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Primary Torsion Dystonia

Torsion Dystonia Fragment Syndrome

Primary torsion dystonia (PTD) is a genetically heterogeneous, isolated form of dystonia.


Presentation

The most important signs by which the patient presents are as follows: difficulty in walking, foot drag, cramps, contortions, difficulty in grasping objects, speech difficulty, physical deformities and muscle contractions.

Some patients may also present with the following signs: twisting of the body, jerking of the head, tremors of the hands or feet and arms or legs and difficulty in writing. Dystonic movements intensify with action. Movements of primary dystonia occur only with specific actions and not at rest. If the disease condition continues to worsen, dystonic movements will be seen at rest as well and the patient eventually develops a sustained posturing [7].

Dystonia tremors which are irregular, rhythmic contractions may be observed in some patients as well. Facial muscles which are affected manifest patterns of sustained contractions on the forehead, eyelids and lower face [7].

Limbs which are affected may show an increased intensity of contractions because of specific voluntary tasks which may cause it. Writing of an individual is affected when the upper extremities are affected. The pattern of muscle contractions in dystonia is consistent and predictable. However, with changing position and tasks, involuntary movements may vary. Other physical and neurologic findings may be present in addition to dystonia.

Dutch
  • In this Dutch cervical dystonia cohort, no significant association was found with TOR1A variants. In the meta-analysis (eight studies, 1332 adult-onset primary dystonia patients) no variant reached overall significance.[ncbi.nlm.nih.gov]
  • A prospective cohort study between March 2008 and March 2011, including 676 FPTD patients attending the botulinum toxin outpatient clinics of six Dutch movement disorder centres.[ncbi.nlm.nih.gov]
  • RESULTS:In this Dutch cervical dystonia cohort, no significant association was found with TOR1A variants. In the meta-analysis (eight studies, 1332 adult-onset primary dystonia patients) no variant reached overall significance.[foundationdystoniaresearch.org]
Blepharospasm
  • In 12 families with adult-onset PTD, the index cases presented with cervical dystonia (CD); of the 22 affected relatives, 17 had CD, 2 had writer's cramp, 1 had blepharospasm, and 2 had spasmodic dysphonia.[ncbi.nlm.nih.gov]
  • Abnormal TDTs were found in 36 of 37 (97.3%) cervical dystonia, 12 of 14 (85.7%) writer's cramp, 8 of 9 (88.8%) blepharospasm, 10 of 11 (90.1%) spasmodic dysphonia patients and 5 of 8 (62.5%) musicians.[ncbi.nlm.nih.gov]
  • Defazio G, Matarin M, Peckham EL, et al.: The TOR1A polymorphism rs1182 and the risk of spread in primary blepharospasm. Mov Disord 2009, 24:613–616. CrossRef PubMed Google Scholar 36.[link.springer.com]
  • Originally published in the Benign Essential Blepharospasm Research Foundation Newsletter, Volume 28, Number 5, pages 6, 13 (2009) Home Blepharospasm index Top of this page[blepharospasm.org]
  • Blepharospasm is the second most common focal dystonia. It causes involuntary contraction of the eyelids and can hold them closed for indefinite periods of time.[cbc.arizona.edu]
Dystonia
  • Primary torsion dystonia (PTD) is a genetically heterogeneous, isolated form of dystonia.[symptoma.com]
  • Meta-analysis does not show association with common variants in TOR1A in adult-onset primary dystonia, except for the functional variant rs1801968 in familial focal dystonia cases.[ncbi.nlm.nih.gov]
  • Forty-six of them had segmental dystonia and 59 had focal dystonia.[ncbi.nlm.nih.gov]
  • To evaluate the contribution of these genetic loci to other families with familial "non-DYT1" dystonia five large families with dystonia were studied using genetic markers spanning the DYT6 and DYT7 regions.[ncbi.nlm.nih.gov]
  • With a stronger family history, a significantly lower AaO was seen in all focal dystonias. In both the sporadic and familial focal dystonia groups, AaO had an effect on the distribution of dystonia, with a caudal to cranial tendency.[ncbi.nlm.nih.gov]
Tremor
