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.

Keywords: metabolism; metabolic diseases; endocrinology; genetics; diabetes; monogenic inheritance; polygenic inheritance

Figure 1.

Intracellular energy metabolism. Both glycolysis and the beta‐oxidation of free fatty acids are generating acetyl‐CoA, which enters the Krebs cycle. If insulin is lacking, acetyl‐CoA is produced in large amounts by beta‐oxidation of fatty acids. Two molecules of acetyl‐CoA can generate acetoacetate (ketones). GT: glucose transporter; HK: hexokinase; PFK: phosphofruktokinase; LDH: lactate dehydrogenase; PDH: pyruvate dehydrogenase; ATP: adenosine triphosphate; and FFA: free fatty acids.

Figure 2.

Genes in the vicinity of genetic loci associated with increased risk for type 2 diabetes.

Figure 3.

Effects of risk alleles on insulin secretion and sensitivity. Changes in diabetes‐related phenotypes over time for 380 individuals from the Botnia cohort at high genetic risk for diabetes (more than 12 risk alleles; red) and for 471 individuals at low risk (less than 8 risk alleles; blue). Upper left shows similar increases in BMI in individuals at high and low risk. Upper right shows that insulin sensitivity deteriorates to the same extent over time in the two groups. Lower left demonstrates increased corrected insulin response over time. The increase is larger in individuals at low genetic risk. Lower right shows a decreased beta‐cell function (disposition index) over time in subjects at high risk compared to those at low risk. Among individuals at low risk, the disposition index increased somewhat to compensate for enhanced insulin resistance. Bars denote standard errors. (Reproduced with permission from Lyssenko et al., , © Massachusetts Medical Society.)

Figure 4.

Enzymatic defects in steroid synthesis.

Figure 5.

Metabolism of phenylalanine and tyrosine.

Figure 6.

Urea cycle: (1) carbamyl phosphate synthetase; (2) ornithine carbamyl transferase; (3) argininosuccinate synthetase; (4) arginonsuccinase; and (5) arginase.

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Groop, Leif, and Rosengren, Anders(Dec 2011) Metabolism: Hereditary Errors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005512.pub2]