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 (Maturity-Onset 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 non-diabetic 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 Gluco- kinase HNF-1α IPF-1 HNF-1β NeuroD1 Distri-bution Rare 8-63% (2nd common) 21-64% (most common) Unknown Age at Diagnosis Adolescent Childhood Early adulthood Adulthood Associated features - Reduced birth wt glucose threshhold for glycosuria Renal cysts Genital mal-formation Severity Severe Mild Progressive Mod-Severe Mild? Treatment Sulfonylurea Diet Sulfonylurea Insulin Insulin Complica-tions Frequent

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)

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