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Late Diagnosis of Maturity-Onset Diabetes of the Young (MODY) 12 With Catastrophic Consequences.

ABSTRACT: Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous group of diseases characterized by autosomal dominant monogenic non-ketogenic diabetes mellitus, usually with early-onset, with a prevalence of 1-5% of all diabetes cases. A 72-year-old female was admitted with intestinal occlusion, anorexia, vomiting, and weight loss for four months. Medical history of type 2 diabetes mellitus, chronic pancreatitis with abnormal pancreatic development, and acute obstructive jaundice due to a mass in the head of the pancreas with duodenum extension four months before. Assuming surgically unresectable pancreatic neoplasm, digestive bypass surgery was performed. The pathologic examination of surgical specimens was negative for neoplasm. Abdominal imaging showed the pancreatic mass, proximal bowel distension and ascites, which was negative for neoplastic cells. A percutaneous biopsy of the mass revealed adenocarcinoma. Palliative chemotherapy was started. Next-generation sequencing revealed the variant c.-8G>T in the 5' untranslated region (UTR) region of the adenosine triphosphate (ATP) binding cassette subfamily C member 8 (ABCC8) gene in heterozygosity, associated with the MODY 12 subtype. We report a possible case of MODY 12 diabetes with a phenotype not previously described: a non-neoplastic pancreatic mass that appears in a previously abnormally developed pancreas, with evolution to neoplasm along with the late development of diabetes mellitus. Although this ABCC8 gene mutation could be incidental, there could be a relationship between this mutation, pancreatic malformation, chronic pancreatitis and pancreatic neoplasm. Investigation of new phenotypes is critical, including the potential role of the ABCC8 gene in oncogenesis.

SUBMITTER: Carreira NR

PROVIDER: S-EPMC7935225 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Late Diagnosis of Maturity-Onset Diabetes of the Young (MODY) 12 With Catastrophic Consequences.

Carreira Nuno R NR Gonçalves Catarina C Wahnon Alexandra A Dâmaso Sara S Martins Joao J

Cureus 20210205 2

Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous group of diseases characterized by autosomal dominant monogenic non-ketogenic diabetes mellitus, usually with early-onset, with a prevalence of 1-5% of all diabetes cases. A 72-year-old female was admitted with intestinal occlusion, anorexia, vomiting, and weight loss for four months. Medical history of type 2 diabetes mellitus, chronic pancreatitis with abnormal pancreatic development, and acute obstructiv ...[more]

PMID: 33728157

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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.

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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Late Diagnosis of Maturity-Onset Diabetes of the Young (MODY) 12 With Catastrophic Consequences.

Publications

Late Diagnosis of Maturity-Onset Diabetes of the Young (MODY) 12 With Catastrophic Consequences.

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