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01-10-2016 | Original Article

GCK-MODY in the US National Monogenic Diabetes Registry: frequently misdiagnosed and unnecessarily treated

Authors: David Carmody, Rochelle N. Naylor, Charles D. Bell, Shivani Berry, Jazzmyne T. Montgomery, Elizabeth C. Tadie, Jessica L. Hwang, Siri Atma W. Greeley, Louis H. Philipson

Published in: Acta Diabetologica | Issue 5/2016

Abstract

Aims

GCK-MODY leads to mildly elevated blood glucose typically not requiring therapy. It has been described in all ethnicities, but mainly in Caucasian Europeans. Here we describe our US cohort of GCK-MODY.

Methods

We examined the rates of detection of heterozygous mutations in the GCK gene in individuals referred to the US Monogenic Diabetes Registry with a phenotype consistent with GCK-MODY. We also assessed referral patterns, treatment and demography, including ethnicity, of the cohort.

Results

Deleterious heterozygous GCK mutations were found in 54.7 % of Registry probands selected for GCK sequencing for this study. Forty-nine percent were previously unnecessarily treated with glucose-lowering agents, causing hypoglycemia and other adverse effects in some of the subjects. The proportion of probands found to have a GCK mutation through research-based testing was similar across each ethnic group. However, together African-American, Latino and Asian subjects represented only 20.5 % of screened probands and 17.2 % of those with GCK-MODY, despite higher overall diabetes prevalence in these groups.

Conclusions

Our data show that a high detection rate of GCK-MODY is possible based on clinical phenotype and that prior to genetic diagnosis, a large percentage are inappropriately treated with glucose-lowering therapies. We also find low minority representation in our Registry, which may be due to disparities in diagnostic diabetes genetic testing and is an area needing further investigation.

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Chakera AJ, Spyer G, Vincent N et al (2014) The 0.1% of the population with glucokinase monogenic diabetes can be recognized by clinical characteristics in pregnancy: the atlantic diabetes in pregnancy cohort. Diabetes Care. doi:10.2337/dc13-2248 PubMed

Sagen JV, Odili S, Bjørkhaug L et al (2006) From clinicogenetic studies of maturity-onset diabetes of the young to unraveling complex mechanisms of glucokinase regulation. Diabetes 55:1713–1722. doi:10.2337/db05-1513 CrossRefPubMed

Negahdar M, Aukrust I, Molnes J et al (2014) GCK-MODY diabetes as a protein misfolding disease: the mutation R275C promotes protein misfolding, self-association and cellular degradation. Mol Cell Endocrinol 382:55–65. doi:10.1016/j.mce.2013.08.020 CrossRefPubMed

Matschinsky FM (2002) Regulation of pancreatic beta-cell glucokinase: from basics to therapeutics. Diabetes 51(Suppl 3):S394–S404. doi:10.2337/diabetes.51.2007.S394 CrossRefPubMed

Davis EA, Cuesta-Munoz A, Raoul M et al (1999) Mutants of glucokinase cause hypoglycaemia- and hyperglycaemia syndromes and their analysis illuminates fundamental quantitative concepts of glucose homeostasis. Diabetologia 42:1175–1186. doi:10.1007/s001250051289 CrossRefPubMed

Byrne MM, Sturis J, Clément K et al (1994) Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations. J Clin Investig 93:1120–1130. doi:10.1172/JCI117064 CrossRefPubMedPubMedCentral

Beer NL, Osbak KK, van de Bunt M et al (2012) Insights into the pathogenicity of rare missense GCK variants from the identification and functional characterization of compound heterozygous and double mutations inherited in cis. Diabetes Care 35:1482–1484. doi:10.2337/dc11-2420 CrossRefPubMedPubMedCentral

Osbak KK, Colclough K, Saint-Martin C et al (2009) Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat 30:1512–1526. doi:10.1002/humu.21110 CrossRefPubMed

Steele AM, Tribble ND, Caswell R et al (2011) The previously reported T342P GCK missense variant is not a pathogenic mutation causing MODY. Diabetologia 54:2202–2205. doi:10.1007/s00125-011-2194-5 CrossRefPubMed

10.

