CLCN2 – Leukoencephalopathy with mild cerebellar ataxia and white matter edema

CLCN2-related leukoencephalopathy (CC2L) is a rare autosomal recessive disorder caused by biallelic loss-of-function variants in CLCN2, characterized by intramyelinic white matter edema. Affected individuals present with mild to moderate cerebellar ataxia, scanning speech, tremor, and cognitive decline, often accompanied by vertigo, tinnitus, headache, and visual disturbances on ophthalmologic examination (PMID:31291907; PMID:32173090; PMID:36583195). Brain MRI shows symmetrical high‐intensity signals on T2-weighted and diffusion-weighted images in the posterior limbs of the internal capsules, cerebral and middle cerebellar peduncles, and brainstem tracts, often coined the “bright tree appearance” during acute episodes (PMID:31291907; PMID:32173090).

Genetic analyses in multiple case reports and a Japanese cohort have identified homozygous and compound heterozygous LoF variants in CLCN2 in CC2L, including c.2257C>T (p.Arg753Ter) (PMID:31291907), c.61dup (p.Leu21ProfsTer27) (PMID:32173090; PMID:40199115), c.1828C>T (p.Arg610Ter) (PMID:39443882), and c.1382_1386del (p.Pro461LeufsTer13) (PMID:38028614). A founder effect for c.61dup in Japanese patients suggests a population-specific allele frequency of 0.002152 (PMID:40199115).

Functional studies demonstrate that LoF mutations abolish or markedly reduce ClC-2 chloride currents in heterologous systems, consistent with a loss-of-function mechanism. Electrophysiological recordings in Xenopus oocytes and HEK-293 cells show nonfunctional channels for truncating variants and altered gating kinetics for missense mutations (PMID:28905383; PMID:15252188). Inhibition of ATP-dependent endocytosis increases surface expression of ClC-2, highlighting regulation of channel trafficking under metabolic stress (PMID:17620322).

Animal models further corroborate the human phenotype: Clcn2 knockout and chemically induced stop mutations in mice recapitulate leukoencephalopathy, photoreceptor degeneration, and male infertility with reduced ERG light peak, confirming the critical role of ClC-2 in myelin and retinal homeostasis (PMID:20071672).

Rescue experiments reveal that co-expression of GlialCAM and MLC1 stabilizes mutant ClC-2 at the plasma membrane and restores channel gating, identifying the GlialCAM/ClC-2 complex as a therapeutic target (PMID:28905383). Patient-derived iPSC lines retaining CLCN2 mutations maintain pluripotency and can serve as drug screening platforms (PMID:32278302), and CRISPR correction in RPE cells rescues chloride conductance and outer segment phagocytosis (PMID:36964785).

Together, the genetic, functional, cellular, and animal evidence establishes a definitive association between biallelic LoF variants in CLCN2 and Leukoencephalopathy with mild cerebellar ataxia and white matter edema. Recognition of the characteristic MRI pattern and targeted genetic testing enables early diagnosis, accurate genetic counseling, and guides the development of targeted therapies. Key take-home: screen for CLCN2 mutations in unexplained leukoencephalopathy with ataxia and white matter edema.

References

• BMC neurology • 2019 • CLCN2-related leukoencephalopathy: a case report and review of the literature. PMID:31291907
• Brain & development • 2020 • A case of CLCN2-related leukoencephalopathy with bright tree appearance during aseptic meningitis. PMID:32173090
• Clinical case reports • 2022 • A Tunisian patient with CLCN2-related leukoencephalopathy. PMID:36583195
• BMC neurology • 2024 • CLCN2-related leukoencephalopathy with novel compound heterozygous variants followed with magnetic resonance imaging over 17 years: a case report. PMID:39443882
• Pediatric radiology • 2023 • Brain imaging findings in CLCN2-related leukoencephalopathy. PMID:36565320
• Frontiers in genetics • 2023 • Case report: A frameshift mutation in CLCN2-related leukoencephalopathy and retinopathy. PMID:38028614
• Journal of the neurological sciences • 2025 • Clinical, neuroimaging and genetic findings in the Japanese case series of CLCN2-related leukoencephalopathy. PMID:40199115
• The Journal of physiology • 2017 • Leukoencephalopathy-causing CLCN2 mutations are associated with impaired Cl- channel function and trafficking. PMID:28905383
• Investigative ophthalmology & visual science • 2010 • Photoreceptor degeneration, azoospermia, leukoencephalopathy, and abnormal RPE cell function in mice expressing an early stop mutation in CLCN2. PMID:20071672
• Human genetics • 2023 • Biallelic CLCN2 mutations cause retinal degeneration by impairing retinal pigment epithelium phagocytosis and chloride channel function. PMID:36964785

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