Wilson Aciduria

A thorough investigation of this type of amino aciduria has led to a more accurate and more complete picture of it (S34). Taurine excretion is low proline, citrulline, and cystine excretion may be abnormally high, and when this is the case there does not seem to be a relation between the cystine output, which may be considerable, and that of lysine. Moreover, whereas the intake of a meal has but little influence on amino aciduria in normals, it has a definite effect on the output of amino acids in the case of Wilson s disease finally the amino acid fasting levels in plasma are at the lower limit of normal. 

A number of inherited conditions are now known in which some degree of renal aciduria has been found. These include diseases as diverse as cystinuria, galactosemia, and Wilson s disease. In the last of these the aminoaciduria is probably a consequence of renal tubular damage secondary to excessive copper deposition (H2). 

The answer is e. (Murray, pp 375-401. Scriver, pp 2663-2704. Sack, pp 121-138. Wilson, pp 287—320.) Orotic aciduria is the buildup of orotic acid due to a deficiency in one or both of the enzymes that convert it to UMP Either orotate phosphoribosyltransferase and orotidylate decarboxylase are both defective, or the decarboxylase alone is defective. UMP is the precursor of UTP, CTP, and TMP All of these end products normally act in some way to feedback-inhibit the initial reactions of pyrimidine synthesis. Specifically, the lack of CTP inhibition allows aspartate transcarbamoylase to remain highly active and ultimately results in a buildup of orotic acid and the resultant orotic aciduria. The lack of CTP, TMP, and UTP leads to a decreased erythrocyte formation and megaloblastic anemia. Uridine treatment is effective because uridine can easily be converted to UMP by omnipresent tissue kinases, thus allowing UTP, CTP, and TMP to be synthesized and feedback-inhibit further orotic acid production. 

The answer is d. (Murray, pp 238-249. Scriver, pp 2165-2194. Sack, pp 121-144. Wilson, pp 287-324.) Propionic acidemia (232000) results from a block in propionyl CoA carboxylase (PCC), which converts propionic to methylmalonic acid. Excess propionic acid in the blood produces metabolic acidosis with a decreased bicarbonate and increased anion gap (the serum cations sodium plus potassium minus the serum anions chloride plus bicarbonate). The usual values of sodium (-HO meq/L) plus potassium ( 4 meq/T) minus those for chloride (-105 meq/L) plus bicarbonate (—20 meq/L) thus yield a normal anion gap of -20 meq/L. A low bicarbonate of 6 to 8 meq/L yields an elevated gap of 32 to 34 meq/L, a gap of negative charge that is supplied by the hidden anion (propionate in propionic acidemia). Biotin is a cofactor for PCC and its deficiency causes some types of propionic acidemia. Vitamin B deficiency can cause methylmalonic aciduria because vitamin Bn is a cofactor for methylmalonyl coenzyme A mutase. Glycine is secondarily elevated in propionic acidemia, but no defect of glycine catabolism is present. 

Wilson V, Thomson ML, and Dent, CE. Amino-aciduria in lead poisoning. A case in childhood. Lancet 1953 66-68. 

A1 Ablin, A., Stephens, B. G., Hirata, T., Wilson, K. and Williams, H. E. Nephropathy, xanthinuria and orotic aciduria complicating Burkitt s lymphoma treated with chemotherapy and allopurinol. Metabolism, 21, 771 (1972)... 

Amino aciduria without cupriuria has been described in some normal relatives of patients with Wilson s disease. It is assumed that such individuals are heterozygotes, and that amino aciduria is the primary defect in Wilson s disease rather than a secondary effect due to the disturbance in copper metabolism. 

Interpretation of Wilson s disease on the basis of disrupted copper metabolism is far from complete. The accumulation of copper in tissues is generally considered responsible for the lesions of the liver (cirrhosis), renal tubules (amino aciduria), and basal ganglia (neurological disorder), but the special affinity of these various tissues for copper remains to be explained, as does the mechanism of copper toxicity in these organs. Penicillamine, a copper-chelating substance, has been administered for treatment of Wilson s disease with some degree of success. In fact, it has even been claimed that asymptomatic victims of Wilson s disease can be treated preventively [56]. 

An early form of therapy involves eliminating the substrate either by excluding the substrate from the diet, as in phenylketonuria, or by administering drugs—such as penicillamine in Wilson s disease or allopurinol in gout. Orotic aciduria can be corrected by the administration of uridine, which provides the substrate for the biosynthesis of the nucleosides used in RNA and DNA synthesis and is also a substrate for the biosynthesis of inhibitors of the carbamyl aspartate synthetase, the first enzyme in the formation of orotic acid. By this feedback inhibition, the levels of orotic acid in the urine are reduced by the administration of uridine. 

Uzman, L., Denny-Brown, D. Amino-aciduria in hepatolenticular degeneration (Wilson s disease). Amer. J. med. Sci. 215, 599-611 (1948)... 

Methylmalonic acidemia Propionic acidemia Carbamyl phosphate synthetase def. Lysinuric protein intolerance Hereditary orotic aciduria Wilson disease... 

Lysinuric protein intolerance Hereditary orotic aciduria Pyrimidine-5-nucleotidase def. Familial LCAT def. Wilson disease Acid lipase def. (Wolman disease) 3-Phosphoglycerate dehydrogenase deL Methylentetrahydrofolate reductase def. Methioninsynthase def. 

Wilson, C.M., Wilson, R.W. and Higgins, J.V. (1973), a-Ketoadipic aciduria A new metabolic error in lysine/tryptophan metabolism. Int. Conf. Birth Defects 4th, No. 297, Excerpta Medica, Amsterdam, p. 37. 

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