This is a historical term for biochemical genetic defects. Generally mutation in single genes blocks or changes the metabolic pathways at a single specific step. The photograph shows the response of an auxotrophic mutant of Arabidopsis unable to synthesize the pyrimidine moiety of thiamine. On basal medium it germinates but fails to grow; its growth is fully restored on the appropriate pyrimidine, PY and thiamine, TH. A slight growth is also seen on the thiazole moiety of thiamine TZ (Rédei, 1965 unpublished). The consequences of the mutation may be alleviated either by providing the missing compound or by avoiding the supply of the accumulated precursors that cannot be further processed because of the defect in the enzymatic step. Although a single enzymatic step is often involved, the lack or overproduction of a metabolite can affect more than a single metabolic process in complex diseases (see Fig. I15). Inborn errors of metabolism include defects in quantitative genes and other intrauterine lesions and infections. In plants auxotrophic mutations are very rare; the number of identified metabolic defects due to genetic causes (mutation, deletion, insertion, rearrangement) is increasing in humans. Defects in humans may be caused by the absence or decrease of a metabolite, the adverse effect of accumulated precursor(s), overproduction, faulty regulation of a pathway and/or adverse effects on more than one pathway in a metabolic network. The defect can be cell autonomous, i.e., affects only a particular cell or it may be non-autonomous and its consequence spreads to other tissues either by diffusion or secretion and active transport. The presence of a metabolic defect can be discovered by simple means; Garrod identified alkaptonuria by the brown spots on the diapers of newborns. The nature of the defect can be identified by chemical analysis, the use of isotope or fluorochrome labeled metabolic tracers, enzymes assays of body fluids or tissues, by microarray hybridization, two-dimensional electrophoresis or mass spectrometry, nuclear magnetic resonance spectrometry (NMR) and other tools of proteomics. The treatment of the disease varies according to its nature. Phenylketonuria or fructose intolerance requires metabolic restrictions, in Wilson disease avoidance of copper helps. In other cases dietary supplements can help, e.g., consuming starch in glycogen storage diseases or taking biotin in biotidinase deficiency or avoiding fasting in some forms of fatty acid metabolism disorders. In Gaucher disease enzyme replacement, in Hurler’s syndrome enzyme replacement and bone marrow transplantation are used. For several diseases somatic gene therapy is available. The implantation of embryonic stem cells may be helpful for a range of human lesions and disease. Avoidance of several diseases is possible by genetic counseling, screening for carriers and neonatal screening. Screening newborns for inborn metabolic errors by tandem mass spectrometry revealed a frequency of 1.57 × 10−4 (Wilcken B et al 2003 New England J Med 348:2304). auxotrophy, one gene — one enzyme theorem, biochemical genetics; Garrod AE 1902 Lancet 2:1616; see individual entries for diseases and other terms; excellent review: Lanpher B et al 2006 Nature Rev Genet 7:449.