Steele AM, Shields BM, Wensley KJ et al (2014) Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. JAMA 311:279–286. doi:10.1001/jama.2013.283980 CrossRefPubMed

11.

Stride A, Shields B, Gill-Carey O et al (2014) Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia. Diabetologia 57:54–56. doi:10.1007/s00125-013-3075-x CrossRefPubMed

12.

Singh R, Pearson ER, Clark PM, Hattersley AT (2007) The long-term impact on offspring of exposure to hyperglycaemia in utero due to maternal glucokinase gene mutations. Diabetologia 50:620–624. doi:10.1007/s00125-006-0541-8 CrossRefPubMed

13.

Bacon S, Schmid J, McCarthy A et al (2015) The clinical management of hyperglycemia in pregnancy complicated by maturity-onset diabetes of the young. Am J Obstet Gynecol 213(236):e1–e7. doi:10.1016/j.ajog.2015.04.037 PubMed

14.

Naylor RN, John PM, Winn AN et al (2014) Cost-effectiveness of MODY genetic testing: translating genomic advances into practical health applications. Diabetes Care 37:202–209. doi:10.2337/dc13-0410 CrossRefPubMed

15.

Schnyder S, Mullis PE, Ellard S et al (2005) Genetic testing for glucokinase mutations in clinically selected patients with MODY: a worthwhile investment. Swiss Med Wkly 135:352–356PubMed

16.

Pinelli M, Acquaviva F, Barbetti F et al (2013) Identification of candidate children for maturity-onset diabetes of the young type 2 (MODY2) gene testing: a seven-item clinical flowchart (7-iF). PLoS ONE 8:e79933. doi:10.1371/journal.pone.0079933 CrossRefPubMedPubMedCentral

17.

Shields BM, Hicks S, Shepherd MH et al (2010) Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia 53:2504–2508. doi:10.1007/s00125-010-1799-4 CrossRefPubMed

18.

Velho G, Blanch H, Vaxillaire M et al (1997) Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. Diabetologia 40:217–224. doi:10.1007/s001250050666 CrossRefPubMed

19.

Estalella I, Rica I, De Nanclares GP et al (2007) Mutations in GCK and HNF-1α explain the majority of cases with clinical diagnosis of MODY in Spain. Clin Endocrinol (Oxf) 67:538–546. doi:10.1111/j.1365-2265.2007.02921.x

20.

Lorini R, Klersy C, d’Annunzio G et al (2009) Maturity-onset diabetes of the young in children with incidental hyperglycemia: a multicenter Italian study of 172 families. Diabetes Care 32:1864–1866. doi:10.2337/dc08-2018 CrossRefPubMedPubMedCentral

21.

American Diabetes Association (ADA) (2015) Standards of medical care in diabetes—2015: summary of revisions. Diabetes Care 38(Suppl):S4–S4. doi: 10.2337/dc15-S003

22.

Porter JR, Rangasami JJ, Ellard S et al (2006) Asian MODY: are we missing an important diagnosis? Diabet Med 23:1257–1260. doi:10.1111/j.1464-5491.2006.01958.x CrossRefPubMed

23.

Greeley SAW, Naylor RN, Cook LS et al (2011) Creation of the Web-based University of Chicago Monogenic Diabetes Registry: using technology to facilitate longitudinal study of rare subtypes of diabetes. J Diabetes Sci Technol 5:879–886CrossRefPubMedPubMedCentral

24.

Vionnet N, Stoffel M, Takeda J et al (1992) Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature 356:721–722. doi:10.1038/356721a0 CrossRefPubMed

25.

