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Apr 03, 2018

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    Diagnostic Diabetes:diagnosing maturity-onset

    diabetes of the young(MODY)

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    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

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    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

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    Young-adult diabetes (15-30yrs)

    Diabetes is a diagnostic speciality

    Type 1

    Genetic Syndromes

    MODY

    Type 2

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    Diabetes in Young Adults (15-30 years)

    Age of diagnosis

    5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90

    Type 2

    Type 1

    MODY

    MIDD

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    Diagnostic criteria for MODY

    Tattersall (QJM 1974)

    Early-onset diabetes

    Not insulin-dependent

    diabetes

    Autosomal dominant

    inheritance

    Caused by a single gene defect

    altering beta-cell function,

    obesity unusual

    Diagnosis of diabetes before 25 yearin at least 1 & ideally 2 family

    members

    Off insulin treatment or measurable

    C-peptide at least 3 (ideally 5) yearsafter diagnosis

    Must be diabetes in one parent (2

    generations) and ideally a

    grandparent or child ( 3 generations

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    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

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    MODY

    11%

    MODY

    75%

    Transcription factors14%

    Glucokinase(MODY2) 3%

    HNF169%HNF1(MODY3)

    3%

    HNF4

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    Two subtypes of MODY

    Glucokinase and Transcription factor

    0

    4

    8

    12

    16

    20

    0 20 40 60 80 100

    Age (yr..)

    Glucose

    (mmol/l)..

    Normal

    Glucokinase

    Transcriptionfactor

    (HNF-1)

    Pearson, et al Diabetes

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    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!

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    HNF1 (MODY3)

    Commonest cause of MODYMay be misdiagnosed as type 1

    Typically develop 12-30 yr

    FPG maybe normal initially

    Large rise (>5mmol/l) in OGTTWorsening glycaemia with age

    Low renal threshold (glycosuria)

    Not obese (usually)

    Parents and grandparents

    usually diabetic

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    OGTT Results GCKand HNFEuropean MODY Consortium (n =364) - Stride et al Diabetologia 02

    0

    2

    4

    6

    8

    10

    12

    14

    16

    0 30 60 90 120Time (mins)

    ***

    ***

    *** p < 0.001

    Separating HNF1 (MODY3) fromGlucokinase (MODY 2) when moderate

    hyperglycaemia on an OGTTPlasma

    Glucose

    mmol/lHNF1

    GCK

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    Transcription factor

    mutationsGlucokinase

    mutations

    Glucokinase and Transcription factor diabetesrather thanMODY

    MODY

    Onset at birth

    Stable hyperglycaemia

    Diet treatmentComplications rare

    Adolescence/young adult ons

    Progressive hyperglycaemia

    1/3 diet, 1/3 OHA, 1/3 InsulinComplications frequent

    (HNF-1, HNF-1, HNF-4

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    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

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    Young adult diabetes diagnosis

    NOT on a single clinical criteria

    or a single investigation

    multi - facetted approach needed

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    MODY Type1

    Non insulin dependent Yes No

    Parents affected 1 0-1

    Age of onset < 25yr Yes Yes

    MODY diagnostic criteria separate wellfrom Type 1

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    MODY Type 2 Type1

    Non insulin dependent Yes Yes No

    Parents affected 1 1-2 0-1

    Age of onset < 25yr Yes unusual Yes

    MODY diagnostic criteria do not separatewell from early-onset Type 2

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    MODY Type 2 Type1

    Non insulin dependent Yes Yes No

    Parents affected 1 1-2 0-1

    Age of onset < 25yr Yes unusual Yes

    Obesity +/- + + + +/-

    Acanthosis - + + -Nigricans

    Racial groups low high low(Type 2 prevalence)

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    Clinical Assessment of Non-Type 1

    Young Adult Diabetes

    Clinical Assessment

    - Diabetes characteristics

    - Non-pancreatic manifestations- Family History

    Investigations

    - General & Specific Diagnostic Tests

    Key for

    diabetes syndrom

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    Diabetes +

    DIDMOA

    MIDDOther

    Cystic fibrosis

    Renal cysts & Diabet

    Deafness

    Prader-Willi

    Obesity ++ Neurological

    Acanthosis

    nigricans

    Alstrom

    Bardet-Biedl

    Lawrence-Moon

    Retinitis

    pigmentosa

    Type A IRLipodystrophy

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    Renal cysts Often seen on anti-natal scanning - variable

    Renal function variable - mild impairment - endstage

    renal failure 50% require dialysis

    Different renal histologyDiabetes

    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 GenBingham et al 2000 Kidney Int, Bingham et al 2001 AmJ Hum Gen,Bingham et al 2002 Kidney Int,

    HNF-1 mutations: a new genetic syndrome

    Renal Cysts And Diabetes(RCAD) MODY5

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    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

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    Non genetic Investigations

    MODY

    Variable

    Not present

    Usually detectable

    (0-1 nmol/l)

    normal

    (HDL>1.2

    MODY3)

    Type 1

    Variable

    >95% diagnosis

    not measurable

    > 3-5 years

    (1nmol/l)

    HDL low

    TG high

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    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

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    Diagnostic Genetic Testing: why do it?

    Makes diagnosis : defines monogenic and definessubtype

    Differentiates from type 1

    Helps define prognosis Helps family counselling

    Helps treatment decisions

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    Diagnostic Testing : why do it?

    www.diabetesgenes.org

    Glucokinase:

    Safely leave children off treatment

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    Diagnostic Testing : why do it?HNF1:very sensitive to sulphonylureas

    4

    6

    8

    10

    12

    8 9 10 11 12 13

    Glibenclamide stopped

    Metformin started

    Glibenclamide started

    Metformin stopped

    HbA1c

    (%)

    Years since diagnosis(Pearson et al Diab Med 2000)

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    Diagnosing MODY: conclusion

    Use both diagnostic criteria and clinical informationand non-genetic investigation to suggest a diagnosis

    Genetic testing makes diagnosis : defines MODY,

    defines subtype helps with counselling, prognosis an

    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

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    Spare slides:

    Differential diagnosis

    Type 1 & Type 2

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    Consider in type 1 diabetic young adults when.

    Familial 2 generations 96% HNF1 14% Type 3 generations 74% HNF1 2 % Type

    Separating HNF1 (MODY3) from Type 1

    C peptide present or not insulin 100% HNF1 5 % Typetreated 3 yrs post diag.

    Pancreatic Auto - antibody -ve 98% HNF1 5 % TypeConsider HNF1testing in any Type 1 young adult who has 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

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    So use different data for answeringdifferent questions!

    p g )

    Type 1 are useless for

    differentiating from Type 2 young adults!

    Familial 2 generations 96% HNF1 80% Type 2 3 generations 74% HNF1 50 % Type 2C peptide present or not insulin 100% HNF1 100 % Type 2treated 3 yrs post diagnosis

    Pancreatic Auto - antibody -ve 98% HNF1 90% Type 2

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    Consider in type 2 diabetic young adults when.

    Not obese 86% HNF1 25% Type 2 Not over weight 64% HNF1 4 % Type 2

    Separating HNF1 (MODY3) from Type 2

    Not acanthosis nigricans 100% HNF1 20% Type 2HDL > 1.2 mmol/l 83% HNF1