Practical clues for diagnosing WWOX encephalopathy

The WW domain‐containing oxidoreductase gene is implicated in autosomal recessive disorders of the central nervous system, expressed either as spinocerebellar ataxia or as a severe form with early‐infantile epileptic encephalopathy. Here, we describe the electroclinical evolution of these disorders, adding new diagnostic clues based on a case study. The patient, a boy with early‐onset epilepsy, presented with profound global developmental delay, persistent hypsarrhythmia, and epileptic spasms, associated with progressive cerebral atrophy without microcephaly. Metabolic disease was excluded. Whole‐exome sequencing showed mutations in the WW domain‐containing oxidoreductase gene. Our findings extend the phenotypic traits of this aggressive epileptic encephalopathy, with persistent epileptic spasms and hypsarhythmia as a part of the electroclinical phenotype, demonstrating that microcephaly is not mandatory for diagnosis, even when associated with progressive cerebral atrophy. These mutations might be more frequent than expected among early‐onset epileptic encephalopathies. We present practical clues for the diagnosis of WWOX encephalopathy in order to avoid unnecessary investigations and ensure appropriate genetic counselling for the families.