Diagnostic Diabetes: diagnosing maturity-onset diabetes of the young (MODY)

Diagnosing MODY
What is MODY? Different types of MODY - Glucokinase MODY - Transcription factor MODY Separating from Type 1, Type 2 and genetic syndromes Investigations for MODY

Diagnosing MODY
What is MODY? Different types of MODY - Glucokinase MODY - Transcription factor MODY Separating from Type 1, Type 2 and genetic syndromes Investigations for MODY

Young-adult diabetes (15-30yrs)

Diabetes is a diagnostic speciality

Type 1

Type 2

MODY

Genetic Syndromes

Diabetes in Young Adults (15-30 years)

Type 2 Type 1

MODY MIDD

10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90

Age of diagnosis

Diagnostic criteria for MODY

Early-onset diabetes Not insulin-dependent
diabetes
Diagnosis of diabetes before 25 years in at least 1 & ideally 2 family members Off insulin treatment or measurable C-peptide at least 3 (ideally 5) years after diagnosis Must be diabetes in one parent (2 generations) and ideally a grandparent or child ( 3 generations)

Autosomal dominant
inheritance

Caused by a single gene defect

altering beta-cell function, obesity unusual
Tattersall (QJM 1974)

Diagnosing MODY
What is MODY? Different types of MODY - Glucokinase MODY - Transcription factor MODY Separating from Type 1, Type 2 and genetic syndromes Investigations for MODY

The Genetic Causes of MODY MODY

75% 11% 14% Transcription factors MODY x Glucokinase (MODY2) 69% 3% 3% <1% <1% HNF1 HNF4 HNF1 IPF1 NeuroD1 (MODY3) Frayling, et al Diabetes 2001

Two subtypes of MODY Glucokinase and Transcription factor

20 16 12 8
.

Transcription factor (HNF-1)

Glucose (mmol/l)

Glucokinase Normal
0 20 40 60 80 100

4 0

Age (yr..)
Pearson, et al Diabetes 2001

Glucokinase (MODY2)
Rare in hospital diabetic clinics Incidental hyperglycaemia in children Common in gestational diabetes Persistent raised fasting glucose (5.5-9 mmol/l) from birth Little rise (< 3mmol/l) in OGTT No extra-pancreatic features Not obese (usually) Often asymptomatic TEST PARENTS!

HNF1 (MODY3)
Commonest cause of MODY May be misdiagnosed as type 1 Typically develop 12-30 yr FPG maybe normal initially Large rise (>5mmol/l) in OGTT Worsening glycaemia with age Low renal threshold (glycosuria) Not obese (usually) Parents and grandparents usually diabetic

Separating HNF1 (MODY3) from Glucokinase (MODY 2) when moderate hyperglycaemia on an OGTT
Plasma Glucose mmol/l
16 14 12 10 8 6 4 2 0

*** HNF1 *** GCK

30

60 Time (mins)

90

120

*** p < 0.001

OGTT Results GCK and HNF

European MODY Consortium (n =364) - Stride et al Diabetologia 02

Glucokinase and Transcription factor diabetes rather than MODY

MODY
Glucokinase mutations
Onset at birth Stable hyperglycaemia Diet treatment Complications rare

Transcription factor mutations (HNF-1, HNF-1, HNF-4)

Adolescence/young adult onset Progressive hyperglycaemia 1/3 diet, 1/3 OHA, 1/3 Insulin Complications frequent

Diagnosing MODY
What is MODY? Different types of MODY - Glucokinase MODY - Transcription factor MODY Separating from Type 1, Type 2 and genetic syndromes Investigations for MODY

Young adult diabetes diagnosis

NOT on a single clinical criteria or a single investigation

multi - facetted approach needed

MODY
Non insulin dependent Yes

Type1
No

Parents affected
Age of onset < 25yr

1
Yes

0-1
Yes

MODY diagnostic criteria separate well from Type 1

MODY
Non insulin dependent Yes

Type 2
Yes

Type1
No

Parents affected
Age of onset < 25yr

1
Yes

1-2
unusual

0-1
Yes

MODY diagnostic criteria do not separate well from early-onset Type 2

MODY
Non insulin dependent Parents affected Age of onset < 25yr Yes 1 Yes

Type 2
Yes 1-2 unusual

Type1
No 0-1 Yes

Obesity
Acanthosis Nigricans Racial groups (Type 2 prevalence)

+/low

+++
++ high

+/low

Clinical Assessment of Non-Type 1 Young Adult Diabetes

Clinical Assessment - Diabetes characteristics - Non-pancreatic manifestations - Family History

