Tyrosinosis

Figure 30-12. Intermediates in tyrosine catabolism. Carbons are numbered to emphasize their ultimate fate. (a-KG, a-ketoglutarate Glu, glutamate PLP, pyridoxal phosphate.) Circled numerals represent the probable sites of the metabolic defects in type II tyrosinemia neonatal tyrosinemia alkaptonuria and 0 type I tyrosinemia, or tyrosinosis.

The probable metabohc defect in type I tyrosine-mia (tyrosinosis) is at himarylacetoacetate hydrolase (reaction 4, Figure 30-12). Therapy employs a diet low in tyrosine and phenylalanine. Untreated acute and chronic tyrosinosis leads to death from liver failure. Alternate metabolites of tyrosine are also excreted in type II tyrosinemia (Richner-Hanhart syndrome), a defect in tyrosine aminotransferase (reaction 1, Figure 30-12), and in neonatal tyrosinemia, due to lowered y>-hydroxyphenylpyruvate hydroxylase activity (reaction 2, Figure 30-12). Therapy employs a diet low in protein. 

Following transamination, the carbon skeleton of tyrosine is degraded to ftimarate and acetoacetate. Metabohc diseases of tyrosine catabohsm include tyrosinosis, Richner-Hanhart syndrome, neonatal ty-rosinemia, and alkaptonuria. 

Sakai, K., and Kitagawa, T., An atypical case of tyrosinosis (1-parahydroxy-phenyl lactic acid uria), Jikeikai Med. J. 4, 1-15 (1957). 

Some inborn errors of metabolism can be characterized by excessive urinary excretion of aromatic acid metabolites. These acids are distinct from the vanillyl acids discussed in a previous section. Phenylketonuria, alkaptonuria, and tyrosinosis can be diagnosed by determination of the aromatic acid metabolites. Aromatic acid profiles are characteristic of specific metabolic defects, and can be used to confirm diagnoses obtained from amino acid and other studies. Quantification of the individual aromatic acid gives information as to the fate of ingested amino acid in diseases such as phenylketonuria, where there is a block in the metabolic pathway involving the particular amino acid. 

M8. Medes, G., A new error of tyrosine metabolism tyrosinosis. The intermediary metabolism of tyrosine and phenylalanine. Biochem. J. 26, 917-940 (1932). 

Additional errors of phenylalanine and tyrosine metabolism include tyrosinosis, or hereditary tyrosinemia, neonatal tyrosinemia, and alcaptonuria. In the first case, there is a probable defect in p-hydroxyphenylpyruvate oxidase. In neonatal tyrosinemia, the problem is transient and may be solved by the administration of ascorbic acid. Ascorbic acid is apparently a cofactor for p-hydroxy-phenylpyruvate oxidase. Alcaptonuria is a benign disorder in which homogen-tisic acid oxidase is inoperative and homogentisic acid is excreted in the urine. Air oxidizes the homogentisic acid to a pigment, giving urine a black color. This pigment also accumulates in the patient s tissues. 

Neonatal adrenoleucodystrophia Nieman-Pick disease Non-alcoholic steatohepatitis Porphyria cutanea tarda Seip-Lawrence syndrome Thalassaemia Tyrosinosis (type I)... 

G18. Gjessing, L. R., Symposium on Tyrosinosis, Norwegian Monogr. on Med. Sei. Oslo Universitetsforlaget, Oslo, 1966. 

Tyrosinosis and Other Cases of p-Hydroxyphenylpyruvic Acid Excretion... 

It is fortunate that Medes was available to make such a complete and able investigation, as no further eases of tyrosinosis have been reported and the metabolic defect must therefore be exceedingly rare. (There having been only one case recorded nothing is, of course, known of the genetics of its inheritance). Recently, however, other cases of p-hydroxyphenyl-pyruvic acid excretion have been observed, and though these are probably of a different type it is convenient to consider them here. 

The influence of ascorbic acid on tyrosine metabolism in man and intact animals has been discussed under alkaptonuria and tyrosinosis q.v.). Ty-rosyluria, also called hydroxyphenyluria, i.e., the excretion of p-hydroxy-phenyl compounds in the urine, can be affected by factors other than ascor-... 

