Identification of a novel CLCN2 homozygous variant in a man with leukoencephalopathy and infertility: a case report and literature review

Leukoencephalopathy with ataxia (LKPAT), also known as <i>CLCN2</i>-related leukoencephalopathy, is a rare autosomal recessive disorder caused by pathogenic variants in <i>CLCN2,</i> which encodes ClC-2, a ubiquitously expressed chloride channel protein. However, due to high variability in clinical presentation leading to underdiagnosis, very few cases have been reported since its first description in 2013. The prevalence and genotype-phenotype correlations of LKPAT remain unclear, as do the pathogenic mechanisms of <i>CLCN2</i> variants. In this study, we reported a Chinese man who presented with dizziness, weakness of the left lower limb, and mild cerebellar ataxia. Notably, the patient had a history of azoospermia. Brain MRI showed symmetrical and confluent white matter abnormalities with hypointense signals on T1-weighted images and hyperintense signals on T2-weighted images. In this patient, a novel biallelic missense variant p.A506V was identified in <i>CLCN2</i>. Through <i>in silico</i> analysis, we observed that substitution of A506 with V506 altered hydrogen bond formation at chloride-binding sites. In addition, the A506V variant impacted the interaction of ClC-2 with GlialCAM, a ClC-2 auxiliary subunit that can physically bind ClC-2 and regulate its biophysical properties and subcellular localization in glial cells. Furthermore, we reviewed the literature and identified potential genotype-phenotype correlations in <i>CLCN2</i>-related diseases. Our results highlight the need for <i>CLCN2</i> genetic analysis to establish a definitive diagnosis when strong diagnostic clues are present. This study expands the genotypic spectrum of LKPAT, indicates the potential pathogenesis of the <i>CLCN2</i> A506V variant, and provides valuable insights into further investigation into therapeutics of <i>CLCN2</i>-related leukoencephalopathy.