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.
Divisions of Pediatric Neurology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
Brahim
B
Tabarki
Division of Genetics, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
Amal
A
AlHashem
Divisions of Pediatric Neurology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
Saad
S
AlShahwan
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
Fowzan S
FS
Alkuraya
Department of Pediatric Neurology, Nationwide Children Hospital, Ohio State University, Columbus, Ohio.
Satyanarayana
S
Gedela
Pediatric Neuroradiology, Children Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, Pennsylvania.
Giulio
G
Zuccoli
D058540:Aicardi Syndrome / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics*; D005260:Female; D006720:Homozygote; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D059906:Neuroimaging / Q000379:methods; D010088:Oxidoreductases / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011379:Prognosis; D013036:Spasms, Infantile / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000074584:WW Domain-Containing Oxidoreductase
D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human
epileptic encephalopathy; microcephaly; spasticity