Metabolic diseases (human)

Human metabolic diseases are primarily caused by single gene alleles that code for enzymes important in metabolic pathways. These diseases areordinarily life-long and incurable, but many 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. Cures for some of these diseases have been explored through gene therapy and organ transplant. Accordingly, in amny 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.

In 1902, Archibald E Garrod proposed that the disease alcaptonuria had a recessive mode of transmission. Dr.Garrod had mapped out pedigrees of affected individuals and showed that the occurance of the disease followed Gregor Mendel's principles. 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 acticve enzyme that ordinarily broke down the the benzene ring of homogentisic acid. He also, correctly, postuated 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.

Initially, although the inherited basis of these diseases was always kept in mind in terms of diagnosis, a family history being of particluar 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 acidf 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.

References

Urban M. Early observations of genetic diseases. [Historical Article. Journal Article] Lancet. 354 Suppl:SIV21, 1999 Dec. UI: 10691432