Epileptic Encephalopathy, Early Infantile, 73

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-73 (EIEE73) is caused by heterozygous mutation in the RNF13 gene (609247) on chromosome 3q25.

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

Clinical Features

Edvardson et al. (2019) reported 3 unrelated children with a severe neurodevelopmental and neurodegenerative disorder. Abnormally high alpha-fetoprotein (AFP) in maternal blood was noted in the only pregnancy tested (patient 1). The patients had a small head circumference at birth (-2 to -3) and showed feeding difficulties, restlessness, and abnormally increased muscle tone. They developed refractory tonic, clonic, and myoclonic seizures between 7 weeks and 7 months of age. EEG showed slowing of background activity, with interictal nonsynchronous spikes and sharp waves, as well as focal ictal discharges. All affected individuals had cortical visual impairment with roving eye movements and a pupillary response to light, but failure to fixate or track. A discrepancy in the article regarding hearing loss in the patients was clarified by one of the authors (Moldovan, 2019): 2 patients had profound sensorineural deafness and 1 had mild hearing impairment. None of the patients achieved any developmental milestones; they had no voluntary movements or communication and were tube fed. They had failure to thrive, increased muscle tone, limb contractures, and scoliosis. Head circumference ranged from -5.5 to -2 SD. Dysmorphic features included midface hypoplasia, narrow forehead, short nose, small chin, and narrow nasal bridge. One patient had cataracts, 2 had inguinal hernia, and 1 had hip dysplasia with delayed bone age. Brain imaging performed in 2 patients showed thin corpus callosum; 1 had delayed myelination. One patient died at 33 months, whereas the other 2 were alive at 21 months and 8 years.

Molecular Genetics

In 3 unrelated patients with EIEE73, Edvardson et al. (2019) identified de novo heterozygous missense mutations in the RNF13 gene (L311S, 609247.0001 and L312P, 609247.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not found in the gnomAD database. Both mutations occurred in a highly conserved region important for posttranslational modification. In vitro functional expression studies of cells derived from the patient with the L311S mutation showed enhanced signaling of endoplasmic reticulum (ER) stress and increased ER stress-induced apoptosis compared to controls, consistent with a gain-of-function effect.