Genetics and pathophysiology of neonatal diabetes mellitus

Neonatal diabetes mellitus (NDM) is the term commonly used to describe diabetes with onset before 6 months‐of‐age. It occurs in approximately one out of every 100,000–300,000 live births. Although this term encompasses diabetes of any etiology, it is recognized that NDM diagnosed before 6 months‐of‐age is most often monogenic in nature. Clinically, NDM subgroups include transient (TNDM) and permanent NDM (PNDM), as well as syndromic cases of NDM. TNDM often develops within the first few weeks of life and remits by a few months of age. However, relapse occurs in 50% of cases, typically in adolescence or adulthood. TNDM is most frequently caused by abnormalities in the imprinted region of chromosome 6q24, leading to overexpression of paternally derived genes. Mutations in KCNJ11 and ABCC8, encoding the two subunits of the adenosine triphosphate‐sensitive potassium channel on the β‐cell membrane, can cause TNDM, but more often result in PNDM. NDM as a result of mutations in KCNJ11 and ABCC8 often responds to sulfonylureas, allowing transition from insulin therapy. Mutations in other genes important to β‐cell function and regulation, and in the insulin gene itself, also cause NDM. In 40% of NDM cases, the genetic cause remains unknown. Correctly identifying monogenic NDM has important implications for appropriate treatment, expected disease course and associated conditions, and genetic testing for at‐risk family members. Early recognition of monogenic NDM allows for the implementation of appropriate therapy, leading to improved outcomes and potential societal cost savings. (J Diabetes Invest, doi:10.1111/j.2040‐1124.2011.00106.x, 2011)