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

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.

SUBMITTER: Carmody D

PROVIDER: S-EPMC5016218 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Carmody David D Naylor Rochelle N RN Bell Charles D CD Berry Shivani S Montgomery Jazzmyne T JT Tadie Elizabeth C EC Hwang Jessica L JL Greeley Siri Atma W SA Philipson Louis H LH

Acta diabetologica 20160422 5

<h4>Aims</h4>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.<h4>Methods</h4>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 th ...[more]

PMID: 27106716

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Project description:Maturity-onset diabetes of the young, or MODY-monogenic diabetes, is a not-so-rare collection of inherited disorders of non-autoimmune diabetes mellitus that remains insufficiently diagnosed despite increasing awareness. These cases are important to efficiently and accurately diagnose, given the clinical implications of syndromic features, cost-effective treatment regimen, and the potential impact on multiple family members. Proper recognition of the clinical manifestations, family history, and cost-effective lab and genetic testing provide the diagnosis. All patients must undergo a thorough history, physical examination, multigenerational family history, lab evaluation (glycated hemoglobin A1c [HbA1c], glutamic acid decarboxylase antibodies [GADA], islet antigen 2 antibodies [IA-2A], and zinc transporter 8 [ZnT8] antibodies). The presence of clinical features with 3 (or more) negative antibodies may be indicative of MODY-monogenic diabetes, and is followed by genetic testing. Molecular genetic testing should be performed before attempting specific treatments in most cases. Additional testing that is helpful in determining the risk of MODY-monogenic diabetes is the MODY clinical risk calculator (>25% post-test probability in patients not treated with insulin within 6 months of diagnosis should trigger genetic testing) and 2-hour postprandial (after largest meal of day) urinary C-peptide to creatinine ratio (with a ≥0.2 nmol/mmol to distinguish HNF1A- or 4A-MODY from type 1 diabetes). Treatment, as well as monitoring for microvascular and macrovascular complications, is determined by the specific variant that is identified. In addition to the diagnostic approach, this article will highlight recent therapeutic advancements when patients no longer respond to first-line therapy (historically sulfonylurea treatment in many variants).Learning objectivesUpon completion of this educational activity, participants should be able to.Target audienceThis continuing medical education activity should be of substantial interest to endocrinologists and all health care professionals who care for people with diabetes mellitus.

Project description:ObjectiveInactivating heterozygous mutations in the GCK gene are a common cause of MODY and result in mild fasting hyperglycaemia, which does not require treatment. We aimed to identify the frequency, clinical and molecular features of GCK mutations in a Turkish paediatric cohort.Design and patientsFifty-four unrelated probands were selected based on the following criteria: age of diagnosis ≤17 years, family history of diabetes in at least two generations, anti-GAD/ICA negative, BMI<95.p and follow-up with diet, oral antidiabetic drug or low-dose insulin treatment (≤0·5U/kg/d). A MODY probability score (www.diabetesgenes.org) was calculated and 21 patients with a score ≥75%, HbA1c levels ≤7·5% (58·5 mmol/mol) and fasting blood glucose (FBG) levels 99-145 mg/dl (5·5-8·0 mmol/l) were selected for Sanger sequencing of the GCK gene. Targeted next-generation sequencing for all known monogenic diabetes genes was undertaken for any patient without a GCK gene mutation.ResultsGCK gene mutations (pathogenic or likely pathogenic variants) and a novel intronic variant of uncertain significance (c.208 + 3A>T) were identified in 13/54 probands (24%). Twelve of these patients had a MODY probability score ≥75%. FBG level and 2-h glucose level in OGTT were 123 ± 14 mg/dl (6·8 ± 0·7 mmol/l) (107-157 mg/dl) and 181 ± 30 mg/dl (10·1 ± 1·6 mmol/l) (136-247 mg/dl), respectively. Average of glucose increment in OGTT was 58 ± 27 mg/dl (3·2 ± 1·5 mmol/l) (19-120 mg/dl), and mean HbA1c level was 6·5 ± 0·5% (47·5 ± 5·5 mmol/mol) (5·9-7·6%). Five novel missense mutations were identified (p.F123S, p.L58P, p.G246A, p.F419C, and p.S151C). Two patients treated with low-dose insulin before the molecular analysis were able to stop treatment.ConclusionsApproximately 1 in 4 MODY cases in this Turkish paediatric cohort have a GCK mutation. Selection of patients for GCK gene analysis using the MODY probability score was an effective way of identifying most (11/12) patients with a GCK mutation.

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

Publications

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

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