Tyrosinosis is presumably due to fumarylacetoacetate hydrolase deficiency and has a high prevalence in the French-Canadian population of Quebec. It is associated with abnormal liver function, renal tubular dysfunction, anemia, and vitamin D-resistant rickets. Transient tyrosinemia of the newborn, particularly in premature infants, is the most common form of tyrosinemia in infancy. 

H19. Henning, U., and Ammon, R., Uber die Ausscheidung von p-Hydtoxyphenyl-brenztraubensaure, PhenylbrenztraubensSure und anderen o-Ketosauren im Ham gesunder Menschen, zugleich ein Beitrag zum Problem der Tyrosinosis. Z. physiol. Chem. 306, 221 (1957). 

Tyrosinemia I (also called tyrosinosis) is caused by a genetic deficiency of fumary-lacetoacetate hydrolase. The acute form is associated with liver failure, a cabbagelike odor, and death within the first year of life. 

Williams and Sweeley (1964) have given methods for the chromatographic separation of many urinary aromatic acids and have discussed diagnostic applications to (1) secreting tumors, e.g., malignant carcinoid, pheochromocytoma, and neuroblastoma, and (2) inborn errors of metabolism, e.g., tyrosinosis, phenylketonuria, Hartnup disease (involves aminoaciduria), and other inherited diseases. These authors referred to the use of infrared spectroscopy for verification of the identity of fractions of volatile organic anesthetics in blood. Chlorpromazine, pentobarbitone, and amphetamine, are examples of pharmacological substances that have been separated (Scott, 1966). 

HeroHtary tyrosinemia typell, or Tyrosinosis typelL or Hypatyrosinania typell, or Richna Hanhart syndrome. 

Hereditary tyrosinemia type I, or Tyrosinosis, or Hereditary hepatorenal dysfunction (see Fig. 2). 

Drug-Induced Hemolytic Anemia 170 Inborn Errors of Aromatic Amino Acid Metabolism 172 Phenylketonuria Tyrosinosis Alkaptonuria Albinism Histidinemia... 

Despite the relatively few steps in intermediary metabolism of the aromatic amino acids, a large number of metabolic errors have been reported. Some, like phenylketonuria, lead to dramatic clinical situations, whereas others, like alkaptonuria, are less clinically important, and still others, like tyrosinosis, have no clinical significance. The reasons for many errors in a given pathway are not understood. Metabolic errors may be as common in other metabolic pathways, but they are not observed either because they do not lead to clinical alterations or because they are lethal. However, the genes concerned with the appearance of each enzyme involved in a specific metabolic pathway may be located on adjacent loci in the chromosome, and these loci are perhaps more prone to spontaneous mutation. 

Parahydroxyphenylpyruvic, phenylacetic, and phenyllactic acids inhibit tyrosinase, but whereas the first of these compounds is a potent inhibitor, the others are only weak inhibitors. It seems that if this inhibitory effect were important in phenylketonuria, pigment metabolism would be more apparently altered in tyrosinosis than in phenylketonuria, which seems not to be the case. However, the enzyme block might explain why small doses or dietary amounts of tyrosine have no effect on the pigmentation of patients with phenylketonuria. Only when large doses of the amino acid are administered are pigmentation and epinephrine biosynthesis restored to normal, probably because tyrosine competes with phenylalanine metabolites for melanocyte tyrosinase and dopa decarboxylase. 

Medes observed further that the excretion of this compound paralleled the patient s protein or tyrosine intake and that administration of homogentisic acid did not affect urine composition. These findings suggested that the disease is due to a block of the transformation of tyrosine to homogentisic acid. Although this is the most probable interpretation, it has not yet received direct confirmation by analysis of enzyme activity in the liver. Furthermore, determination of the abnormal metabolite in the blood has not been included in the studies of tyrosinosis. The possibility of an abnormal excretion of the compound at the level of the renal tubules cannot be excluded entirely. 

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