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GCK Mutation in a Child with Maturity Onset Diabetes of the Young, Type 2.

ABSTRACT: BACKGROUND:Maturity onset diabetes of the young type 2 (MODY) is an inherited disorder due to mutations in glucokinase (GCK) gene, which lead to mild fasting hyperglycemia. CASE PRESENTATION:Herein an otherwise healthy 9-year old boy with hyperglycemia is presented in whom the diagnosis of MODY2 was suspected. Genetic studies showed heterozygous inactivating GCK gene mutation in exon 8 (c.1010delA) in this patient. The same mutation was found in his father as well. The patient received some dietary advices without any medication. CONCLUSION:The identification of GCK mutation and diagnosis of MODY2 helps the clinicians to predict the disease course, prognosis and to exclude other types of diabetes.

SUBMITTER: Noorian S

PROVIDER: S-EPMC3663319 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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GCK Mutation in a Child with Maturity Onset Diabetes of the Young, Type 2.

Noorian Shahab S Sayarifard Fatemeh F Farhadi Elham E Barbetti Fabrizio F Rezaei Nima N

Iranian journal of pediatrics 20130401 2

<h4>Background</h4>Maturity onset diabetes of the young type 2 (MODY) is an inherited disorder due to mutations in glucokinase (GCK) gene, which lead to mild fasting hyperglycemia.<h4>Case presentation</h4>Herein an otherwise healthy 9-year old boy with hyperglycemia is presented in whom the diagnosis of MODY2 was suspected. Genetic studies showed heterozygous inactivating GCK gene mutation in exon 8 (c.1010delA) in this patient. The same mutation was found in his father as well. The patient rec ...[more]

PMID: 23724189

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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.

Project description:It is important to identify patients with Maturity-onset diabetes of the young (MODY) as a molecular diagnosis determines both treatment and prognosis. Genetic testing is currently expensive and many patients are therefore not assessed and are misclassified as having either type 1 or type 2 diabetes. Biomarkers could facilitate the prioritisation of patients for genetic testing. We hypothesised that patients with different underlying genetic aetiologies for their diabetes could have distinct metabolic profiles which may uncover novel biomarkers. The aim of this study was to perform metabolic profiling in urine from patients with MODY due to mutations in the genes encoding glucokinase (GCK) or hepatocyte nuclear factor 1 alpha (HNF1A), type 2 diabetes (T2D) and normoglycaemic control subjects. Urinary metabolic profiling by Nuclear Magnetic Resonance (NMR) and ultra performance liquid chromatography hyphenated to Q-TOF mass spectrometry (UPLC-MS) was performed in a Discovery set of subjects with HNF1A-MODY (n = 14), GCK-MODY (n = 17), T2D (n = 14) and normoglycaemic controls (n = 34). Data were used to build a valid partial least squares discriminate analysis (PLS-DA) model where HNF1A-MODY subjects could be separated from the other diabetes subtypes. No single metabolite contributed significantly to the separation of the patient groups. However, betaine, valine, glycine and glucose were elevated in the urine of HNF1A-MODY subjects compared to the other subgroups. Direct measurements of urinary amino acids and betaine in an extended dataset did not support differences between patients groups. Elevated urinary glucose in HNF1A-MODY is consistent with the previously reported low renal threshold for glucose in this genetic subtype. In conclusion, we report the first metabolic profiling study in monogenic diabetes and show that, despite the distinct biochemical pathways affected, there are unlikely to be robust urinary biomarkers which distinguish monogenic subtypes from T2D. Our results have implications for studies investigating metabolic profiles in complex traits including T2D.

Dataset Information

GCK Mutation in a Child with Maturity Onset Diabetes of the Young, Type 2.

Publications

GCK Mutation in a Child with Maturity Onset Diabetes of the Young, Type 2.

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