Dystonia

INDEX

 

TUBB4 (DYT4) Hereditary “whispering dysphonia,” later designated DYT4, was first described in an Australian family with 20 affected family members1.

Genetics

A novel mutation was identified in the tubulin beta-4 (TUBB4) gene as the likely genetic cause of “whispering dysphonia”.

Pathophysiology

TUBB4 expression was subsequently analyzed in three different cell types revealing that the amount of the TUBB4 protein in the heterozygous mutation carrier was significantly reduced compared to controls. Furthermore, a second missense mutation was found in an independent patient with familial craniocervical dystonia.
The spectrum of TUBB4 mutations has now been shown to be much broader and includes hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) and similar phenotypes], thereby challenging the classification of DYT4 as an isolated form of dystonia.

Mode of Inheritance

DYT4 dystonia follows an autosomal dominant mode of inheritance with seemingly high penetrance based on lack of unaffected obligate carriers and a high number of affected individuals in large sibships.

Clinical Presentation

The phenotype of this disease is clinically characterized by craniocervical dystonia with prominent spasmodic dysphonia and shows variable expressivity within the family. The dystonia frequently generalizes and is at least partially responsive to alcohol and propranolol. In addition, affected individuals have characteristic clinical features beyond the motor phenotype, ie, a thin face and body habitus that completely co- segregated with the dystonia phenotype.

 

Video 1. Patient with TUBB4 mutation, with severe dysphonia.

Response to treatment (beta blocker, tetrabenazine) shown.

(vv)Queensland.mp4(tt)

 

 

 

 

 

(vv)Queensland.mp4(tt)

References

1            Martino D, Espay AJ, Fasano A, Morgante F. Disorders of Movement: A Guide to Diagnosis and Treatment. Berlin-Heidelberg: Springer, 2016.