Mohammadi Mahsa, Ravanbod Moez, Ghasemi Aida, Gharebaghian Hadi, Nafissi Shahriar, Alavi Afagh
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
Neuromuscular Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Pediatr Neurol. 2025 Mar;164:41-52. doi: 10.1016/j.pediatrneurol.2024.12.011. Epub 2024 Dec 30.
Spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) is an ultrarare neurodegenerative disorder inherited in an autosomal recessive manner, mainly marked by progressive ataxia and axonal polyneuropathy. SCAN1 is mainly caused by the c.1478A>G:p.His493Arg mutation in the TDP1 gene. In this study, we present the first Iranian family, and the fifth family totally, diagnosed with the SCAN1, which carries the common variant c.1478A>G. Additionally, we conducted a systematic review to identify all reported probably disease-related variants of TDP1.
Whole exome sequencing was performed on the proband, who was initially diagnosed with axonal neuropathy. The data were analyzed, and the variant was confirmed via Sanger sequencing. Cosegregation analysis was used to validate the variant within the family. Following PRISMA 2020 guidelines, we performed a systematic review using the terms TDP1, tyrosyl-DNA phosphodiesterase, SCAN1, and spinocerebellar ataxia with axonal neuropathy in four major databases.
Whole exome sequencing results identified the known TDP1:c.1478A>G variant, which correlated with the disease status in the family. Clinical and paraclinical findings were consistent with SCAN1. Our systematic review identified 16 variants in 20 families associated with various neurological or non-neurological disorders. Among these families, four were SCAN1. Although four of five families with SCAN1, including our family, shared the same TDP1 variant, c.1478A>G, they exhibited some clinical heterogeneity.
Given that all these cases were from the Middle East, we suggested this mutation may be a founder mutation in this region. Since only a few families with SCAN1 have been reported, further research is needed to fully understand this disorder.
伴轴索性神经病的脊髓小脑共济失调1型（SCAN1）是一种极为罕见的常染色体隐性遗传神经退行性疾病，主要特征为进行性共济失调和轴索性多发性神经病。SCAN1主要由TDP1基因中的c.1478A>G:p.His493Arg突变引起。在本研究中，我们报告了首个被诊断为SCAN1的伊朗家族，也是全球第五个携带常见变异c.1478A>G的家族。此外，我们进行了一项系统综述，以确定所有已报道的可能与TDP1疾病相关的变异。
对最初被诊断为轴索性神经病的先证者进行全外显子组测序。对数据进行分析，并通过Sanger测序确认变异。共分离分析用于验证家族内的变异。遵循PRISMA 2020指南，我们在四个主要数据库中使用术语TDP1、酪氨酰-DNA磷酸二酯酶、SCAN1和伴轴索性神经病的脊髓小脑共济失调进行了系统综述。
全外显子组测序结果确定了已知的TDP1:c.1478A>G变异，该变异与家族中的疾病状态相关。临床和辅助检查结果与SCAN1一致。我们的系统综述在20个与各种神经或非神经疾病相关的家族中确定了16个变异。在这些家族中，有4个是SCAN1。虽然包括我们家族在内的5个SCAN1家族中有4个共享相同的TDP1变异c.1478A>G，但它们表现出一些临床异质性。
鉴于所有这些病例均来自中东地区，我们认为该突变可能是该地区的奠基者突变。由于仅报道了少数SCAN1家族，因此需要进一步研究以全面了解这种疾病。
