ADHD, learning difficulties and sleep disturbances associated with KCNJ11 -related neonatal diabetes

Abstract

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.

Hypoglycemia in sulfonylurea‐treated KCNJ11 ‐neonatal diabetes: Mild‐moderate symptomatic episodes occur infrequently but none involving unconsciousness or seizures

“…Of the 459 individuals with an established monogenic etiology for diabetes within the University of Chicago Monogenic Diabetes Registry at the time of this study, we distributed surveys to the 72 who had a KCNJ11 mutation and received responses from 30 subjects, all with permanent NDM (28 probands and 2 affected family members; and proband responders (n = 28) and non-responders (n = 24) were similar by all characteristics, including household income and age at assessment, as reported previously. 15 The majority of responses were from parents or guardian caregivers who completed the questionnaire on behalf of subjects, who were mostly children (mean age: other less common variants (one each of G53D, H46L, I182T, Q52L, and V59A, and two with H186D). 4 The median age at diagnosis was 0.15 years (0.09-0.29 IQR), the median age at SU initiation was 1.2 years (0.3-5.8 IQR), and the median HbA1c at the time of survey collection was 5.7% (39 mmol/mol) (5.5%-6.1% IQR; who reported hypoglycemia as "once a week" or "more than once a…”

Update of variants identified in the pancreatic β‐cell K ATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes

“…Since these initial reports, studies on larger cohorts of individuals affected with K ATP channel NDM have characterized the neurological features in more detail. Additional features reported include autism and attention deficit hyperactivity disorder (ADHD), anxiety and sleep disorders, dyspraxia, and learning difficulties, resulting in impaired attention, memory, visuospatial abilities, and executive function (Beltrand et al, 2015; Bowman et al, 2016; Bowman et al, 2017; Bowman, Day, et al, 2018; Busiah et al, 2013; Landmeier, Lanning, Carmody, Greeley, & Msall, 2017). More important, it is now recognized that some degree of impairment can be detected on neuropsychological testing in the majority of patients with K ATP channel mutations, even if there is no obvious CNS involvement (Busiah et al, 2013; Carmody et al, 2016).…”

Neuropsychological impairments in children with KCNJ11 neonatal diabetes

“…Landmeier et al . reported disturbances in parent‐reported social–emotional and regulatory behaviours, attention, sleep and learning that occurred in all KCNJ11 mutation subtypes studied . Furthermore, Busiah et al .…”