Permanent diabetes during the first year of life: multiple gene screening in 54 patients

doi:10.1007/s00125-011-2094-8

. 2011 Jul;54(7):1693-701.

doi: 10.1007/s00125-011-2094-8. Epub 2011 Mar 10.

Permanent diabetes during the first year of life: multiple gene screening in 54 patients

Collaborators, Affiliations

Collaborators

ISPED Early Diabetes Study Group:
R Lera, V Cherubini, A R Fifi, C Torelli, E Frezza, L Cavallo, S Zucchini, B Pasquino, P Kaufmann, P Frongia, N Zedda, C Ripoli, A La, M Cicchetti, D Lo Presti, F Citriniti, M Pocecco, F Chiarelli, S Tumini, M Del Donno, M R De Marco, N Lazzaro, P Banin, S Toni, L Lenzi, R Lorini, G D'Annunzio, S Lucchesi, F Mammì, C Meossi, F Bontempi, Massa Carrara, D Pardi, R Taccardi, F Lombardo, F Meschi, R Bonfanti, L Iughetti, A Franzese, P Buono, F Prisco, D Iafusco, F Cadario, A F Milia, L Bellu, G Piredda, C M Monciotti, F Cardella, M Vanelli, G Chiari, V Calcaterra, G De Giorgi, G Federico, F Citro, A Marsciani, M Cappa, C Bizzarri, N Sulli, F Barbetti, M L Manca Bitti, San Giovanni Rotondo, M Delvecchio, M Cotellessa, A M Marinaro, R Pesavento, F Cerutti, I Rabbone, F Fontana, V Cauvin, M Bellizzi, L Gargantini, G Tonini, E Faleschini, A Salvatoni, M Trada, L Pinelli, C Araldi, A Vergerio

Affiliation

¹ Laboratory of Mendelian Diabetes, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.

PMID: 21544516
PMCID: PMC3110270
DOI: 10.1007/s00125-011-2094-8

Permanent diabetes during the first year of life: multiple gene screening in 54 patients

L Russo et al. Diabetologia. 2011 Jul.

. 2011 Jul;54(7):1693-701.

doi: 10.1007/s00125-011-2094-8. Epub 2011 Mar 10.

Collaborators

ISPED Early Diabetes Study Group:
R Lera, V Cherubini, A R Fifi, C Torelli, E Frezza, L Cavallo, S Zucchini, B Pasquino, P Kaufmann, P Frongia, N Zedda, C Ripoli, A La, M Cicchetti, D Lo Presti, F Citriniti, M Pocecco, F Chiarelli, S Tumini, M Del Donno, M R De Marco, N Lazzaro, P Banin, S Toni, L Lenzi, R Lorini, G D'Annunzio, S Lucchesi, F Mammì, C Meossi, F Bontempi, Massa Carrara, D Pardi, R Taccardi, F Lombardo, F Meschi, R Bonfanti, L Iughetti, A Franzese, P Buono, F Prisco, D Iafusco, F Cadario, A F Milia, L Bellu, G Piredda, C M Monciotti, F Cardella, M Vanelli, G Chiari, V Calcaterra, G De Giorgi, G Federico, F Citro, A Marsciani, M Cappa, C Bizzarri, N Sulli, F Barbetti, M L Manca Bitti, San Giovanni Rotondo, M Delvecchio, M Cotellessa, A M Marinaro, R Pesavento, F Cerutti, I Rabbone, F Fontana, V Cauvin, M Bellizzi, L Gargantini, G Tonini, E Faleschini, A Salvatoni, M Trada, L Pinelli, C Araldi, A Vergerio

Affiliation

¹ Laboratory of Mendelian Diabetes, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.

PMID: 21544516
PMCID: PMC3110270
DOI: 10.1007/s00125-011-2094-8

Abstract

Aims/hypothesis: The aim of this study was to investigate the genetic aetiology of permanent diabetes mellitus with onset in the first 12 months of age.

Methods: We studied 46 probands with permanent, insulin-requiring diabetes with onset within the first 6 months of life (permanent neonatal diabetes mellitus [PNDM]/monogenic diabetes of infancy [MDI]) (group 1) and eight participants with diabetes diagnosed between 7 and 12 months of age (group 2). KCNJ11, INS and ABCC8 genes were sequentially sequenced in all patients. For those who were negative in the initial screening, we examined ERN1, CHGA, CHGB and NKX6-1 genes and, in selected probands, CACNA1C, GCK, FOXP3, NEUROG3 and CDK4. The incidence rate for PNDM/MDI was calculated using a database of Italian patients collected from 1995 to 2009.

Results: In group 1 we found mutations in KCNJ11, INS and ABCC8 genes in 23 (50%), 9 (19.5%) and 4 (8.6%) patients respectively, and a single homozygous mutation in GCK (2.1%). In group 2, we identified one incidence of a KCNJ11 mutation. No genetic defects were detected in other loci. The incidence rate of PNDM/MDI in Italy is estimated to be 1:210,287.

