3. HISTORY
• ELLIOT JOSLIN OBSERVED BEFORE THE DISCOVERY OF INSULIN THAT SOME
YOUNG PATIENTS WITH DIABETES AND A STRONG FAMILY HISTORY OF THE
CONDITION SURVIVED MUCH LONGER THAN EXPECTED.
• SIMILAR CLINICAL REPORTS MAY BE TRACED IN THE SUBSEQUENT
LITERATURE, BUT THE HISTORY OF MODY REALLY BEGAN IN 1974 WHEN
TATTERSALL AND PYKE DESCRIBED THREE FAMILIES WITH EARLY ONSET
DIABETES TRANSMITTED AS AN AUTOSOMAL DOMINANT TRAIT,
RESPONSIVE TO SULPHONYLUREAS, AND WITH A RELATIVELY BENIGN
PROGNOSIS.
• FAJANS HAD INDEPENDENTLY DESCRIBED A GROUP OF PATIENTS
DIAGNOSED WITH DIABETES UNDER THE AGE 25 YEARS WHO HAD NOT
PROGRESSED TO INSULIN AFTER MANY YEARS ON SULPHONYLUREAS.
• TATTERSALL AND FAJANS JOINED FORCES TO COIN THE SOMEWHAT
UNFORTUNATE TERM MATURITY ONSET DIABETES OF THE YOUNG (MODY),
WHICH THEY DEFINED AS 'FASTING HYPERGLYCAEMIA DIAGNOSED UNDER
AGE 25 WHICH COULD BE TREATED WITHOUT INSULIN FOR MORE THAN
TWO YEARS'.
4. • MATURITY ONSET DIABETES OF THE YOUNG (MODY) IS A
CLINICALLY GROUP OF HETEROGENEOUS DISORDER
CHARACTERIZED BY NON-INSULIN DEPENDENT DIABETES
DIAGNOSED AT A YOUNG AGE (<25 YEARS) WITH AUTOSOMAL
DOMINANT TRANSMISSION AND LACK OF AUTOANTIBODIES
4
DEFINITION-MODY
5. • EARLY ONSET DIABETES (<25 years)
• NON-INSULIN DEPENDENT
• AUTOSOMAL DOMINANT INHERITANCE
• CAUSED BY A SINGLE GENE DEFECT ALTERING BETA
CELL FUNCTION
• OBESITY UNUSUAL
• PRIMARY DEFECT IN INSULIN SECRETION
BACKGROUND
8. • COMMONEST CAUSE
OF MODY
• MAY BE
MISDIAGNOSED AS
TYPE 1
• TYPICALLY DEVELOPS
BEFORE 25 YEARS
• FBG 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
INTRODUCTION
9. • HNF1 HOMEOBOX A (HEPATOCYTE NUCLEAR FACTOR 1 HOMEOBOX A), ALSO
KNOWN AS HNF1A, IS A HUMAN GENE WHICH IS LOCATED ON
CHROMOSOME 12Q24.2
• THE PROTEIN ENCODED BY THIS GENE IS A TRANSCRIPTION FACTOR THAT IS
HIGHLY EXPRESSED IN THE PANCREAS.
• IT REGULATES EXPRESSION OF THE INSULIN GENE AND OTHER GENES
ENCODING PROTEINS INVOLVED IN GLUCOSE TRANSPORT AND METABOLISM.
• HNF1 A MUTATIONS MAY CONTRIBUTE TO ABNORMAL PANCREATIC ISLET CELL
DEVELOPMENT DURING FETAL LIFE, AS WELL AS IMPAIRED TRANSCRIPTIONAL
REGULATION OF GENES INVOLVED IN NORMAL ISLET CELL FUNCTION
• ITS MUTATIONS ALSO INFLUENCE EXPRESSION OF HNF4A(MODY1). THIS
SUGGESTS THAT THE MODY TRANSCRIPTION FACTORS FORM A REGULATOR
NETWORK THAT IS NECESSARY TO MAINTAIN GLUCOSE HOMOSTASIS.
