Metabolism: Hereditary Errors

Abstract

Inherited metabolic diseases can be both monogenic and polygenic. The monogenic forms are usually rare and are characterised by early onset. Examples include maturity‐onset diabetes of the young (MODY), phenylketonuria and glycogen storage diseases. The polygenic metabolic diseases result from a complex interaction of genetic variants and environmental factors. Type 1 and type 2 diabetes are typical examples. Important progress has been made in unravelling the genetic background of the common forms of diabetes. For type 2 diabetes, close to 50 loci have been consistently associated with increased disease risk. The findings have provided novel pathophysiological insights and suggest that type 2 diabetes occurs when the pancreatic islets fail to compensate for the increased insulin demands in states of insulin resistance. The exact disease mechanisms associated with the genetic variants are however in most cases not completely known. Novel approaches, including deoxyribonucleic acid (DNA) sequencing, are likely to give a more comprehensive picture of the genetic background. Key Concepts: Genetic factors play an important role in most metabolic disorders. Monogenic metabolic diseases such as MODY have high penetrance and early onset. The common metabolic disorders have typically a polygenic inheritance. Type 1 and type 2 diabetes have a complex pathogenesis and result from a combination of environmental and genetic factors. Genome‐wide association studies have identified a large number of disease susceptibility variants for type 2 diabetes. Identification of genetic risk variants is invaluable for improving the pathophysiological understanding.