Autoimmune Epilepsy: Some Epilepsy Patients Harbor Autoantibodies to Glutamate Receptors and dsDNA on both Sides of the Blood-brain Barrier, which may Kill Neurons and Decrease in Brain Fluids after Hemispherotomy

Purpose: Elucidating the potential contribution of specific autoantibodies (Ab's) to the etiology and/or pathology of some human epilepsies. Methods: Six epilepsy patients with Rasmussen's encephalitis (RE) and 71 patients with other epilepsies were tested for Ab's to the –B— peptide (amino acids 372-395) of the glutamate/AMPA subtype 3 receptor (GluR3B peptide), double-stranded DNA (dsDNA), and additional autoimmune disease-associated autoantigens, and for the ability of their serum and cerebrospinal-fluid (CSF) to kill neurons. Results: Elevated anti-GluR3B Ab's were found in serum and CSF of most RE patients, and in serum of 17/71 (24%) patients with other epilepsies. In two RE patients, anti-GluR3B Ab's decreased drastically in CSF following functional-hemispherotomy, in association with seizure cessation and neurological improvement. Serum and CSF of two RE patients, and serum of 12/71 (17%) patients with other epilepsies, contained elevated anti-dsDNA Ab's, the hallmark of systemic-lupus-erythematosus. The sera (but not the CSF) of some RE patients contained also clinically elevated levels of –classical— autoimmune Ab's to glutamic-acid-decarboxylase, cardiolipin, β2-glycoprotein-I and nuclear-antigens SS-A and RNP-70. Sera and CSF of some RE patients caused substantial death of hippocampal neurons. Conclusions: Some epilepsy patients harbor Ab's to GluR3 and dsDNA on both sides of the blood-brain barrier, and additional autoimmune Ab's only in serum. Since all these Ab's may be detrimental to the nervous system and/or peripheral organs, we recommend testing for their presence in epilepsy, and silencing their activity in Ab-positive patients

Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy

Objective: The MAST family of microtubule-associated serine–threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum. Methods: Using exome sequencing, we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells. Results: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at \u3c2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wild-type. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally. Interpretation: In summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex. ANN NEUROL 2021;90:274–284

An Emerging 1q21.1 Deletion-Associated Neurodevelopmental Phenotype

Abstract In this study, we describe the neurodevelopmental and epileptic phenotypes in a family with an inherited 1q21.1 deletion. During the pregnancy with the proband, increased nuchal translucency and oligohydramnion were detected. The proband showed mild global developmental delay and ataxic gait. Seizures started in the proband at the age of 2 years and manifested as generalized tonic-clonic seizures, atypical absence seizures, head drops, and drop attacks with no abnormal findings on interictal electroencephalogram. We performed an Agilent Human Genome CGH (comparative genomic hybridization) Microarray 105A, and a microdeletion on chromosome 1q21.1 was identified in both the patient and his asymptomatic father. This deletion encompasses 1.65 Mb and is larger than the reported recurrent class I deletions in this region. Cryptic cytogenetic abnormalities should be considered in patients with neurodevelopmental problems and atypical presentation of epilepsy with a normal electroencephalography (EEG)

Autoimmune Epilepsy: Some Epilepsy Patients Harbor Autoantibodies to Glutamate Receptors and dsDNA on both Sides of the Blood–brain Barrier, which may Kill Neurons and Decrease in Brain Fluids after Hemispherotomy

Purpose: Elucidating the potential contribution of specific autoantibodies (Ab’s) to the etiology and/or pathology of some human epilepsies. Methods: Six epilepsy patients with Rasmussen’s encephalitis (RE) and 71 patients with other epilepsies were tested for Ab’s to the “B ” peptide (amino acids 372–395) of the glutamate/AMPA subtype 3 receptor (GluR3B peptide), double-stranded DNA (dsDNA), and additional autoimmune disease-associated autoantigens, and for the ability of their serum and cerebrospinal-fluid (CSF) to kill neurons. Results: Elevated anti-GluR3B Ab’s were found in serum and CSF of most RE patients, and in serum of 17/71 (24%) patients with other epilepsies. In two RE patients, anti-GluR3B Ab’s decreased drastically in CSF following functional-hemispherotomy, in association with seizure cessation and neurological improvement. Serum and CSF of two RE patients, and serum of 12/71 (17%) patients with other epilepsies, contained elevated anti-dsDNA Ab’s, the hallmark of systemic-lupus-erythematosus. The sera (but not the CSF) of some RE patients contained also clinically elevated levels of “classical