The role of DYT1 in primary torsion dystonia in Europe

Abstract

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous movement disorder. DYT1 on chromosome 9q34 was the first PTD gene to be mapped. A 3-bp (GAG) deletion in this gene was reported to account for almost all early limb-onset generalized PTD. No relationship has been found with DYT1 in patients with prominent craniocervical involvement. To elucidate the DYT1-associated phenotype, we analysed the DYT1 mutation in 150 PTD patients, either sporadic or index cases from small PTD families. Twenty-two patients were positive for the GAG deletion in the DYT1 gene. Fifteen of them presented with the typical DYT1 phenotype (early, limb-onset generalized dystonia without spread to craniocervical muscles), four had limb-onset dystonia with spread to craniocervical muscles, two patients had arm-onset segmental dystonia and one had focal right-arm dystonia. One-hundred and twenty-eight patients were negative for the DYT1 mutation. Forty-six of them had segmental dystonia and 59 had focal dystonia. The other 23 patients presented with generalized dystonia, either with craniocervical involvement (13 patients) or without spread to the craniocervical region (typical DYT1 phenotype-10 patients). These data confirm the importance of the GAG deletion in European cases of PTD, and indicate phenotypic and genotypic heterogeneity.

Inherited and de novo mutations in sporadic cases of DYT1-dystonia

“…16 Solitary cases of DYT1-dystonia have been reported in studies where molecular analyses of the DNA of the parents were not done. 10,11 Apparently sporadic cases because of the low penetrance have also been reported earlier. 20 The difficulties in genetic counselling concerning dystonia is partly due to the low penetrance of many of the hereditary forms of dystonia and partly due to the variable phenotype within the same type of dystonia and, as shown in our study, the occurrence of de novo mutations.…”

“…10,11 DYT1-dystonia is by clinical and later also molecular genetic studies shown to be inherited as an autosomal, dominant trait with 30 ± 40% penetrance and localised on chromosome 9q34. 12 The gene encodes an ATP-binding protein, TorsinA.…”

Genetic evaluation for TOR1-A (DYT1) in Brazilian patients with dystonia

“…We found an in-frame 3-bp deletion (GAG deletion), in TOR1-A gene, in two familial patients. To date, a GAG deletion in exon 5 of TOR1-A was related with almost all cases of DYT1 dystonia 3,4,5 . Our two patients with TOR1-A mutation presented typical DYT1 clinical features, with onset of symptoms by legs spraying to generalization, except for cervical involvement.…”

“…The majority of the patients DYT1 present generalization, caudal to rostral, in a time frame of 5 years. However, cranialcervical involvement has also been described as part of exceptional phenotypes of DYT1 dystonia, even focal or segmental disease 5,6,7,8 . We did not find DYT1 cases started by neck or staying in focal or segmental types.…”

“…A 3-base pair (GAG) deletion in the coding region of the TOR1-A gene, located at chromosome 9q34, causes the expression of an abnormal protein named torsinA, a protein . Patients with TOR1-A mutations (delE302/303) usually have the onset in a limb with rapid spread to generalized dystonia, with cranio-cervical sparing 4,5,6,7 . However, the spectrum of dystonia produced by the TOR1-A GAG deletion is broad and severity may vary in patients even within siblings.…”