT-TOR1A and 70% will not.

Nomenclature

Terms used for DYT-TOR1A in the past include the following:

• Dystonia muscularum deformans
• Primary torsion dystonia (PTD)

The three forms of genetic dystonias, based on associated clinical features, are:

• Isolated dystonia. Dystonia is the only motor feature except possible tremor.
• Combined dystonia. Dystonia is combined with another movement disorder (e.g., myoclonus, parkinsonism).
• Complex dystonia. Dystonia co-occurs with other neurologic or systemic manifestations; dystonia is not necessarily the most prominent disease manifestation and may even be an inconsistent feature.

Prevalence

DYT-TOR1A is a common form of early-onset isolated dystonia [Lange et al 2021].

The prevalence of early-onset dystonia in the Ashkenazi Jewish population is estimated at 1:3,000-9,000. Because of the reduced penetrance (i.e., 30%), the frequency of heterozygosity for the TOR1A pathogenic variant is estimated to be 1:1,000-3,000 [Risch et al 1995, Frédéric et al 2007, Yang et al 2009, Park et al 2019]. Among individuals who are not of Jewish ancestry, the prevalence is lower.

The increased prevalence of DYT-TOR1A in Ashkenazim is the result of the 3-bp deletion c.907_909delGAG founder variant involving the highly conserved GAGGAG sequence in exon 5 that appeared approximately 350 years ago [Risch et al 1995].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with DYT-TOR1A, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for DYT-TOR1A. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields. A movement disorder specialist should be involved at an early stage to discuss pharmacologic and surgical treatment options.

Treatment is aimed at relieving manifestations of dystonia [Balint et al 2018, Albanese et al 2019, Fan et al 2023].

Timely medical intervention and referral for consideration of globus pallidus internus (GPi) deep brain stimulation (DBS) is recommended in order to optimally treat manifestations, minimize disability, and prevent long-term orthopedic complications such as joint contractures or spine deformities.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Agents/Circumstances to Avoid

Unless medically necessary, avoid immobilization with bracing or casting of the parts of the body affected by dystonia, which can worsen the dystonia.

Evaluation of Relatives at Risk

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

Pregnancy Management

Oral medications. Data on the use of the oral medications typically used for treatment of dystonia during pregnancy are limited. 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, Seier & Hiller 2017].

Botulinum toxin injections. A few case reports of treatment of dystonia with botulinum toxin injections during pregnancy have not found adverse effects on the expectant mother or the fetus [Krug et al 2015]. Note: A 29-year retrospective analysis of safety data in pregnant women exposed to onabotulinum toxin A (most frequently used for aesthetic purposes and treatment of migraine/headache) found that the prevalence of major birth defects among live births was consistent with the prevalence reported in the general population. Data on second- or third-trimester exposure were limited [Brin & Blitzer 2023].

Bilateral GPi DBS. No adverse fetal or maternal outcomes were reported in two series that included four women with DYT-TOR1A who had had implantation for GPi DBS prior to pregnancy [Scelzo et al 2015, Ziman et al 2016].

More recently, King et al [2022] reported that GPi DBS during pregnancy did not have a high perinatal complication profile in the 29 pregnancies of 27 women who had had implantation for GPi DBS prior to pregnancy and had received active neuromodulation treatment throughout their pregnancies. The most common reported concern (10%) was GPi DBS device discomfort.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

