Molecular and Phenotypic Characterization of the RORB-Related Disorder.

BACKGROUND AND OBJECTIVES: Heterozygous variants in RAR-related orphan receptor B (RORB) have recently been associated with susceptibility to idiopathic generalized epilepsy. However, few reports have been published so far describing pathogenic variants of this gene in patients with epilepsy and intellectual disability (ID). In this study, we aimed to delineate the epilepsy phenotype associated with RORB pathogenic variants and to provide arguments in favor of the pathogenicity of variants. METHODS: Through an international collaboration, we analyzed seizure characteristics, EEG data, and genotypes of a cohort of patients with heterozygous variants in RORB. To gain insight into disease mechanisms, we performed ex vivo cortical electroporation in mouse embryos of 5 selected variants, 2 truncating and 3 missense, and evaluated on expression and quantified changes in axonal morphology. RESULTS: We identified 35 patients (17 male, median age 10 years, range 2.5-23 years) carrying 32 different heterozygous variants in RORB, including 28 single-nucleotide variants or small insertions/deletions (12 missense, 12 frameshift or nonsense, 2 splice-site variants, and 2 in-frame deletions), and 4 microdeletions; de novo in 18 patients and inherited in 10. Seizures were reported in 31/35 (89%) patients, with a median age at onset of 3 years (range 4 months-12 years). Absence seizures occurred in 25 patients with epilepsy (81%). Nineteen patients experienced a single seizure type: absences, myoclonic absences, or absences with eyelid myoclonia and focal seizures. Nine patients had absence seizures combined with other generalized seizure types. One patient had presented with absences associated with photosensitive occipital seizures. Three other patients had generalized tonic-clonic seizures without absences. ID of variable degree was observed in 85% of the patients. Expression studies in cultured neurons showed shorter axons for the 5 tested variants, both truncating and missense variants, supporting an impaired protein function. DISCUSSION: In most patients, the phenotype of the RORB-related disorder associates absence seizures with mild-to-moderate ID. In silico and in vitro evaluation of the variants in our cohort, including axonal morphogenetic experiments in cultured neurons, supports their pathogenicity, showing a hypomorphic effect.

Hypothalamic hamartoma and epilepsy in children: illustrative cases of possible evolutions.

The progresses of neuroimaging have allowed an earlier detection of hypothalamic hamartoma in children presenting with gelastic or dacrystic seizures. Associated symptoms can include other types of seizures, precocious puberty, and behavioral or cognitive deterioration. Combination of all these features is not constant and, when present, their evolution may be variable. When epilepsy proves intractable, surgery may be a solution but is not without risks. Therefore, it can only be justified on the basis of a considerable degree of certainty on the progressive character of the disorder, both in terms of epilepsy and global development. Even though epilepsy is a major and usually the most important problem, it is not always possible to predict its course and to be able to evaluate its potential effects on development. Available data suggests that deterioration is partly related to the epileptogenic activity. We reviewed data from 16 personal cases and discussed the possible evolutions of the epilepsy syndrome on the basis of 6 illustrative cases and a review of the literature. We point out that seizures may start early in life and evolve either towards a catastrophic encephalopathy or may be transiently severe and will progressively settle down. Intermediate situations also exist as well as cases presenting with a mild epilepsy. In almost all cases cognitive difficulties are present and may be associated with behavioral disturbances. They are of variable severity, usually in relation to the severity of the epilepsy and the evolution of the EEG abnormalities. Some of our cases also illustrate that, in young children whose seizures are limited to "a sensation of a pleasant feeling", "a pressure to laugh" or "smiling", early detection of the hamartoma may still be difficult and the epilepsy pattern may be misdiagnosed as an epilepsy temporal or frontal origin. Detailed analysis of the electro-clinical evolution of representative cases highlights the variable expression of the epilepsy syndrome and renders difficult any dogmatic position on early surgery. However, recent data suggests that a surgical solution must be sought early. Prospective studies are needed to evaluate, not only outcome in terms of control the seizures without unacceptable side effects but also on the evolution of the cognitive and behavioral profile of children with HH and epilepsy are needed.