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Maturity-Onset Diabetes of the Young (MODY) Dr. VŨ CHÍ DŨNG National Hospital of Pediatrics Case No. 1 DOB: June 25.1996 History • 14.5 year old boy • 2 months before admission: polydipsia, polyuria, unknown weight loss • 3 days before admission: vomiting, no fever, abdominal pain, polyuria, lethargy then coma On admission • • • • • • • • • Weight: 30 kg Height: 138 cm (< 3 percentile); BMI 16 (3rd percentile) SpO2: 100%, BP: 110/60 mmHg BR: 35b/m; HR: 100b/m Clear pulse Coma: V/AVPU Dehydration (+) Others: unremarkable Investigations • BG: 97 mmol/l; HbA1C: 20.4% • Insulin: 142 μU/ml; C-peptide: 0.296 ng/ml • pH: 7.25; pCO2: 28.8 mmHg; HCO3-: 12 mmol/l; BE -13 mmol/l • Urea: 31.6 mmol/; Creatinine: 351 Mmol/l • GOT: 17 UI/l; GPT: 44 UI/l • Na: 113 mmol/l (corected 145.6); K: 3.5 mmol/l; Cl 86 mmol/l; Ca: 2.2 mmol/l • Urinary glucose (500 mg/dl), ketonuria (5 mg/dl) Diagnosis & Management DKA Management – Infusion: NaCl 9% + KCl (40mmol/l) – Insulin: 0.1 UI/kg/hour – After 2 day of treatment: alert, no dehydration, pH: 7.42; HCO3: 20 mmol/l; no ketonuria; high blood glucose levels 24 – 35 mmol/l & still kidney failure (creatinine 247-318 mol/l) Investigations Abdominal ultrasound: R kidney 80 x 42 mm, multi cyst 3 – 5 mm, pyelectasis L kidney 80 x 38 mm, nhu mô tăng âm nhẹ, trong multi cyst 3 – 5 mm, pyelectasis Investigations • Abdominal CT scan: Pancreatic body & tail were not seen Pancreatic head had dimension of 13 x 17 mm Right kidney 13.0 x 4.3 x 3.2 mm. Left kidney 15.0 x 4.5 x 3.4 mm In kidneys some cysts with dimension of 3 mm & pyelectasis were seen Case Summary 14.5 year old boy Polydipsia, polyuria, DKA No obese Unclear family history of diabetes BG: 97 mmol/l kidney failure & kidney multi cysts, pancreatic atrophy Diagnosis: MODY type 5 ??? Heterozygous HNF-1β missense mutation, S148L (c.443C>T) Case No. 2 DOB: 18 Nov 1996 History • 1st child, full team, WOB 2200 gram • Jaundice at 3 months of age • Treated at department of hepatology during 10 days (diagnosis: hepatitis) • Normal moto-mental development At 7 years of age • Right kidney atrophy was identified using sintigraphy. • Urea 10.6 mmol/l, creatinine 147 µmol/l, Na+ 142 mmol/l, K+ 3.4 mmol/l, Cl- 109 mmol/l, AST 408 U/l, ALT 729 U/l • following up by nephrologist at NHP At 14 years of age • Polyuria, polydipsia, weight loss (2 kg/w) • Plasma glucose: very high • HbA1C 13.6%, urea 10.1 mmol/l, creatinin 250 µmol/l, AST 178 UI/l, ALT 123 UI/l • Ultrasound: bilateral kidney atrophy: R 44 x 22 mm; L 73 x 36 mm Mutation analysis • Heterozygous for a novel HNF1B missense mutation, p.Y169H. • This mutation results in the substitution of the amino acid histidine (charged polar) for tyrosine (uncharged polar) at codon 169. • No mutation in parents de novo mutation Monogenic Diabetes • Single gene mutation that regulate beta-cell function • Dominantly or recessively inherited or may be a de novo mutation & hence a spontaneous case • Rare: 1-5% of total diabetes cases • Primary defects of insulin secretion • Treatment: Oral agents/insulin • Forms: neonatal diabetes and MODY (MaturityOnset Diabetes of the Young) Β-Cell Diagnosis Why diagnose monogenic diabetes? • Predict clinical course of patient • Explain other associated clinical features • Most importantly guide the most appropriate treatment • Implications for other family members often correcting the diagnosis and treatment • Appropriate genetic counseling Diagnosis Clinical presentation of monogenic diabetes • Neonatal diabetes & diabetes diagnosed within the first 6 months of life • Familial diabetes with an affected parent • Mild (5.5–8.5 mmol/l) fasting hyperglycaemia especially if young or familial • Diabetes associated with extra pancreatic features MODY • OMIM: describes MODY 1-11 Genes encode glucokinase, the transcription factors, and insulin promoter • Testing available for MODY 1-6 • Often discovered during routine blood testing • Not overweight • No risk factors for Type 2 Diabetes or metabolic syndrome • Autosomal dominant inheritance • Family history of successive generations Common characteristics • • • • • Mild/moderate hyperglycemia (5.5 – 8.5 mmol/l) First degree relative/similar degree of diabetes