DYT-TOR1A is inherited in an autosomal dominant manner with reduced penetrance and broad intrafamilial variability.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with DYT-TOR1A inherited a TOR1A pathogenic variant from a parent who may or may not have clinical features of the disorder (~70% of individuals who have the TOR1A 3-bp deletion c.907_909delGAG are asymptomatic). Note: In a cohort of 694 individuals (from 638 families) with a heterozygous pathogenic variant in TOR1A, 98% of individuals had the c.907_909delGAG deletion [Lange et al 2021].
• Rarely, individuals diagnosed with DYT-TOR1A have the disorder as the result of a de novo TOR1A pathogenic variant. To date, four individuals have been reported with de novo TOR1A c.907_909delGAG deletions [Klein et al 1998, Hjermind et al 2002, De Carvalho Aguiar et al 2010, Saunders-Pullman et al 2014].
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of reduced penetrance (many heterozygous parents are asymptomatic) or failure to recognize the disorder in family members with mild clinical features (e.g., writer's cramp only). Therefore, de novo occurrence of a TOR1A deletion cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the TOR1A pathogenic variant .
• If the TOR1A pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo TOR1A pathogenic variant.
  • The proband inherited a TOR1A pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells 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 a TOR1A pathogenic variant, the risk to sibs of inheriting the pathogenic variant is 50%.
  • The penetrance for the TOR1A c.907_909delGAG deletion is approximately 30%. Thus, on average, 30% of individuals who inherit the TOR1A c.907_909delGAG deletion develop dystonia and 70% do not develop dystonia (see Penetrance).
  • DYT-TOR1A is associated with significant intrafamilial variability; the dystonia in an affected individual may be more or less severe than the parent from whom the TOR1A pathogenic variant was inherited.
• If the TOR1A pathogenic variant identified in the proband is not detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population and is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016]. No instances of gonadal mosaicism have been reported, although it remains a possibility.
• If the parents of the proband are clinically unaffected but their genetic status is unknown, sibs of the proband are presumed to be at increased risk for DYT-TOR1A because of the significant possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with DYT-TOR1A has a 50% chance of inheriting the TOR1A pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the TOR1A pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 adult relatives

• Testing of at-risk asymptomatic relatives of an individual with DYT-TOR1A is possible once the molecular diagnosis has been confirmed in an affected family member. Such testing should be performed in the context of formal genetic counseling.
• Asymptomatic adults rarely develop manifestations, particularly after age 26 years, and individuals who develop mild manifestations in adulthood 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 DYT-TOR1A.

Testing of asymptomatic individuals younger than age 18 years at risk for DYT-TOR1A should be discussed in the context of formal genetic counseling. The autonomy of the minor is a primary concern, and consideration should be given to delay of genetic testing until the at-risk individual is capable of informed decision making.

Testing is appropriate to consider in symptomatic individuals in a family with an established diagnosis of DYT-TOR1A regardless of age.

Prenatal Testing and Preimplantation Genetic Testing

Once the TOR1A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for DYT-TOR1A are possible. Although such testing can determine whether the TOR1A pathogenic variant has been inherited, the results of such testing cannot be used to predict clinical manifestations or their severity.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

TOR1A encodes torsin-1A, a member of the AAA + family of adenosine triphosphatases (ATPases) involved in a variety of cellular functions including protein trafficking, degradation, folding, and response to endoplasmic reticulum (ER) stress. Exactly how these compromised functions lead to disease is still unknown [Thomsen et al 2024].

Risch et al [2007] suggested that the TOR1A polymorphism p.Asp216His is a genetic modifier of TOR1A expression that contributes to the reduced penetrance of TOR1A pathogenic variants; this finding was replicated in a study by Kamm et al [2008]. However, data from another study in the French population did not support this observation [Frédéric et al 2009].

Mechanism of disease causation is thought to be dominant-negative with mutated torsin-1A recruiting wild-type torsin-1A into multimeric complexes.

Author Notes

The authors are actively involved in research aimed at understanding the genetic causes of isolated dystonia and are interested in hearing from clinicians treating multiplex families with dystonia in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this disorder.

Acknowledgments

We would like to thank all dystonia patients and their families who contributed to our understanding of DYT-TOR1A. Research support related to TOR1A gene identification included NIH grants NS26656 (Dr Susan Bressman) and NS28384, 037409, and 087997. We are grateful to the Dystonia Medical Research Foundation for their support of work leading to the TOR1A gene identification and subsequent continued support of research and clinical work in DYT-TOR1A and other forms of dystonia. Thanks to our colleagues and past authors of this chapter, Dr Susan Bressman and Deborah Raymond, for their foundational work on TOR1A dystonia, their prior contributions to this chapter, and current editorial input.

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

• 20 November 2025 (bp) Comprehensive update posted live
• 17 November 2016 (sw) Comprehensive update posted live
• 2 January 2014 (me) Comprehensive update posted live
• 1 July 2008 (me) Comprehensive update posted live
• 5 April 2005 (me) Comprehensive update posted live
• 21 January 2003 (me) Comprehensive update posted live
• 14 April 1999 (pb) Review posted live
• 2 December 1998 (ddl) Original submission

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