Inborn errors of metabolism. Vitamin-responsive genetic disease

The several ways in which vitamin administration may bring about a biochemical response in genetic abnormalities have been discussed. Two major interrelated lessons emerge from what we now know about vitamin-responsive genetic disease. First, it is possible to enhance metabolite flow through partially deficient reactions by suitable manipulation of the environment in which a fixed amount of enzyme functions or by changing the concentration of the enzyme itself. The latter approach may be the most versatile in the long run since there may be agents other than vitamins which increase enzyme concentrations. A striking example of such an effect in mammals is furnished by the work of Pitot and his collaborators, who by administration of casein hydrolysate to rats, increased threonine dehydratase activity several hundred-fold (Peraino and Pitot, 1964) by increasing the rate of enzyme synthesis (Jost, Khairallah, and Pitot, 1968). Other means of enhancing enzyme activities, ranging from tissue transplantation to transfer of genetic material, have been discussed elsewhere (for example, see Brady, 1973). These procedures will not be discussed here, other than to mention a recent report (Mukherjee and Krasner, 1973) who transferred several small plugs of liver tissue (approximately 5% of the liver) from normal rats to the livers of rats genetically deficient in bilirubin uridine diphosphate glucuronyltransferase activity. Twelve weeks later the specific activity of glucuronyltransferase had risen in the livers of the recipient rats to 6-23% of normal, and the serum bilirubin of these rats, which had initially been elevated, had fallen to close to, or within, the normal range. Thus liver grafts between suitably matched individuals, may in the near future, become a means of increasing hepatic activities of deficient enzymes to extents which are therapeutically meaningful. The second lesson to be learned from the review presented here is that enhancement of enzyme activity may be therapeutically beneficial even though the increase is small and the activity attained is still reduced relative to normal. It will be well to bear this in mind in any attempts to treat inborn errors of metabolism.