Conclusions/interpretation: Genetic mutations were identified in ~75% of non-consanguineous probands with PNDM/MDI, using sequential screening of KCNJ11, INS and ABCC8 genes in infants diagnosed within the first 6 months of age. This percentage decreased to 12% in those with diabetes diagnosed between 7 and 12 months. Patients belonging to the latter group may either carry mutations in genes different from those commonly found in PNDM/MDI or have developed an early-onset form of autoimmune diabetes.

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Figures

**Fig. 1**
Pedigrees of four families with mutations in *ABCC8*; from top to bottom: mutation, phenotype, age at presentation/diagnosis of diabetes, current age and initial therapy for diabetes. For the two grandparents of proband nd-FI/1, OGTT tests were performed at 70 (W688R) and 74 (V324M) years of age. GD, gestational diabetes; IGT, impaired glucose tolerance; INS, insulin

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References

1. Aguilar-Bryan L, Bryan J. Neonatal diabetes mellitus. Endocr Rev. 2008;29:265–291. doi: 10.1210/er.2007-0029. - DOI - PMC - PubMed
1. Murphy R, Ellard S, Hattersley AT. Clinical implications of a molecular genetic classification of monogenic β-cell diabetes. Nat Clin Pract Endocrinol Metab. 2008;4:200–213. doi: 10.1038/ncpendmet0778. - DOI - PubMed
1. Gloyn AL, Pearson ER, Antcliff JF, et al. Activating mutations in the gene encoding the ATP-sensitive potassium channel subunit Kir6.2 gene and permanent neonatal diabetes. N Engl J Med. 2004;350:1838–1849. doi: 10.1056/NEJMoa032922. - DOI - PubMed
1. Babenko AP, Polak M, Cave H, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med. 2006;355:456–466. doi: 10.1056/NEJMoa055068. - DOI - PubMed
1. Støy J, Edghill EL, Flanagan SE, et al. Neonatal Diabetes International Collaborative Group. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci USA. 2007;104:15040–15044. doi: 10.1073/pnas.0707291104. - DOI - PMC - PubMed

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[1] Aguilar-Bryan L, Bryan J. Neonatal diabetes mellitus. Endocr Rev. 2008;29:265–291. doi: 10.1210/er.2007-0029. - DOI - PMC - PubMed

[2] Aguilar-Bryan L, Bryan J. Neonatal diabetes mellitus. Endocr Rev. 2008;29:265–291. doi: 10.1210/er.2007-0029. - DOI - PMC - PubMed

[3] Murphy R, Ellard S, Hattersley AT. Clinical implications of a molecular genetic classification of monogenic β-cell diabetes. Nat Clin Pract Endocrinol Metab. 2008;4:200–213. doi: 10.1038/ncpendmet0778. - DOI - PubMed

[4] Murphy R, Ellard S, Hattersley AT. Clinical implications of a molecular genetic classification of monogenic β-cell diabetes. Nat Clin Pract Endocrinol Metab. 2008;4:200–213. doi: 10.1038/ncpendmet0778. - DOI - PubMed

[5] Gloyn AL, Pearson ER, Antcliff JF, et al. Activating mutations in the gene encoding the ATP-sensitive potassium channel subunit Kir6.2 gene and permanent neonatal diabetes. N Engl J Med. 2004;350:1838–1849. doi: 10.1056/NEJMoa032922. - DOI - PubMed

[6] Gloyn AL, Pearson ER, Antcliff JF, et al. Activating mutations in the gene encoding the ATP-sensitive potassium channel subunit Kir6.2 gene and permanent neonatal diabetes. N Engl J Med. 2004;350:1838–1849. doi: 10.1056/NEJMoa032922. - DOI - PubMed

[7] Babenko AP, Polak M, Cave H, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med. 2006;355:456–466. doi: 10.1056/NEJMoa055068. - DOI - PubMed

[8] Babenko AP, Polak M, Cave H, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med. 2006;355:456–466. doi: 10.1056/NEJMoa055068. - DOI - PubMed

[9] Støy J, Edghill EL, Flanagan SE, et al. Neonatal Diabetes International Collaborative Group. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci USA. 2007;104:15040–15044. doi: 10.1073/pnas.0707291104. - DOI - PMC - PubMed

[10] Støy J, Edghill EL, Flanagan SE, et al. Neonatal Diabetes International Collaborative Group. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci USA. 2007;104:15040–15044. doi: 10.1073/pnas.0707291104. - DOI - PMC - PubMed

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Permanent diabetes during the first year of life: multiple gene screening in 54 patients

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Permanent diabetes during the first year of life: multiple gene screening in 54 patients

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