ABSTRACT
Synaptic Vesicle Glycoprotein 2 A (SV2A) is a membrane protein of synaptic vesicles and the binding site of antiepileptic drug levetiracetam. Biallelic Arg383Gln is reported in a family with intractable epilepsy earlier. Here, we report on the second family with early onset drug resistant epilepsy. We identified homozygous Arg289Ter variant by exome sequencing that segregated with the phenotype in the family. The affected children in these two families are normal at birth and developed recurrent seizures beginning in the second month of life and developed secondary failure of growth and development. Knock out mice models earlier had replicated the human phenotype observed in these two families. These findings support that biallelic loss of function variants in SV2A result in early onset intractable epilepsy in humans.
Subject(s)
Drug Resistant Epilepsy , Epilepsy , Animals , Child , Humans , Mice , Anticonvulsants/metabolism , Anticonvulsants/therapeutic use , Epilepsy/drug therapy , Epilepsy/genetics , Glycoproteins/genetics , Glycoproteins/metabolism , Synaptic Vesicles/genetics , Synaptic Vesicles/metabolismABSTRACT
Mitochondrial flavin adenine dinucleotide (FAD) transporter deficiencies are new entities recently reported to cause a neuro-myopathic phenotype. We report three patients from two unrelated families who presented primarily with hypoketotic hypoglycemia. They all had acylcarnitine profiles suggestive of multiple acyl-CoA dehydrogenase deficiency (MADD) with negative next-generation sequencing of electron-transfer flavoprotein genes (ETFA, ETFB, and ETFDH). Whole exome sequencing revealed a homozygous c.272 G > T (p.Gly91Val) variant in exon 2 of the SLC25A32 gene. The three patients shared the same variant, and they all demonstrated similar clinical and biochemical improvement with riboflavin supplementation. To date, these are the first patients to be reported with hypoketotic hypoglycemia without the neuromuscular phenotype previously reported in patients with SLC25A32 deficiency.
Subject(s)
Hypoglycemia , Iron-Sulfur Proteins , Membrane Transport Proteins , Multiple Acyl Coenzyme A Dehydrogenase Deficiency , Oxidoreductases Acting on CH-NH Group Donors , Electron-Transferring Flavoproteins/genetics , Electron-Transferring Flavoproteins/metabolism , Humans , Hypoglycemia/genetics , Iron-Sulfur Proteins/genetics , Membrane Transport Proteins/deficiency , Membrane Transport Proteins/genetics , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/genetics , Mutation , Oxidoreductases Acting on CH-NH Group Donors/genetics , Oxidoreductases Acting on CH-NH Group Donors/metabolism , Riboflavin/metabolismABSTRACT
Myelin pathologies are an important cause of multifactorial, e.g., multiple sclerosis, and Mendelian, e.g., leukodystrophy, neurological disorders. CNP encodes a major component of myelin and its CNS expression is exclusive to myelin-forming oligodendrocytes. Deficiency of CNP in mouse causes a lethal white matter neurodegenerative phenotype. However, a corresponding human phenotype has not been described to date. Here, we describe a multiplex consanguineous family from Oman in which multiple affected members display a remarkably consistent phenotype of neuroregression with profound brain white matter loss. A novel homozygous missense variant in CNP was identified by combined autozygome/exome analysis. Immunoblot analysis suggests that this is a null allele in patient fibroblasts, which display abnormal F-actin organization. Our results suggest the establishment of a novel CNP-related hypomyelinating leukodystrophy in humans.
