1. Maturity-Onset Diabetes of the Young (MODY)
Dr. VŨ CHÍ DŨNG
National Hospital of Pediatrics

2. Case No. 1
DOB: June

3. 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

4. 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

5. Investigations BG: 97 mmol/l; HbA1C: 20.4%
Insulin: 142 μU/ml; C-peptide: 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)

6. 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 mol/l)

7. 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

8. 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 x 4.5 x 3.4 mm
In kidneys some cysts with dimension of 3 mm & pyelectasis were seen

10. 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 ???

12. Heterozygous HNF-1β missense mutation, S148L (c.443C>T)

13. Case No. 2
DOB: 18 Nov 1996

14. 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

15. 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

16. 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

18. 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

19. 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)

20. Β-Cell

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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%)

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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)

38. Thank you very much