  • A few cases had additional voice tremor and/or postural arm tremor. The GAG deletion in the DYT1 gene was excluded in the index case.[ncbi.nlm.nih.gov]
  • Primary torsion dystonia (PTD) is defined as a syndrome in which dystonia is the only clinical sign (except for tremor), and there is no evidence of neuronal degeneration or an acquired cause by history or routine laboratory assessment.[ncbi.nlm.nih.gov]
  • There were no other abnormal signs, apart from dystonia and jerky tremor over a 12-year follow-up. All investigations for other causes of primary and secondary dystonia had normal results.[ncbi.nlm.nih.gov]
  • Some patients may also present with the following signs: twisting of the body, jerking of the head, tremors of the hands or feet and arms or legs and difficulty in writing. Dystonic movements intensify with action.[symptoma.com]
  • Dystonia is the third most common movement disorder after Parkinson's disease and Tremor.[books.google.com]
Involuntary Movements
  • We conclude that aberrant opioid transmission is unlikely to be present in DYT1-PTD and altered opioid transmission is not a common mechanism underlying all disorders of involuntary movement.[ncbi.nlm.nih.gov]
  • However, with changing position and tasks, involuntary movements may vary. Other physical and neurologic findings may be present in addition to dystonia.[symptoma.com]
  • In the neurological examination the dystonic involuntary movements of the neck, trunk and limbs, more expressed on the right side, were observed.[healthatoz.info]
  • This syndrome causes involuntary movements that usual start in the lips, tongue or face. The side effects can become a permanent disability.[krafchick.com]
  • While chorea is the most common involuntary movement in this condition (rapid irregular random jerky movements that may affect face, arm, legs or trunk), dystonia and parkinsonism may also be present.[dystonia-parkinson.org]
Abnormal Gait
  • Because the legs and trunk are so commonly affected in early-onset generalised dystonia, abnormal gait may be common. Symptoms often begin in one area of the body and spread to other areas.[dystonia.ie]
  • Limb, then generalized X-linked dystonia–parkinsonian syndrome (Phillipines; Lubag’s disease) DYT3 X linked TATA-binding protein-associated factor 1 gene (TAF1) Onset typically 30–45 years with focal dystonia, becoming generalized, with abnormal gait,[emedmd.com]
Axial Dystonia
  • In adults, the condition usually presents as a focal dystonia (blepharospasm, oromandibular dystonia, spasmodic dysphonia, torticollis, axial dystonia, or dystonic writer’s cramp).[emedmd.com]
  • dystonia (33 %), and in cervical dystonia secondary to stroke (20 %). 8 . 9 Dystonia has also been associated with substance misuse (13 % of patients), especially in alcohol responsive myoclonic-dystonia. 7 No studies have examined psychiatric morbidity[ispub.com]

Workup

The following should be considered when the history and physical findings of the patient suggest only dystonia and when the age of onset is younger than 26 years: DYT1 with genetic counselling. If the patient tests negative for DYT1, a levodopa trial must be considered. If the patient does not respond even to a levodopa trial, it is advised to perform a MRI and a ceruloplasmin test. A slit-lamp examination can also be done.

If the age of onset is older than 26 years, a MRI and serum ceruloplasmin must be done. The patient must also be assessed for a history of exposure to a dopamine-blocking agent in case of other causes. If there are metabolic or neurodegenerative causes, the following must be done in addition to the above: EEG, CSF analysis, electromyography, chromosomal analysis, antiphospholipid antibody testing, and genetic testing for Huntington ’s disease, mitochondrial diseases, alpha-fetoprotein test and skin, muscle and nerve biopsy [8].

Treatment

Treatment available for dystonias at the moment, are basically symptomatic and palliative. No curative treatment is available at the moment. Only the intensity of the disease symptoms can be controlled which can improve the quality of life of the patients. The intensity can be controlled with the help of oral medications, intramuscular or subcutaneous boutulinum toxin injections and physiotherapy or rehabilitation [1].

