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GNAL was identified as a cause of dystonia in patients from North America, Europe and Asia. In this study, we aimed to investigate the prevalence of GNAL variants in Brazilian patients with dystonia. Ninety-one patients with isolated idiopathic dystonia, negative for THAP1 and TOR1A mutations, were screened for GNAL variants by Sanger sequencing. Functional characterization of the Gαolf protein variant was performed using the bioluminescence resonance energy transfer assay. A novel heterozygous nonsynonymous variant (p.F133L) was identified in a patient with cervical and laryngeal dystonia since the third decade of life, with no family history. This variant was not identified in healthy Brazilian controls and was not described in 63000 exomas of the ExAC database. The F133L mutant exhibited significantly elevated levels of basal BRET and severely diminished amplitude of response elicited by dopamine, that both indicate su bstantial functional impairment of Gαolf in transducing receptor signals, which could be involved in dystonia pathophysiology. GNAL mutations are not a common cause of dystonia in the Brazilian population and have a lower prevalence than THAP1 and TOR1A mutations. We present a novel variant that results in partial Gαolf loss of function.

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.