CLCN2-related leukoencephalopathy

Last revised by Rohit Sharma on 7 Feb 2024

CLCN2-related leukoencephalopathy, also known as leukoencephalopathy with ataxia, is a rare leukodystrophy characterized by mild and slowly progressive ataxia and distinct abnormalities on MRI brain.

The incidence and prevalence of CLCN2-related leukoencephalopathy is not known, but it is widely thought to be very rare 1,2. Among affected patients, a family history of consanguinity may be present 1,2.

The age of onset of symptoms is incredibly varied, with some patients presenting as infants and others presenting into middle-age adulthood 1,2.

Regardless of age of onset, common clinical features include 1-5:

  • ataxia

    • most common clinical feature

    • mild and slowly progressive

    • nearly all patients remain ambulant throughout follow-up

    • may have associated intention tremor

  • cognitive impairment

    • often mild

  • headache

  • visual changes

    • may be due to chorioretinopathy or optic neuropathy

    • blindness does not occur throughout follow-up

  • infertility in males

Relatively uncommonly reported clinical features include 1-5:

  • pyramidal signs

  • seizures

  • psychiatric symptoms

  • hearing impairment

  • vertigo 

CLCN2-related leukoencephalopathy is an autosomal recessive condition caused by a loss of function mutation to CLCN2 on chromosome 3q27 1. This gene encodes for the voltage-gated chloride channel CLC-2, which normally has an important role in ion and water homeostasis 1-4.

Loss of function mutation in CLCN2 results in dysfunction in CLC-2, which results in altered ion and water homeostasis 1-4. This leads to myelin edema and microvacuolisation, likely explaining the observed abnormalities on MRI brain 1-5. A variety of different mutations have been described as pathogenic, with nonsense and missense mutations being most implicated 1,2.

Notably, there is poor genotype-phenotype correlation among patients with CLCN2-related leukoencephalopathy 2. For example, patients with the same genetic mutation can have vastly different clinical phenotypes, including different clinical features and ages of onset 2.

MRI brain is always abnormal and it is thought that radiographic abnormalities may precede evidence of the clinical syndrome 1,2.

The most characteristic changes are bilateral signal abnormalities affecting the posterior limbs of the internal capsules, midbrain cerebral peduncles, and middle cerebellar peduncles (i.e. MCP sign) 1-5. Other regions less commonly affected include the corticospinal tracts in the pons, central tegmental tracts in the brainstem, splenium of the corpus callosum, dentate nuclei, and subcortical cerebral white matter 1-4. Deep grey matter (e.g. putamen, thalamus) involvement has been very rarely reported 2.

These regions demonstrate the following signal characteristics 1-5:

  • T1: hypointense

  • T2/FLAIR: hyperintense

  • DWI/ADC: true diffusion restriction (high diffusion signal and low ADC values) in some regions with abnormal T2/FLAIR signal, which may be more prominent in younger patients

  • T1 C+ (Gd): no contrast enhancement

Advanced MRI techniques have been infrequently described in the literature. In one case report utilizing diffusion tensor imaging, there was decreased fractional anisotropy and reduced fiber number in regions of white matter hyperintensity 1.

No disease-modifying therapy is available, and thus management is essentially supportive in nature (e.g. antiseizure medications) 1,6. Overall, prognosis is good and there have been no deaths directly related to complications arising from CLCN2-related leukoencephalopathy 1.

CLCN2-related leukoencephalopathy was first described in 2013 3.

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