Surgical mode of treatment is indicated in those patients in whom the symptoms are severe and in whom drug therapy fails because of drug reaction. Thalmotomy and bilateral pallidotomy are the preferred surgeries for dystonia [9].

The aim of therapy will be directed towards increasing movement, relieving pain, reducing contractures and lastly, restoring functionality [10].

Prognosis

The prognosis depends on how well the patient responds to the treatment. As there is no cure, the symptoms can only be alleviated for a short period of time by administering oral drugs. Physiotherapy and rehabilitation can improve the quality of life to a certain extent.

Etiology

Dystonia has historically been classified into 2 main etiologic groups: primary (idiopathic) and secondary (symptomatic). Idiopathic dystonia was distinguished from the symptomatic dystonias by its lack of a known cause and the absence of consistent brain pathology. However, it has become clear that idiopathic dystonia consists of a group of clinical syndromes that are likely to have a genetic basis [2].

Primary dystonia is a genetically heterogeneous disease. Hence, the disorder could be hereditary or may be birth-related. There is a possibility of Dystonia being caused due to physical trauma, infection, poisoning or as a reaction to pharmaceutical drugs such as neuroleptics. In hereditary cases, several causative genes have been identified but their genetic bases still remain elusive.

Primary Torsion Dystonia can be due to a monogenic inheritance and many gene loci have been discovered for the autosomal dominant (DYT1/TOR1A; DYT6/THAP1; DYT4/TUBB4a; DYT7; DYT13; DYT21; DYT23/CIZ1; DYT24/ANO3; DYT25/GNAL) and recessive (DYT2; DYT17) forms [1] [5] [7]. In late-onset sporadic cases, the involvement of genetic and environmental factors play an important role [3].

Epidemiology

The relative prevalence and distribution of PTD is difficult to estimate because of the variation in its expression and the tendency for mild cases to go undiagnosed. Several large studies have shown that early-onset primary torsion dystonia is 5-10 times more common in Ashkenazi Jews than in people who were not Jewish or in Jewish individuals not of Ashkenazi heritage. Subsequent studies have found a wide range in the prevalence of dystonia from 6-7,320 persons per million population [1].

Late-onset focal primary dystonia was 10 times more common than early-onset generalized primary torsion dystonia [1]. Childhood- and adolescent-onset primary dystonia is more common in Jews of Eastern European or Ashkenazi ancestry than in other groups. Segmental and focal dystonias are more prevalent in the female population [4].

Sex distribution
Age distribution

Pathophysiology

The precise cause is not known however, the most probable cause for Primary Torsion Dystonia is the result of a genetic mutation. Several of the hereditary primary dystonias implicate altered synaptic communication within the basal ganglia. For example, torsin A which is encoded by the DYT1 (early onset) gene (also known as TOR1A), is expressed at high levels in human dopaminergic neurons. Most cases are associated with asingle mutation in the DYT1 gene, a three base-pair deletion (ΔGAG) that leads to the loss of a glutamicacid residue in the carboxy-terminal region of torsin A [5] [6].

Torsin A is located predominantly within the lumen of the endoplasmic reticulum and nuclear envelope. It is a member of the family of ATPases that are associated with a variety of cellular activities (AAA +) and it is therefore likely to mediate ATP-dependent conformational remodelling reactions involving substrate proteins or protein complexes. It has been proven that torsin A regulates the organization of nuclear envelope and endoplasmic reticulum compartments with respect to the cytoskeleton and participates in the processing of proteins through the secretory pathway [6].

Torsin A binds to lamina-associated polypeptide 1 (LAP1) in the inner nuclear envelope and to a related protein in the endoplasmic reticulum. Recent studies suggest that the ΔGAG deletion results in a loss of torsin A activity. Because AAA + proteins typically function as homo-oligomericcomplexes — usually hexamers — the ΔGAGmutant protein might also exert a dominant-negative effectand decrease wild-type torsinA activity in heterozygous DYT1 patients [6].

Primary Torsion Dystonia may be focal, segmental, and multifocal or generalized depending on the anatomic site involved.

