GNAL mutation in isolated laryngeal dystonia

Abstract

Background: Up to 12% of patients with laryngeal dystonia report a familial history of dystonia, pointing to involvement of genetic factors. However, its genetic causes remain unknown.

Method: Using Sanger sequencing, we screened 57 patients with isolated laryngeal dystonia for mutations in known dystonia genes TOR1A (DYT1), THAP1 (DYT6), TUBB4A (DYT4), and GNAL (DYT25). Using functional MRI, we explored the influence of the identified mutation on brain activation during symptomatic task production.

Results: We identified 1 patient with laryngeal dystonia who was a GNAL mutation carrier. When compared with 26 patients without known mutations, the GNAL carrier had increased activity in the fronto-parietal cortex and decreased activity in the cerebellum.

Conclusions: Our data show that GNAL mutation may represent one of the rare causative genetic factors of isolated laryngeal dystonia. Exploratory evidence of distinct neural abnormalities in the GNAL carrier may suggest the presence of divergent pathophysiological cascades underlying this disorder. © 2016 International Parkinson and Movement Disorder Society.

Keywords: Dystonia; genetic factors; neuroimaging; spasmodic dysphonia.

© 2016 International Parkinson and Movement Disorder Society.

Figures

Figure 1. (I) Mutation identified in the GNAL gene in ADLD patient

Schematic of the exon-intron structure of the short isoform of GNAL with a mutation shown in red. Protein sequence alignment of Gαolf across species is obtained from RefSeq database and aligned using MutationTester. Altered residue is colored in red. (II) Differences in brain activation during symptomatic voice production in the GNAL mutation carrier compared to healthy controls and patients with sporadic and familial LD. (A) Statistically significant differences in brain activation during symptomatic sentence and syllable production between all 27 LD patients, including the GNAL mutation carrier, sporadic and familial cases without known mutations, and 27 healthy controls are presented on a series of axial brains slices in the standard Talairach space (B) with the BOLD percent signal change in each individual shown on the bar charts at an FWE-correction of p ≤ 0.05. (C) Significant differences between one GNAL mutation carrier and 26 sporadic and familial LD patients are shown on a series of axial slices in the standard Talairach space with (D) the corresponding bar charts, depicting the individual levels of BOLD percent signal change during the production of symptomatic sentences and syllables at an FWE-correction p ≤ 0.05.