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.

De Novo Variants in RAB11B Cause Various Degrees of Global Developmental Delay and Intellectual Disability in Children.

BACKGROUND: RAB11B was described previously once with a severe form of intellectual disability. We aim at validation and delineation of the role of RAB11B in neurodevelopmental disorders. METHODS: We present seven novel individuals with disease-associated variants in RAB11B when compared with the six cases described in the literature. We performed a cross-sectional analysis to identify the clinical spectrum and the core phenotype. Additionally, structural effects of the variants were assessed by molecular modeling. RESULTS: Seven distinct de novo missense variants were identified, three of them recurrent (p.(Gly21Arg), p.(Val22Met), and p.(Ala68Thr)). Molecular modeling suggests that those variants either affect the nucleotide binding (at amino acid positions 21, 22, 33, 68) or the interaction with effector molecules (at positions 72 and 75). Our data confirmed the main manifestations as neurodevelopmental disorder with intellectual disability (85%), muscular hypotonia (83%), structural brain anomalies (77%), and visual impairment (70%). Combined analysis indicates a genotype-phenotype correlation; variants impacting the nucleotide binding cause a severe phenotype with intellectual disability, and variants outside the binding pocket lead to a milder phenotype with epilepsy. CONCLUSIONS: We confirm that disease-associated missense variants in RAB11B cause a neurodevelopmental disorder and suggest a genotype-phenotype correlation based on the impact on nucleotide binding functionality of RAB11B.

Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies.

Many patients with developmental and epileptic encephalopathies present with variants in genes coding for GABAA receptors. These variants are presumed to cause loss-of-function receptors leading to reduced neuronal GABAergic activity. Yet, patients with GABAA receptor variants have diverse clinical phenotypes and many are refractory to treatment despite the availability of drugs that enhance GABAergic activity. Here we show that 44 pathogenic GABRB3 missense variants segregate into gain-of-function and loss-of-function groups and respective patients display distinct clinical phenotypes. The gain-of-function cohort (n = 27 patients) presented with a younger age of seizure onset, higher risk of severe intellectual disability, focal seizures at onset, hypotonia, and lower likelihood of seizure freedom in response to treatment. Febrile seizures at onset are exclusive to the loss-of-function cohort (n = 47 patients). Overall, patients with GABRB3 variants that increase GABAergic activity have more severe developmental and epileptic encephalopathies. This paradoxical finding challenges our current understanding of the GABAergic system in epilepsy and how patients should be treated.

Predictive factors and prognostic value for status epilepticus in newborns.

OBJECTIVES: To evaluate the predictive factors for status epilepticus (SE) in neonates and prognostic factors for patient outcomes in newborns suffering either isolated seizures or SE. METHODS: A retrospective single-center study from January 2010 to December 2014, included 91 newborns who had neonatal seizures. Among them, 50 newborns experienced SE and 41 newborns presented isolated seizures only. SE was defined as a single seizure lasting more than 15 min or repeated seizures without return to preictal neurological baseline for more than 15 min. Isolated seizures were defined as one single seizure lasting less than 15 min or more seizures with complete recovery of consciousness between seizures. Perinatal and electroclinical data were recorded. Outcomes were evaluated at one year follow up. RESULTS: In multivariate analysis, the factors identified as being predictive of SE were a severely abnormal initial neurological examination (OR 15.7, 95% CI (3.8-109) p = 0.00075) and hypoglycaemia (OR 6.8, 95% CI (1.5-49.2) p = 0.024), found mostly in newborns with hypoxic-ischemic encephalopathy. When studying our global cohort, SE was found to be a negative prognostic factor for outcome only in univariate analysis. In newborns with isolated seizures only, the postictal clinical examination results were the only independent prognostic factor found, normal results being associated with a more favorable evolution (OR 48.9, 95% CI (7.16-571) p = 0.0003). CONCLUSION: Two independent risk factors for SE in newborns have been identified: a severely abnormal initial neurological examination and hypoglycaemia. In newborns with isolated seizures, the only positive prognostic factor was found to be a normal postictal clinical examination.