DYT6 dystonia: Mutation screening, phenotype, and response to deep brain stimulation

Abstract

Mutations in THAP1, a gene encoding a nuclear pro-apoptotic protein, have been associated with DYT6 dystonia. First reports on the phenotype of DYT6 dystonia show an early onset dystonia with predominant cranio-cervical and laryngeal involvement. Here we assessed the frequency and phenotype of THAP1 mutation carriers in a large Dutch cohort of adult-onset (≥26 years) dystonia (n = 388) and early-onset dystonia (n = 67) patients. We describe the phenotype of DYT6 dystonia patients and their response on GPi DBS. Overall, 3 nonsynonymous heterozygous mutations were detected in the early-onset group (4.5%). Two DYT6 families were identified, showing a heterozygous phenotype. All patients had segmental or generalized dystonia, often associated with profound oromandibular and laryngeal involvement. No nonsynonymous mutations were found in patients with adult-onset focal dystonia. Rare synonymous variants were identified in conserved regions of THAP1, two in the adult-onset cervical dystonia group and one in the control group. Four DYT6 dystonia patients were treated with GPi DBS with moderate to good response on motor function but marginal benefit on speech.

Identification and functional analysis of novel THAP1 mutations

“…Mutation frequency in the literature ranges from about 0.5-1.8% for mainly unselected primary dystonia patients. [9][10][11][12][13]15 Thus, THAP1 mutations are rare in dystonia patients. About 50 different THAP1 mutations have been reported to date.…”

“…About 50 different THAP1 mutations have been reported to date. 2,[6][7][8][9][10][11][12][13][14][15][16][17]22 One-third of the mutations represents missense mutations located in the THAP domain and is thought to interrupt DNA binding. Another one-third of the mutations are considered to disturb the NLS, such as nonsense mutations, small insertions/deletions, or missense mutations within the NLS.…”

“…Interestingly, however, most studies demonstrate a higher (but not significantly higher) frequency of the variant in dystonia patients compared with controls. 9,10,23,24 The association may occur only in subtypes of dystonia. To date, the total number of carriers is too small to obtain significant differences for this rare variant.…”

“…5 About 50 different THAP1 mutations have been reported to date including missense, nonsense, and frameshift mutations. 2,[6][7][8][9][10][11][12][13][14][15][16][17] In addition to the disease-causing mutations, two variants, c.-237_236delinsTT and c.71+9C4A, in the non-coding region of THAP1 may be associated with dystonia. 9,13 DYT6 typically manifests as early-onset generalized or segmental dystonia, frequently with prominent laryngeal involvement and a rostrocaudal evolution of symptoms.…”

“…9,13 DYT6 typically manifests as early-onset generalized or segmental dystonia, frequently with prominent laryngeal involvement and a rostrocaudal evolution of symptoms. [6][7][8][9][10][11][12][13][14][15] The phenotype though is highly variable even within a single family ranging from unaffected carriers to generalized dystonia. 8,9,13 Mutation frequency varies between 0.5% in unselected primary dystonia patients 13 and 25% in non-DYT1 multiplex families in whom at least one individual had non-focal involvement and onset of symptoms by o 22 years.…”