The activity of the enzyme porphobilinogen synthase (EC 4.2.1.24) in erythrocytes from patients with hereditary tyrosinemia was less than 5% of that in a control group and the activity in liver tissue was less than 1% of the reported normal activity. Urine from patients with hereditary tyrosinemia contained an inhibitor that was isolated and identified as succinylacetone (4,6-dioxoheptanoic acid) by gas/liquid chromatography-mass spectrometry. Fresh urine samples contained succinylacetoacetate (3,5-dioxooctanedioic acid) as well as succinylacetone. The inhibition of porphobilinogen synthase explains the high excretion of 5-aminolevulinate observed in hereditary tyrosinemia. Succinylacetone and succinylacetoacetate presumably originate from maleylacetoacetate or fumarylacetoacetate, or both, and their accumulation indicates a block at the fumarylacetoacetase (EC 3.7.1.2) step in the degradation of tyrosine. We suggest that the severe liver and kidney damage in hereditary tyrosinemia may be due to the accumulation of these tyrosine metabolites and that the primary enzyme defect in hereditary tyrosinemia may be decreased activity of fumarylacetoacetase.In the inborn error of metabolism called hereditary tyrosinemia, the main clinical findings are liver failure, which develops into liver cirrhosis in early childhood, and multiple renal tubular defects with hypophosphatemic rickets (1, 2). The derangement in tyrosine metabolism (i.e., hypertyrosinemia and high urinary excretion of 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, and to a lesser extent 4-hydroxyphenylacetate) is due to a low activity of the enzyme 4-hydroxyphenylpyruvate dioxygenase [4-hydroxyphenylpyruvate:oxygen oxidoreductase (hydroxylating, decarboxylating), EC 1.13.11.27] (3), which catalyzes the formation of homogentisate (III) (Fig. 1) from 4-hydroxyphenylpyruvate (II).The increased excretion of these phenolic metabolites of tyrosine does not explain the liver and kidney damage in hereditary tyrosinemia because a similar large excretion has been found also in patients without liver and kidney disease-e.g., in a 5-year-old boy with multiple congenital anomalies and with negligible activity of soluble tyrosine aminotransferase (4) and in at least three other patients who were mentally retarded (2,5,6). A large excretion of the same metabolites has also been found in hereditary fructose intolerance (7).In 1967 we reported on a patient who had symptoms similar to those characteristic of acute intermittent porphyria (8). An increased excretion of 5-aminolevulinate has since then been observed in all patients studied by us, even in those without these symptoms (3, 9), but so far it has not been possible to find a biochemical link between the altered tyrosine metabolism and the increased excretion of a porphyrin precursor. In this report we present evidence for an enzyme defect in tyrosine catabolism in hereditary tyrosinemia that explains the increased excretion of 5-aminolevulinate. We also present a hypothesis

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High plasma tHcy and serum MMA were prevalent and correlated inversely with movement and cognitive performance. Oral B vitamin treatment normalized plasma tHcy and serum MMA concentrations but did not affect movement or cognitive performance. This might have been due to irreversible or vitamin-independent neurocognitive decline or to an insufficient dose or duration of vitamins.

The aim of this study was to investigate the prevalence of pain and its characteristics, and to examine the association of pain with cognitive function and depressive symptoms, in a representative sample of 70-year-old men and women. Data were collected within the gerontological and geriatric population studies in Göteborg, Sweden (H-70). A sample of 124 men and 117 women living in the community took part in the study. A questionnaire was applied which included four different aspects of pain experience: prevalence, frequency of episodes of pain, duration and number of locations. In close connection to this, depressive symptoms were assessed using the Center for Epidemiological Studies Depression Scale. The prevalence of pain during the last 14 days was higher in women (79%; n=91) than in men (53%; n=65) (P<0.001). Women (68%; n=78) also reported pain that had lasted for >6 months to a greater extent than men (38%; n=46) (P<0.001). The frequency of episodes of pain was also higher among women, 64% (n=74) reporting daily pain or pain several days during the last 14 days while 37% of the men (n=45) did so (P<0.001). Women (33%, n=38) also reported pain experience from >/=3 locations more often than men (11%; n=13) (P<0.001). On the other hand, the association between depressive symptoms and pain experience was more evident in men than in women. Women were taking significantly more antidepressants compared to men (P<0.03). The results show that pain is common in 70-year-old people and especially in women. However, associations between depressive symptoms and the four aspects of pain experience were more pronounced among men.