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DYT-TUBB4A (DYT4 dystonia): new clinical and genetic observations

Citation

Bally, Julien (2021), DYT-TUBB4A (DYT4 dystonia): new clinical and genetic observations, Dryad, Dataset, https://doi.org/10.5061/dryad.34tmpg4gt

Abstract

Objective: To report four novel TUBB4A mutations leading to laryngeal and cervical dystonia with frequent generalization.

Background: DYT-TUBB4A, formerly known as DYT4, has only been described in one large family and two individual cases. The clinical picture highlighted in the original family comprises laryngeal and cervical dystonia extending to generalized dystonia, plus a “hobby horse” gait disorder. The variant identified as causative in the original family was a heterozygous missense mutation R2G in exon 1 of the TUBB4A gene.

Methods: We screened four families including a total of eleven definitely affected members with a clinical picture resembling the original description.

Results: Four novel variants in the TUBB4A gene have been identified: D295N, R46M, Q424H, R121W. In silico modeling showed that all variants have similar characteristics to R2G. The variants segregate with the disease in three of the families with evidence of incomplete penetrance in two of them. All four variants would be classified as likely pathogenic. The clinical picture particularly included laryngeal dystonia (often the site of onset), associated with cervical and upper limb dystonia and frequent generalization. Laryngeal dystonia was extremely prevalent (>90%) both in the original cases and in this case series. The “hobby horse” gait was evident in only one patient in this case series. Interpretation: laryngeal involvement is a hallmark feature of DYT-TUBB4A. Nevertheless, TUBB4A mutations remain an exceedingly rare cause of laryngeal or other isolated dystonia.