Epileptic Encephalopathy, Early Infantile, 28

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-28 (EIEE28) is caused by homozygous or compound heterozygous mutation in the WWOX gene (605131) on chromosome 16q23.

Biallelic mutation in the WWOX gene can also cause autosomal recessive spinocerebellar ataxia-12 (SCAR12; 614322), a less severe disorder with some overlapping features.

For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see 308350.

Clinical Features

Abdel-Salam et al. (2014) reported an Egyptian girl, born of consanguineous parents, with a severe lethal neurologic phenotype resulting in death at age 16 months. At age 3 months, the patient had microcephaly (-3.6 SD), poor growth, and lack of psychomotor development. She developed intractable seizures at age 2 months. She had myoclonic movements and hyperreflexia as well as optic atrophy with retinal dysfunction. Brain MRI showed supratentorial atrophy with simplified gyral pattern, hypoplasia of the hippocampus and the temporal lobe, and thin corpus callosum. She was 1 of twins; the other twin was unaffected and heterozygous for the mutation. An older sib had died at age 3 months of a similar disorder. That sib developed seizures at age 40 days and did not follow objects or react to light, suggesting retinal degeneration.

Mignot et al. (2015) reported 5 patients from 4 families with early infantile epileptic encephalopathy. All patients developed pharmacoresistant focal, multifocal, or generalized seizures at a median age of 2 months. All had profoundly delayed psychomotor development; 2 had progressive microcephaly. Other features included axial hypotonia, variable rigidity, spasticity, hyperreflexia, and hypokinesia. Three patients had poor or absent eye contact, and 2 of these 3 also had abnormal electroretinograms. Brain imaging showed thin corpus callosum, myelination delay, and progressive cerebral atrophy. Two of these patients died. Two sibs had a slightly less severe disorder: although they had preserved eye contact, did not show spasticity, and were able to grab and manipulate objects at age 4 years, they still had profoundly delayed psychomotor development and hypotonia. Brain imaging of these 2 sibs was normal. None of the 5 patients acquired walking ability, and cerebellar signs were not present.

Inheritance

The transmission pattern of EIEE28 in the families reported by Mignot et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In an Egyptian girl, born of consanguineous parents, with EIEE28, Abdel-Salam et al. (2014) identified a homozygous nonsense mutation in the WWOX gene (R54X; 605131.0004). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Abdel-Salam et al. (2014) noted that the phenotype was similar to that of the Wwox-null rat, 'lethal dwarfism with epilepsy' (lde) (Suzuki et al., 2009). The findings suggested a role for WWOX in neurodevelopment.

In 5 patients from 4 families with EIEE28, Mignot et al. (2015) identified compound heterozygous deletions and/or nonsense mutations affecting the WWOX gene (see, e.g., 605131.0005-605131.0010). The deletions and mutations, which were found using a combination of chromosomal microarray analysis, direct sequencing, and whole-exome sequencing, segregated with the disorder in all families. Two sibs with a slightly less severe disorder were compound heterozygous for a deletion and a missense mutation, suggesting a possible genotype/phenotype correlation. Mignot et al. (2015) commented on the large number of deletions identified, noting that WWOX is a very large gene with a predisposition for developing deletions.

Animal Model

Suzuki et al. (2009) described a spontaneous rat mutant, 'lethal dwarfism with epilepsy' (lde/lde), characterized by dwarfism, postnatal lethality, male hypogonadism, and a high incidence of epilepsy. Neuropathology showed extracellular vacuoles in the hippocampus and amygdala, and testes analysis showed retarded differentiation of Leydig cells and increased apoptosis of spermatocytes. Sound stimulation induced epileptic seizures in 95% of lde/lde rats, which started as wild running and sometimes progressed to tonic-clonic seizures. The locus was mapped to rat chromosome 19, and a homozygous 13-bp deletion in exon 9 was found in the Wwox gene. Western blot analysis detected Wwox proteins of 47 and 42 kD in normal testes and hippocampi, respectively, whereas both products were undetectable in the testes and hippocampi of homozygous mutant rats, indicating a functionally null mutation.