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    Click here to download slides on diagnosing MODY Click here to download slides on diagnosing MODY Presentation Transcript

    • 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” Genetic Syndromes Type 2 Type 1 MODY
    • 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
    • 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 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)
    • 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
    • MODY 11% MODY x 75% Transcription factors 14% Glucokinase (MODY2) 3% HNF1  69% HNF1  (MODY3  3% HNF4  <1% IPF1 The Genetic Causes of MODY Frayling, et al Diabetes 2001 <1% NeuroD1
    • 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) . . Pearson, et al Diabetes 2001 Normal Glucokinase Transcription factor (HNF-1 
    • 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
    • OGTT Results GCK and HNF European MODY Consortium (n =364) - Stride et al Diabetologia 02 *** *** *** p < 0.001 Separating HNF1  MODY3) from Glucokinase (MODY 2) when moderate hyperglycaemia on an OGTT Plasma Glucose mmol/l HNF1 GCK
    • Transcription factor mutations Glucokinase mutations Glucokinase and Transcription factor diabetes rather than “MODY” MODY Onset at birth Stable hyperglycaemia Diet treatment Complications rare Adolescence/young adult onset Progressive hyperglycaemia 1/3 diet, 1/3 OHA, 1/3 Insulin Complications frequent (HNF-1  HNF-1  HNF-4 
    • 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 Type1 Non insulin dependent Yes No Parents affected 1 0-1 Age of onset < 25yr Yes Yes MODY diagnostic criteria separate well from Type 1
    • 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 separate well from early-onset Type 2
    • 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)
    • 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 syndromes
    • Diabetes + DIDMOAD MIDD Other Cystic fibrosis Renal cysts & Diabetes Deafness Prader-Willi Obesity ++ Neurological Acanthosis nigricans Alstrom Bardet-Biedl Lawrence-Moon Retinitis pigmentosa Type A IR Lipodystrophy
      • 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, HNF-1  mutations: a new genetic syndrome Renal Cysts And Diabetes (RCAD) –MODY5
    • 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
      • Variable
      • Not present
      • Usually detectable (0-1 nmol/l)
      • normal (HDL>1.2 MODY3)
      • Type 1
      • Variable
      • >95% diagnosis
      • not measurable
      • > 3-5 years
      • (<0.33nmol/l)
      • normal
      Glycaemia Autoantibodies ICA, IA2 or GAD C peptide Lipids Type 2 Variable unusual detectable may be high (>1nmol/l) HDL low TG high
    • 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? www.diabetesgenes.org Glucokinase: S afely leave children off treatment
    • Diagnostic Testing : why do it? HNF1  :very sensitive to sulphonylureas HbA1c (%) Years since diagnosis (Pearson et al Diab Med 2000)
    • 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
    • Consider in “type 1” diabetic young adults when….
      • Familial 2 generations 96% HNF1  14% Type 1
      • 3 generations 74% HNF1  2 % Type 1
      Separating HNF1  MODY3) from Type 1
      • C peptide present or not insulin 100% HNF1  5 % Type 1 treated 3 yrs post diag.
      • Pancreatic Auto - antibody -ve 98% HNF1  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)
      • So use different data for answering different questions!
      Criteria Separating HNF1  MODY3) from 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 2
      • C peptide present or not insulin 100% HNF1  100 % Type 2 treated 3 yrs post diagnosis
      • Pancreatic Auto - antibody -ve 98% HNF1  90% Type 2
    • 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 2
      • HDL > 1.2 mmol/l 83% HNF1  <8% Type 2
      • White Caucasian 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