Medical genetics / edited by Victor A. McKusick and Robert Claiborne.

Date:
[1973]
Catalogue details

Licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

Credit: Medical genetics / edited by Victor A. McKusick and Robert Claiborne. Source: Wellcome Collection.

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    inherited enzyme defects with Some Genetically Determined Pathologic Alterations p-OH Phenylpyruvic acid Homogentisic acid Maleylacetoacetic acid Phenylpyruvic acid oxidase SLOWED IN SCURVY fuvi HO- // \ -CH2CCOOH II О Excreted in Scurvy (vitamin С deficiency) Homogentisic acid oxidase ALKAPTONURIA HO- W •OH CH2COOH Excreted in Alkaptonuria (blackens cartilage) HO —< \ COOH -C-OH II CHCOOH Transformed and metabolized completely through citric acid cycle This simplified and abridged map of the main metabolic path¬ ways of phenylalanine and tyrosine illustrates how enzyrriatic abnormalities appear to be involved in three genetic diseases (PKU, albinism, and alkaptonuria) and possibly in a vitamin de¬ ficiency state (scurvy). A functional deficit in phenylalanine hydroxylase is responsible for PKU (see page 67). Melanin is a metabolite of tyrosine and the pigment's absence in albinism may be a result of a genetically determined lack of tyrosinase. The excretion of p-OH phenylpyruvic acid in scurvy patients is believed sequential to accumulation of the substrate due to enzy¬ matic inhibition. In alkaptonuria, the missing enzyme is homo¬ gentisic acid oxidase; the result is accumulation of the acid. Color bands indicate the enzymatic abnormalities, resultant substrate derangements, subsequent diseases and their manifestations. the amino acid to the amounts needed for normal gro-wth. The actual criter¬ ion is provided by blood assays, which are held to slightly above the normal phenylalanine level ( about 2 mg% ) to provide a margin for error. The diet also includes extra tyrosine to replace what would normally be provided by phenylalanine oxidation. I know of no conclusive evidence that this is in fact necessary, but the rationale — to keep the body chemistry as near normal as possible in all respects — is certainly sound enough. Despite all we have learned about PKU, including development of a rea¬ sonably effective treatment, we still do not know precisely how its metabolic defects actually damage the body. As already indicated, there is no very persuasive evidence that the low¬ ering of body tyrosine levels is directly harmful, especially since in the nor¬ mal as well as the affected individual much of the tyrosine in the diet is sim¬ ply utilized for its energy content. There is a good deal of evidence, how¬ ever, that both excess phenylalanine and perhaps some of its abnormal metabolites can derange a number of physiologic processes by inhibiting the action of the enzymes that catalyze these processes. It is quite certain, for example, that p к и lowers the body's production of melanin by interfering with one or more of the metabolic steps by which that substance is man¬ ufactured from tyrosine. Untreated PKU patients typically show low mel¬ anin levels in skin, eyes, and hair; their coloration, though never reach¬ ing frank albinism, is noticeably lighter than what would be expected from comparison with their families. Similar interference with other paths of tyrosine metabolism may per¬ haps lower production of epinephrine; rather more certainly, the body's pro¬ duction of another neurohumor, sero¬ tonin, is reduced through interference with the metabolism of tryptophan, a compound somewhat like phenylala¬ nine itself. These neurohumoral dis¬ orders may help to account for some of the secondary neuropsychiatrie symptoms seen in the disease: agi¬ tated behavior, muscular hyperactive reflexes, hyperkinesis, tremors, and (as already noted) seizures. An addi¬ tional or alternative cause of these manifestations may be certain metabo¬ lites of phenylalanine itself; in the con¬ centrations characteristic of untreated PKU, these appear to possess pharma¬ codynamic activity. Phenylethylamine, for example, stimulates the sympa¬ thetic nervous system. But all of these abnormalities, since they are dependent on high phenylal¬ anine levels, should be reversed when phenylalanine intake is reduced, and in fact many are. Most noticeable, perhaps, is a jump in melanin output, shown by darker hair growth when treatment is instituted. The main fea¬ ture of the disease — с n s damage and its resultant retardation — is not rever¬ sible, however. This fact points to the existence of some additional patho¬ logic mechanism. The most plausible explanation of what this mechanism might be derives from a rather simple fact about pku patients: despite the relatively enor¬ mous quantities of phenylalanine in their blood ( up Ч0 30 times normal ), total serum amino acids are within normal limits. Necessarily, then, the quantities of other amino acids must be subnormal, and indeed assays have shown this to be true, with levels ranging from 85% normal for valine to only 50% normal for arginine. It has been hypothesized, therefore, that brain damage occurs because the cells of the infant's immature and rapidly growing brain are presented with a highly abnormal pattern of am¬ ino acids, with the result that the enormous proportion of phenylalanine crowds out other essential nutrients in whole or in part. The brain thus can- 65