To investigate the genetics of early-onset progressive cerebellar ataxia in Iran, we conducted a study at the Children’s Medical Center (CMC), the primary referral center for pediatric disorders in the country, over a three-year period from 2019 to 2022. In this report, we provide the initial findings from the national registry. We selected all early-onset patients with an autosomal recessive mode of inheritance to assess their phenotype, paraclinical tests, and genotypes. The clinical data encompassed clinical features, the Scale for the Assessment and Rating of Ataxia (SARA) scores, Magnetic Resonance Imaging (MRI) results, Electrodiagnostic exams (EDX), and biomarker features. Our genetic investigations included single-gene testing, Whole Exome Sequencing (WES), and Whole Genome Sequencing (WGS). Our study enrolled 162 patients from various geographic regions of our country. Among our subpopulations, we identified known and novel pathogenic variants in 42 genes in 97 families. The overall genetic diagnostic rate was 59.9%. Notably, we observed PLA2G6, ATM, SACS, and SCA variants in 19, 14, 12, and 10 families, respectively. Remarkably, more than 59% of the cases were attributed to pathogenic variants in these genes. Iran, being at the crossroad of the Middle East, exhibits a highly diverse genetic etiology for autosomal recessive hereditary ataxia. In light of this heterogeneity, the development of preventive strategies and targeted molecular therapeutics becomes crucial. A national guideline for the diagnosis and management of patients with these conditions could significantly aid in advancing healthcare approaches and improving patient outcomes.

中文翻译：

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伊朗早发遗传性共济失调的遗传基础：异质人群国家登记结果

为了调查伊朗早发进行性小脑性共济失调的遗传学，我们在该国儿科疾病主要转诊中心儿童医疗中心 (CMC) 进行了一项研究，为期三年，从 2019 年到 2022 年。在本报告中，我们提供了国家登记处的初步调查结果。我们选择了所有具有常染色体隐性遗传模式的早发患者来评估他们的表型、临床旁测试和基因型。临床数据包括临床特征、共济失调评估和评级量表 (SARA) 评分、磁共振成像 (MRI) 结果、电诊断检查 (EDX) 和生物标志物特征。我们的基因研究包括单基因测试、全外显子组测序 (WES) 和全基因组测序 (WGS)。我们的研究招募了来自我国不同地理区域的 162 名患者。在我们的亚群中，我们在 97 个家族的 42 个基因中鉴定出了已知和新的致病变异。总体基因诊断率为59.9%。值得注意的是，我们分别在 19、14、12 和 10 个家族中观察到 PLA2G6、ATM、SACS 和 SCA 变体。值得注意的是，超过 59% 的病例归因于这些基因的致病变异。伊朗位于中东的十字路口，常染色体隐性遗传性共济失调表现出高度多样化的遗传病因。鉴于这种异质性，预防策略和靶向分子治疗的发展变得至关重要。患有这些疾病的患者的诊断和管理的国家指南可以极大地帮助推进医疗保健方法和改善患者的治疗结果。