HNF1A
10. PATHOPHYSIOLOGY
• MODY3 is caused by mutation in the hepatic transcription factor-
1 gene (TCF1) on chromosome 12q24.2.
11. CLINICAL PRESENTATION
• MILD TO MODERATE HYPERGLYCEMIA (TYPICALLY 130–250 MG/DL, OR 7–
14 MMOL/L) DISCOVERED BEFORE 25 YEARS OF AGE. HOWEVER, ANYONE UNDER
50 CAN DEVELOP MODY.
• A FIRST-DEGREE RELATIVE WITH A SIMILAR DEGREE OF DIABETES.
• USUAL DIABETIC SYMPTOMS LIKE POLYUREA, POLYDYPSIA & POLYPHAGIA.
• ABSENCE OF POSITIVE ANTIBODIES OR OTHER AUTOIMMUNITY (E.G., THYROIDITIS)
IN PATIENT AND FAMILY.
• PERSISTENCE OF A LOW INSULIN REQUIREMENT (E.G., LESS THAN 0.5 U/KG/DAY)
PAST THE USUAL "HONEYMOON" PERIOD.
12. • ABSENCE OF OBESITY (ALTHOUGH OVERWEIGHT OR OBESE PEOPLE CAN
GET MODY) OR METABOLIC
SYNDROME (E.G.,HYPERTENSION, HYPERLIPIDEMIA, POLYCYSTIC OVARY
SYNDROME).
• INSULIN RESISTANCE VERY RARELY HAPPENS.
• CYSTIC KIDNEY DISEASE IN PATIENT OR CLOSE RELATIVES.
• ON-TRANSIENT NEONATAL DIABETES, OR APPARENT TYPE 1 DIABETES WITH
ONSET BEFORE SIX MONTHS OF AGE.
• LIVER ADENOMA OR HEPATOCELLULAR CARCINOMA IN MODY TYPE 3
• THE DIAGNOSIS OF MODY IS CONFIRMED BY SPECIFIC GENE TESTING
AVAILABLE THROUGH COMMERCIAL LABORATORIES.
CLINICAL PRESENTATION
13. • THE MAJORITY OF PATIENTS WITH GENETICALLY PROVEN MONOGENIC
DIABETES ARE INITIALLY INCORRECTLY DIAGNOSED AS TYPE 1 OR TYPE 2
DIABETES.
• IT IS IMPORTANT TO CORRECTLY DIAGNOSE MONOGENIC DIABETES AS IT
CAN PREDICT THE CLINICAL COURSE OF THE PATIENT, EXPLAIN OTHER
ASSOCIATED CLINICAL FEATURES AND MOST IMPORTANTLY GUIDE THE
MOST APPROPRIATE TREATMENT.
• IN ADDITION, MAKING A DIAGNOSIS WILL HAVE IMPLICATIONS FOR
OTHER FAMILY MEMBERS OFTEN CORRECTING THE DIAGNOSIS AND
TREATMENT FOR OTHER DIABETIC FAMILY MEMBERS AS WELL AS
ALLOWING APPROPRIATE GENETIC COUNSELING
WHY DIAGNOSE MODY?
14. 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
15. • FEATURES IN CHILDREN INITIALLY THOUGHT TO HAVE TYPE 1 DIABETES THAT
SHOULD SUGGEST A POSSIBLE DIAGNOSIS OF MONOGENIC DIABETES ARE SHOWN
BELOW. NONE OF THESE ARE ABSOLUTE AND SHOULD BE CONSIDERED AS
TOGETHER RATHER THAN IN ISOLATION(C) 3. THE APPROXIMATE PERCENTAGE OF
PATIENTS WITH TYPE 1 DIABETES IS GIVEN IN BRACKETS
• A DIAGNOSIS OF DIABETES BEFORE 6 MONTHS (B) (<1% TYPE 1 IAFUSCO, 2002
#2514 )
• FAMILY HISTORY OF DIABETES WITH A PARENT AFFECTED (C) (2-4%4)
WHEN TO SUSPECT A DIAGNOSIS OF TYPE 1 DIABETES IN
CHILDREN MAY NOT BE CORRECT?
