Compound heterozygous deletions of the WWOX gene caused a WOREE syndrome associated with severe epileptic encephalopathy

Abstract

Recent studies showed that germline, bi-allelic and pathogenic variants of the WWOX gene have been associated with spinocerebellar ataxia type 12 (SCAR12) and a severe WWOX-related epileptic encephalopathy (WOREE syndrome). The underlying mechanisms of the diseases are poorly understood. Here, we reported the case of a WOREE syndrome patient with early-onset refractory seizures and global neurodevelopmental delay who died at the age of two and a half years. The whole exon sequencing showed homozygous exon 6 deletions in the WWOX gene. Quantitative real-time polymerase chain reaction (PCR) confirmed that deletions were inherited from each parent. An exons 6–8 deletion was inherited from the mother, while an exon 6 deletion plus a microdeletion involving intron 5 was inherited from the father. Due to the structure of the WWOX locus encompassing the FRA16D fragile site, we confirmed the exact breakpoints using whole genomic sequencing combined with long-range PCR. Our findings extend the mutation spectrum of the WOREE syndrome and support an important role for the WWOX gene in neural development.

WWOX and metabolic regulation in normal and pathological conditions

“…This observation allowed the authors to propose that Wwox is involved in the oligodendrocyte differentiation and the myelination process [57]. A magnetic resonance imaging (MRI) of WOREE patients' brains besides the varying brain structural defects usually shows also reduced myelination [13,[65][66][67][68]. Currently, the specific neuronal deletion of murine Wwox which generates phenotypes that resemble what is observed in WOREE patients was characterized by a significant decrease in transcript levels of genes involved in myelination in the mouse cortex and hippocampus and reduction of myelinated axons [61].…”

“…It has been shown that increasing glycolysis may slow neurodegeneration [100]. WWOX has been also implicated in epilepsy [61,68]. It was observed that the anaerobic glycolysis and concentration of lactate in the epileptogenic brain increased in comparison to the control [101].…”