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  1. There are two known disorders of histidine metabolism: histidinemia and urocanic aciduria. Histidinemia is one of the most frequent and well known of the inborn errors of metabolism. A test for it has been included in newborn screening programs, and its incidence was about 1:12,000 in over 20 million screened infants. The frequency is particularly high in Japan (1:9600). It is an autosomal recessive trait and is due to a defect in histidase, which catalyzes the conversion of histidine to urocanic acid. This enzyme defect is most readily identified in the stratum corneum of skin. The biochemical consequences of the metabolic block include increased concentrations of histidine in blood, urine, and cerebrospinal fluid (CSF); decreased concentration of urocanic acid in blood and skin; and increased concentrations of histidine metabolites in urine. Histidinemia seems to be benign in most affected individuals, although, under certain unusual circumstances, the disorder may be harmful and produce the central nervous system disease noted in a few histidinemic patients. Dietary treatment lowers the blood histidine level but seems not to be indicated, at least for most patients, given the apparent lack of consequences of the disorder. Urocanic aciduria is an apparently autosomal recessive disorder. It is probably benign. An increased concentration of urocanic acid in urine is the only known metabolic finding.

  2. The prominence of histidinemia has stimulated the study of histidase, an enzyme expressed primarily in liver and skin and regulated in a complex developmental, hormonal, and tissue-specific manner. At the molecular level, the enzyme is unusual in having a rare modified amino acid, dehydroalanine, in its active site. Full-length cDNAs of human, rat, and mouse liver histidase have been isolated. The human gene has also been cloned and characterized: It is a single-copy gene spanning approximately 25 kb and consisting of 21 exons. Several liver- and epidermis-specific transcription factor-binding sites have been identified in the 5′ flanking region. A polymorphism has been identified in exon 16. The gene has not yet been studied for mutations in histidinemic patients.

  3. The deficiency of urocanic acid in histidinemia could have implications for either or both of two proposed functions of urocanic acid—as a natural sunscreen against ultraviolet (UV) light and as a mediator of ultraviolet light-induced systemic immunosuppression. As yet, there has been no evidence for impairment of either of these proposed functions in histidinemia, but further study of this question might be warranted.

  4. Atypical histidinemia is a biochemically milder form of the disorder and may account for a substantial minority of persons with histidinemia. The reported individuals have been clinically normal. They have higher residual skin histidase activities and lower elevations of histidine and histidine metabolites than individuals with the classic disorder. Histidinemia may be a biochemically heterogeneous disorder, perhaps due to several allelic mutations.

  5. Maternal histidinemia is probably benign. The 61 offspring from untreated pregnancies of 23 histidinemic mothers whose cases have been followed have generally been normal.

  6. An animal model with the biochemical features of human histidinemia has been identified. The histidinemic mouse has a missense mutation in the coding region of the histidase structural gene that reduces the stability of the enzyme. The histidinemic mouse does not exhibit clinical abnormalities unless it is the offspring of a histidinemic mother, in which case both histidinemic (his/his) and heterozygous (his/+) offspring will have balance defects characterized by circling behavior and/or head tilting. This offspring effect depends on the maternal histidine level and is prevented or ameliorated if the mother is treated with a histidine-restricted diet during pregnancy. The effect is also modulated by the fetal genotype, with homozygous (his/his) fetuses more severely affected than heterozygous (his/+) fetuses, and by other loci, as evidenced by the decrease in the frequency of the effect in offspring when selection for high incidence of abnormalities is relaxed.

  7. Histidinuria without histidinemia has been described in five children. Four were mentally retarded and two had myoclonic seizures, but an association between the histidinuria and the central nervous system manifestations has not been established. All had substantially reduced renal tubular reabsorption of histidine, with normal reabsorption of other amino acids, indicating that there is a histidine-specific transport system that is defective in this disorder. Two sibs and a third unrelated child also had evidence of an intestinal defect in histidine transport. This disorder seems to be transmitted as an autosomal recessive trait.

  8. The enzyme defect in urocanic aciduria is in urocanase, which catalyzes the conversion of trans-urocanic acid to imidazolonepropionic acid. The defect has been proved by liver biopsy in three patients. Urocanic aciduria has been found in at least eight children. The four discovered by specific testing have been mentally retarded, but the four identified by newborn urine screening have been normal, the latter suggesting that the mental retardation may not be related to the metabolic disorder. Four of the eight children have had growth retardation. Urocanic aciduria is diagnosed on the basis of increased urocanic acid in urine with normal or only mildly increased levels of histidine and histidine metabolites.

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