Epileptic Encephalopathy, Early Infantile, 38

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-38 (EIEE38) is caused by homozygous mutation in the ARV1 gene (611647) on chromosome 1q42.

For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).

Clinical Features

Alazami et al. (2015) and Palmer et al. (2016) reported a highly consanguineous Saudi Arabian family (08DGRC00077) in which 3 children had early-onset epileptic encephalopathy, profound intellectual disability, ataxia, and unspecified visual impairment. One of the patients died at age 4 years.

Palmer et al. (2016) reported a female infant, born of consanguineous Lebanese parents, with a severe neurodevelopmental disorder. By 6 weeks of life she had roving eye movements, visual inattention, retinal dystrophy, central hypotonia, peripheral hypertonia, extensor posturing, and dystonia. She presented in status epilepticus at 4 months of age and subsequently had an intractable seizure disorder with hypsarrhythmia. She did not obtain developmental milestones and died at age 12 months. Brain imaging showed mild sulcal simplification in the frontal lobes, although myelination appeared normal. She also had some abnormal signals in the gray matter on T2-weighted MRI. Muscle biopsy showed an increase in type 1 oxidative fibers and some lipid droplets in close contact with clumped mitochondria, but respiratory enzymes were normal.

Inheritance

The transmission pattern of EIEE38 in the family reported by Alazami et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 affected members of a consanguineous Saudi Arabian family with EIEE38, Alazami et al. (2015) identified a homozygous missense mutation in the ARV1 gene (G189R; 611647.0001). The family was part of a large cohort of 143 multiplex consanguineous families with various neurodevelopmental disorders who underwent whole-exome sequencing. Functional studies of the variant were not performed.

In a female infant, born of consanguineous Lebanese parents, with EIEE38, Palmer et al. (2016) identified a homozygous splice site mutation in the ARV1 gene (611647.0002). The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies showed that the splice site variant was unable to rescue a growth defect in arv1-null yeast, whereas the G189R mutation retained some activity. The findings were consistent with a loss of function.

Animal Model

Palmer et al. (2016) found that both male and female Arv1-null mice had an increase in the abundance of type 1 oxidative muscle fibers in the diaphragm, but only female mice showed similar changes in the extensor digitorum longus, which is usually rich in glycolytic type 2 fibers. Mice with conditional knockout of the Arv1 gene in the brain had a lean phenotype with decreased body mass, showed abnormal circling behavior, were prone to severe seizures, and had decreased survival compared to controls.