Intellectual Disability in KATP Channel Neonatal Diabetes

Abstract

OBJECTIVE Neonatal diabetes has been shown to be associated with high neuropsychiatric morbidity in a genotype-phenotype–dependent manner. However, the specific impact of different mutations on intellectual functioning is still insufficiently characterized. Specifically, only a small number of subjects with developmental delay have been comprehensively assessed, creating a knowledge gap about patients carrying the heaviest burden. RESEARCH DESIGN AND METHODS We assessed the intellectual functioning and mental health of the complete Norwegian population with KATP channel neonatal diabetes. Eight sulfonylurea-treated children (five with the p.V59M genotype [KCNJ11]) were assessed using age-matched control subjects with type 1 diabetes. The investigations included a physical and motor developmental examination, cerebral MRI, psychometrical examination, and questionnaires assessing intellectual capabilities and psychiatric morbidity. RESULTS A strong genotype-phenotype correlation was found, revealing the p.V59M genotype as highly associated with substantial intellectual disability, with no significant correlation with the time of sulfonylurea initiation. Consistent with previous studies, other genotypes were associated with minor cognitive impairment. Cerebral MRI verified normal brain anatomy in all but one child. CONCLUSIONS We here presented a comprehensive assessment of intellectual functioning in the largest cohort of p.V59M subjects to date. The level of intellectual disability revealed not only changes the interpretation of other psychological measures but downplays a strong protective effect of sulfonylurea. Within the scope of this study, we could not find evidence supporting an early treatment start to be beneficial, although a weaker effect cannot be ruled out.

The clinical consequences of heterogeneity within and between different diabetes types

“…Genetic diagnosis of potassium-channel neonatal diabetes is extremely important because affected neonates can be treated with sulfonylurea tablets [34]. In KCNJ11 PNDM, the genetic mutations are correlated with the severity of the neurological abnormalities, which were thought to improve with sulfonylureas, although recent data casts doubts on this concept [35]. Mutations in key pancreas development transcription genes (e.g.…”

Transient Neonatal Diabetes Mellitus Managed with Continuous Subcutaneous Insulin Infusion (CSII) and Continuous Glucose Monitoring

“…1) . Early SU therapy may improve speech, motor, and cognitive disabilities, and re cent studies have identified a higher prevalence of neurodevelop mental disorders in particular geno types, although the correla tion of the genotypes with neurodeve lopmental impairment along with underlying pathophysiology re mains to be charac terized 22,23) . Although variations of genes enco ding the KATP channel are known to be the most common and second most common causes of PNDM and TNDM, respectively, genetic confirmation requires a considerable amount of time; how ever, recent literature suggests considering early SU therapy before a genetic diagnosis is made, to avoid the potential adverse effects of delayed therapy 1,24) .…”

Intellectual Disability and Potassium Channelopathies: A Systematic Review

“…Several variants with gain-of-function properties have been associated with ID: V59M, Y330C, V59A, G53D, R201C, C166Y, V59G, and Q52R. Most cases carry the V59M variant Supplementary Table 1, which shows clear association with ID symptoms (Svalastoga et al, 2020). Notably, Lin et al (2013) reported a case with gain-offunction derived from the S225T mutation and P226_P232del, suggesting that both gain-and loss-of-function mutations could lead to I-DEND.…”

“…Sulfonylureas act as inhibitors of KATP channels and represent an optimum treatment for diabetes and they can ameliorate the related neurological disorders (Pearson et al, 2006). However, other studies have not detected any benefits of sulfonylureas on neurological symptoms (Sagen et al, 2004;Klupa et al, 2005;Svalastoga et al, 2020), suggesting that sulfonylureas can partially cross the blood-brain barrier, and that the improved neurological symptoms observed resulted from increased cerebellar perfusion (Fendler et al, 2013). Thus, ID could be initiated from gain-of-function or as a complication of neonatal diabetes or due to unknown mechanisms associated with KATP channel, which the partial effects of sulfonylureas on neurological symptoms cannot confirm.…”