Prevention

Since it has a genetic basis, there is no method for prevention available yet.

Summary

Dystonias are heterogeneous hyperkinetic neurological movement disorders where there are sustained muscle contractions that cause twisting and repetitive movements and abnormal postures. In 1908, Schwalbe first described primary, or idiopathic, torsion dystonia in a Jewish family. In 1911, Oppenheim termed this dystonia as musculorum deformans (DMD). In earlier times, dystonia was attributed as a symptom of hysteria, however primary torsion dystonia eventually became established to be a neurological disease with genetic basis.

Treatment for Primary Torsion Dystonia (PTD) is usually palliative. Primary Torsion Dystonia also termed as Idiopathic Dystonia, refers to pure primary forms characterized by dystonia alone. It can further be divided based on the age of onset and the distribution of the dystonia which can be focal, segmental or generalized. Early onset dystonias are commonly seen in people who suffer from it because of hereditary factors; however, late onset Primary Torsion Dystonia is usually sporadic and tends to remain focal or segmental in distribution [1].

Patient Information

Primary Torsion Dystonia is a neurological condition which is generally hereditary or birth-related. The cause is not clearly known. However, it is postulated to be caused due to genetic mutation. It is more prevalent amongst Ashkenazi Jews and mostly seen in females than in males. It is a progressive disease with a poor outcome, however in this type of dystonia there is no damage to the brain seen. It is characterized by repetitive twisting movements and sustained muscle contraction which can lead to abnormal postures of the body.

If a person tests positive for DYT1, then the person is said to be suffering from Primary Torsion Dystonia (PTD). Other tests conducted to diagnose this disease includes, MRI and serum ceruloplasmin. People suffering from this illness usually present with difficulty in walking, difficulty to hold on to anything (because of which the writing of a person can also suffer), cramps, physical deformities and muscle contractions [9].

There is no cure for this disease however the standard of living of these patients can be improved by alleviating the symptoms by administering oral medications. For patients who develop a reaction to the drug administered and those who do not respond to oral medication, surgery is an option that is usually taken into consideration. However, resorting to physiotherapy, rehabilitation and relaxation techniqueshelp improve the quality of life of the patient. Braces and assistive devices may help increase mobility, improve strength and prevent contractures from forming.

References

Article

  1. Grundman K. Primary torsion dystonia. Arch Neurol. 2005;62(4):682-5.
  2. Petrucci S, Valente EM. Genetic issues in the diagnosis of dystonias. Front Neurol, 2013 April 10; 4:34.
  3. Groen JL, Kallen MC, van de Warrenburg BP, Speelman JD, et al. Phenotypes and genetic architecture of focal primary torsion dystonia. J Neurol Neurosurg Psychiatry, 83(10), 1006–1011.
  4. Ritesh A. Ramdhani, Kristina Simonyan. Primary Dystonia: Conceptualizing the Disorder through a Structural Brain Imaging Lens.Tremor Other Hyperkinet Mov. N Y). 2013; 3: tre-03-152-3638-4.
  5. Fuchs T, Ozelius LJ. Genetics of Dystonia. Semin Neurol, 2011 Nov;31(5):441-8.
  6. Bruggeman N, Klein C. Genetics of primary torsion dystonia. Curr Neurol Neurosci Rep, 2010 May; 10(3):199-206.
  7. Valente EM, Albanese A. Advances in the genetics of primary torsion dystonia. F 1000 Biol Rep. 2010 Jun 16;2.
  8. Breakefield XO, Blood AJ, Li Y, Hallett M et al. The Pathophysiological basis of dystonias. Nat Rev Neurosci. 2008 Mar;9(3):222-34.
  9. Kimmich O, Bradley D, Whelan R, Mulrooney N, et al. Sporadic adult onset primary torsion dystonia is a genetic disorder by the temporaldiscrimination test. Brain, 2011 Sep;134(Pt 9):2656-63.
  10. Bressman SB, Greene PE. Dystonia. Curr Treat Options Neurol. May 2000;2(3):275-285.

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Last updated: 2018-06-21 22:30