| Background Diabetes mellitus(DM) is a group of metabolic diseases characterized by chronic hyperglycemia resulting from either defects in insulin secretion or resistance, or a combination of these disorders. The fast growing prevalence of this disease has become a major health problem worldwide, especially in the developing countries. Recently an estimated number of around 92 million Chinese are diagnosed with diabetes, which makes China one of the world’s leading countries with increased diabetes prevalence. Maturity onset diabetes of the young(MODY) is a form of monogenic diabetes, which is caused by mutation in a specific gene. MODY is usually diagnosed during late childhood, adolescence or early adulthood(age 25 years or younger). Heterozygous mutations in the gene encoding hepatocyte nuclear factor 1 alpha(HNF 1α), also known as maturity onset diabetes of the young(MODY) 3, are the cause of young onset diabetes, characterized by autosomal dominant inheritance, early age of onset, progressive β-cell failure and increased sensitivity to sulfonylureas. Patients with MODY are often mistaken as having type 1or type 2 DM because of early onset and some similarities in clinical presentation. This misdiagnosis may lead to unnecessary treatment with insulin. It is more significant to make exact molecular and genetic diagnosis for the optimal treatment and can also help in identifying other family members with MODY.Aim/hypothesis to identify the exact genetic abnormality in the family with diabetes in three successive generations, with one family member diagnosed at an early age(before 25 of years) and the absence of pancreatic autoantibodies. Based on clinical features, dominant inheritance and laboratory findings the case is strongly suspected to be MODY3.Materials and methods We screened for mutations in the HNF-1α gene a family with the case of 19 years old male with an early onset diabetes, with strong family history of diabetes(three generations), pancreatic autoantibodies negative, not overweight and with a good response for sulfonylureas. The proband’s mother and paternal grandmother were involved in molecular genetic analysis. Functional studies of the mutant HNF-1α were carried out.Case reportPresent history: A 19 years old male presented to hospital with polyuria, polydipsia and weight loss. On physical examination, his blood pressure was 140/80 mm Hg, heart rate 90 beats/min, weight 87 kg and height 180 cm, body mass index 26.85 kg/m2 with normal development. Family history revealed an autosomal dominant pedigree. The paternal grandmother was diagnosed with type 2 diabetes at 52 years of age and has a cervical vessel plaque. The proband’s father was also suffering from type 2 diabetes. He was diagnosed three years ago when he was 43 years old.Laboratory findingsPatient was found to have fasting hyperglycemia(FBG) of 17.6 mmol/l and ketone bodies in urinalysis +++. He was diagnosed as diabetic ketosis and hospitalized for further analysis. His fasting blood glucose(FBG) level was 19.77 mmol/l, fasting serum insulin(Fins) 18.64 u U/ml, fasting serum C-peptide(FCP) 1.42 ng/ml and Hb A1 c 12.30%(normal range 3.8–5.8%). His pancreatic autoantibodies(GADA, IAA) were negative. On a mixed meal insulin stimulation test, his one-hour blood glucose(1h BG) 23.57 mmol/l, one-hour serum insulin(1h Ins) 28.42 u U/ml, one-hour serum C-peptide(1h CP) 2.21 ng/ml and 2h BG 27.0 mmol/l, 2h Ins 18.29 u U/ml, 2h CP 1.91 ng/ml and his Hb A1 c was 12.30%.The abdominal computed tomography(CT) scan showed a mild fatty liver. The grandmother’s self-monitoring of blood glucose levels(SMBG) were around 7-8 mmol/l for fasting and around 11-12 mmol/l for post meal with Hb A1 c of 8.30 %. The father’s SMBG were around 8-9 mmol/l for fasting and around 10-11mmol/l for post meal with Hb A1 c 7.6 %.Treatment: The patient’s diabetes is now being managed with oral hypoglycemic therapy(Metformin 0.5 g once a day, Acarbose 50 mg three times a day, Glimepiride 2 mg once a day) and a diet/exercise regimen. The grandmother is currently receiving 30 units of insulin(16 units in the morning and 14 units in the evening). The father is also being treated with insulin without any diabetic complication.Results Genomic DNA was extracted from peripheral blood lymphocytes using the Takara DNA extraction kit according to the manufacturer’s instructions. All ten exons and promoter regions of the HNF-1α gene were amplified and sequenced. We found the common polymorphism of HNF1α gene c.1460 G>A p.S487 N in his grandmother.Conclusion DNA sequencing identified a previously described common polymorphism of HNF1α gene p.S487N(c.1460 G>A) in the proband’s paternal grandmother, but no mutation in the proband and his mother. Therefore, it is possible that our proband without mutation in HNF-1α may have another type of MODY and the examination of glucokinase, HNF-4α, IPF and HNF-1β genes could have detected other genetic mutations. |
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