Key for diabetes syndromes

Investigations - General & Specific Diagnostic Tests

Diabetes +
Obesity ++ Acanthosis nigricans Neurological Deafness Retinitis pigmentosa DIDMOAD MIDD Other Cystic fibrosis Renal cysts & Diabetes

Type A IR Lipodystrophy
Prader-Willi Alstrom Bardet-Biedl Lawrence-Moon

HNF-1 mutations: a new genetic syndrome Renal Cysts And Diabetes (RCAD) MODY5
Renal cysts Often seen on anti-natal scanning - variable Renal function variable - mild impairment - endstage renal failure 50% require dialysis Different renal histology Diabetes Diagnosis 22 (10 - 47) yr., often on insulin Other extra-pancreatic features uterine abnormalities, insulin resistance and gout
Nishigori et al Diabetes 1998, Lindner et al 1999 Hum Mol Gen Bingham et al 2000 Kidney Int, Bingham et al 2001 AmJ Hum Gen, Bingham et al 2002 Kidney Int,

Diagnosing MODY
What is MODY? Different types of MODY - Glucokinase MODY - Transcription factor MODY Separating from Type 1, Type 2 and genetic syndromes Investigations for MODY

Non genetic Investigations

MODY
Glycaemia
Autoantibodies ICA, IA2 or GAD C peptide

Type 1
Variable
>95% diagnosis

Type 2
Variable
unusual

Variable
Not present

Usually detectable (0-1 nmol/l)

not measurable > 3-5 years (<0.33nmol/l) normal

detectable may be high (>1nmol/l) HDL low TG high

Lipids

normal (HDL>1.2 MODY3)

Diagnostic Genetic Testing in UK

Monogenic Diabetes
Glucokinase, HNF1, HNF4 , (Diagnostic Exeter)

MIDD (Diagnostic Exeter & other UK labs) Neonatal diabetes (Research Salisbury/Exeter)

Monogenic Diabetes +
Prader Willi, Cystic fibrosis (many UK labs) Wolfram syndrome (Research Birmingham) ISPAD rare diabetes collection (Research Exeter)

For info: www.diabetesgenes.org

Diagnostic Genetic Testing: why do it?

Makes diagnosis : defines monogenic and defines subtype Differentiates from type 1 Helps define prognosis Helps family counselling Helps treatment decisions

Diagnostic Testing : why do it?

Glucokinase: Safely leave children off treatment

www.diabetesgenes.org

Diagnostic Testing : why do it?

HNF1:very sensitive to sulphonylureas
12
Glibenclamide started Metformin stopped

HbA1c (%)

10
Glibenclamide stopped Metformin started

4
8 9 10 11 12 13

(Pearson et al Diab Med 2000)

Years since diagnosis

Diagnosing MODY: conclusion

Use both diagnostic criteria and clinical information and non-genetic investigation to suggest a diagnosis Genetic testing makes diagnosis : defines MODY, defines subtype helps with counselling, prognosis and treatment BUT .Expensive 1-400- - only do if alter management Test ordered guided by clinical criteria as to likely gene. Discuss each case before testing

Spare slides: Differential diagnosis Type 1 & Type 2

Separating HNF1 (MODY3) from Type 1

Consider in type 1 diabetic young adults when.
Familial 2 generations 3 generations
C peptide present or not insulin treated 3 yrs post diag. Pancreatic Auto - antibody -ve

96% HNF1 14% Type 1 74% HNF1 2 % Type 1

100% HNF1 98% HNF1 5 % Type 1 5 % Type 1

Consider HNF1 testing in any Type 1 young adult who has a diabetic parent and is autoantibody -ve at diagnosis (2% UK) Especially if C peptide preserved in child and parent UK Data on HNF1 Exeter, Type 1 Bristol (Lambert, Gale, Bingley)

Criteria Separating HNF1 (MODY3) from Type 1 are useless for differentiating from Type 2 young adults!
Familial 2 generations 3 generations
C peptide present or not insulin treated 3 yrs post diagnosis Pancreatic Auto - antibody -ve

96% HNF1 80% Type 2 74% HNF1 50 % Type 2

100% HNF1 100 % Type 2 98% HNF1 90% Type 2

So use different data for answering different questions!

Separating HNF1 (MODY3) from Type 2

Consider in type 2 diabetic young adults when.
Not obese Not over weight
Not acanthosis nigricans HDL > 1.2 mmol/l White Caucasian

86% HNF1 25% Type 2 64% HNF1 4 % Type 2

100% HNF1 20% Type 2 83% HNF1 <8% Type 2 94% HNF1 30% Type 2

Consider HNF1 testing in any Type 2 young adult who is not obese, does not have AN, or low HDL especially if white Caucasian
UK Data on HNF1/Type 2 Hattersley, Barrett, Ehtisham, Owen, Pearson unpublished