UNASSIGNED: DYT-TUBB4A, formerly known as DYT4, has not been comprehensively described as only one large family and three individual cases have been published. We have recently described an in depth genetic and protein structural analysis of eleven additional cases from four families with four new pathogenic variants. We aim to report on the phenomenology of these cases suffering from DYT-TUBB4A and to perform a comprehensive review of the clinical presentation and treatment responses of all DYT-TUBB4A cases reported in the literature.
UNASSIGNED: The clinical picture was typically characterized by laryngeal dystonia (more than three quarters of all cases), associated with cervical dystonia, upper limb dystonia and frequent generalization. Extension of the dystonia to the lower limbs, creating the famous \"hobby horse\" gait, was present in more than 20% of cases (in only one of ours). Globus pallidus pars interna (GPi) deep brain stimulation (DBS), performed in 4 cases, led to a good improvement with greatest benefit in motoric and less benefit in laryngeal symptoms. Medical treatment was generally rather poorly effective, except some benefit from propranolol, tetrabenazine and alcohol intake.
UNASSIGNED: Laryngeal involvement is a hallmark of DYT-TUBB4A. Symptomatic treatment with GPi-DBS led to the greatest benefit in motoric symptoms. Nevertheless, TUBB4A mutations remain an exceedingly rare cause of laryngeal or other isolated dystonia and regular screening of TUBB4A mutations for isolated dystonias has a very low yield.

BACKGROUND: Mutations in TUBB4A have recently been implicated in two seemingly different disease entities, namely DYT4-isolated dystonia and hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), a disorder characterized by considerable clinical variability. While several follow-up studies confirmed the importance of TUBB4A mutations in the development of H-ABC, their contribution to isolated dystonia remains uncertain.
METHODS: We screened the TUBB4A coding regions in a large population of 709 isolated dystonia patients of German/Austrian ancestry as well as in 376 ancestry-matched control subjects by means of Sanger sequencing and high-resolution melting. In addition, we assessed the overall frequency of rare non-synonymous TUBB4A genetic variation in the huge exome dataset released by the Exome Aggregation Consortium (ExAC).
RESULTS: We were unable to identify any possibly pathogenic sequence alteration in either patients or controls. According to ExAC, the overall prevalence of rare missense and loss-of-function alleles in the TUBB4A gene can be estimated at ∼1:706.
CONCLUSIONS: In accordance with previous work, our data indicate that TUBB4A coding mutations do not play a critical role in the broad population of isolated dystonia patients. Rather, isolated dystonia as seen in DYT4 might be an exceptional feature occurring in the heterogeneous phenotypic spectrum due to TUBB4A mutations.

Recently, mutations in the TUBB4A gene have been found to underlie hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) syndrome, a rare neurodegenerative disorder of infancy and childhood. TUBB4A mutations also have been described as causative of DYT4 (\"hereditary whispering dysphonia\"). However, in DYT4, brain imaging has been reported to be normal and, therefore, H-ABC syndrome and DYT4 have been construed to be different disorders, despite some phenotypic overlap. Hence, the question of whether these disorders reflect variable expressivity or pleiotropy of TUBB4A mutations has been raised. We report four unrelated patients with imaging findings either partially or totally consistent with H-ABC syndrome, who were found to have TUBB4A mutations. All four subjects had a relatively homogenous phenotype characterized by severe generalized dystonia with superimposed pyramidal and cerebellar signs, and also bulbar involvement leading to complete aphonia and swallowing difficulties, even though one of the cases had an intermediate phenotype between H-ABC syndrome and DYT4. Genetic analysis of the TUBB4A gene showed one previously described and two novel mutations (c.941C>T; p.Ala314Val and c.900G>T; p.Met300Ile) in the exon 4 of the gene. While expanding the genetic spectrum of H-ABC syndrome, we confirm its radiological heterogeneity and demonstrate that phenotypic overlap with DYT4. Moreover, reappraisal of previously reported cases would also argue against pleiotropy of TUBB4A mutations. We therefore suggest that H-ABC and DYT4 belong to a continuous phenotypic spectrum associated with TUBB4A mutations.