Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of single-gene disorders.1,2 MODY is characterized by early onset of nonketotic diabetes mellitus caused by defective insulin production from the pancreatic beta-cells; it follows an autosomal dominant mode of inheritance. Patients can present with mild fasting hyperglycemia for many years, whereas others have varying degrees of glucose intolerance for several years before the onset of persistent fasting hyperglycemia.1 Because of its frequently mild presentation, it is one of the most easily missed causes of diabetes.3
MODY subtype, clinical phenotype and the most effective treatment options will differ depending on the defective gene and molecular characterization of the pathogenic variant is important.1,4
- >100/1,000,000. The prevalence of MODY in racial and ethnic minorities may be underrepresented as many individuals with MODY remain undiagnosed and studies to date have largely involved white populations.3
- MODY is thought to account for at least 1%-3% of all diabetes.3,4
- Early-onset (<25 years) diabetes
- Non-insulin dependent diabetes
- Can be mild, often asymptomatic
- Mild fasting hypoglycemia
- Glucose intolerance
- Classic diabetes symptoms such as Polyuria, Polydipsia and polyphagia
- Increased blood pressure >135/80 mm Hg
- Abdominal pain (especially for variants in CEL gene)
- The characteristic features of type 1 diabetes (severe osmotic symptoms, ketoacidosis) or type 2 diabetes (obesity, acanthosis nigrans, hypertension, hyperlipidemia) are typically absent in the patient with MODY.
5 major diagnostic criteria for MODY are usually accepted:5
- Hyperglycemia usually diagnosed before age 25 years in at least 1 and ideally 2 family members.
- Autosomal dominant inheritance, with a vertical transmission of diabetes through at least 3 generations, and a similar phenotype shared by diabetic family members.
- Absence of insulin therapy at least 5 years after diagnosis or significant C-peptide levels even in a patient on insulin treatment.
- Insulin levels that are often in the normal range, although inappropriately low for the degree of hyperglycemia, suggesting a primary defect in beta-cell function.
- Overweight or obesity is rarely associated (and is not required for the development of diabetes).
- Pancreatic islet cell autoantibody testing can be helpful in distinguishing between MODY and type 1 diabetes.6
- Maintained levels of C-peptide would be anticipated in MODY.7
- Molecular genetic testing to defined MODY subtype and causative gene and pathogenic variant.
MODY subtype identified by phenotype and/or molecular genetic characterization can influence treatment choices and efficacy.1,4
- Oral hypoglycemic agent, insulin (MODY 1,3,4)
- Insulin therapy (ABCC8, GCK, HNF1A, HNF1B, HNF4A)
- Sulfonylureas (ABCC8, HNF1A, HNF1B, HNF4A, KCNJ11)
- Diet and exercise (ABCC8, CEL, GCK, HNF1A, HNF1B, HNF4A, KLF11).
- Type 2 diabetes mellitus
- Type 1 diabetes mellitus
To confirm/establish the diagnosis of MODY, CENTOGENE offers the following tests:
- NGS Panel
- NGS Panel Genomic
- Deletion/Duplication testing (MLPA/qPCR)
- Individuals with a family history of disease and presentation of the most common symptoms.
- Individuals without a positive family history, but with symptoms resembling this disease.
- Individuals with a negative but suspected family history to identify risk and to allow proper genetic counselling.
MODY is initially misdiagnosed in 90% of cases, resulting in inappropriate advice and treatment. Confirmation by molecular genetic testing of the MODY subtype is important, as it enables correct diagnosis enabling treatment optimization and allowing monitoring of asymptomatic family members.8
Table 1. Overview of the genes in CENTOGENE´s MODY panel:
|Gene||OMIM (Gene)||Associated diseases (OMIM)||Inheritance||CentoMD® exclusive variant numbers (++)|
|ABCC8||600509||noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; leucine-sensitive hypoglycemia of infancy; familial hyperinsulinemic hypoglycemia type 1; permanent neonatal diabetes mellitus; transient neonatal diabetes mellitus type 2||AD, AR||34|
|BLK||191305||MODY type 11||AD||15|
|CEL||114840||MODY type 8||AD||38|
|GCK||138079||MODY type 2; noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Hyperinsulinemic hypoglycemia, familial, 3; permanent neonatal diabetes mellitus||AD, AR||36|
|HNF1A||142410||noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Renal carcinoma, chromophobe, somatic; Diabetes mellitus, insulin-dependent-1; MODY type 3||AD, AR||21|
|HNF1B||189907||noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; MODY type 5; Renal carcinoma, chromophobe, somatic||AD||15|
|HNF4A||600281||MODY type 1; noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young||AD||16|
|INS||176730||Diabetes Mellitus, Insulin-Dependent, 2; permanent neonatal diabetes mellitus; MODY type 10||AD, AR||6|
|KCNJ11||600937||noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; familial hyperinsulinemic hypoglycemia type 2; permanent neonatal diabetes mellitus; transient neonatal diabetes mellitus type 3; MODY type 13||AD, AR||6|
|KLF11||603301||MODY type 7||10|
|NEUROD1||601724||noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; MODY type 6||AD||4|
|PAX4||167413||noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Maturity-onset diabetes of the young, type IX||AD, AR||10|
|PDX1||600733||noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Pancreatic Agenesis, Congenital; MODY type 4||AD, AR||12|
|ZFP57||612192||Diabetes mellitus, transient neonatal, 1||8|
AD autosomal dominant; AR autosomal recessive; XL R X-linked recessive