Monogenic diabetes is a group of rare disorders occurring as a result of single gene mutations; the mutation most commonly reduces the body’s capacity for normal insulin production. More than 20 different genes have been linked to monogenic diabetes.81 Types of monogenic diabetes include neonatal diabetes, with onset during the first year of life, and maturity onset diabetes of the young (MODY), which occurs in children and adolescents. MODY can be misdiagnosed as type 1 or type 2 diabetes.82
Few studies have explored the epidemiology of monogenic diabetes (Table 29), and no thorough studies have been completed in the US.
|Norwegian Childhood Diabetes Registry, 2002-2012||Children 0-14 years of age with newly diagnosed diabetes in Norway||3.1 per 100,000||Irgens et al. 20136|
|Referral data for genetic testing, 1996-2009||UK children||10.8 per 100,000||Shields et al. 20107|
The UK study found that fewer than 20% of MODY cases are diagnosed by molecular testing.7
Given these numbers, and the similarity in ethnic backgrounds between the US and UK populations, monogenic diabetes prevalence in the US is likely approximately 50 to 100 cases per year. Monogenic diabetes can be accurately diagnosed by DNA sequencing, but monogenic diabetes often remains undiagnoseds.83
Rates of diagnosis of monogenic diabetes are increasing among those with clinical features of type 1 or type 2 diabetes as genetic studies become available, but population-based data on incidence and prevalence show wide variation due to lack of standardisation in the studies.84
Two international studies show results ranging from 2.5%-4.2% of children with diabetes (Table 30).
|Poland||4.2– 4.6/100,000 , or 3.1%–4.2% of children with diabetes||Fendler et al. 201282|
|New Zealand||~2.5% of children with diabetes||Wheeler et al. 201385|
There is little information available on life expectancy and mortality in individuals with monogenic diabetes. However, an increased risk of cardiovascular mortality at younger ages was found among family members with HNF1A mutations in comparison with familial control subjects. 66% of mutation carriers died from a cardiovascular-related illness compared with 43% of control subjects.86
Extended genetic testing of young adult-onset diabetes patients revealed that about 0.8% of those diagnosed with type 1 diabetes had HNF1A mutations and 4% of those diagnosed with type 2 diabetes had HNF1A, HNF4A, or GCK mutations. This genetic testing approach identified twice the number of MODY cases than that of current clinical practice, suggesting a possible need to incorporate molecular testing into existing diagnosis protocols.87
In neonates with monogenic diabetes, early sulfonylurea therapy can improve glycemic control and potentially improve neurodevelopmental outcomes. In an observational study of 154 subjects with neonatal diabetes within the University of Chicago Monogenic Diabetes Registry, 73 (47%) had a mutation in KCNJ11 or ABCC8. In 9 of the children in the trial, an empiric sulfonylurea trial was initiated within 28 days of diabetes diagnosis. A genetic cause was subsequently found in 8 cases, and insulin was discontinued within 14 days of sulfonylurea initiation in all of these cases. 88 A subsequent study found that earlier age at initiation of sulfonylurea therapy was associated with improved therapeutic response.89 Sulfonylurea therapy appears to be safe and often successful in neonatal diabetes patients before genetic testing results are available; however, larger numbers of cases must be studied. In a case study of a Chinese girl whose treatment of persistent hyperglycemia with insulin was not effective, long-term glycemic control was achieved with sulfonylurea therapy initiated at the age of 3 years. Fewer episodes of hypoglycemia occurred on sulfonylurea than on insulin therapy.90 Furthermore, in adults with monogenic diabetes who were misdiagnosed and treated with insulin for decades, sulfonylureas have been shown to restore endogenous insulin secretion.91