Human gene for torsion dystonia located on chromosome 9q32-q34

doi:10.1016/0896-6273(89)90188-8

Neuron

Volume 2, Issue 5, May 1989, Pages 1427-1434

https://doi.org/10.1016/0896-6273(89)90188-8 Get rights and content

Abstract

Torsion dystonia is a movement disorder of unknown etiology characterized by loss of control of voluntary movements appearing as sustained muscle contractions and/or abnormal postures. Dystonic movements can be caused by lesions in the basal ganglia, drugs, or gene defects. Several hereditary forms have been described, most of which have autosomal dominant transmission with variable expressivity. In the Ashkenazi Jewish population the defective gene frequency is about $1 10,000$ . Here, linkage analysis using polymorphic DNA and protein markers has been used to locate a gene responsible for susceptibility to dystonia in a large, non-Jewish kinship. Affected members of this family have a clinical syndrome similar to that found in the Jewish population. This dystonia gene (ITD1) shows tight linkage with the gene encoding gelsolin, an actin binding protein, and appears by multipoint linkage analysis to lie in the q32–q34 region of chromosome 9 between ABO and D9S26, a region that also contains the locus for dopamine-β-hydroxylase.

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Investigating DYT1 in a Taiwanese dystonia cohort
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A heterozygous three-nucleotide (GAG) in-frame deletion in the TOR1A gene causes the rare disease, dystonia (DYT1), which typically presents as focal limb dystonia during adolescence, then spreads to other limbs. This study investigated the frequency and clinical features of DYT1 in a Taiwanese dystonia cohort.
We performed targeted next generation sequencing in 318 patients with primary dystonia. We identified one DYT1 family with various types of dystonia, and we described the clinical presentations observed in this family during a 30-year follow-up. We compared the clinical characteristics to those reported in previous studies on DYT1 from 2000 to 2020.
Among 318 patients, we identified only one DYT1 patient (0.3%) with an autosomal dominant family history of dystonia. The proband was a 43-year-old man that experienced progressive onset of focal lower limb dystonia from age 11 years. The disease spread caudal-rostrally to the upper limbs and cervical muscles. Prominent cervical dystonia was noted during follow-up, which was an atypical presentation of DYT1. Clinical assessments of other family members showed intrafamily variability. The proband's father and an affected sibling demonstrated only mild right-hand writer's cramp. A systematic review of previously reported DTY1 cases showed that Asian patients had a higher frequency of cervical dystonia (44.8%) than groups of Ashkenazi Jews (35%) and Non-Jewish Caucasians (30.5%) (P = 0.04).
Our findings revealed that DYT1 is rare in a Taiwanese dystonia cohort. The presentation of marked cervical dystonia could be the main feature of Asian patients with DYT1.
Deep Brain Stimulation of the Globus Pallidus Internus for Secondary Dystonia: Clinical Cases and Systematic Review of the Literature Regarding the Effectiveness of Globus Pallidus Internus versus Subthalamic Nucleus
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Deep brain stimulation (DBS) is a frequently applied therapy in primary dystonia. For secondary dystonia, the effects can be less favorable. We share our long-term findings in 9 patients with severe secondary dystonia and discuss these findings in the light of the literature.
Patients who had undergone globus pallidus internus (GPi)-DBS for secondary dystonia were included. Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores, clinical improvement rates, follow-up periods, stimulation parameters and the need for internal pulse generator replacements were analyzed. The PubMed and Google Scholar databases were searched for articles describing GPi-DBS and subthalamic nucleus (STN)-DBS only for secondary dystonia cases. Keywords were “dystonia,” “deep brain stimulation,” “GPi,” “dystonia,” “deep brain stimulation,” and “STN.”
A total of 9 secondary dystonia patients (5 male, 4 female) had undergone GPi-DBS with microelectrode recording in our units. The mean follow-up period was 29 months. The average BFMDRS score was 58.2 before the surgery, whereas the mean value was 36.5 at the last follow-up of the patients (mean improvement, 39%; minimum, 9%; maximum, 63%). In the literature review, we identified 264 GPi-DBS cases (mean follow-up, 19 months) in 72 different articles about secondary dystonia. The mean BFMDRS improvement rate was 52%. In 146 secondary dystonia cases, reported in 19 articles, STN-DBS was performed. The average follow-up period was 20 months and the improvement in BFMDRS score was 66%.
Although GPi-DBS has favorable long-term efficacy and safety in the treatment of patients with secondary dystonia, STN seems a promising target for stimulation in patients with secondary dystonia. Further studies including a large number of patients, longer follow-up periods, and more homogenous patients are necessary to establish the optimal target for DBS in the management of secondary dystonias.
Principles and Practice of Movement Disorders
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Dystonia and Parkinson's disease: What is the relationship?
2019, Neurobiology of Disease
Dystonia and Parkinson's disease are closely linked disorders sharing many pathophysiological overlaps. Dystonia can be seen in 30% or more of the patients suffering with PD and sometimes can precede the overt parkinsonism. The response of early dystonia to the introduction of dopamine replacement therapy (levodopa, dopamine agonists) is variable; dystonia commonly occurs in PD patients following levodopa initiation. Similarly, parkinsonism is commonly seen in patients with mutations in various DYT genes including those involved in the dopamine synthesis pathway. Pharmacological blockade of dopamine receptors can cause both tardive dystonia and parkinsonism and these movement disorders syndromes can occur in many other neurodegenerative, genetic, toxic and metabolic diseases. Pallidotomy in the past and currently deep brain stimulation largely involving the GPi are effective treatment options for both dystonia and parkinsonism. However, the physiological mechanisms underlying the response of these two different movement disorder syndromes are poorly understood. Interestingly, DBS for PD can cause dystonia such as blepharospasm and bilateral pallidal DBS for dystonia can result in features of parkinsonism. Advances in our understanding of these responses may provide better explanations for the relationship between dystonia and Parkinson's disease.
Deletion variant rs35153737 in TOR1A is associated with isolated dystonia in a Southwestern Chinese Population
2017, Neuroscience Letters
Citation Excerpt :
With ongoing research on the genetic factors causing dystonia, more than 20 loci have been found to be associated with its occurrence [4,5]. The TOR1A (also named DYT1) gene, which was the first gene discovered to be associated with dystonia, plays a very important role in early-onset dystonia [6]. In recent years, TOR1A has been thought to be related to late-onset dystonia [7].
TOR1A plays a very important role in early-onset isolated dystonia. Studying the association between the common variants of this gene and dystonia can help us understand the connection between TOR1A mutations and this disease.
The TOR1A exon 5 was sequenced in 223 isolated dystonia patients and 210 age-adjusted controls. Patients and controls all came from Southwest China.
The following two common variants were found in the 3′-UTR of TOR1A: NM_000113.2:c.*414delG (rs35153737) and NM_000113.2:c.*824delG (rs3842225). The rs35153737 variant showed a statistically significant association with dystonia using the allele model (P = 0.035) and the dominant genetic model (P = 0.018); however, no association between rs3842225 and dystonia was found.
Our study suggests that there is an association between rs35153737 and dystonia in a southwestern Chinese population, and it may be caused by high linkage disequilibrium between this deletion and potential pathogenic variants in TOR1A.
2016 William Allan Award: Human Disease Research: Genetic Cycling and Re-cycling
2017, American Journal of Human Genetics

