title: Homozygous KCNMA1 mutation as a cause of cerebellar atrophy, developmental delay and seizures.
abstract: Dominant gain-of-function mutations of the KCNMA1 gene, encoding the pore-forming subunit of the large conductance voltage- and Ca2+-activated K+ channel, have been described in a few patients with the syndrome of epilepsy, paroxysmal dyskinesias and developmental delay. In this report, we describe the loss-of-function phenotype of this newly described disease gene. In two siblings from a consanguineous family with epilepsy, developmental delay and severe cerebellar atrophy, combined exome/autozygome analysis identified a homozygous frameshift duplication in KCNMA1 (c.2026dupT; p. (Tyr676 Leufs*7)) in both children. Our report defines a novel autosomal recessive KCNMA1-related epileptic phenotype that encompasses cerebellar atrophy without paroxysmal dyskinesia, and highlights the sensitivity of the developing brain to both increased and decreased activity of the KCNMA1-encoded channels.
authors: Division of Neurology, Department of Pediatrics, Prince Sultan Military Medical City, PO Box 7889, Riyadh, 11159, Saudi Arabia. btabarki@hotmail.com.
authors: Brahim
authors: B
authors: Tabarki
authors: Division of Neurology, Department of Pediatrics, Prince Sultan Military Medical City, PO Box 7889, Riyadh, 11159, Saudi Arabia.
authors: Nabil
authors: N
authors: AlMajhad
authors: Division of Genetics, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
authors: Amal
authors: A
authors: AlHashem
authors: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors: Ranad
authors: R
authors: Shaheen
authors: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors: Fowzan S
authors: FS
authors: Alkuraya
mesh_terms: D001284:Atrophy / Q000235:genetics* / Q000473:pathology; D002658:Developmental Disabilities / Q000235:genetics* / Q000473:pathology; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology; D059472:Exome; D005260:Female; D006720:Homozygote; D006801:Humans; D007223:Infant; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D012640:Seizures / Q000235:genetics* / Q000473:pathology
chemical_list: C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits