Patients with KCNJ11‐related diabetes frequently have neuropsychological impairments compared with sibling controls

Abstract

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.

Neuropsychological impairments in children with KCNJ11 neonatal diabetes

“…Our findings using a different battery of tests are consistent with the study by Carmody et al . , where only 2/9 children with global developmental delay were able to complete any neuropsychological tests, and scores in tests they did complete were the lowest of the group. In those children without global developmental delay, compared with unaffected sibling controls, Carmody et al .…”

“…We support the findings of Carmody et al . , who offered new insights into the neurological phenotype of people with KCNJ11 neonatal diabetes. Neurological features result from the K ATP channel affected by these mutations being expressed in the brain as well as the pancreas .…”

“…Carmody et al . described neuropsychological impairments in children with KCNJ11 mutations and compared their cognitive functioning with unaffected sibling controls, concluding that affected children without global developmental delay had lower IQs and performed worse on a range of assessments of academic achievement and executive function than their unaffected siblings .…”

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

“…Although certain KATP mutations have consistently been reported to be associated with significant developmental delay and/or seizures termed DEND (developmental delay, epilepsy, neonatal diabetes), it has not been clear whether those without obvious developmental delay may in fact have more mild neurodevelopmental and/or behavioral challenges. A study of KCNJ11 patients ( n =23) and their unaffected siblings ( n = 20) revealed that even patients with more mild KCNJ11 mutations (“without global developmental delay”) had significant differences in performance on standardized tests compared to their siblings [16•]. These differences were present in areas such as IQ, academic achievement, and executive function, while those patients with global developmental delay also exhibited differences in social awareness and behavior.…”

Diabetes and childhood

“…The first paper describes how children with KCNJ11 mutations, with and without global developmental delay, had significant differences on a range of assessments including IQ, measures of academic achievement and executive function compared with their unaffected siblings. In those with global delay, there were differences in behavioural symptoms, which had effects across all aspects of daily living [7]. Psychiatric features may also occur as described in the paper by Bowman et al [8], who systematically characterize the types of psychiatric disorders in children with KCNJ11 mutations and their effects.…”