Unraveling Molecular Mechanisms of THAP1 Missense Mutations in DYT6 Dystonia.

Mutations in THAP1 (THAP domain-containing apoptosis-associated protein 1) are responsible for DYT6 dystonia. Until now, more than eighty different mutations in THAP1 gene have been found in patients with primary dystonia, and two third of them are missense mutations. The potential pathogeneses of these missense mutations in human are largely elusive. In the present study, we generated stable transfected human neuronal cell lines expressing wild-type or mutated THAP1 proteins found in DYT6 patients. Transcriptional profiling using microarrays revealed a set of 28 common genes dysregulated in two mutated THAP1 (S21T and F81L) overexpression cell lines suggesting a common mechanism of these mutations. ChIP-seq showed that THAP1 can bind to the promoter of one of these genes, superoxide dismutase 2 (SOD2). Overexpression of THAP1 in SK-N-AS cells resulted in increased SOD2 protein expression, whereas fibroblasts from THAP1 patients have less SOD2 expression, which indicates that SOD2 is a direct target gene of THAP1. In addition, we show that some THAP1 mutations (C54Y and F81L) decrease the protein stability which might also be responsible for altered transcription regulation due to dosage insufficiency. Taking together, the current study showed different potential pathogenic mechanisms of THAP1 mutations which lead to the same consequence of DYT6 dystonia.

Analysis of DYT1 and DYT6 in Thai patients with primary dystonia

@# DYT1 and DYT6 dystonias are the two most common genetic primary dystonias. However, they are rare in the Asian population and have never been reported in Thailand. DYT6 dystonia typically presents with craniosegmental dystonia with speech involvement, whereas DYT1 dystonia typically presents with lower limb dystonia, which tends to become generalized over time. Methods: Blood samples were collected from 14 patients with primary dystonia evaluated in five tertiary hospitals in Thailand. Genotyping of the TOR1A and THAP1 gene was performed. Results: Two patients were found to have a missense mutation, p.M143V (c.427A>G), in exon 3 of the THAP1 gene confirming the diagnosis of DYT6 dystonia. One patient was a woman who developed blepharospasm and lower cranial dystonia at the age of 38 years. Her dystonia spread to the neck and arm six months later. The other patient developed focal hand dystonia at the age of 34 years. The TOR1A mutation was not identified in any of these 14 patients.

Long-term effect on dystonia after pallidal deep brain stimulation (DBS) in three members of a family with a THAP1 mutation.

Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an established treatment in patients with severe dystonia. However, factors predicting outcome are largely unknown and motor improvement in DYT6 patients after DBS has been reported to be poorer as compared to, e.g., DYT1 patients. Here, we report the course of clinical improvement for up to 11 years of pallidal DBS in three male patients belonging to the same family with early-onset generalized or segmental dystonia due to a heterozygous THAP1 gene mutation (DYT6). All patients showed an initial effective response to pallidal DBS with a mean of 56.9 ± 11.7% improvement in the Burke-Fahn-Marsden Dystonia motor and 45.5 ± 22.4% in the disability score at 1-year follow-up. The long-term outcome of pallidal DBS was favorable in two patients (39, 67% motor improvement, respectively). Our findings demonstrate that motor improvement is variable and may depend on disease severity, disease duration, and clinical presentation. Overall, our observation supports pallidal DBS as an important treatment option in patients with DYT6 dystonia.

Pallidal deep brain stimulation for the treatment of DYT6 dystonia: a case report and review of literature.

Little is known about the results of pallidal deep brain stimulation (DBS) in DYT6 dystonia. This will be the first report of DYT6 dystonia treated with pallidal DBS from Iran. A 21 years old male patient with DYT6 dystonia underwent bilateral deep brain stimulation. The target of DBS was the sensorimotor region of the posteroventral globus pallidus internus (GPi). DBS parameters included an amplitude of 2.7 V, frequency of 160 Hz, and pulse width of 90 µs which were adjusted according to the patient's response 12 months after surgery. Treatment outcome was measured by the patient's Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) score. Before surgery, the patient's BFMDRS score was 32. However, BFMDRS score reduced to 7 at one year follow up after surgery (78% improvement of total score). Dystonic symptoms of extremities and mouth completely resolved. Also speech and swallowing function significantly improved. Although previous observations reported a poor to moderate response in speech, we found DBS as an effective treatment not only for dystonic features, but also for speech improvement of DYT6 dystonia.