THAP1 (DYT6) mutations are a frequent cause of generalized dystonia with prominent spasmodic dysphonia

Objective: To evaluate the mutational spectrum of THAP1 in different types of dystonia.

Background: DYT6 is a form of primary early-onset torsion dystonia. Unlike in DYT1 dystonia, symptoms seem to frequently involve the cranio-cervical region. Recently, two mutations in the THAP1 gene have been identified.

Patients and methods: We comprehensively screened THAP1 by sequence analysis and quantitative real-time PCR in 160 dystonia patients with an early age at onset, generalized dystonia, a positive family history, and/or with facial/laryngeal involvement. Another 160 dystonia patients were tested for the reported mutations and novel THAP1 variants, and at least 280 neurologically healthy controls were screened for the novel changes.

Results: We identified two small deletions (c.388_389delTC; c.474delA) among the 160 comprehensively tested patients (1.2%). No mutations were found in the other screened samples as well as in the index patient of the DYT4 family with dysphonia. Both mutation carriers had disease onset in childhood with laryngeal dystonia and later developed generalized dystonia. Thus, two of three patients with early-onset generalized dystonia with oromandibular involvement (67%) carried THAP1 mutations. For one patient, two family members with subtle motor signs were found to carry the same mutation. A rare variant in the 5'UTR (-236,235GA>TT) of the transcript was found in 20/320 patients and in 7/355 controls (p=0.0054).

Conclusions: Mutations in THAP1 seem to play only a minor role in patients with different, mainly focal forms of dystonia. However, they are associated with early-onset generalized dystonia with spasmodic dysphonia. This combination of features may be a red flag towards DYT6 dystonia. In addition to the identified mutations, a rare non-coding variant in THAP1 may increase the risk for dystonia.