Inborn errors Aromatic amino acid

As a result of a high index of clinical suspicion and, on occasion, supporting biochemical data from other investigations, one of the first specialist investigations to ascertain whether a patient has an inborn error of biogenic amine metabolism is, as mentioned above, analysis of the CSF concentrations of HVA and 5HIAA. This is often performed in conjunction with the measurement of 3-methyldopa (3-MD), also known as 3-methoxytyrosine. 3-MD is formed from L-dopa via COMT activity and accumulates in conditions where aromatic amino acid decarboxylase activity is impaired. The chemical structures of HVA, 5HIAA and 3-MD are shown in Fig. 6.2.1. 

Table 6.2.2 Typical CSF profiles of HVA, 5HIAA and 3-methyldopa (3-MD) for the inborn errors of metabolism associated with a disruption of biogenic amine metabolism. A downward-pointing arrow indicates that a particular metabolite is below the established reference range. An upward pointing arrow is indicative that a metabolite is above the established reference range. WR indicates that the concentration of the metabolite is likely to be within the reference range. AADC Aromatic amino acid decarboxylase, PNPO pyridox(am)ine-5 -phosphate oxidase...

The metabolism of phenylalanine will now be considered in some detail, as two inborn errors of metabolism are known that affect this pathway. Phenylalanine is first hydroxylated by phenylalanine hydroxylase to form another aromatic amino acid tyrosine (Fig. 8). The coenzyme for this reaction is the reductant tetrahydrobiopterin which is oxidized to dihydrobiopterin. Phenylalanine hydroxylase is classified as a monooxygenase as one of the atoms of 02 appears in the product and the other in HzO. The tyrosine is then trans-aminated to p-hydroxyphenylpyruvate, which is in turn converted into homogentisate by p-hydroxyphenylpyruvate hydroxylase. This hydroxylase is an example of a dioxygenase, as both atoms of 02 become incorporated into the product (Fig. 8). The homogentisate is then cleaved by homogentisate oxidase, another dioxygenase, before fumarate and acetoacetate are produced... 

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

Inborn Errors of Aromatic Amino Acid Metabolism... 

Alkaptonuria is another disease of intermediate metabolism of aromatic amino acids. It was the first of a group of diseases discovered by Sir Archibald Garrod [84] called inborn errors of metabolism. The transformation of homogentisic acid into maleylacetoace-tate is blocked in alkaptonuria. Direct evidence for the location of the metabolic block was obtained by researchers who demonstrated a specific enzymatic block in the liver of alkaptonurics. These studies also indicated that the metabolic block was due to an absence of the enzyme rather than to the presence of an inhibitor or the lack of a cofactor. Consequently, whereas the urine of normal individuals contains no homogentisic acid (the renal threshold for that compound is low in both normal and diseased individuals), large amounts are recovered from the urine of alkap-tonuric patients, and the amount excreted parallels the patients protein and tyrosine intake. 

An aromatic amino acid found in increased levels in the blood and urine in the inborn error of metabolism, phenylketonuria. It can be estimated by microbiological assay (the Guthrie test, q.v.) or by its reaction with ninhydrin to form a fluorescent compound. This fluorescence is enhanced by the addition of the dipeptide, L-leucylalanine. 

An aromatic amino acid which is a precursor of melanin, catecholamines and thyroxine. It is derived both from the diet and the hydroxylation of phenylalanine. Excess tyrosine excretion occurs in the two inborn errors of metabolism, tyrosinosis and tyrosinaemia. 

Hyland K, Surtees RAH, Rodeck C, Clayton PT (1992) Aromatic 1 amino acid decarboxylase deficiency clinical features, diagnosis and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology 42 1980-1988... 

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. 

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