Cognitive, Neurological, and Behavioral Features in Adults With <i>KCNJ11</i> Neonatal Diabetes.

Abstract

Central nervous system (CNS) features in children with permanent neonatal diabetes (PNDM) due to <i>KCNJ11</i> mutations have a major impact on affected families. Sulfonylurea therapy achieves outstanding metabolic control but only partial improvement in CNS features. The effects of <i>KCNJ11</i> mutations on the adult brain and their functional impact are not well understood. We aimed to characterize the CNS features in adults with <i>KCNJ11</i> PNDM compared with adults with <i>INS</i> PNDM. Adults with PNDM due to <i>KCNJ11</i> mutations (<i>n</i> = 8) or <i>INS</i> mutations (<i>n</i> = 4) underwent a neurological examination and completed standardized neuropsychological tests/questionnaires about development/behavior. Four individuals in each group underwent a brain MRI scan. Test scores were converted to <i>Z</i> scores using normative data, and outcomes were compared between groups. In individuals with <i>KCNJ11</i> mutations, neurological examination was abnormal in seven of eight; predominant features were subtle deficits in coordination/motor sequencing. All had delayed developmental milestones and/or required learning support/special schooling. Half had features and/or a clinical diagnosis of autism spectrum disorder. <i>KCNJ11</i> mutations were also associated with impaired attention, working memory, and perceptual reasoning and reduced intelligence quotient (IQ) (median IQ <i>KCNJ11</i> vs. <i>INS</i> mutations 76 vs. 111, respectively; <i>P</i> = 0.02). However, no structural brain abnormalities were noted on MRI. The severity of these features was related to the specific mutation, and they were absent in individuals with <i>INS</i> mutations. <i>KCNJ11</i> PNDM is associated with specific CNS features that are not due to long-standing diabetes, persist into adulthood despite sulfonylurea therapy, and represent the major burden from <i>KCNJ11</i> mutations.