Psychiatric morbidity in children with KCNJ11 neonatal diabetes

Abstract

AimsMutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the pancreatic KATP channel, cause neonatal diabetes. KCNJ11 is also expressed in the brain, and ~ 20% of those affected have neurological features, which may include features suggestive of psychiatric disorder. No previous studies have systematically characterized the psychiatric morbidity in people with KCNJ11 neonatal diabetes. We aimed to characterize the types of psychiatric disorders present in children with KCNJ11 mutations, and explore their impact on families.MethodsThe parents and teachers of 10 children with neonatal diabetes due to KCNJ11 mutations completed the Strengths and Difficulties Questionnaire and the Development and Wellbeing Assessment. Strengths and Difficulties Questionnaire scores were compared with normative data. Diagnoses from the Development and Wellbeing Assessment were compared with known clinical diagnoses.ResultsStrengths and Difficulties Questionnaire scores indicated high levels of psychopathology and impact. Psychiatric disorder(s) were present in all six children with the V59M or R201C mutation, and the presence of more than one psychiatric disorder was common. Only two children had received a formal clinical diagnosis, with a further one awaiting assessment, and the coexistence of more than one psychiatric disorder had been missed. Neurodevelopmental (attention deficit hyperactivity disorder and autism) and anxiety disorders predominated.ConclusionsSystematic assessment using standardized validated questionnaires reveals a range of psychiatric morbidity in children with KCNJ11 neonatal diabetes. This is under‐recognized clinically and has a significant impact on affected children and their families. An integrated collaborative approach to clinical care is needed to manage the complex needs of people with KCNJ11 neonatal diabetes.

Neonatal Diabetes and the K ATP Channel: From Mutation to Therapy

“…This accounts for the fact that approximately 20% of patients with ND have profound neurological deficits. These include delayed motor and mental development, attention deficit, hyperactivity, autism, aggression, intellectual disability, and (occasionally) seizures 4 , 65 , 66 . Hand–eye coordination is also impaired [67] .…”

“…In general, these features are confined to patients with the most functionally severe mutations and are mainly (but not invariably [68] ) associated with mutations in Kir6.2. The motor and behavioral problems are usually ameliorated by sulfonylurea therapy, in some cases markedly so 65 , 69 , and seizures may cease 13 , 30 , However, the neurological problems often persist or are only partially improved 65 , 66 , 70 . The motor problems of patients with iDEND/DEND are recapitulated in mice expressing an activating K ATP channel mutation specifically in their neurones (nV59M mice), but no effect was seen when the same mutation was expressed in muscle [71] .…”

“…Anxiety disorders, attention deficit hyperactivity disorder (ADHD), and autism are frequently observed in patients with iDEND (especially those with the V59M mutation) [66] . Similarly, nV59M mice show hyperactivity and increased exploratory behavior 72 , 74 .…”

K_ATP Channel Mutations and Neonatal Diabetes

“…However, recent reports suggest the existence of psychiatric disorders. Some patients with causative mutations of DEND syndrome are reported to show signs of attention deficit hyperactivity disorder (ADHD), autism or sleeping disorder ( 54 , 55 ). In a mouse model, mice with neural tissue with DEND-causing V59M mutations displayed hyperactivity, increased exploratory behavior and reduced anxiety, which is consistent with the symptoms of ADHD and autism ( 56 ).…”

Congenital Diabetes: Comprehensive Genetic Testing Allows for Improved Diagnosis and Treatment of Diabetes and Other Associated Features

“…In addition to neurodevelopmental delays, patients with KCNJ11 mutations were significantly more likely than their sibling controls to be diagnosed with ADHD (43 vs. 8%, p <0.05) and to have sleep difficulties ( p <0.01) [18]. Psychiatric disorders, such as anxiety and autism, were identified frequently in a separate research study [19•]. However, most of these disorders had not been clinically identified prior to that study, emphasizing the importance of screening children with KCNJ11 -related diabetes for a variety of neuropsychiatric conditions.…”