16. • EVIDENCE OF ENDOGENOUS INSULIN PRODUCTION OUTSIDE THE
‘HONEYMOON’ PHASE (AFTER 3 YEARS OF DIABETES) WITH DETECTABLE C
PEPTIDE (>200NMOL/L) WHEN GLUCOSE > 8 MMOL/L. (1-5% TYPE 1).
• WHEN PANCREATIC ISLET AUTOANTIBODIES ARE ABSENT, ESPECIALLY IF
MEASURED AT DIAGNOSIS (3-30% TYPE 1 PATIENTS.
WHEN TO SUSPECT A DIAGNOSIS OF TYPE 1 DIABETES IN
CHILDREN MAY NOT BE CORRECT?
17. WHEN TO SUSPECT A DIAGNOSIS OF TYPE 2 DIABETES IN
CHILDREN MAY NOT BE CORRECT?
• NOT MARKEDLY OBESE OR DIABETIC FAMILY MEMBERS WHO ARE NORMAL
WEIGHT (20%)
• ACANTHOSIS NIGRICANS NOT DETECTED (10%)
• ETHNIC BACKGROUND FROM A LOW PREVALENCE TYPE 2 DIABETES RACE
E.G. EUROPEAN CAUCASIAN (0-45%)
• NO EVIDENCE OF INSULIN RESISTANCE WITH FASTING C PEPTIDE WITHIN
THE NORMAL RANGE (0-20%8-11)
19. 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
Must be diabetes in one
parent (2 generations) and
ideally a grandparent or child
( 3 generations)
ON CLINICAL
BASIS
Off insulin treatment or measurable C-
peptide at least 3 (ideally 5) years after
diagnosis
20. WHEN THERE IS A HIGH INDEX OF SUSPICION I.E.
1. FAMILIAL DIABETES WITH AUTOSOMAL DOMINANT PATTERN OF
INHERITANCE (>2 GENERATIONS),
2. ONSET <25 YEARS,
3. NON-OBESE,
4. NEGATIVE ISLET AUTOANTIBODIES
GENETIC TESTING
22. Diagnostic Testing : why do
it?
HNF1a: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)
23. • RECENT WORK DONE BY TIM J, MCDONALD… SHOWED THAT HIGH SENSITIVITY C-
REACTIVITY LEVELS ARE LOWER IN HNFA1 THAN TYPE 1, TYPE 2 SIABETES OR
GLUCOKINASE (GCK) – MODY (DIABETES CARE JOURNAL)
• METHOD : HS-CRP LEVELS WERE ASSESSED IN 750 PATIENTS (220
HNF1A, 245 GCK, 54 HNF4A, 21 HNF1B, 53 TYPE 1 AND 157 TYPE 2
DIABETES.
• RESULTS : HS-CRP WAS LOWER IN HNF1A-MODY (MEDIAN 0.3 [0.1-0.6])
THAN TYPE 2 DIABETES ( MEDIAN 1.40 [ 0.60-3.45] MG/L) THAN TYPE 1
(1.10 [0.50-1.85] MG/DL) THAN HNF1B-MODY (0.60 [0.10-2.8] MG/DL)
THAN GCK-MODY(0.60 [0.30-1.8]MG/DL)
• CONCLUSION: HS-CRP LEVELS ARE LOWER IN HNF1A-MODY THAN OTHER
FORMS OF DIABETES AND MAY BE USED A S A BIOMARKER TO SELECT
PATIENTS FOR DIAGNOSTIC HNF1A GENETIC TESTING.
