CLCN2-related leukoencephalopathy
General description
CLCN2-related leukoencephalopathy is a rare autosomal recessive disorder caused by pathogenic variants in the CLCN2 gene on chromosome 3q27. This gene encodes a voltage-gated chloride channel, CLC-2, which plays a crucial role in ion and water homeostasis. The condition presents with a wide range of onset ages, from infancy to middle adulthood, and follows a mild, slowly progressive course.
The primary clinical feature is mild ataxia, often accompanied by action tremor and gait instability. Cognitive impairment is typically mild but can occasionally be severe. Some individuals experience psychiatric symptoms, such as depression or schizophrenia-like presentations. Other common findings include intermittent, severe headaches and auditory symptoms like hearing loss, tinnitus, or vertigo. Visual impairment may result from chorioretinopathy or optic atrophy, but blindness does not occur. Additionally, affected males may experience infertility.
Bilateral lesions
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Internal capsulePosterior limb
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Middle cerebellar peduncle
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Superior cerebellar peduncle
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Corpus callosumSplenium
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Dentate nucleus
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CerebellumCerebellar white matter
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CerebrumCerebral white matter
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BrainstemMidbrainDecussation of the superior cerebellar peduncle
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Corticospinal tract
CLCN2-related leukoencephalopathy is characterized by bilateral signal abnormalities primarily affecting the posterior limbs of the internal capsules, midbrain cerebral peduncles, and middle cerebellar peduncles. In addition to the primary sites, abnormalities may also be seen in the pyramidal tracts of the pons, central tegmental tracts across the brainstem, superior cerebellar peduncles, decussation of the superior cerebellar peduncles, splenium of the corpus callosum, dentate nuclei, cerebellar white matter, and cerebral white matter.
On MRI, affected regions typically exhibit high signal intensity on T2WI and FLAIR, and diffusion restriction.