West syndrome, developmental and epileptic encephalopathy, and severe CNS disorder associated with WWOX WWOX mutations

摘要

ABSTRACT Aims . Mutations in the WWOX gene have been reported in a number of patients with various neurological disorders including spino‐cerebellar ataxia, intellectual disability, epilepsy, and epileptic encephalopathy. We aimed to study the clinical, electrographic, and imaging features of two new cases with WWOX mutations and compare them to previously reported cases with WWOX mutations. Methods . We assessed two unrelated children from two consanguineous families who had severe neurological disorder including early‐onset spastic quadriplegia, profound developmental delay, epilepsy, and West syndrome. Results . Based on whole‐exome sequencing, we identified homozygous null mutations in WWOX in both children, and further addressed the genotype‐phenotype correlation. In addition, we provide a detailed review of the previously reported cases of WWOX ‐related neurological disorders and compare them to the children in this report. Conclusions . The findings in this report expand the clinical phenotype associated with WWOX mutations and confirm a well characterised severe central nervous system disorder in association with biallelic null mutations in WWOX. This syndrome consists of profound psychomotor delay, early‐onset spastic quadriplegia, and refractory epilepsy including epileptic encephalopathy, acquired microcephaly, and growth restriction. This can be associated with progressive brain atrophy, suggestive of neurodegeneration. Identification of this phenotype by clinicians may help with early diagnosis and appropriate genetic counselling.