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Lancet Diabetes Endocrinol. 2013 Nov;1(3):199-207. doi: 10.1016/S2213-8587(13)70059-7. Epub 2013 Sep 6.

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

Author information

1
INSERM U845, Université Paris Descartes, Sorbonne Paris Cité, Department of Paediatric Endocrinology, Gynaecology, and Diabetology, Necker-Enfants Malades Teaching Hospital, Assistance Publique-Hôpitaux de Paris, IMAGINE affiliate, Paris, France.
2
Department of Genetics, Robert-Debré Teaching Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
3
Inserm UMR-S0669 Université Paris Sud, Paris Descartes, Sorbonne Paris Cité, Department of Paediatrics, Cochin Teaching Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
4
CNRS-UMR-8199, Lille Pasteur Institute, Lille, France; EGID-FR3508, Lille, France; Lille 2 University, Lille, France.
5
Department of Paediatrics, André Mignot Hospital, Le Chesnay, France.
6
Department of Paediatric Endocrinology, Gynaecology, and Diabetology, Necker-Enfants Malades Teaching Hospital, Assistance Publique-Hôpitaux de Paris, IMAGINE affiliate, Paris, France.
7
Clinical Research Unit, Necker-Enfants Malades Teaching Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
8
The Jesse Z and Sara Lea Shafer Institute of Endocrinology and Diabetes, The National Center for Childhood Diabetes, Schneider Children's Medical Centre of Israel, Petah Tikva, Israel.
9
Department of Paediatric Endocrinology and Diabetology, Robert-Debré Teaching Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
10
Department of Paediatrics, Brest Teaching Hospital, Brest, France.
11
Department of Paediatrics, Besançon Hospital, France.
12
Department of Paediatrics, Rennes Teaching Hospital, Rennes, France.
13
Department of Paediatrics, Jeanne de Flandre Teaching Hospital, Lille, France.
14
Department of Paediatric Endocrinology and Diabetology, A Harouchi Paediatric Teaching Hospital, Casablanca, Morocco.
15
Department of Paediatrics, American Memorial Hospital, Reims, France.
16
Department of Paediatrics, Paediatric Teaching Hospital, Toulouse, France.
17
Université Paris Descartes, Sorbonne Paris Cité, INSERM U845, Paris, France.
18
CNRS-UMR-8199, Lille Pasteur Institute, Lille, France; EGID-FR3508, Lille, France; Lille 2 University, Lille, France; Department of Genomics of Common Disease, School of Public Health, Hammersmith Hospital, Imperial College London, London, UK.
19
INSERM U845, Université Paris Descartes, Sorbonne Paris Cité, Department of Paediatric Endocrinology, Gynaecology, and Diabetology, Necker-Enfants Malades Teaching Hospital, Assistance Publique-Hôpitaux de Paris, IMAGINE affiliate, Paris, France. Electronic address: michel.polak@nck.aphp.fr.
20
Department of Genetics, Robert-Debré Teaching Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

Erratum in

  • Lancet Diabetes Endocrinol. 2013 Nov;1(3):e14.

Abstract

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, KATP-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 KATP channel subunits). In-depth neuropsychomotor investigations were done at median age 7 years (IQR 1-15) in 27 index patients with mutations in KATP 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 KATP 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<0·0001), and early diagnosis (median age 5·0 days, IQR 1·0-14·5 vs 45·5 days, IQR 27·2-95·0; p<0·0001). Remission of neonatal diabetes mellitus occurred in 89 (51%) index patients at a median age of 17 weeks (IQR 9·5-39·0; median follow-up 4·7 years, IQR 1·5-12·8). Recurrence was common, with no difference between the groups who had 6q24 abnormalities versus mutations in KATP 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 Société Francophone du Diabète-Association Française du Diabète, the Association Française du Diabète, Aide aux Jeunes Diabétiques, a CIFRE grant from the French Government, HRA-Pharma, the French Ministry of Education and Research, and the Société Française de Pédiatrie.

Comment in

PMID:
24622368
DOI:
10.1016/S2213-8587(13)70059-7
[Indexed for MEDLINE]

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