Raslan Ivana R, Silva Thiago Yoshinaga Tonholo, Kok Fernando, Rodrigues Marcelo M, Aragão Marcelo M, Pinho Ricardo S, França Marcondes C, Barsottini Orlando G, Pedroso José Luiz
From the Department of Ataxia Unit of the Federal University of São Paulo (UNIFESP) (I.R.R., T.Y.T.S., O.G.B., J.L.P.); Neurology Department (F.K.), Hospital das Clínicas da Universidade de São Paulo and Mendelics; Department of Neurology and Neurosurgery (M.M.R., M.M.A., R.S.P.), Universidade Federal de São Paulo (UNIFESP); and Department of Neurology (M.C.F.), Universidade de Campinas (UNICAMP), Brazil.
Neurol Genet. 2024 Apr 23;10(3):e200153. doi: 10.1212/NXG.0000000000200153. eCollection 2024 Jun.
Congenital ataxias are rare hereditary disorders characterized by hypotonia and developmental motor delay in the first few months of life, followed by cerebellar ataxia in early childhood. The course of the disease is predominantly nonprogressive, and many patients are incorrectly diagnosed with cerebral palsy. Despite significant advancements in next-generation sequencing in the past few decades, a specific genetic diagnosis is seldom obtained in cases of congenital ataxia. The aim of the study was to analyze the clinical, radiologic, and genetic features of a cohort of Brazilian patients with congenital ataxia.
Thirty patients with a clinical diagnosis of congenital ataxia were enrolled in this study. Clinical and demographic features and neuroimaging studies were analyzed. Genetic testing (whole-exome sequencing) was also performed.
A heterogeneous pattern of genetic variants was detected. Eighteen genes were involved: , , , , , , , , , , , , , , , , and . Pathogenic/likely pathogenic variants involving 11 genes (, , , , , , , , , , and ) were identified in 46.7% of patients. Variants of uncertain significance involving 8 genes were detected in 33.3% of patients. Congenital ataxias were characterized by a broad phenotype. A genetic diagnosis was more often obtained in patients with cerebellar-plus syndrome than in patients with a pure cerebellar syndrome.
This study re-emphasizes the genetic heterogeneity of congenital ataxias and the absence of a clear phenotype-genotype relationship. A specific genetic diagnosis was established in 46.7% of patients. Autosomal dominant, associated with sporadic cases, was recognized as an important genetic inheritance. The results of this analysis highlight the value of whole-exome sequencing as an efficient screening tool in patients with congenital ataxia.
先天性共济失调是一种罕见的遗传性疾病，其特征为出生后最初几个月出现肌张力减退和发育性运动迟缓，随后在幼儿期出现小脑性共济失调。该疾病病程多为非进行性，许多患者被误诊为脑瘫。尽管在过去几十年里新一代测序技术取得了显著进展，但先天性共济失调病例很少能获得特定的基因诊断。本研究的目的是分析一组巴西先天性共济失调患者的临床、放射学和基因特征。
本研究纳入了30例临床诊断为先天性共济失调的患者。分析了临床和人口统计学特征以及神经影像学研究结果。还进行了基因检测（全外显子测序）。
检测到基因变异的异质性模式。涉及18个基因：[此处未列出具体基因名称]。在46.7%的患者中鉴定出涉及11个基因（[此处未列出具体基因名称]）的致病/可能致病变异。在33.3%的患者中检测到涉及8个基因的意义未明变异。先天性共济失调具有广泛的表型特征。小脑加综合征患者比单纯小脑综合征患者更常获得基因诊断。
本研究再次强调了先天性共济失调的基因异质性以及缺乏明确的表型-基因型关系。46.7%的患者获得了特定的基因诊断。常染色体显性遗传，与散发病例相关，被认为是一种重要的遗传方式。该分析结果突出了全外显子测序作为先天性共济失调患者有效筛查工具的价值。
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