RESUMO
The association between KCTD3 gene and neurogenetic disorders has only been published recently. In this report, we describe the clinical phenotype associated with 2 pathogenic variants in KCTD3 gene. Seven individuals (including one set of monozygotic twin) from 4 consanguineous families presented with developmental epileptic encephalopathy, global developmental delay, central hypotonia, progressive peripheral hypertonia, and variable dysmorphic facial features. Posterior fossa abnormalities (ranging from Dandy-Walker malformation to isolated hypoplasia of the cerebellar vermis) were consistently observed in addition to other variable neuroradiological abnormalities such as hydrocephalus and abnormal brain myelination. One patient also had a multicystic kidney. Whole exome sequencing revealed 2 probably pathogenic homozygous variants in KCTD3 gene that fully segregated with the disease. KCTD3 gene belongs to a family of accessory subunits that regulate the biophysical properties of ion channels, and is highly expressed in the kidney and brain. In this largest series to date on KCTD3-mutated patients, we show that biallelic loss of function mutations in KCTD3 lead to a consistent phenotype of developmental epileptic encephalopathy and abnormal cerebellum on brain imaging.
Assuntos
Síndrome de Dandy-Walker/genética , Sequenciamento do Exoma , Canais de Potássio/genética , Espasmos Infantis/genética , Alelos , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Criança , Pré-Escolar , Síndrome de Dandy-Walker/diagnóstico por imagem , Síndrome de Dandy-Walker/patologia , Feminino , Predisposição Genética para Doença , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/patologia , Lactente , Mutação com Perda de Função/genética , Masculino , Mutação , Fenótipo , Espasmos Infantis/diagnóstico por imagem , Espasmos Infantis/patologiaRESUMO
SLC25A42 gene encodes an inner mitochondrial membrane protein that imports Coenzyme A into the mitochondrial matrix. A mutation in this gene was recently reported in a subject born to consanguineous parents who presented with mitochondrial myopathy with muscle weakness and lactic acidosis. In this report, we present 12 additional individuals with the same founder mutation who presented with variable manifestations ranging from asymptomatic lactic acidosis to a severe phenotype characterized by developmental regression and epilepsy. Our report confirms the link between SLC25A42 and mitochondrial disease in humans, and suggests that pathogenic variants in SLC25A42 should be interpreted with the understanding that the associated phenotype may be highly variable.