Maturity-Onset Diabetes of the

Young (MODY)

Dr. VŨ CHÍ DŨNGNational 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 Summary14.5 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

DiagnosisWhy 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

DiagnosisClinical 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)

Rare Unknown Rare

Age at Diagnosis

Adolescent Childhood Adolescent Early adulthood

Adolescent Adulthood

Associated features

- Reduced birth wt

glucose threshhold for glycosuria

- Renal cystsGenital mal-formation

-

Severity Severe Mild ProgressiveMod-Severe

Mild? Mild? Unknown

Treatment Sulfonylurea Diet Sulfonylurea Sulfonylurea Insulin

Insulin Insulin

Complica-tions

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