CDC—National Diabetes Statistics Report, 2014—publications—diabetes DDT. http://www.cdc.gov/diabetes/pubs/statsreport14.htm. Accessed 26 Feb 2016

26.

Naylor R, Philipson LH (2011) Who should have genetic testing for maturity-onset diabetes of the young? Clin Endocrinol (Oxf) 75:422–426. doi:10.1111/j.1365-2265.2011.04049.x CrossRef

27.

Steele AM, Wensley KJ, Ellard S et al (2013) Use of HbA1c in the identification of patients with hyperglycaemia caused by a glucokinase mutation: observational case control studies. PLoS ONE 8:e65326. doi:10.1371/journal.pone.0065326 CrossRefPubMedPubMedCentral

28.

Shields BM, McDonald TJ, Ellard S et al (2012) The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes. Diabetologia 55:1265–1272. doi:10.1007/s00125-011-2418-8 CrossRefPubMedPubMedCentral

29.

Vigersky RA, Fish L, Hogan P et al (2014) The clinical endocrinology workforce: current status and future projections of supply and demand. J Clin Endocrinol Metab 99:3112–3121. doi:10.1210/jc.2014-2257 CrossRefPubMed

30.

Carmody D, Bell CD, Hwang JL et al (2014) Sulfonylurea treatment before genetic testing in neonatal diabetes: pros and cons. J Clin Endocrinol Metab 99:E2709–E2714. doi:10.1210/jc.2014-2494 CrossRefPubMedPubMedCentral

31.

Alkorta-Aranburu G, Carmody D, Cheng YW et al (2014) Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach. Mol Genet Metab 113:315–320. doi:10.1016/j.ymgme.2014.09.007 CrossRefPubMedPubMedCentral

32.

Ellard S, Allen HL, De Franco E et al (2013) Improved genetic testing for monogenic diabetes using targeted next-generation sequencing. Diabetologia 56:1958–1963. doi:10.1007/s00125-013-2962-5 CrossRefPubMedPubMedCentral

33.

Bonnefond A, Philippe J, Durand E et al (2014) Highly sensitive diagnosis of 43 monogenic forms of diabetes or obesity through one-step PCR-based enrichment in combination with next-generation sequencing. Diabetes Care 37:460–467. doi:10.2337/dc13-0698 CrossRefPubMed

34.

Pihoker C, Gilliam LK, Ellard S et al (2013) Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth. J Clin Endocrinol Metab 98:4055–4062. doi:10.1210/jc.2013-1279 CrossRefPubMedPubMedCentral

35.

Gloyn AL, van de Bunt M, Stratton IM et al (2009) Prevalence of GCK mutations in individuals screened for fasting hyperglycaemia. Diabetologia 52:172–174. doi:10.1007/s00125-008-1188-4 CrossRefPubMed

36.

Ellard S, Thomas K, Edghill EL et al (2007) Partial and whole gene deletion mutations of the GCK and HNF1A genes in maturity-onset diabetes of the young. Diabetologia 50:2313–2317. doi:10.1007/s00125-007-0798-6 CrossRefPubMed

37.

Herman S, Varga D, Deissler HL et al (2012) Medium-sized deletion in the BRCA1 gene: limitations of Sanger sequencing and MLPA analyses. Genet Mol Biol 35:53–56CrossRefPubMedPubMedCentral

Title: GCK-MODY in the US National Monogenic Diabetes Registry: frequently misdiagnosed and unnecessarily treated
Authors: David Carmody
Rochelle N. Naylor
Charles D. Bell
Shivani Berry
Jazzmyne T. Montgomery
Elizabeth C. Tadie
Jessica L. Hwang
Siri Atma W. Greeley
Louis H. Philipson
Publication date: 01-10-2016
Publisher: Springer Milan
Published in: Acta Diabetologica / Issue 5/2016
Print ISSN: 0940-5429
Electronic ISSN: 1432-5233
DOI: https://doi.org/10.1007/s00592-016-0859-8

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Conclusions

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