Clinical and Genetic Characterization of a Cohort of Brazilian Patients With Congenital Ataxia

Abstract

Background and objectives: 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.

Methods: 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.

Results: A heterogeneous pattern of genetic variants was detected. Eighteen genes were involved: ALDH5A1, BRF1, CACNA1A CACNA1G, CC2D2A, CWF19L1, EXOSC3, ITPR1, KIF1A, MME, PEX10, SCN2A, SNX14, SPTBN2, STXBP1, TMEM240, THG1L, and TUBB4A. Pathogenic/likely pathogenic variants involving 11 genes (ALDH5A1, CACNA1A, EXOSC3, MME, ITPR1, KIF1A, STXBP1, SNX14, SPTBN2, TMEM240, and TUBB4A) 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.

Discussion: 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.

Figure 1. Phenotype Features and Cerebellar Pattern on Brain MRI in Brazilian Patients With Congenital Ataxia

Figure 2. Brain MRI Findings in Brazilian Patients With Congenital Ataxia

(A) Sagittal T1-weighted showing global cerebellar hypoplasia in a patient with a pathogenic heterozygous mutation in the ITPR1 gene. (B) Axial FLAIR-weighted and (C) coronal T2-weighted showing global cerebellar hypoplasia in a patient with a pathogenic homozygous mutation in the ALDH5A1 gene. (D) Sagittal T1-weighted and (E) axial FLAIR-weighted showing global cerebellar hyperplasia in a patient with unknown genetic etiology. (F) Sagittal T1-weighted showing global cerebellar hypoplasia in a patient with a VUS in the THG1L gene. (G) Axial T2-weighted showing normal cerebellar structure in a patient with unknown genetic etiology. (H) Coronal T2-weighted brain MRI showing unilateral cerebellar hemisphere hypoplasia in a patient with unknown genetic etiology. (I) Sagittal T1-weighted showing global cerebellar hypoplasia in a patient with a monoallelic pathogenic mutation in the KIF1A gene. (J) Sagittal T1-weighted showing global cerebellar hypoplasia in a patient with a VUS in the SCN2A gene. (K) Coronal T2-weighted showing cerebellar dysplasia, followed by hypoplasia of the left cerebellar hemisphere and cortical polymicrogyria in a patient with a novel pathogenic monoallelic mutation in the MME gene. (L) Axial T2-weighted showing abnormal fusion of the basal ganglia, cortical polymicrogyria, and cerebellar dysplasia in patient with a pathogenic mutation in the MME gene. FLAIR = fluid-attenuated inversion recovery.

Figure 3. Relationships Between Cerebellar Structural Abnormalities on Brain MRI and Genetic Features of Brazilian Patients With Congenital Ataxia