DYT-TUBB4A (DYT4 Dystonia) New Clinical and Genetic Observations

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Bally, Julien F. ^{[1, 2, 3, 4, 5]} ; Camargos, Sarah ^[6] ; dos Santos, Camila Oliveira ^[7] ; Kern, Drew S. ^{[8, 9]} ; Lee, Teresa ^[9] ; da Silva-Junior, Francisco Pereira ^[10] ; Puga, Renato David ^[7] ; Cardoso, Francisco ^[6] ; Barbosa, Egberto Reis ^[10] ; Yadav, Rachita ^[11] ; Ozelius, Laurie J. ^[11] ; Aguiar, Patricia de Carvalho ^{[7, 10]} ; Lang, Anthony E. ^{[2, 3]}

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^[1] Univ Lausanne, Lausanne - Switzerland

^[2] Toronto Western Hosp, Edmond J Safra Program Parkinsons Dis, Toronto, ON - Canada

^[3] Toronto Western Hosp, Morton & Gloria Shulman Movement Disorders Clin, Toronto, ON - Canada

^[4] Univ Geneva, Dept Neurol, Geneva - Switzerland

^[5] Lausanne Univ Hosp, Dept Clin Neurosci, Serv Neurol, Lausanne - Switzerland

^[6] Univ Fed Minas Gerais, Dept Internal Med, Belo Horizonte, MG - Brazil

^[7] Hosp Israelita Albert Einstein, Sao Paulo, SP - Brazil

^[8] Univ Colorado, Sch Med, Dept Neurosurg, Aurora, CO - USA

^[9] Univ Colorado, Sch Med, Dept Neurol, Aurora, CO - USA

^[10] Univ Fed Sao Paulo, Dept Neurol & Neurosurg, Sao Paulo, SP - Brazil

^[11] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 - USA

• Tipo de documento: Artigo Científico
• Fonte: Neurology; v. 96, n. 14, p. E1887-E1897, APR 6 2021.
• Citações Web of Science: 0

Resumo

Objective To report 4 novel TUBB4A mutations leading to laryngeal and cervical dystonia with frequent generalization. Methods We screened 4 families including a total of 11 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, and R121W. In silico modeling showed that all variants have characteristics similar to R2G. The variants segregate with the disease in 3 of the families with evidence of incomplete penetrance in 2 of them. All 4 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 1 patient in this case series. Conclusions Our interpretation is that laryngeal involvement is a hallmark feature of DYT-TUBB4A. Nevertheless, TUBB4A mutations remain an exceedingly rare cause of laryngeal or other isolated dystonia. (AU)

• Processo FAPESP: 16/17211-2 - Pesquisa de variantes genéticas em pacientes brasileiros com distonia idiopática.
• Beneficiário: Camila Oliveira dos Santos Alves
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 14/17128-2 - Rede brasileira para o estudo das distonias: estudo de variantes em novos genes (GNAL, CIZ1, ANO3, e TUBB4) em pacientes com distonia idiopática
• Beneficiário: Patrícia Maria de Carvalho Aguiar
• Modalidade de apoio: Auxílio à Pesquisa - Regular