Epileptic Encephalopathy, Early Infantile, 70
A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-70 (EIEE70) is caused by heterozygous mutation in the PHACTR1 gene (608723) on chromosome 6p24.
For a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).
Clinical FeaturesDe Ligt et al. (2012) reported a 28-year-old woman with EIEE70. She had her first seizures at 3 weeks of age and thereafter showed severely delayed psychomotor development. She learned to sit and could speak a few words, but later lost these skills. Epilepsy could be relatively controlled with medication. As an adult, she had low normal height, small head circumference (-2.5 SD), spastic tetraparesis with joint contractures, and scoliosis.
Hamada et al. (2018) reported 2 unrelated Japanese children, aged 4 and 5 years, with EIEE70. They presented with seizures in the first months of life and also showed global developmental delay. EEG showed hypsarrhythmia in both. One patient was more severely affected, with poor seizure response to medication and no head control. Brain imaging showed cortical atrophy and delayed myelination. He also had cryptorchidism. The other patient had favorable seizure response to ACTH and normal brain imaging; he walked at 18 months and had a few words at 24 months. He was diagnosed with autism spectrum disorder. This patient had mild dysmorphic facial features.
Molecular GeneticsIn a 28-year-old woman (trio 90) with EIEE70, de Ligt et al. (2012) identified a de novo heterozygous missense mutation in the PHACTR1 gene (R521C; 608723.0001). The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed. The patient was ascertained from a larger cohort of 100 patients with severe intellectual disability who underwent exome sequencing.
In 2 unrelated patients with EIEE70, Hamada et al. (2018) identified de novo heterozygous missense mutations in the PHACTR1 gene (L500P, 608723.0002 and N479I, 608723.0003). The mutations were found by whole-exome sequencing. In vitro functional expression studies showed that these mutations interrupted actin binding, whereas R521C interrupted PP1 (see 176875) binding. The mutations were unable to rescue the neuronal migration defects in Phactr1-null mice (see ANIMAL MODEL), suggesting that they are pathogenic. In addition, expression of the mutations in mice induced migration defects and caused abnormal cortical architecture in a dominant-negative manner.
Animal ModelHamada et al. (2018) found that knockdown of the Phactr1 gene in embryonic mouse brain resulted in neuronal migration defects and abnormal cortical architecture.