Phenotypic spectrum of nervous system diseases in children associated with KCNMA1 gene mutations

Objective To summarize the clinical phenotypes and genetic mutations of children with KCNMA1 gene mutations. Methods A retrospective analysis was performed for the clinical data of ten children with heterozygous KCNMA1 gene mutations who attended Pediatric Medical Center of Peking University First Hospital from March 2013 to May 2023, and their cli-nical manifestations, cranial radiological features, and electroencephalogram (EEG) features were summarized. Results Among the ten children with KCNMA1 mutations, there were eight boys and two girls. Nine different KCNMA1 gene mutations were identified, including five missense mutations, three frame-shifting mutations, and one splice site mutation, among which there were seven de novo mutations and two inheritable mutations. Among the ten children with KCNMA1 mutation, six presented with seizures alone, three presented with seizures and paroxysmal movement disorders, and one presented with paroxysmal movement disorders alone. For the nine children with seizures, the age of onset ranged from 3 days to 1 year and 8 months, with a median age of onset of 8 months, and the types of seizures included focal seizures (six children), epileptic spasm (four children), myoclonic seizures (two children), atypical absence seizures (two children), generalized tonic-clonic seizures (two children), myoclonic-ato-nic seizures (one child), and atonic seizures (one child), with multiple types of seizures in five children. For the children who met the diagnostic criteria for epilepsy syndrome, one child was diagnosed with infantile epileptic spasms, and one was diagnosed with myoclonic-atonic epilepsy. For the four children with movement disorders, the age of onset ranged from 15 days to 1 year and 6 months, and movement disorders mainly manifested as paroxysmal non-kinesigenic dystonia, with paroxysmal movement disorders comorbid with abnormal eye movement in one child. Among the ten children with KCNMA1 mutation, there were four children with abnormal cranial MRI findings, including ventriculomegaly (three children), subarachnoid space widening (two children), dysgenesis of corpus callosum (two children), and delayed white matter myelination (one child). EEG showed slow background activity in five children, and epileptiform discharges were observed in all ten children during the interictal period, manifesting as focal discharges, multifocal discharges, or generalized discharges, with hypsarrhythmia in four children and electrical status epilepticus during sleep in one child. Seizure were observed in four children, among whom three had epileptic spasms and one had atypical absence seizures. All 10 children had developmental delay. Conclusion The phenotypic spectrum of nervous system diseases in children with KCNMA1 gene mutations mainly include epilepsy, paroxysmal non-kinesigenic dystonia, and developmental delay. Epilepsy usually occurs before the age of 2 years and has multiple seizure types, with focal seizures as the most common type. Paroxysmal movement disorders mainly manifest as paroxysmal dystonia.