Clinical and genetic investigation of ataxia with vitamin E deficiency (AVED), a treatable form of neuro-muscular disease

A Ataxia por Deficiencia de Vitamina E (AVED) e uma doenca neurodegenerativa e progressiva caracterizada principalmente por ataxia espinocerebelar progressiva, arreflexia, disartria, propriocepcao prejudicada e acentuada deficiencia de vitamina E no plasma. Possui alta semelhanca clinica com a forma mais comum de ataxia autossomica recessiva, a ataxia de Friedreich (AF), na qual e muitas vezes confundida. A AVED desenvolve-se em decorrencia de mutacao no gene que codifica a proteina de transferencia de alfa-tocoferol (TTPA) e possui padrão de heranca autossomica recessiva. O tratamento consiste em suplementacao com altas doses diarias de vitamina E. O presente estudo teve como objetivo avaliar, do ponto de vista clinico e genetico, uma serie de 9 pacientes diagnosticados com AVED em acompanhamento no Ambulatorio de Neurogenetica do Hospital das Clinicas de Sao Paulo (HC-FMUSP) e comparar os dados obtidos com a literatura mundial, assim como oferecer Aconselhamento Genetico aos pacientes e suas familias. A coleta de dados foi realizada no Ambulatorio de Neurogenetica do HC-FMUSP. Para a avaliacao funcional, foi utilizada a escala Scale for the Assessment and Rating of Ataxia (SARA). O material genético dos participantes foi sequenciado por sequenciamento de nova geração (NGS) e analisado por programas de bioinformatica. Ao todo, 5 mutações foram identificadas, sendo a p.Thr172Leufs*5 a mais frequente, seguida da p.Glu249Asnfs*15, ambas relatadas na literatura como sendo responsáveis por uma forma grave da doenca. Tambem foi identificada a mutacao missense p.Ala120Thr e duas variantes nunca antes descritas na literatura: p.Ala58Pro e p.Arg134Pro. Este estudo demonstrou que, em concordancia com a literatura, a suplementacao com vitamina E em pacientes com AVED cessou a progressao da doenca nos pacientes investigados. De modo geral, mutacoes que causem a perda de funcao do gene estao associadas a inicio precoce dos sintomas e progressao rapida, enquanto que variantes missense tendem a causar um quadro mais leve da doenca. Esta relacao, entretanto, tem exceções. A investigação molecular do gene TTPA dos pacientes com diagnostico clinico e bioquimico de AVED deve ser preconizado, uma vez que auxilia no Aconselhamento Genético e prognóstico da doençaAtaxia with vitamin E deficiency (AVED) is a progressive and neurodegenerative disease mainly characterized by progressive spinocerebellar ataxia, areflexia, dysarthria, impaired proprioception and marked reduced plasma levels of vitamin E. Clinically, it resembles the most common form of recessive autosomal ataxia, Friedreich ataxia (FA). AVED develops as a result of mutation in the gene encoding alpha-tocopherol transfer protein (TTPA) and is inherited in an autosomal recessive inheritance pattern. The treatment consists of supplementation with high doses of vitamin E. The present study aimed to evaluate, from the clinical and genetic point of view, 9 patients diagnosed with AVED under follow-up at the Neurogenetics Out-Patient Service of Hospital das Clinicas de Sao Paulo (HC-FMUSP) and compare the data obtained with the world literature, as well as offer genetic counseling to patients and their families. Data collection was performed at the Neurogenetics Ambulatory of HC-FMUSP. For a functional assessment, the Scale for the Assessment and Rating of Ataxia (SARA) was performed. Participants\' genetic material was sequenced by next generation sequencing (NGS) and analyzed by bioinformatics softwares. At all, 5 mutations were identified. The p.Thr172Leufs*5 mutation was the most frequent, followed by p.Glu249Asnfs*15, both reported in the literature associated as a severe form of the disease. It was also identified the missense mutation p.Ala120Thr and two variants never reported in the literature before: p.Ala58Pro and p.Arg134Pro. This study showed that, in accordance with the literature, vitamin E supplementation in patients with AVED ceased disease progression in the investigated patients. In general, mutations that cause loss of gene function are associated with early onset of symptoms and rapid progression, while missense variants tend to cause a milder picture of the disease. This relationship, however, has exceptions. Molecular investigation of the TTPA gene of patients with clinical and biochemical diagnosis of AVED should be recommended, as it helps in genetic counseling and disease prognosi