Severe CNS involvement in WWOX mutations: Description of five new cases

Recently, mutations in WWOX have been identified in the setting of central nervous system (CNS) disorders, highlighting a previously unrevealed role of this gene in the normal development and function of the CNS. In this report, we add five patients from two seemingly unrelated families presenting with a primarily neurological phenotype. All the children were product of consanguineous marriages. Whole exome sequencing revealed the same homozygous mutation (NM_016373.3:c.606-1G>A) of WWOX in all five patients. All patients and carriers in the family share the same haplotype indicating the families are in fact related to one another. The clinical presentation included progressive microcephaly, early onset of spasticity in the first 3 months of life, intractable epilepsy, severe failure to thrive, and profound developmental delay. Retinopathy was observed in two patients. All five patients died before their third birthday. Neuroimaging showed extensive neurodegeneration characterized by periventricular white matter volume loss and atrophy of the corpus callosum. Additional degeneration selectively affecting the mediodorsal nucleus of the thalamus was observed in one patient. Our findings in five new patients affected by WWOX mutation with early infantile phenotype confirm the features of the disease represented by early infantile epileptic encephalopathy. We suggest that neuroimaging in these patients reveals a characteristic pattern of neurodegeneration in which the cerebellum is spared that could help with early diagnosis in the appropriate clinical setting.