Epilepsy, Idiopathic Generalized, Susceptibility To, 15

A number sign (#) is used with this entry because of evidence that susceptibility to idiopathic generalized epilepsy-15 (EIG15) is caused by heterozygous mutation in the RORB gene (601972) on chromosome 9q22.

Description

Susceptibility to idiopathic generalized epilepsy-15 (EIG15) is an autosomal dominant seizure disorder characterized by onset of variable types of seizures in the first decade. Absence seizures are the most common manifestation, but most patients also develop other types, including clonic or generalized tonic-clonic seizures. EEG tends to show 3-Hz spike-wave discharges, whereas brain imaging is normal. The majority of patients also have developmental delay associated with impaired intellectual development apparent from infancy or early childhood (summary by Rudolf et al., 2016).

For a general phenotypic description and a discussion of genetic heterogeneity of idiopathic generalized epilepsy, see EIG (600669).

Clinical Features

Rudolf et al. (2016) reported a 4-generation French family in which 4 individuals (patients 4, 13, 14, and 20) had onset of absence seizures and rare generalized tonic-clonic seizures between 3 and 11 years of age. EEG showed generalized polyspikes followed by typical 3-Hz spike-and-wave absence seizures with loss of consciousness, ocular elevation, eyelid myoclonia, and neck and shoulder myoclonia of limited amplitude, mostly triggered by intermittent photic stimulation (IPS) at eye closure. The epilepsy was controlled by medication. Three patients were noted to have mild intellectual disability (IQ range from 62 to 73). There was evidence of possible incomplete penetrance and/or phenocopies within the family: the RORB variant was also found in patient 10, who had isolated photoparoxysmal response (PPR) during IPS, but whose seizure state could not be confirmed, and in patient 23, who reportedly had 1 absence seizure at age 9 years, but refused EEG investigations. In addition, there were 3 family members (11, 15, and 21) who had isolated PPR during IPS, but they did not carry the variant; these 3 patients did not have seizures.

Rudolf et al. (2016) subsequently identified 4 unrelated patients with early-onset seizures and impaired intellectual development. Patient AG1 was an 18-year-old woman who developed febrile seizures at age 3 years that progressed to febrile and nonfebrile generalized tonic-clonic seizures. Initially refractory, the seizures eventually were controlled with medication, and she became seizure-free off medication during her teenage years. She had developmental delay since age 15 months, abnormal behaviors such as stereotypies, compulsive behaviors, and aggression, autism spectrum disorder, significant sleep disturbances, and moderate to severe cognitive deficits (IQ of 40). Patient RO1 was a 4-year-old boy who developed clonic seizures at age 4 months, followed by clonic-atonic and atypical absence seizures. The seizures were refractory to medication, and EEG showed background slowing and frequent multifocal spikes. He had developmental delay beginning around 10 months of age, and later showed severe intellectual impairment with a developmental quotient of 50%. The remaining 2 patients had onset of absence and/or generalized seizures between 2 and 4 years of age. A 10-year-old girl (patient GE0705) had refractory seizures, eyelid myoclonia triggered by IPS, and global developmental delay with learning difficulties, speech impairment, and IQ less than 50. She also had strabismus and hypermetropia. A 28-year-old man (patient EC-CAE300) had variable seizure types that were partially responsive to treatment, learning difficulties, dyslexia, and behavioral problems with aggressive features. Brain imaging was normal in all 4 patients.

Inheritance

The transmission pattern of EIG15 in the family reported by Rudolf et al. (2016) was consistent with autosomal dominant inheritance with possible incomplete penetrance.

Molecular Genetics

In 4 affected members of a 4-generation French family with EIG15, Rudolf et al. (2016) identified a heterozygous nonsense mutation in the RORB gene (R66X; 601972.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed that the mutant transcript escaped nonsense-mediated mRNA decay, but no mutant protein was detected in the nucleoplasm of transfected COS7 cells, consistent with a loss of function. There was evidence of possible incomplete penetrance and/or phenocopies within the family. Three additional unrelated patients with a similar phenotype were found to have de novo heterozygous point mutations or intragenic deletions in the RORB gene (601972.0002-601972.0004). Molecular modeling suggested that some of these mutations would interfere with DNA binding or be pathogenic; additional functional studies of the variants and studies of patients cells were not performed. Three additional patients with a similar phenotype who had larger or more complex deletions or translocations involving the RORB gene were also identified, suggesting that RORB plays a role in neurodevelopment and possibly neuronal hyperexcitability.