Aims KCNJ11-related diabetes is the most common form of permanent neonatal diabetes and has been associated with a spectrum of neurodevelopmental problems. We compared neurodevelopmental outcomes in subjects with KCNJ11 mutations and their sibling controls. Methods Through our Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu/), we evaluated 23 subjects with KCNJ11 mutations with (n=9) and without (n=14) global developmental delay successfully treated with sulfonylurea and 20 healthy sibling controls, using a battery of targeted neuropsychological and behavioural assessments with scaled scores that are comparable across a wide range of ages. Results Subjects with KCNJ11-related diabetes without global developmental delay had significant differences compared to sibling controls on a range of assessments including IQ, measures of academic achievement and executive function. KCNJ11 subjects with global delay exhibited significant differences in behavioural symptoms with a tendency to avoid social contact and displayed a reduced ability to adapt to new circumstances. Parents reported more immature behaviour, gross mood swings, bizarre thoughts, other unusual and severe behaviours and there were also significant deficits in all subdomains of daily living skills. Conclusions This series represents the largest and most comprehensive study of neuropsychological and behavioural dysfunction of individuals with KCNJ11-diabetes and is the first to compare outcome with sibling controls. Our data demonstrates the variety of neurodevelopmental problems seen in those with KCNJ11 mutations, even in those without recognized global developmental delays. These data can be used to counsel families and guide structured neurodevelopmental assessments and treatments based on the initial genetic diagnosis in patients with neonatal diabetes.

Objectives Mutations in KCNJ11 are the most common cause of permanent neonatal diabetes mellitus (NDM). Approximately 25% of patients have obvious neurological dysfunction, but whether milder related problems might be more common has been unclear. We sought to assess the prevalence of parental concerns about learning, behavior, attention deficit hyperactivity disorder (ADHD), social competency, and sleep in subjects with KCNJ11-related NDM compared to unaffected sibling controls. Study design Subjects or their guardians in the University of Chicago Monogenic Diabetes Registry completed a survey examining learning, behavior, ADHD and sleep. 30 subjects with KCNJ11-related NDM and 25 unaffected sibling controls were assessed. Data were analyzed using GraphPad Prism 6. Nonparametric analysis was performed using Fisher’s exact test for group comparisons. Results 13 (43%) individuals with KCNJ11-related NDM had treatment for or a diagnosis of ADHD compared to 2 (8%) of the sibling controls (p<0.05). Compared to their sibling controls, individuals with KCNJ11 mutations had significant differences in behavior difficulties, social awareness, academic achievement and the need for an Individualized Education Plan (IEP). As seen in other neurodevelopmental disorders, individuals with KCNJ11 mutations also had significantly higher rates of sleep difficulties (p<0.01). Conclusion Patients with KCNJ11-related NDM are at an increased risk for delays in learning, social-emotional and behavioral development, ADHD and sleep difficulties based on parent report. Early identification, along with integrated medical and developmental support, may promote better neurodevelopmental outcomes for this unique population. Further investigation utilizing detailed neuropsychological testing will better define the neurodevelopmental consequences of KATP mutations.

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