Epileptic Encephalopathy, Early Infantile, 8

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-8 (EIEE8) is caused by mutation in the ARHGEF9 gene (300429) on chromosome Xq22.1.

Description

Early infantile epileptic encephalopathy-8 is an X-linked disorder characterized by seizure onset before 2 years of age and severe developmental delay. Some patients have hyperekplexia (summary by Shimojima et al., 2011).

For general phenotypic descriptions and discussions of genetic heterogeneity of early infantile epileptic encephalopathy and hyperekplexia, see EIEE1 (308350) and hereditary hyperekplexia (149400), respectively.

Clinical Features

Harvey et al. (2004) reported a patient with clinical symptoms of both hyperekplexia and early infantile epileptic encephalopathy. The child was the first-born of a 32-year-old woman, delivered at 36 weeks' gestation. Cyanosis and muscular stiffness were noted immediately after delivery, and the child appeared to stare. During the following weeks, the child developed tonic seizures that were provoked by tactile stimulation. Although the treatment of seizures was initially effective, after 3.5 months of age the seizures recurred and were often precipitated by extreme emotion. At 4 months of age, a diagnosis for hyperekplexia was made, but therapy with clonazepam was unsuccessful. EEG monitoring coupled with ambulatory video demonstrated that the seizures were both hyperekplectic and epileptic in origin. During the following years, the child suffered from frequent long-lasting seizures accompanied by the arrest and later decline of psychomotor development. Eventually, a progressive epileptic encephalopathy as well as hyperekplexia became evident, and poly-drug treatment failed to provide adequate long-term seizure control. At 4 years of age, the subject was severely retarded and suffered almost daily severe long-lasting fits, both epileptic and nonepileptic in origin, eventually leading to death at the age of 4 years and 4 months.

Shimojima et al. (2011) reported a Japanese boy with X-linked mental retardation and epilepsy. He had psychomotor delay beginning in early infancy and developed intractable seizures at age 20 months. EEG showed continuous spike and wave patterns during sleep, and brain MRI showed right frontal polymicrogyria. At age 5 years and 5 months, he had severe developmental delay, could not speak, and was ataxic.

Cytogenetics

Marco et al. (2008) reported a girl with mental retardation and sensory hyperarousal associated with a balanced de novo paracentric inversion (X)(q11.1;q27.3) that disrupted 1 allele of the ARHGEF9 gene between exons 1 and 3. At age 18 months, she showed hyperarousal to noise and social situations as well as global developmental delay. The hyperarousal severely limited her activities and family life. As a teen, other features included slightly dysarthric speech, difficulty with smooth eye pursuit, mild bilateral lower extremity spasticity with brisk reflexes and extensor plantar responses, and wide-based gait. Laboratory studies showed completely skewed X inactivation in favor of the abnormal X chromosome and decreased ARHGEF9 mRNA at 9% of control levels.

Shimojima et al. (2011) reported a 5-year-old boy with severely delayed psychomotor development and seizures who had a de novo 737-kb deletion of Xq11.1 including the ARHGEF9, SPIN4, and LOC92249 genes. His seizures began at age 2 years, were well-controlled, and were of complex-partial type. EEG showed separate spikes at the temporal regions. He also showed generalized overgrowth and trigonocephaly, but no other dysmorphic features.

Molecular Genetics

In a boy with hyperekplexia and epilepsy, Harvey et al. (2004) detected a heterozygous gly55-to-ala mutation in the ARHGEF9 gene (300429.0001).

In a Japanese boy with X-linked mental retardation and refractory epilepsy, Shimojima et al. (2011) identified a loss-of-function mutation in the ARHGEF9 gene (Q2X; 300429.0002). The patient's unaffected mother was heterozygous for the mutation. The patient was identified from a larger cohort of 23 boys with mental retardation.