Identification of a novel THAP1 mutation at R29 amino‐acid residue in sporadic patients with early‐onset dystonia

Dystonia is a movement disorder characterized by involuntary, sustained muscular contractions affecting one or more sites of the body and abnormal postures. The clinical spectrum of dystonia is diverse: however, the most common form of the disease is primary torsion dystonia (PTD). PTD usually onsets in infancy or adolescence and affects the trunk, neck, or limbs. Two genes are associated with PTD, DYT1 (OMIM 128100; TOR1A) and DYT6 (OMIM 609520; THAP1). Mutations in THAP1 were, first, identified in families presenting with cranial or cervical dystonia that frequently progressed to involve other body regions, and later, in families presenting with early-onset generalized dystonia with prominent spasmodic dysphonia. Here, 24 patients presenting with either generalized (6) or cervical dystonia (18) were investigated for the presence of THAP1 mutations. The mean age at onset was 48 years (range 9–77 years). All patients provided written informed consent to participate in this study. Sequencing analysis of the coding region of the THAP1 gene revealed the presence of a novel c.86G>A transition resulting in p.Arg29Gln in two sporadic cases suffering from early-onset cervical dystonia and early-onset generalized dystonia, respectively. This novel mutation, located in exon 2 of the THAP1 gene, affects an amino-acid previously identified as mutated in families presenting with multifocal and generalized dystonia. Furthermore, R29 amino acid is conserved between species; suggesting, p.Arg29Gln is likely to be pathogenic. Although both p.Arg29Gln mutation carriers are from the same geographical region, there is no evidence of a common founder. A novel silent, mutation which resulted in c.81T>C transition causing p.Leu27Leu was also identified in a sporadic, late-onset dystonia patient presenting with involuntary movements in the neck at the age of sixty; however, its pathogenic role remains unclear. Both novel THAP1 mutations were absent in a Spanish series of 182 control chromosomes. We concluded that pathogenic mutations were only found in early-onset cases. THAP1 mutations occur throughout the entire gene; however, many seem to cluster in the THAP domain of the protein, including the novel THAP1 mutations described here (Fig. 1). It has been suggested that mutations in the THAP domain may reduce the DNA binding ability of THAP; therefore we speculate that mutations at R29 may also act via this mechanism. Clinical features of both patients carrying p.Arg29Gln mutation are described below. This case is a 55 years old man who, at the age of 9, presented with a right-sided torticollis which persisted for more than a year. A surgical intervention was given around his neck and in the right upper limb. Since then, no improvement was determined however the disease showed slow progression. At 54, he noted having cognitive changes and difficulties in speech and ingestion. There was no family history of movement disorders and his mother died with cognitive decline of late onset. Dystonia was mainly present in the face and proximal left upper limb. Left sided torticollis was found with a tendency of retrocollis and fluctuating involvement of both platysma. The trapezia and ECMs were hypertrophic. MRI brain was normal. The cervical spine showed mild disc protrusion at C5-C6 and C6-C7 without radicular involvements. To control the dystonia, increased dose of Botulinum toxin (Dysport), up to 700 units, was required. This case is a 33 years old man who, at the age of 14, presented with abnormal pain sensation in the left upper limb. He progressed to develop dystonic movements in the hand which usually presented as wrist flexion on the radial side and, occasionally, on the ulnar side. In addition, the left upper limb showed forced abduction. Dystonia has now spread to the left foot. His grandmother was diagnosed as having Parkinson’s disease and his great-aunt with possible blepharospasm. Brain MRI was normal and cervical spine showed minimal disc protrusion at C5-C6 without any compression noted. The arm abduction was controlled with botulinum toxin; however, dystonia remained uncontrolled and no additional medication was given. Serum copper, ceruloplasmin, calcium, phosphate, ferritin, and glucose were normal in both cases. To summarize, THAP1 mutations may be present in sporadic, early-onset, cervical, and generalized dystonia.