Metabolic diseases (human)

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Human metabolic diseases are primarily caused by single gene alleles that code for enzymes important in metabolic pathways. In many of the metabolic diseases, the chemical substrate of the missing or defective enzyme builds up and is excreted out of the body, often by the kidneys and so into the urine. The names of these diseases, like alkaptonuria or phenylketonuria (PKU) - refer to the excess waste chemical found in the urine (the sufix -uria meaning "in the urine), or "maple syrup disease" refer to an abnormal odor detected in the affected persons' urine. In other cases, the abnormal quantity of an intermediate in metabolism is not excreted out of the body, but stays there - sometimes building up in the intracellular organelles called lysosomes. That set of diseases, the lysosomal storage diseases, become more evident with age.

These diseases are ordinarily life-long and incurable, but some of them can be managed such that the person who has such a metabolic defect may remain well if strict modifications in diet are followed. For example, in phenylketonuria, it is the amino acids that cannot be broken down and if the lack of the enzyme is picked up in the newborn nursery, and the baby is kept strictly on a free diet, then the signs and symptoms of the disease will never develop, or at least be minimized. Cures for some of these diseases have been explored through gene therapy and organ transplant. Accordingly, in many countries, newborn infants are screened for these diseases so that, if present, modifications in diet may start immediately. Since the metaboloc diseases are (generally) inherited, those individual who have them, or who have biological children who have them, are advised to seek genetic counseling to learn the risks of passing the disease, and how to best manage the metabolic defects in those who have them.

Metabolic diseases in the history of medicine

See historical review.[1]

In 1902, Archibald E Garrod proposed that the disease alcaptonuria had a recessive mode of transmission. In this disease, affected individuals have black urine, due to the presence of a compound called homogentisic acid. Dr.Garrod had mapped out pedigrees of affected individuals and showed that the occurrence of the disease followed Gregor Mendel's principles of heredity. This was the first report of a connection had been between a human disease and Mendel's laws of inheritance. Garrod conceived of this abnormality as an "inborn error of metabolism". He correctly discovered that those individuals with alcaptonuria lacked a fully active enzyme that ordinarily broke down the benzene ring of homogentisic acid. He also, correctly, postulated that this particular inborn error of metabolism was only one of very many. Further, he connected the variations in chemical metabolism with resistance to disease and fitness to adapt to a given diet and environment, and so understood these variations as a mark of individual differences that related to natural selection.[2]

Initially, although the inherited basis of these diseases was always kept in mind in terms of diagnosis, a family history being of particular importance, the clinical physician and human physiologist considered the biochemical aspects of the illness. Although it was clear to these early physiologists that enzymes were lacking for steps in metabolism, it the fact that enzymes were proteins whose activities were dependant upon their amino acid sequence would not be clear for another 40 years. With the discovery of DNA, in 1953, and understanding that DNA made up genes passed through generations, and that these genes coded for proteins, another level of understanding of metabolic diseases came to pass. With the explosion of biotechnology based on molecular genetics, the genes themselves now receive the primary focus of medical research.

Current care of patients with metabolic diseases

Human geneticists


  1. Urban M. (1999) Early observations of genetic diseases. [Historical Article. Journal Article] The Lancet. Volume 354, Supplement 4, Page SIV21 PMID 10691432
  2. Garrod AE (1923) Inborn Errors of Metabolism. 2nd Edition. Henry Frowde and Hodder & Stoughton, The Lancet Building, London.