WWOX-associated encephalopathies: identification of the phenotypic spectrum and the resulting genotype-phenotype correlation

Abstract

Epileptic encephalopathies are a group of disorders in which epileptiform abnormalities cause progressive deterioration in cerebral function. Genetic causes have been described in several of the epileptic encephalopathies, and many previously unknown genes have been identified. WW domain-containing oxidoreductase (WWOX) has recently been implicated in autosomal recessive spinocerebellar ataxia type 12 (SCAR12) and severe early-onset epileptic encephalopathy. With whole-exome sequencing, we identified a homozygous WWOX missense mutation, p.Leu239Arg, in a girl from a consanguineous family with psychomotor developmental delay, acquired microcephaly, and epileptic seizures. WWOX-related epileptic encephalopathy is a rare condition but it should be considered in cases having early epileptic spasms and parental consanguinity.

The WWOX gene in brain development and pathology

“…The condition manifests as cerebellar ataxia, tonic-clonic epilepsy, intellectual impairment, and significant spasticity. 30 , 45 In the second form, the presence of premature STOP codons in two alleles results in a complete lack of WWOX expression and the development of WOREE WWOX-related epileptic encephalopathy (MIM 616211). This syndrome is characterized by severe developmental delay, intense and drug-resistant epilepsy with variable attack types (tonic, clonic, tonic-clonic, myoclonic, etc.…”

“…A detailed review of clinical and molecular data in patients with WWOX-related encephalopathies has recently been published by Serin et al. 30 …”

“…Up to date, disturbances in WWOX expression have been associated with cholesterol level disorders, 27 , 28 type 2 diabetes, 29 spinal-cerebellar ataxia and childhood encephalopathy, 30 and various types of cancer. 5 , 13 , 31 – 36 …”

“…37 – 40 Growing evidence suggests that it has also a considerable influence on the development of the central nervous system (CNS). 30 To date, WWOX has been shown to contribute to the signaling pathways regulating CNS development and neural differentiation such as WNT, Hedgehog, TGFβ, and Hippo. 16 , 20 , 21 , 41 , 42 Noteworthy, Dvl1 and Dvl2, core components of WNT pathway, were amongst the highest confidence protein interactors identified in TAP-MS WWOX protein interactome study.…”

Early onset epileptic encephalopathy caused by novel compound heterozygous mutation of WWOX gene

“…Since 2014, more than 17 articles have reported the clinical data of WWOX-related epileptic encephalopathy (WOREE ; Table S1; Abdel-Salam et al, 2014;Ben-Salem, Al-Shamsi, John, Ali, & Al-Gazali, 2015;Davids et al, 2019;Ehaideb, Al-Bu Ali, Al-Obaid, Aljassim, & Alfadhel, 2018;Elsaadany, El-Said, Ali, Kamel, & Ben-Omran, 2016;Gribaa et al, 2007;Johannsen et al, 2018;Mallaret et al, 2014;Mignot et al, 2015;Piard et al, 2019;Serin, Simsek, Isik, & Gokben, 2018;Shaukat, Hertecant, El-Hattab, Ali, & Suleiman, 2018;Tabarki et al, 2015;Tarta-Arsene, Barca, Craiu, & Iliescu, 2017;Valduga et al, 2015;Weisz-Hubshman et al, 2019;Yang, Zhang, Song, Yi, & Li, 2019). Here we summarized the clinical features and genetic data of a Chinese infant, and analyzed the characteristics of genotype and clinical phenotype of this kind of disease by reviewing the relevant literatures.…”