Absence of diabetes autoantibodies Absence of other autoimmunity Presence of low insulin requirement (<0.5 u/kg/d) past the usual “honeymoon” period • Absence of obesity, hyperlipidemia, PCOS • History of cystic kidney disease (MODY 5) • Non-transient neonatal diabetes or DM1 before 6 months of age MODY3 - Hepatocyte Nuclear Factor HNF1A mutation • Young-onset diabetes shows characteristics of not being insulin dependent • Family history of diabetes. This may be treated with insulin and considered to be ‘T1DM’ • Oral glucose tolerance tests (OGTTs) in early stages tend to show a very large glucose increment, usually >5 mmol/L. Some subjects may have a normal fasting value but still rise into the diabetic range at 2 h MODY3 - Hepatocyte Nuclear Factor HNF1A mutation • Glycosuria at relatively normal blood glucose levels is often seen • Marked sensitivity to sulfonylureas resulting in hypoglycaemia • Treatment - first treatment to be used in children should be low-dose sulfonylureas MODY1: HNF4A gene mutations • Children & young adults with diabetes & a strong family history of diabetes • Less common than diabetes due to mutations of HNF1A gene but has similar characteristics, except no low renal threshold & age of diagnosis may be later MODY1: HNF4A gene mutations • HNF4A mutations should be considered when HNF1A sequencing is negative but clinical features were strongly suggestive of HNF1A • Treatment - Patients are often sensitive to sulfonylureas MODY2 - glucokinase mutations • Strong family history of diabetes. Parents may have ‘T2DM’ or may not be diabetic • Fasting hyperglycemia is persistent & stable over a period of months or years • HbA1c is typically just below or just above upper limit of normal range (5.5–5.7%) MODY2 - glucokinase mutations • OGTT: increment (2-h glucose – fasting glucose) is small (typically <3.5 mmol/L) • Treatment: do not need treating in paediatric age range. There is very little, if any, response to either oral hypoglycemic agents or insulin MODY5: Renal cysts & diabetes syndrome due to a HNF1B mutation • Patients with mutations in HNF1B rarely present with isolated diabetes. • Renal developmental disorders, especially renal cysts & renal dysplasia, are present in almost all patients • Other features which may be present in children include uterine & genitalia developmental anomalies, hyperuricemia, gout, and abnormal liver function tests MODY5: Renal cysts & diabetes syndrome due to a HNF1B mutation • Diagnosis of HNF1B should be considered in any child with diabetes who also has nondiabetic renal disease • Patients with HNF1B mutations usually require insulin treatment. • Pancreatic size is reduced reflecting a reduction in both the endocrine and exocrine pancreas, and subclinical exocrine deficiency is present in most patients MODY5 at NHP, Hanoi 3/286 (1%) children with diabetes • Case No. 3 (first case) confirmed diagnosis using molecular analysis in 1/2011 • 1 case 14.5 years of age was confirmed in 4/2011: kidney failure from 7 years, diabetes from 13 years of age, right kidney atrophy & pancreas MRI showed only tissue of head of pancreas, novel mutation HNF1B: c.505T>C or p.Tyr169His (p.Y169H) • Other case: miss follow up Other causes of familial diabetes • Insulin promoter factor 1 (IPF1) (MODY4) • NeuroD1 (MODY6) • KLF11 (MODY7) • carboxyl ester lipase (CEL) (MODY8) • PAX4 (MODY9) • Insulin (MODY 10) • B lymphocyte kinase (BLK ) (MODY 11) → but these are unusual MODY 1 MODY2 MODY3 MODY4 MODY5 MODY6 Locus 20q 7p 12q 13q 17cen-q21.3 2 Gene HNF-4α Glucokinase HNF-1α IPF-1 HNF-1β NeuroD1 Distri-bution Rare 8-63% (2nd common) 21-64% (most common) Rare Unknown Rare Age at Diagnosis Adolescent Childhood Adolescent Early adulthood Adolescent Adulthood Associated features - Reduced birth wt glucose threshhold for glycosuria - Renal cysts Genital malformation - Severity Severe Mild Progressive Mod-Severe Mild? Mild? Unknown Treatment Sulfonylurea Diet Sulfonylurea Sulfonylurea Insulin Insulin Insulin Complications Frequent Rare Frequent Rare Rare Unknown 80 children with MODY 38/80 (48.1%) had mutation • 18/38: GCK mutations (MODY2) • 11/38: HNF1A mutations (MODY3) • 3/38: HNF4A mutations (MODY1) • 6/38: HNF1B mutations (MODY5) Thank you very much