Monogenic Forms of Diabetes

Types 1 and 2 diabetes have multiple and complex genetic influences that interact with environmental triggers, such as viral infections or nutritional excesses, to result in their respective phenotypes: young, lean, and insulin-dependence for type 1 diabetes patients or older, overweight, and often manageable by lifestyle interventions and oral medications for type 2 diabetes patients. A small subset of patients, comprising ~2%–3% of all those diagnosed with diabetes, may have characteristics of either type 1 or type 2 diabetes but have single gene defects that interfere with insulin production, secretion, or action, resulting in clinical diabetes. These types of diabetes are known as MODY, originally defined as maturity-onset diabetes of youth, and severe early-onset forms, such as neonatal diabetes mellitus (NDM). Defects in genes involved in adipocyte development, differentiation, and death pathways cause lipodystrophy syndromes, which are also associated with insulin resistance and diabetes. Although these syndromes are considered rare, more awareness of these disorders and increased availability of genetic testing in clinical and research laboratories, as well as growing use of next generation, whole genome, or exome sequencing for clinically challenging phenotypes, are resulting in increased recognition. A correct diagnosis of MODY, NDM, or lipodystrophy syndromes has profound implications for treatment, genetic counseling, and prognosis. This chapter summarizes the clinical findings, genetic basis, and prognosis for the more common forms of these entities. MODY typically appears before age 25–35 years, in those with a strong family history affecting two to three successive generations, occurs in all races, affects both males and females, and is often misdiagnosed as type 1 or type 2 diabetes. Autoantibodies to islet components are absent, whereas residual insulin secretion is retained, as demonstrated by the concentration of C-peptide in serum at diagnosis. Patients who present with these features should be considered for genetic testing. Three genetic defects (MODY3, MODY2, and MODY1, in order of frequency) comprise ≥85% of all known forms of these entities. MODY3 (more so) and MODY1 patients often respond to oral sulfonylureas, especially at younger ages, and may not require insulin injections. MODY2 patients generally do not require any medication, except during pregnancy to protect the fetus from hyperglycemia, which may cause either macrosomia or small birth weight depending on whether both mother and child have the mutation or not. A correct molecular diagnosis is cost-effective in savings from avoiding insulin, offers precise genetic counseling for a 50% chance of occurrence in each offspring of an affected individual, and generally has a substantially better prognosis for avoidance of the long-term complications of type 1 or type 2 diabetes. NDM presents as transient or permanent diabetes in the newborn, may be corrected by sulfonylurea medication in specific gene mutations, or may be associated with specific syndromes of congenital malformations. Some forms represent familial inheritance, with less severe defects in the same genes masquerading as type 2 diabetes in first-degree relatives, while many represent spontaneous new mutations. NDM is rare, with an estimated incidence of ~1:100,000 live births; the incidence of NDM is significantly higher in populations with high rates of consanguinity. MODY and NDM gene defects have been associated with “typical” type 1 and type 2 diabetes clinical presentation; thus, these single gene defects play an important role in the global burden of diabetes. The autosomal recessive congenital generalized lipodystrophy (CGL) and autosomal dominant familial partial lipodystrophy (FPL) are the two most common types of genetic lipodystrophies. Patients with CGL present with near total lack of body fat, while those with FPL have variable loss of fat, mainly from the extremities. Both disorders present with severe insulin resistance, premature diabetes, hypertriglyceridemia, and hepatic steatosis. Mutations in , and have been reported in CGL and in , and in FPL. Management of diabetes in patients with genetic lipodystrophies involves low-fat diet and high doses of insulin and other antihyperglycemic agents. Metreleptin replacement therapy improves glycemic control, especially in patients with generalized lipodystrophies, and is approved for this specific use in the United States.