Asunto(s)
Ejercicio Físico/fisiología , Enfermedades Neuromusculares , Adulto , Contractura/etiología , Creatina Quinasa/sangre , Terapia por Ejercicio , Fatiga/etiología , Cardiopatías/etiología , Humanos , Enfermedades Pulmonares/etiología , Miopatías Mitocondriales/complicaciones , Miopatías Mitocondriales/terapia , Debilidad Muscular/etiología , Distrofias Musculares/complicaciones , Distrofias Musculares/terapia , Miopatías Estructurales Congénitas/complicaciones , Miopatías Estructurales Congénitas/terapia , Trastornos Miotónicos/complicaciones , Trastornos Miotónicos/terapia , Enfermedades Neuromusculares/complicaciones , Enfermedades Neuromusculares/genética , Enfermedades Neuromusculares/terapia , Dolor/etiología , Modalidades de Fisioterapia , Entrenamiento de FuerzaRESUMEN
Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.