Epileptic Encephalopathy, Early Infantile, 59

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-59 (EIEE59) is caused by heterozygous mutation in the GABBR2 gene (607340) on chromosome 9q22.

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

Clinical Features

The EuroEPINOMICS-RES Consortium et al. (2014) reported 2 unrelated patients, a 3-year-old girl (NLES8) and an 18-year-old man (NLES10), with EIEE59. The patients had onset of seizures within the first 3 months of life. The girl had multiple seizure types, whereas the male had infantile spasms that mostly resolved by age 5 months, although he had a few focal dyscognitive seizures and nonepileptic apneic spells later in life. Both patients had hypsarrhythmia on EEG. The girl had profound intellectual disability with no head control, inability to speak, and severe hypotonia, and she was fed by a G-tube. She reacted to music but not to people. The older patient had severe intellectual disability, autism spectrum disorder, no speech, mild ataxia, sleeping disorder, and automutilation behavior, and he could walk only with support.

Hamdan et al. (2017) reported a 14-year-old boy (HSJ0048), born of unrelated French Canadian parents, who presented with severe developmental delay and onset of brief focal seizures at 11 months of age. The seizures sometimes progressed, and were controlled by medication. EEG showed modified hypsarrhythmia. Refractory seizures of variable types recurred at age 4.5 years. At age 14, he had severe intellectual disability with inability to sit on his own, absent language, poor eye contact, lack of interest in the environment, drooling, hypotonia, scoliosis, and bouts of aggression. Brain imaging showed enlarged ventricles.

Molecular Genetics

In 2 unrelated patients with EIEE59, the EuroEPINOMICS-RES Consortium et al. (2014) identified de novo heterozygous missense mutations in the GABBR2 gene (S695I, 607340.0004 and I705N, 607340.0005). The mutations were found by exome sequencing of a cohort of 356 trios in which the proband had early infantile epileptic encephalopathy. Functional studies of the variants and studies of patient cells were not performed, but the authors noted that GABBR2 is involved in synaptic transmission.

In a 14-year-old boy (HSJ0048) with EIEE59, Hamdan et al. (2017) identified a de novo heterozygous missense mutation in the GABBR2 gene (G693W; 607340.0006). The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing; the patient was part of several cohorts of patients with developmental delay or epilepsy who underwent whole-exome or whole-genome sequencing. Functional studies of the variants and studies of patient cells were not performed, but the authors noted that GABBR2 is involved in synaptic inhibition.

Using in vitro cellular transfection studies and animal models, Yoo et al. (2017) demonstrated that the GABBR2 S695I and I705N mutations, associated with EIEE59, reduced GABA signaling activity. Based on molecular modeling, the S695I and I705N mutations, located in transmembrane 6, were predicted to affect the structural integrity of the receptor.

Animal Model

Yoo et al. (2017) found that tadpoles injected with the EIEE59-associated GABBR2 mutations showed abnormal swimming patterns and increased frequencies of seizure-like behavior compared to wildtype. The variants could not rescue the defect in tadpoles with morpholino knockdown of the Gabbr2 gene, consistent with a loss of function. The addition of baclofen, a GABAB receptor agonist, to the water partially rescued the phenotype of animals, suggesting a potential therapeutic target in patients with GABBR2 mutations.