HIGH SENSITIVE CRP
24. • RECENT WORK DONE S. A. MUGHAL, R. PARK… SHOWED THAT SERUM APOM
LEVELS ARE LOWER IN HNFA1 THAN TYPE 1. (DIABETES MED JOURNAL)
• METHOD : APO M LEVELS WERE ASSESSED IN 69 HNF1A, 50 TYPE 1, 120
TYPE 2 DIABETES AND 100 HEALTHY CONTROL.
• RESULTS : MEAN SERUM APO M CONCENTRATION WAS SIGNIFICANTLY
LOWER FOR SUBJECTS WITH HNF1A-MODY [0.86(0.29)] THAN THOSE WITH
TYPE 1 AND CONTROL SUBJECTS [1.34(0.22)
• CONCLUSION: APO M LEVELS ARE LOWER IN HNF1A-MODY THAN IN
CONTROLS. ALSO IT PROVIDES A GOOD DISCRIMINATION BETWEEN HNF1A
MODY AND TYPE 1 DIABETIC PATIENTS.
APOLIPOPROTEIN M
25. • 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 - ONLY DO IF ALTER MANAGEMENT
• TEST ORDERED GUIDED BY CLINICAL CRITERIA AS TO LIKELY GENE.
DISCUSS EACH CASE BEFORE TESTING
DIAGNOSIS CONCLUSION
26. MANAGEMENT
• Unfortunately, chronic hyperglycemia of any cause can
eventually cause blood vessel damage and the microvascular
complications of diabetes.
• The principal treatment goals for people with MODY — keeping
the blood sugars as close to normal as possible ("good glycemic
control"), while minimizing other vascular risk factors — are the
same for all known forms of diabetes.
27. PRIMARY MANAGEMENT
• PATIENTS WITH HNF-1a GENE MUTATIONS CAN INITIALLY BE TREATED WITH
DIET AND EXERCISE ALTHOUGH THEY WILL HAVE MARKED POST PRANDIAL
HYPERGLYCAEMIA HIGH CARBOHYDRATE FOOD AS THE BETA-CELL DEFECT
RESULTS IN INSUFFICIENT INCREASE IN INSULIN SECRETION WITH
HYPERGLYCAEMIA.
• MOST PATIENTS WILL NEED PHARMACOLOGICAL TREATMENT AS THEY
SHOW PROGRESSIVE DETERIORATION IN GLYCAEMIC CONTROL
THROUGHOUT LIFE AND ARE AT RISK OF CONSIDERABLE MICRO-VASCULAR
AND MACRO-VASCULAR COMPLICATIONS.
28. • THE CURRENT INTERNATIONAL SOCIETY FOR PEDIATRIC AND
ADOLESCENT DIABETES/INTERNATIONAL DIABETES
FEDERATION (ISPAD/IDF) GUIDELINES PUBLISHED IN 2009
SUGGEST SWITCHING PATIENTS WITH PROFEN HNF1A
MUTATION (HNF1A–MODY) FROM INSULIN TO
SULFONYLUREA.
• DESPITE THIS, 40% OF HNF1A PATIENTS WITH PAEDIATRIC
AND ADOLESCENT-ONSET DIABETES CONTINUED TO RECEIVE
INSULIN TREATMENT.
• INSULIN TREATMENT WAS ASSOCIATED WITH HIGHER HBA1C
AND A HIGHER RISK OF HYPOGLYCAEMIA.
29. 1. SULPHONYLYUREAS
• THE FIRST TREATMENT TO BE USED IN CHILDREN WHO ARE NOT
CONTROLLED ON INSULIN SHOULD BE LOW DOSE SULPHONYLUREAS
WHICH RESULTS IN A 4 FOLD GREATER LOWERING OF GLUCOSE THAN
METFORMIN.
