GABRA1-Related Disorders: From Genetic to Functional Pathways.

OBJECTIVE: Variants in GABRA1 have been associated with a broad epilepsy spectrum, ranging from genetic generalized epilepsies to developmental and epileptic encephalopathies. However, our understanding of what determines the phenotype severity and best treatment options remains inadequate. We therefore aimed to analyze the electroclinical features and the functional effects of GABRA1 variants to establish genotype-phenotype correlations. METHODS: Genetic and electroclinical data of 27 individuals (22 unrelated and 2 families) harboring 20 different GABRA1 variants were collected and accompanied by functional analysis of 19 variants. RESULTS: Individuals in this cohort could be assigned into different clinical subgroups based on the functional effect of their variant and its structural position within the GABRA1 subunit. A homogenous phenotype with mild cognitive impairment and infantile onset epilepsy (focal seizures, fever sensitivity, and electroencephalographic posterior epileptiform discharges) was described for variants in the extracellular domain and the small transmembrane loops. These variants displayed loss-of-function (LoF) effects, and the patients generally had a favorable outcome. A more severe phenotype was associated with variants in the pore-forming transmembrane helices. These variants displayed either gain-of-function (GoF) or LoF effects. GoF variants were associated with severe early onset neurodevelopmental disorders, including early infantile developmental and epileptic encephalopathy. INTERPRETATION: Our data expand the genetic and phenotypic spectrum of GABRA1 epilepsies and permit delineation of specific subphenotypes for LoF and GoF variants, through the heterogeneity of phenotypes and variants. Generally, variants in the transmembrane helices cause more severe phenotypes, in particular GoF variants. These findings establish the basis for a better understanding of the pathomechanism and a precision medicine approach in GABRA1-related disorders. Further studies in larger populations are needed to provide a conclusive genotype-phenotype correlation. ANN NEUROL 2023.

Nocturnal motor events in epilepsy: Is there a defined physiological network?

OBJECTIVE: Paroxysmal nocturnal movements in epilepsy are a recognised phenomenon, however, the mechanisms that produce them and the effect of the underlying epilepsy still remains elusive. In this study, 10 patients were studied to define the cerebral networks corresponding to these movements and explore how epileptiform activity modulated them. METHODS: We compared the change in power of the 25-250 Hz frequency band using event-related synchronization of all stereo-EEG electrodes implanted, during a baseline segment, during nocturnal movements and seizures. RESULTS: The underlying network activated during these paroxysmal movements comprised the insula, anterior cingulate, premotor areas and orbitofrontal regions. Three groups emerged, (1) complete overlap, (2) no overlap and (3) partial overlap of ERS changes of the epileptogenic zone within the proposed network and correlation of semiology between nocturnal movements and seizures. CONCLUSION: We conclude that nocturnal movements are due to a complex interplay within this physiological network of defined anatomical regions. Epileptic activity had significant impact on nocturnal movements but was not required for generation. SIGNIFICANCE: Where the semiology of the first clinical sign of a seizure consistently matches a patient's nocturnal movements, we suggest that the underlying epileptogenic zone is potentially located within this defined network.

Refractory chronic epilepsy associated with neuronal auto-antibodies: could perisylvian semiology be a clue?

We report a case series of 10 patients with chronic medically refractory antibody-positive autoimmune epilepsy and assess their common clinical features. Immune-mediated seizures are most commonly reported in the context of encephalitis or encephalopathy, with few reports focusing on lone, chronic epilepsy in the outpatient setting. Our aim was to define the potential diagnostic clues that might be present in these cases, leading to consideration of an autoimmune cause of the epilepsy. We performed a retrospective review of all patients presenting to the outpatient department of our unit who underwent autoimmune screening. All patients with chronic epilepsy and a positive result for an antibody known to be associated with epilepsy were included. Sixty-three patients underwent testing. Thirteen returned a positive result, however, only 10 of these were patients which chronic epilepsy who did not present with an acute illness. Common features in these cases included: perisylvian semiology, EEG abnormalities in the mid temporal region, normal or non-specific MRI findings, depression, and head injury. In cases of medically refractory, lesion-negative epilepsy, with predominantly perisylvian semiology, clinicians should have a high level of suspicion for the diagnosis of autoimmune aetiologies and a low threshold to perform autoantibody screening. This is especially true if there are atypical electrographic findings, a previous history of head injury, or co-morbid depression.