ORIGINAL RESEARCH article
Front. Genet.
Sec. Neurogenomics
Identification of a novel CLCN2 homozygous variant in a man with leukoencephalopathy and infertility: Case report and literature review
Provisionally accepted
- Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
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Abstract Leukoencephalopathy with ataxia (LKPAT), also known as CLCN2-related leukoencephalopathy, is a rare autosomal recessive disorder caused by pathogenic variants in CLCN2, which encodes ClC-2, a ubiquitously expressed chloride channel protein. However, with high variability in clinical presentation leading to under-diagnosis, very few cases have been reported since the first description in 2013. It remains unclear about the prevalence and genotype-phenotype correlations of LKPAT, as well as pathogenic mechanisms of CLCN2 variants. Here, we reported a Chinese man presented with dizziness, weakness in left lower limb and mild cerebellar ataxia. Of note, the patient had a history of azoospermia. Brain MRI showed symmetrical and confluent white matter abnormalities with hypointense signals on T1-weighted image and hyperintense signals on T2-weighted image. In the patient, a novel biallelic missense variant p.A506V was identified in CLCN2. Through in silico analysis, we observed that substitution of A506 with V506 altered hydrogen bond formation in chloride binding sites. In addition, A506V variant impacted the interaction of ClC-2 with GlialCAM, a ClC-2 auxiliary subunit which can physically bind ClC-2 and regulate its biophysical properties and subcellular localization in glial cells. Furthermore, we conducted review of the literature and showed potential genotype-phenotype correlations of CLCN2-related diseases. Our results highlight the need for CLCN2 genetic analysis to make definitive diagnosis when strongly diagnostic clues are present. Our study expands the genotypic spectrum of LKPAT, indicates potential pathogenesis of CLCN2 A506V variant and provides valuable insights into further investigation toward the therapeutics of CLCN2-related leukoencephalopathy.
Keywords: chloride ion channel, ClC-2, CLCN2, Leukoencephalopathy with ataxia, loss-of-function variant
Received: 16 Dec 2025; Accepted: 04 Feb 2026.
Copyright: © 2026 Lijia, Jiang, Cao, Geng and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jingjiong Chen
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