SORDD: mutation frequency and phenotype in predominantly axonal Charcot-Marie-Tooth disease of undefined genetic cause.

IF 1.8 4区 医学 Q3 GENETICS & HEREDITY Journal of neurogenetics Pub Date : 2024-06-01 Epub Date: 2024-07-08 DOI:10.1080/01677063.2024.2374898
Annabelle Arlt, Esra Akova-Öztürk, Anja Schirmacher, Bernhard Schlüter, Stephan Rust, Gerd Meyer Zu Hörste, Heinz Wiendl, Sarah Wiethoff
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Abstract

Pathogenic, biallelic variants in SORD were identified in 2020 as a novel cause for autosomal-recessive Charcot-Marie-Tooth disease (CMT) type 2, an inherited neuropathy. SORD codes for the enzyme sorbitol dehydrogenase. Loss of this enzyme's activity leads to an increase of sorbitol in serum. We retrospectively screened 166 patients with axonal neuropathy (predominantly CMT type 2, but including intermediate form of CMT and distal hereditary motor neuropathy (dHMN)) without identified genetic etiology for SORD mutations at a single large German neuromuscular center. Clinical and electrophysiology exam findings were analyzed for genotype-phenotype correlation. Five patients of the total cohort of 166 patients harbored pathogenic variants in SORD (3%). The homozygous frameshift variant c.757delG (p.Ala253Glnfs*27) was the most common (4/5). One additional case carried this variant on one allele only and an additional pathogenic missense variant c.458C > A (p.Ala153Asp) on the other allele. Age of onset ranged from early infancy to mid-twenties, and phenotypes comprised axonal CMT (4) and dHMN (1). Our findings strengthen the importance of screening for pathogenic variants in SORD, especially in patients with genetically unconfirmed axonal neuropathy, especially CMT type 2 and dHMN.

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SORDD:遗传原因不明的主要轴索型夏科-玛丽-牙病的突变频率和表型。
2020 年,SORD 的致病性双倍拷贝变体被确定为常染色体隐性夏科-玛丽-牙病(CMT)2 型(一种遗传性神经病)的新病因。SORD 编码山梨醇脱氢酶。这种酶活性的丧失会导致血清中山梨醇的增加。我们在德国一家大型神经肌肉中心对 166 名轴索神经病患者(主要是 CMT 2 型,也包括中间型 CMT 和远端遗传性运动神经病 (dHMN))进行了回顾性筛查,未发现 SORD 基因突变的遗传病因。对临床和电生理学检查结果进行了基因型与表型相关性分析。在166名患者中,有5名患者携带SORD致病变异(3%)。其中最常见的是同基因框移变异 c.757delG(p.Ala253Glnfs*27)(4/5)。另有一个病例仅在一个等位基因上携带该变异,另一个等位基因上携带致病性错义变异 c.458C > A (p.Ala153Asp)。发病年龄从婴儿期到二十多岁不等,表型包括轴索型 CMT(4 例)和 dHMN(1 例)。我们的研究结果加强了筛查 SORD 致病变体的重要性,尤其是在遗传学上未经证实的轴索神经病患者中,特别是 CMT 2 型和 dHMN 患者。
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来源期刊
Journal of neurogenetics
Journal of neurogenetics 医学-神经科学
CiteScore
4.40
自引率
0.00%
发文量
13
审稿时长
>12 weeks
期刊介绍: The Journal is appropriate for papers on behavioral, biochemical, or cellular aspects of neural function, plasticity, aging or disease. In addition to analyses in the traditional genetic-model organisms, C. elegans, Drosophila, mouse and the zebrafish, the Journal encourages submission of neurogenetic investigations performed in organisms not easily amenable to experimental genetics. Such investigations might, for instance, describe behavioral differences deriving from genetic variation within a species, or report human disease studies that provide exceptional insights into biological mechanisms
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