Metabolism: Hereditary Errors


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.



Altshuler D, Hirschhorn JN, Klannemark M et al. (2000) The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nature Genetics 26: 76–80.

Barrett JC, Clayton DG, Concannon P et al. (2009) Genome‐wide association study and meta‐analysis find that over 40 loci affect risk of type 1 diabetes. Nature Genetics 41: 703–707.

Chandrasekhharappa SC, Guru SC, Manickam P et al. (1997) Positional cloning of the gene for multiple endocrine neoplasia type 1. Science 276: 404–406.

Dina C, Meyre D, Gallina S et al. (2007) Variation in FTO contributes to childhood obesity and severe adult obesity. Nature Genetics 39: 724–726.

Enattah NS, Sahi T, Savilahti E et al. (2002) Identification of a variant associated with adult‐type hypolactasia. Nature Genetics 30: 233–237.

Frayling TM, Timpson NJ, Weedon MN et al. (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316: 889–894 (Washington, DC).

Gaulton K, Nammo T, Pasquali K et al. (2010) A map of open chromatin in human pancreatic islets. Nature Genetics 42: 255–59.

Glans F, Elgzyri T, Shaat N et al. (2008) Immigrants from the Middle‐East have a different form of Type 2 diabetes compared with Swedish patients. Diabetic Medicine 25: 303–07.

Gloyn AL, Pearson ER, Antcliff JF et al. (2004) Activating mutations in the gene encoding the ATP‐sensitive potassium‐channel subunit Kir6.2 and permanent neonatal diabetes. New England Journal of Medicine 350: 1838–1849.

Goldstein JL and Brown MS (1979) The LDL receptor locus and genetics of familial hypercholesterolemia. Annual Review of Genetics 113: 259–289.

Grant SF, Thorleifsson G, Reynisdottir I et al. (2006) Variant of transcription factor 7‐like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nature Genetics 38: 320–323.

Grarup N, Andersen G, Krarup NT et al. (2008) Association testing of novel type 2 diabetes risk alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 loci with insulin release, insulin sensitivity, and obesity in a population‐based sample of 4,516 glucose‐tolerant middle‐aged Danes. Diabetes 57: 2534–2540.

Groop L, Forsblom C, Lehtovirta M et al. (1996) Metabolic consequences of a family history of NIDDM (the Botnia study): evidence for sex‐specific parental effects. Diabetes 45: 1585–1593.

Heshmati HM and Hofbauer LC (1997) Multiple endocrine neoplasia type 2: recent progress in diagnosis and management. European Journal of Endocrinology 137: 572–578.

Kadowaki T, Kadowaki H, Mori Y et al. (1994) A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. New England Journal of Medicine 330: 962–968.

Köbberling J and Tillil H (1982) Empirical risk figures for first‐degree relatives of non‐insulin dependent diabetics. In: Köbberling J and Tattersall R (eds) The Genetics of Diabetes Mellitus, pp. 201–209. London: Academic Press.

Lyssenko V, Jonsson A, Almgren P et al. (2008) Clinical risk factors, DNA variants, and the development of type 2 diabetes. New England Journal of Medicine 359: 2220–2232.

Lyssenko V, Lupi R, Marchetti P et al. (2007) Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. Journal of Clinical Investigation 117: 2155–2163.

Lyssenko V, Nagorny CL, Erdos MR et al. (2009) Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nature Genetics 41: 82–88.

Miller WL (1994) Genetics, diagnosis and management or 21‐hydroxylase deficiency. Journal of Clinical Endocrinology and Metabolism 78: 241–246.

Orho M, Bosshard NU, Buist NRM et al. (1998) Mutations in the liver glycogen synthase, gene in children with hypoeglycemia due to glycogen storage disease type 0. Journal of Clinical Investigation 102: 507–515.

Parma J, Duprez L, Van Sande J et al. (1993) Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenoma. Nature 365: 649–651.

Pearce SHS and Brown EM (1996) Disorders of calcium ion sensing. Journal of Endocrinology and Metabolism 81: 2030–2035.

Rosengren AH, Jokubka R, Tojjar D et al. (2010) Overexpression of alpha2A‐adrenergic receptors contributes to type 2 diabetes. Science 327: 217–220 (Washington, DC).

Saxena R, Voight BF, Lyssenko V et al. (2007) Genome‐wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316: 1331–1336 (Washington, DC).

Sladek R, Rocheleau G, Rung J et al. (2007) A genome‐wide association study identifies novel risk loci for type 2 diabetes. Nature 445: 881–885.

Smyth DJ, Cooper JD, Bailey R et al. (2006) A genome‐wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon‐induced helicase (IFIH1) region. Nature Genetics 38: 617–619.

Voight BF, Scott LJ, Steinthorsdottir V et al. (2010) Twelve type 2 diabetes susceptibility loci identified through large‐scale association analysis. Nature Genetics 42: 579–589.

Yamagata K, Oda N, Kaisaki P et al. (1996) Mutations in the hepatocyte nuclear factor‐1α gene in maturity‐onset diabetes of the young (MODY3). Nature 384: 455–458.

Further Reading

Ahlqvist E, Ahluwalia T and Groop L (2011) Genetics of type 2 diabetes. Clinical Chemistry 57: 241–254.

Angelin B (2002) Metabolic disorders. In: Wass AH and Shalet SM (eds) Oxford Textbook of Endocrinology and Diabetes. Oxford, UK/New York, NY: Oxford University Press.

Howell RR, Williams JC (1983) The glycogen storage disease. In: Stanbury JB, Wyngaarden JB and Fredrickson DS et al. (eds) The Metabolic Basis of Inherited Disease, 5th edn. New York, NY: McGraw‐Hill.

Ling C and Groop L (2009) Epigenetics: a molecular link between environmental factors and type 2 diabetes. Diabetes 58: 2718–2725.

McCarthy M (2010) Genomics, type 2 diabetes and obesity. New England Journal of Medicine 363: 2339–2350.

New MI, Crawford C and Wilson RC (1996) Genetic disorders of the adrenal steroidogenic enzymes. In: Emery AEH and Rimoin D (eds) Principles and Practice of Medical Genetics, 3rd edn, pp. 1441–1476. New York, NY: Churchill Livingstone.

Owen K and Hattersley AT (2001) Maturity‐onset diabetes of the young: from clinical description to molecular genetic characterization. Best Practice and Research. Clinical Endocrinology and Metabolism 15: 309–323.

Pociot F, Alkokar B, Concannon P et al. (2010) Genetics of type 1 diabetes. What next? Diabetes 59: 1561–1571.

Refetoff S, Weiss RE and Usala SJ (1993) The syndromes of resistance to thyroid hormone. Endocrine Reviews 14: 348–399.

Roe CR, Coates PM (1997) Disorders of mitochondrial fatty acid oxidation. In: Scriver CR, Beaudet AL and Sly WS et al. (eds) The Metabolic and Molecular Basis of Inherited Disease, 7th edn. New York, NY: McGraw‐Hill.

Thakker RV (1998) Multiple endocrine neoplasia – syndromes of the twentieth century. Journal of Clinical Endocrinology and Metabolism 83: 2617–2620.

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