Dados do Trabalho

Título

CLCN2-related leukoencephalopathy: a scarce case report

Apresentação dos casos

Case report: We present two cases of leukoencephalopathy with ataxia, a rare leukodystrophy due to a variant of the CLCN2 gene. To start with, a 3-year-old male, son of a non-consanguineous couple, was previously diagnosed with Autism Spectrum Disorder (ASD). During a complication of acute otitis media the boy was subjected to magnetic resonance imaging of the brain, and it showed a leucodistrophy pattern. The MRI was described with T1 hypodensity, T2/FLAIR hyperintense lesions in the midbrain, and middle cerebellar peduncles (MCP sign). Then, he was referred to our service. His physical exam showed a delay in speech, hyperactivity, learning disabilities, and irritability. An exome sequencing was requested, and it resulted in a homozygous pathogenic variant at chr3:184.354.113; consequence c. 1709 G> A; p. (Trp570*) on the CLCN2 gene. Due to his symptoms, Risperidone was given. The second one, an 18-month-old female, began with one single episode of afebrile seizure. Due to this episode, she was submitted to an MRI, which revealed T1 hypodensity, T2/FLAIR hyperintense lesions in the central tegmental tracts in the brainstem, thalamus, internal capsules, and middle cerebellar peduncles. An exome sequencing was performed, and she had one pathogenic variant at chr3:184.357.686 (TC>C); in consequence Asn236Thrfs*106 and also one variant of uncertain significance at chr3:184.354.562 in consequence p.Gly498Asp, both on the CLCN2 gene in heterozygous. Her neurological exam was normal. She had non-consanguineous parents and no previous medical history.

Discussão

Discussion: CLCN2-related leukoencephalopathy is an autosomal recessive condition caused by a loss of function mutation to CLCN2 on chromosome 3q27. It is caused by a mutation in the chloride channel 2 gene, which normally has an important role in ion and water homeostasis. Usually, an MRI of the brain is abnormal, and it may precede evidence of the clinical syndrome. The most common clinical feature is a mild and slowly progressive ataxia and headache, but it also has a variable clinical feature even in patients with the same mutation, highlighting the complexity of the condition. There are two peaks of onset, childhood and middle-aged adulthood.

Comentários finais

Final comments: The parents of the infant with a heterozygous compound will have the sequencing of CLCN2 due to the VUS, but the leukodystrophy pattern on MRI and mild symptoms are common in both cases.

Referências

Blanz J, Schweizer M, Auberson M, Maier H, Muenscher A, Hübner CA, Jentsch TJ. Leukoencephalopathy upon disruption of the chloride channel ClC-2. J Neurosci. 2007 Jun 13;27(24):6581-9. doi: 10.1523/JNEUROSCI.0338-07.2007. PMID: 17567819; PMCID: PMC6672451.
Guo Z, Lu T, Peng L, Cheng H, Peng F, Li J, Lu Z, Chen S, Qiu W. CLCN2-related leukoencephalopathy: a case report and review of the literature. BMC Neurol. 2019 Jul 10;19(1):156. doi: 10.1186/s12883-019-1390-7. PMID: 31291907; PMCID: PMC6617604.
Depienne, C., Bugiani, M., Dupuits, C., Galanaud, D., Touitou, V., Postma, N., van Berkel, C., Polder, E., Tollard, E., Darios, F., Brice, A., de Die-Smulders, C. E., and 12 others. Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. Lancet Neurol. 12: 659-668, 2013
OMIM #615651

Palavras Chave

CLCN2; Leucoencephalopathy; ataxia