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BRIEF PROPOSAL HYPOASCORBEMIA, THE GENETIC DISEASE CAUSING THE HUMAN REQUIREMENT FOR EXOGENOUS ASCORBIC ACID IRWIN STONE* In the course ofhuman history there have been many theories on the cause ofscurvy. The dominating hypothesis for the past half-century postulates that scurvy is the result ofa nutritional disorder due to the lack ofthe trace nutrient, vitamin C (ascorbic acid), in foodstuffs. The work on the mammalian biosynthesis of ascorbic acid [1-3] during the last decade indicates that this "vitamin" theory b an oversimplification ofpresently available evidence. Like all oversimplifications, it can lead to misinterpretations and false impressions. It is proposed that the biochemical lesion, which sets man apart from nearly all other mammals and produces the human need for exogenous sources of ascorbic acid, is the absence ofthe active enzyme, L-gulonolactone oxidase, from the human liver [4]. The lack ofthis enzyme, the final one in the series for converting glucose to ascorbic acid, completely blocks the endogenous synthesis of this vital substance in man. A defect in the gene controlling the synthesis of this enzyme produces an inactive enzyme (or no enzyme at all) [5]. Presumably the whole human race and some of the other primates carry this defective gene [6]. The probable origin ofthis genetic defect is a conditional lethal mutation [7] in a remote primate ancestor ofman. Since then, all progenies ofthis mutated animal have been unable to produce ascorbic acid in their livers. Their survival depends on their obtaining ascorbic acid in their food. Because of this enforced reliance on foodstuffs for the traces of ascorbic acid needed for survival and the avoidance offrank clinical scurvy, this condition came to be regarded as a nutritional disorder. Instead, it is a true genetic-disease process, due to the inherited lack of a specific vital liver enzyme, L-gulonolactone oxidase, resulting in a clear-cut typical enzymic dysfunction which causes an "inborn error of metabolism." Thus, it is similar in etiology to other now-recognized genetic diseases in which a missing enzyme causes the pathologic syndrome—phenylketonuria, galactosemia, and alkaptonuria, to name only a few. This genetic disease has been named "hypoascorbemia" because of the low levels of blood ascorbic acid which are pathognomonic ofthis condition [8]. Scurvy no longer should be considered a specific disease entity, merely the extreme sequela ofhypoascorbemia . All degrees ofhypoascorbemia can exist, from the totally "uncorrected," frank clinical scurvy to the symptom-free, non-clinical state approaching "full correction." * 208 Winchester Avenue, Staten Island, New York 10312. I33 "Full correction" of this genetic disease is defined as supplying to the afflicted individual ascorbic acid in amounts the liver would be synthesizing had this mutation not occurred. It is assumed that the ascorbic acid requirements in man's physiology are not much different from those ofother mammals capable ofcarrying out this synthesis. Thus, the required amounts would fluctuate because ascorbic acid production in the mammals is regulated in accord with the superimposed stresses. Based on the scant data on mammalian synthesis, presently available only for the rat, a 70-kg. individual would produce 1.8 gm. [9] to 4.0 gm. [10] ofascorbic acid per day in the unstressed condition. Under stress, up to 15.2 gm. [11] could be produced daily. When this estimated daily production of many grams per day is contrasted with the recommended adult daily intake of 70 mg., considered as adequate under the "vitamin" hypothesis [12], the disparity is striking. Since orally administered ascorbic acid is rapidly absorbed and assimilated, "full correction " may be safely established by ingestion ofthe required amounts ofascorbic acid, preferably in solution, in several spaced doses throughout the day. While the "vitamin" hypothesis is deeply entrenched in present-day tradition, it fits inadequately into current knowledge. Because ofthe implied low dosage levels incident to any "vitamin" hypothesis, this theory tends to inhibit clear and critical thinking as to proper dosage levels of ascorbic acid used throughout much of the clinical research conducted in the past thirty years for the therapy ofdiseases other than scurvy. Dosages measured in milligrams ofascorbic acid per day were employed without notable success (many grams per day may have given more clear-cut therapeutic results). This geneticdisease concept provides the necessary...