Neuropsychological dysfunction and developmental defects associated with genetic changes in infants with neonatal diabetes mellitus: a prospective cohort study

Summary Background Neonatal diabetes mellitus is a rare genetic form of pancreatic β-cell dysfunction. We compared phenotypic features and clinical outcomes according to genetic subtypes in a cohort of patients diagnosed with neonatal diabetes mellitus before age 1 year, without β-cell autoimmunity and with normal pancreas morphology. Methods We prospectively investigated patients from 20 countries referred to the French Neonatal Diabetes Mellitus Study Group from 1995 to 2010. Patients with hyperglycaemia requiring treatment with insulin before age 1 year were eligible, provided that they had normal pancreatic morphology as assessed by ultrasonography and negative tests for β-cell autoimmunity. We assessed changes in the 6q24 locus, K ATP -channel subunit genes ( ABCC8 and KCNJ11 ), and preproinsulin gene ( INS ) and investigated associations between genotype and phenotype, with special attention to extra-pancreatic abnormalities. Findings We tested 174 index patients, of whom 47 (27%) had no detectable genetic defect. Of the remaining 127 index patients, 40 (31%) had 6q24 abnormalities, 43 (34%) had mutations in KCNJ11 , 31 (24%) had mutations in ABCC8 , and 13 (10%) had mutations in INS . We reported developmental delay with or without epilepsy in 13 index patients (18% of participants with mutations in genes encoding K ATP channel subunits). In-depth neuropsychomotor investigations were done at median age 7 years (IQR 1–15) in 27 index patients with mutations in K ATP channel subunit genes who did not have developmental delay or epilepsy. Developmental coordination disorder (particularly visual-spatial dyspraxia) or attention deficits were recorded in all index patients who had this testing. Compared with index patients who had mutations in K ATP channel subunit genes, those with 6q24 abnormalities had specific features: developmental defects involving the heart, kidneys, or urinary tract (8/36 [22%] vs 2/71 [3%]; p=0·002), intrauterine growth restriction (34/37 [92%] vs 34/70 [48%]; p vs 45·5 days, IQR 27·2–95·0; p ATP channel subunit genes (82% vs 86%; p=0·36). Interpretation Neonatal diabetes mellitus is often associated with neuropsychological dysfunction and developmental defects that are specific to the underlying genetic abnormality. A multidisciplinary assessment is therefore essential when patients are diagnosed. Features of neuropsychological dysfunction and developmental defects should be tested for in adults with a history of neonatal diabetes mellitus. Funding Agence Nationale de la Recherche-Maladies Rares Research Program Grant, the Transnational European Research Grant on Rare Diseases, the Societe Francophone du Diabete–Association Francaise du Diabete, the Association Francaise du Diabete, Aide aux Jeunes Diabetiques, a CIFRE grant from the French Government, HRA-Pharma, the French Ministry of Education and Research, and the Societe Francaise de Pediatrie.