Dataset Information

Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene.

ABSTRACT: OBJECTIVE:A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family. METHODS:Genome-wide linkage analysis was carried out in 14 family members followed by genome sequencing in 2 individuals. The index patient underwent a detailed neurological follow-up examination, including electrophysiological studies and magnetic resonance imaging scanning. Biopsies of the skin and olfactory mucosa were obtained, and expression levels of TUBB4 mRNA were determined by quantitative real-time polymerase chain reaction in 3 different cell types. All exons of TUBB4 were screened for mutations in 394 unrelated dystonia patients. RESULTS:The disease-causing gene was mapped to a 23cM region on chromosome 19p13.3-p13.2 with a maximum multipoint LOD score of 5.338 at markers D9S427 and D9S1034. Genome sequencing revealed a missense variant in the TUBB4 (tubulin beta-4; Arg2Gly) gene as the likely cause of disease. Sequencing of TUBB4 in 394 unrelated dystonia patients revealed another missense variant (Ala271Thr) in a familial case of segmental dystonia with spasmodic dysphonia. mRNA expression studies demonstrated significantly reduced levels of mutant TUBB4 mRNA in different cell types from a heterozygous Arg2Gly mutation carrier compared to controls. INTERPRETATION:A mutation in TUBB4 causes DYT4 dystonia in this Australian family with so-called whispering dysphonia, and other mutations in TUBB4 may contribute to spasmodic dysphonia. Given that TUBB4 is a neuronally expressed tubulin, our results imply abnormal microtubule function as a novel mechanism in the pathophysiology of dystonia.

SUBMITTER: Lohmann K

PROVIDER: S-EPMC6956988 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene.

Lohmann Katja K Wilcox Robert A RA Winkler Susen S Ramirez Alfredo A Rakovic Aleksandar A Park Jin-Sung JS Arns Björn B Lohnau Thora T Groen Justus J Kasten Meike M Brüggemann Norbert N Hagenah Johann J Schmidt Alexander A Kaiser Frank J FJ Kumar Kishore R KR Zschiedrich Katja K Alvarez-Fischer Daniel D Altenmüller Eckart E Ferbert Andreas A Lang Anthony E AE Münchau Alexander A Kostic Vladimir V Simonyan Kristina K Agzarian Marc M Ozelius Laurie J LJ Langeveld Antonius P M AP Sue Carolyn M CM Tijssen Marina A J MA Klein Christine C

Annals of neurology 20130417 4

<h4>Objective</h4>A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family.<h4>Methods</h4>Genome-wide linkage analysis was carried out in 14 family members followed by genome sequencing in 2 individuals. The index patient underwent a detailed neurological follow-up examination, including electrophysiological studi ...[more]

PMID: 23595291

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Project description:Background:Although considerable research has focused on the etiology and symptomology of adductor focal laryngeal dystonia (AD-FLD), little is known about the correlation between clinicians' ratings and patients' perception of this voice disturbance. This study has five objectives: first, to determine if there is a relationship between subjects' symptom-severity and its impact on their quality of life; to compare clinicians' ratings with subjects' perception of the individual characteristics and severity of AD-FLD; to document the subjects' perception of changes in dysphonia since diagnosis; to record the frequency of voice arrest during connected speech; and, finally, to calculate inter-clinician reliability based on results from the Unified Spasmodic Dysphonia Rating Scale (USDRS) (Stewart et al, J Voice 1195-10, 1997). Methods:Sixty subjects with AD-FLD who were receiving ongoing injections of BoNT participated in this study. Subjects' mean age was 60.78 years and their mean duration of symptoms was 16.1 years. Subjects completed the Disease Symptom Questionnaire (DSQ) (specifically designed for this study) and the Voice Handicap Index-10 (VHI-10) (Jacobson et al, Am J Speech Lang Pathol 6:66-70, 1997) to measure the symptoms of their dysphonia and the impact of the disease on their quality of life.Two speech-language pathologists and two laryngologists used the Voice Arrest Measure (VAM) (specifically designed for this study) and the USDRS to independently rate voice recordings of 56/60 subjects. Results:The mean VHI-10 score was 21.3 which is clinically significant. The results of the DSQ and the USDRS were highly correlated. The most severe symptoms identified by both subjects and clinicians were roughness, strain-strangled voice quality, and increased expiratory effort. Voice arrest, aphonia, and tremor were uncommon. Subjects rated their current voice quality at the time of reinjection (i.e., at the time of the study) as significantly better than at the time of their initial AD-FLD diagnosis (p < 0.0001). Inter-clinician reliability on the USDRS was significant at the 0.001 level. Conclusions:The findings from the VHI-10 suggest that AD-FLD has a profound impact on quality of life. The results of the DSQ and the USDRS suggest that there is a strong correlation between subjects' perception and clinicians' assessment of the individual symptoms and the severity of the dysphonia. The findings from the VAM suggest that voice arrests are infrequent in subjects with AD-FLD who are receiving ongoing BoNT injections. The strong inter-clinician reliability on the USDRS suggests that it is an appropriate measure for identifying symptoms and severity of AD-FLD.

Dataset Information

Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene.

Publications

Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene.

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