• THESE PATIENTS ARE EXTREMELY SENSITIVE TO SULPHONYLUREAS AND AS
LONG AS THEY DO NOT HAVE PROBLEMS WITH HYPOGLYCAEMIA CAN BE
MAINTAINED ON THESE FOR MANY DECADES .
• GLYCAEMIC CONTROL IN SULPHONYLUREAS IS OFTEN BETTER THAN THAT
ACHIEVED ON INSULIN ESPECIALLY IN CHILDREN AND YOUNG ADULTS.
• THE DOSE OF SULPHONYLUREAS SHOULD INITIALLY BE LOW (¼ - OF THE
NORMAL STARTING DOSE IN ADULTS) TO AVOID HYPOGLYCAEMIA .
• IF THERE IS HYPOGLYCAEMIA DESPITE DOSE TITRATION OF A ONCE OR
TWICE DAILY SULPHONYLUREA PREPARATION SUCH AS GLICLAZIDE A SLOW
RELEASE PREPARATION OR MEAL TIME DOSES WITH A SHORT ACTING
AGENTS LIKE NATEGLINIDE MAY BE CONSIDERED.
PHARMACOLOGICAL RX
30.
31. 2. MEGLITINIDE ANALOGUES
• MARIANNE BECKER, ANGELA GALLER AND KLEMENS RAILE HAD PUBLISHED
CASE REPORTS SUGGESTING THAT MEGLITINIDES CAN BE USED AS SINGLE OR
COMBINED BASED THERAPY FOR MODY 3 PATIENTS.
• The Hba1c with the use of meglitinide was 51 mmol/mol , 6.8% whereas with
insulin was 58 mmol/mol, 7.5%.
• In combination with Insulin Hba1c was 55 mmol/ml and 7.2%
PHARMACOLOGICAL RX
32. 3. GLUCAGON LIKE PEPTIDE – 1 RECEPTOR AGONIST THERAPY
• Maricor, Charles, Christine, kevin published a Case study report of three
patients saying that GLP-1 receptor agonist therapy may be of value in
managing glycemia in patients with MODY 3
• In all 3 patients C-peptide levels went 3-fold after 3 days of liraglutide.
• They also experienced significant weight loss (10-15%)
• Hb1ac was 7.4%, 6.4 % and 6.8 % respectively.
• With the help of GLP 1, they were able to discontinue Insulin.
33. 1. UPTODATE
2. YAMAGATA, K; ODA, N; KAISAKI, PJ; MENZEL, S; FURUTA, H; VAXILLAIRE, M;
SOUTHAM, L; COX, RD; LATHROP, GM; BORIRAJ, VV; CHEN, XN; COX, NJ; ODA, Y;
YANO, H; LEBEAU, MM; YAMADA, S; NISHIGORI, H; TAKEDA, J; FAJANS, SS;
HATTERSLEY, AT; IWASAKI, N; HANSEN, T; PEDERSEN, O; POLONSKY, KS; TURNER, RC;
VELHO, G; CHEVRE, JC; FROGUEL, P; BELL, GI. (1996) "MUTATIONS IN THE
HEPATOCYTE NUCLEAR FACTOR-1 ALPHA GENE IN MATURITY-ONSET DIABETES OF
THE YOUNG (MODY3)." NATURE 384(6608): 455-458.
3. MARIANNE BECKER, MD, ANGELA GALLER, MD, AND KLEMENS RAILE, MD
“MEGLITINIDE ANALOGUES IN ADOLESCENT PATIENTS WITH HNF1A-MODY (MODY
3)” PEDIATRICS VOLUME NO. 133 NO.3 MARCH 1, 2014. PP. E775-E779
4. MCDONALD TJ, SHIELDS BM, LAWRY J, ET AL. HIGH-SENSITIVITY CRP DISCRIMINATES
HNF1A-MODY FROM OTHER SUBTYPES OF DIABETES. DIABETES
CARE2011;34(8):1860-1862. DOI:10.2337/DC11-0323.
REFERENCES
