WWOX – Developmental and Epileptic Encephalopathy

Autosomal recessive developmental and epileptic encephalopathy (IEE) is caused by biallelic loss-of-function variants in WWOX, a gene encoding a WW domain-containing oxidoreductase highly expressed in the central nervous system and critical for neuronal development. Patients present with severe psychomotor impairment, pharmacoresistant seizures in the neonatal period, acquired microcephaly and premature death, distinguishing this phenotype from the milder spinocerebellar ataxia associated with hypomorphic WWOX alleles.

Genetic studies identified seven probands from five unrelated consanguineous families harboring biallelic WWOX variants, including four intragenic deletions, a four-base-pair frameshifting deletion, one missense and two nonsense mutations (8 probands) (PMID:25411445). Segregation analysis demonstrated concordant genotypes in two affected siblings in one family, confirming autosomal recessive inheritance. The variant spectrum is enriched for null alleles, consistent with a loss-of-function mechanism.

Phenotype–genotype correlations reveal that individuals with two predicted null alleles exhibit profound developmental arrest, absent eye contact and intractable epilepsy from the first weeks of life, whereas those with at least one hypomorphic allele display a milder ataxic phenotype. In a separate case report, a 13-month-old girl with a homozygous splice-donor disruption manifested infantile spasms that responded to vigabatrin, underscoring therapeutic implications (PMID:39101447).

Functional assessment using minigene splicing assays confirmed that disruption of the canonical splice donor leads to exon skipping and premature truncation. Patient fibroblast analyses demonstrated absence of WWOX protein despite normal transcript levels, corroborating a loss-of-function effect and mechanistic haploinsufficiency.

Collectively, robust genetic evidence, familial segregation and concordant functional data support a Strong association between WWOX and autosomal recessive developmental and epileptic encephalopathy. This knowledge underpins diagnostic genetic testing, informs genetic counseling and highlights potential targeted anticonvulsant strategies.

References

• Unknown • • Homozygous mutations in WWOX were reported in eight individuals of two families with spinocerebellar ataxia type 12 and in patients with infantile epileptic encephalopathy; further biallelic WWOX alterations identified in additional families. PMID:25411445
• Molecular genetics & genomic medicine • 2024 • Developmental epileptic encephalopathy caused by homozygosity of a c.172+1G>C variant in the WWOX gene. PMID:39101447

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