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Neuron

ArticleHuman gene for torsion dystonia located on chromosome 9q32-q34

Abstract

Cell

Cell

Neurol. Clin.

Cell

J. Biol. Chem.

Genomics

Cell

Meth. Enzymol.

Possible involvement of brain noradrenergic neurons in dystonia

Adv. Neurol.

Use of cyclosporin A in establishing Epstein-Barr virus-transformed human lymphoblastoid cell lines

In Vitro

Linkage analysis in a family with dominantly inherited torsion dystonia: exclusion of the pro-opiomelanocortin and glutamic acid decarboxylase genes and other chromosomal regions using DNA polymorphisms

J. Neurogenet.

Paroxysmal nonkinesigenic dystonia

Adv. Neurol.

Inheritance of idiopathic torsion dystonia among Ashkenazi Jews

Adv. Neurol.

Autosomal dominant dystonia in a large North American family: clinical features

Neurology

An analysis of the clinical course of non-Jewish autosomal dominant torsion dystonia

Movement Disorders

Comparison of the clinical course of the Jewish and nonJewish, juvenile-onset, familial torsion dystonias

Neurology

Secondary dystonia

Adv. Neurol.

Isolation and mapping of a polymorphic DNA sequence pMCT136 on chromosome 9q (D9S10)

Nucl. Acids Res.

Localization of the human dopamine beta hydroxylase (DBH) gene to chromosome 9q34

Cytogenet. Cell Genet.

The “singles” method for segregation analysis under ascertainment

Ann. Hum. Genet.

Intracerebral infusion of norepinephrine produces dystonia in the rat

Neurology

Biochemical findings in symptomatic dystonias

Adv. Neurol.

Dystonia musculorum-an inherited disease of the nervous system in the mouse

Adv. Neurol.

The torsion dystonias: literature review: genetic and clinical studies

Neurology

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Clin. Neuropharmacol.

X-linked recessive dystonia and Parkinsonism in Filipino males

Ann. Neurol.

Classification and investigation of dystonia

Linkage studies in families with dystonia: linkage analysis as a tool to locate and characterize the gene(s) for dystonia

Adv. Neurol.

Addendum to “A technique for radiolabeling DNA restriction fragments to high specific activity”

Anal. Biochem.

Actions of cytochalasins on the organization of actin filaments and microtubules in a neuronal growth cone

J. Cell Biol.

Autosomal dominant torsion dystonia in a Swedish family

Adv. Neurol.

Precise localization of human beta-globin gene complex on chromosome 11

Primary dystonias: a review of the pathology and suggestions for new directions of study

Adv. Neurol.

Age-of-onset correction available for linkage analysis (LIPED)

Am. J. Hum. Genet.

Biochemical evidence for brain neurotransmitter changes in idiopathic torsion dystonia (dystonia musculorum deformans)

Postural asymmetry and movement disorder after unilateral microinjection of adrenocorticotropin 1–24 in rat brainstem

Science

Article
Human gene for torsion dystonia located on chromosome 9q32-q34