Adolescents at Risk for MODY3 Diabetes Prefer Genetic Testing Before Adulthood

Abstract

Mutations in the hepatocyte nuclear factor (HNF)-1α gene cause an autosomally, dominantly inherited form of diabetes, maturity-onset diabetes of the young (MODY) type 3, which is characterized by poor insulin secretion in response to glucose together with good sensitivity to insulin and sulfonylurea medication and low renal threshold for glucose (1). The lifetime risk of diabetes may be as high as 95% for individuals carrying the most common Pro291fsinsC mutation. Glucose tolerance deteriorates in most cases during the pubertal years (2–5). However, because of fasting normoglycemia, clinical diagnosis is often delayed despite high postprandial glucose concentrations and an increased A1C value. Diabetes complications are common, and proliferative retinopathy has been detected already at diagnosis of diabetes in a 19-year-old carrier (6). On the other hand, while the incidence of diabetes among mutation carriers steeply increases in puberty, at least 20% remain nondiabetic until their 30s (2,4,5). Abnormal glucose tolerance in subjects at risk for MODY3 can be diagnosed with an oral glucose tolerance test. Urine glucose analysis after a large oral glucose load has also been advocated as a noninvasive screening tool in young children (7). Although an aberrant result from these tests has diagnostic value for diabetes and a certain predictive value in identification of probable carriers, they are not specific for MODY, and a normal result cannot exclude future risk. A genetic test seems to be warranted before adulthood, either to confirm carrier status in these prescreened subjects or in all at-risk subjects. A predictive test, whether a clinical or specific gene …