An estimated 5% of all cases of diabetes mellitus in the US are due to autosomal dominant loss-of-function mutations in any one of at least six different genes (1). Such autosomal dominant diabetes is generally known as MODY, or maturity-onset diabetes of the young, because differential diagnosis based on clinical presentation is only possible in young, non-obese individuals. However, MODY can occur at any age and is caused by a limited capacity of the pancreas to release insulin, rather than by the insulin resistance typical of type 2 diabetes (1, 2).
Treatment and clinical outlook for MODY depends on the exact genetic cause and may differ greatly from those of type 1 and type 2 diabetes. While one subtype (MODY2) can generally be managed by diet and exercise alone, others (MODY1, 3, and 4) are highly responsive to sulfonylurea therapy; yet another (MODY5) may require treatment for multiple organ abnormalities.
Genetic testing for MODY helps diagnose the exact subtype in about 85% of all cases (2), enabling the physician to select the most appropriate treatment. Among family members of MODY patients, genetic testing can identify asymptomatic individuals who harbor a MODY-associated mutation and are therefore likely to develop diabetes.
Types and Causes of MODY
| MODY Subtype | Affected Gene | Affected Protein | Prevalence in the US and Europe |
| MODY1* | HNF4A** | hepatocyte nuclear factor 4 α | uncommon |
| MODY2* | GCK** | glucokinase | common |
| MODY3* | TCF1** | hepatic nuclear factor 1 α | most common |
| MODY4* | IPF1** | insulin promotor factor 1 | uncommon |
| MODY5* | TCF2** | hepatic nuclear factor 1 ß | uncommon |
| MODY6* | NEUROD1** | Neurogenic differentiation factor 1 | very rare |
** click on gene name for direct link to NCBI "Entrez Gene" website
MODY2
Clinical Presentation of MODY
All types of MODY are characterized by non-ketotic hyperglycemia, which is often diagnosed during the second or third decade of life, but can occur at any age. MODY is not necessarily associated with obesity; however, presence of obesity can lower the age of onset, since obesity-related insulin resistance raises insulin requirements. Except for MODY2, all types of MODY are characterized by glucose intolerance and progressive ß-cell failure and can lead to the long-term complications typical of diabetes. MODY2 is associated with persistent mild fasting hyperglycemia and only mild glucose intolerance, which do not progress in severity with time and rarely lead to long-term problems. The exact clinical presentation of MODY may vary depending on the underlying genetic cause.
MODY2 is often diagnosed in association with pregnancy (gestational diabetes), obesity, or old age.
MODY3-associated defects in HNF-1α also lead to decreased renal re-absorption of glucose, resulting in glycosuria.
MODY5-associated defects in HNF-1ß have been linked to renal cysts and other abnormalities in renal development, which can lead to chronic renal insufficiency and kidney failure. In addition, internal genital abnormalities and atrophy of the pancreas, leading to exocrine as well as endocrine pancreatic deficiency, have been observed.
Diagnosis of MODY
MODY can be distinguished from type 1 diabetes by the absence of diabetes antibodies (anti-insulin, anti-islet, anti-GAD). In non-obese, but not in obese individuals, MODY can be differentiated from type 2 diabetes by the absence of insulin resistance. MODY2 can be discriminated from the other types of MODY because it leads to only mild glucose intolerance. Presence of renal disease can be indicative of MODY5, but may also be a sign of diabetic nephropathy.
Genetic testing can establish a firm diagnosis of MODY in patients of any age, based on a single blood draw. Genetic testing is also useful for family screening, as it can detect mutations associated with MODY in individuals who are not yet diabetic. In these individuals, increased vigilance and changes in lifestyle may help to prevent the persistence of unrecognized hyperglycemia.
Figure 1: An approach to diagnosing MODY
Treatment of MODY
MODY2 generally has an excellent prognosis. It is non-progressive, rarely requires drug or insulin therapy, and can usually be managed by exercise and diet alone.
MODY5 may require several different treatments because it leads to multiple organ abnormalities (12).
In overweight patients, who are likely to show insulin resistance, weight loss will improve hyperglycemia due to MODY.
Genetics of MODY
Homozygosity for MODY2-linked loss-of-function mutations in GCK or MODY4-linked loss-of-function mutations in IPF1 does not lead to MODY, but to the more severe neonatal diabetes mellitus (14,15).
Genetic Testing for MODY
The Monogenic Diabetes (MODY) Evaluation allows identification of genetic defects linked to MODY1, MODY2, MODY3, MODY4, or MODY5 and can detect about 85% of all cases of MODY in the US population. Genetic testing for MODY should be considered in all non-ketotic, non-obese diabetes patients, regardless of age, as well as in all young or middle-aged non-ketotic, obese diabetes patients. In addition, the Monogenic Diabetes (MODY) Evaluation permits family screening for MODY.
How Is Genetic Testing for MODY Performed?
DNA for sequencing is obtained from leukocytes present in a small blood sample. The coding sequences of HNF4A, GCK, TCF1, IPF1, and TCF2 are amplified in a highly specific manner through a polymerase chain reaction (PCR), and all PCR products are fully sequenced. Sequencing results are interpreted, and a detailed result report is sent to the patient's physician.
Ordering testing Monogenic Diabetes (MODY), click here.
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