Urine fumaric acid

Defects of the Krebs cycle. Fumarase deficiency was reported in children with mitochondrial encephalomyop-athy. Usually, there is developmental delay since early infancy, microcephaly, hypotonia and cerebral atrophy, with death in infancy or early childhood. The laboratory hallmark of the disease is the excretion of large amounts of fumaric acid and, to a lesser extent, succinic acid in the urine. The enzyme defect has been found in muscle, liver and cultured skin fibroblasts [16]. 

Fates of tyrosine. Tyrosine can be degraded by oxidative processes to ace-toacetate and fumarate which enter the energy generating pathways of the citric acid cycle to produce ATP as indicated in Figure 38-2. Tyrosine can be further metabolized to produce various neurotransmitters such as dopamine, epinephrine, and norepinephrine. Hydroxylation of tyrosine by tyrosine hydroxylase produces dihydroxyphenylalanine (DORA). This enzyme, like phenylalanine hydroxylase, requires molecular oxygen and telrahydrobiopterin. As is the case for phenylalanine hydroxylase, the tyrosine hydroxylase reaction is sensitive to perturbations in dihydropteridine reductase or the biopterin synthesis pathway, anyone of which could lead to interruption of tyrosine hydroxylation, an increase in tyrosine levels, and an increase in transamination of tyrosine to form its cognate a-keto acid, para-hydroxyphenylpyruvate, which also would appear in urine as a contributor to phenylketonuria. 

Tyrosine Catabolism - The catabolism of tyrosine to fumarate and acetoacetate is depicted in Figure 21.21. A hereditary deficiency of the enzyme homogentisic acid dioxygenase causes a disease called alkaptonuria where homogentisic acid accumulates and is excreted in large amounts in the urine. It oxidizes on standing, causing the urine to become dark. 

Fig. 13.4 Chromatogram of organic acids extracted using DEAE-Sephadex with solvent re-extraction from the urine of the same patient illustrated in Fig. 13.2 and 13.3. Derivatized and separated as described in the legend to Fig. 13.3. Peak identifications are detailed in the legend to Fig. 13.3 additional identificatons are 4, cresol 12, fumarate 17, trihydroxybenzene. (The horizontal axis represents the time elapsed in minutes from sample injection.)... 

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