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SNOMEDCT: 69525003; ORPHA: 30; DO: 0050833;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q21.2 | Orotic aciduria | 258900 | Autosomal recessive | 3 | UMPS | 613891 |
A number sign (#) is used with this entry because orotic aciduria can be caused by compound heterozygous mutation in the UMPS gene (613891), which encodes a bifunctional enzyme with orotate phosphoribosyltransferase (OPRT) and orotidylic decarboxylase (ODC) activity, on chromosome 3q21.
Orotic aciduria is a rare autosomal recessive disorder characterized by megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001).
Bailey (2009) stated that only 2 cases of orotic aciduria without megaloblastic anemia (OAWA) had been reported.
The phenotypic features of orotic aciduria are megaloblastic anemia that is unresponsive to vitamin B12 and folic acid, hypochromic, microcytic circulating erythrocytes that persist with administration of iron or pyridoxine, large amounts of orotic acid in the urine, and correction of anemia and reduction in orotic acid excretion when uridylic acid and cytidylic acid are administered (Huguley et al., 1959). Fallon et al. (1964) studied extensively the heterozygotes in the first family described (Huguley et al., 1959). A second family was discovered in New Zealand and a third in Texas (Haggard and Lockhart, 1965). In the last patient, urinary obstruction was produced by the high urinary excretion of orotic acid. Rogers et al. (1968) described another case, from North Carolina.
Girot et al. (1983) stated that only 9 cases had been reported; they added 2 more, sibs with a defect in cellular immunity. Humoral immunity was normal. Severe infections had been reported in some patients; 1 died of varicella and another of meningitis. The patients reported by Girot et al. (1983) were Senegalese and the offspring of first cousins.
Becroft et al. (1984) questioned the conclusion of Girot et al. (1983) that immunodeficiency can be an integral feature of orotic aciduria. They provided follow-up on the longest surviving patient, aged 21 years, treated with uridine from the age of 17 months (Becroft et al., 1969). In later years his dose of uridine had been 3 g/d by mouth and he was in good health and had regular employment. No evidence of immunodeficiency was found with or without uridine therapy.
Rogers and Porter (1968) devised a screening test for orotic aciduria that is effective in detecting either homozygotes or heterozygotes.
Orotic Aciduria
Two enzymatic functions are defective in this disorder: orotate phosphoribosyltransferase (OPRT; EC 2.4.2.10) and OMP decarboxylase (ODC; EC 4.1.1.23), which catalyze the last 2 steps in uridine monophosphate biosynthesis (Fallon et al., 1964). These 2 enzymes are present in a single polypeptide, so that there is a single bifunctional enzyme (UMPS) (summary by Bailey, 2009).
Worthy et al. (1974) concluded that the mutation causing orotic aciduria is structural because orotidine-5-prime-phosphate decarboxylase from homozygous cells was abnormally thermolabile and showed electrophoretic abnormality.
Winkler and Suttle (1988) found no decrease in the amount of UMP synthase mRNA and no detectable difference in the size of UMP synthase mRNA from cultured cells deficient in the enzyme activity (which varied from 2 to 7% of normal). Analysis of the mRNA by hybridization with a nearly full-length UMP synthase cDNA followed by S1 nuclease digestion showed no alteration in the mRNA structure. The mRNA appears to code for a mutant enzyme that has reduced stability or altered kinetic properties.
Proposed Type II Orotic Aciduria
Fox et al. (1969) identified a case of orotic aciduria in which only 1 enzyme, orotidine-5-prime-phosphate decarboxylase (ODC), was proposed to be defective. Recessive inheritance was supported by intermediate enzyme activity or urinary excretion of orotic acid in the patient's mother and brother and probably father. Orotidine-5-prime-pyrophosphorylase (also known as orotate phosphoribosyltransferase, OPRT) activity was increased. This case had been classified as type II orotic aciduria (Fox et al., 1973). Fox et al. (1973) provided follow-up on this patient. Over a 3-year period with uridine therapy, red cell OPRT, which was high normal on first determination, decreased to a level about 2% of normal. Bailey (2009) showed that the ratio of urinary outputs of orotidine to orotate provides a means of testing for particular forms of enzyme defect, and found that experimental urinary orotate/orotidine (OA/OR) values in the patient of Fox et al. (1969) were in disagreement with the product spectrum expected for a selective defect in ODC. However, the ratio was in satisfactory agreement for the type I defect. Given that the measured enzyme ratios did not remain consistent, that this apparent type II case was 'clinically indistinguishable' from a type I case diagnosed by the same team, that no confirmatory report had been found in the forty years since the initial report, and that the urinary OA/OR values did not indicate a selective defect in ODC, Bailey (2009) concluded that evidence for a separate category for this case was insecure.
Orotic Aciduria without Megaloblastic Anemia
Bailey (2009) noted that 2 cases of orotic aciduria without megaloblastic anemia (OAWA) had been reported. They pointed out that in type I patients the ratio of urinary OA/OR was greater than 10, whereas in the OAWA patients it was approximately equal to 1. This is the product spectrum expected of a defect in ODC. This form is the only one that appears to have a qualitatively different UMPS. Bailey (2009) suggested that in these cases the UMPS is sufficiently active to relieve potential anemia.
Bensen et al. (1989) described the occurrence of hereditary orotic aciduria in a family carrying a pericentric inversion of chromosome 4. Bensen et al. (1991) described 2 pregnancies in a 25-year-old woman whose hereditary orotic aciduria was managed prenatally with uridine supplementation. The first pregnancy resulted in an infant with multiple congenital anomalies and a bizarre karyotype. The proposita was found to be the carrier of a de novo 11;22 translocation and a pericentric inversion of chromosome 4. Subsequently, several carriers of orotic aciduria in this family were identified with the inverted chromosome 4. The second pregnancy resulted in a normal male with an inverted chromosome 4.
Webster et al. (2001) stated that they knew of only 15 cases of orotic aciduria, of which 14 had been established by direct measurement of UMPS.
Girot et al. (1983) noted that replacement therapy with uridine usually leads to a clinical and hematologic remission and reduction in the urinary excretion of orotic acid.
Suchi et al. (1997) detected compound heterozygosity for mutations in the UMPS gene (613891.0001-613891.0002) in a Japanese patient (patient YF) with orotic aciduria who was originally described by Morishita et al. (1986). Expression of human UMPS cDNAs containing these mutations in pyrimidine auxotrophic E. coli and in recombinant baculovirus-infected Sf21 cells demonstrated impaired activity presumably associated with the urinary orotic acid substrate accumulations observed in vivo.
Orotate is a normal constituent of bovine milk and is produced in the udder. Robinson et al. (1983) demonstrated heterozygosity for deficiency of this enzyme in many cows of the Holstein-Friesian breed, descendant from what was called 'America's Favorite Brood Cow' (Shanks et al., 1984), and postulated that homozygosity might be responsible for fetal wastage. Heterozygous cows show orotic aciduria during lactation, as well as orotic acidemia and concentrations of orotate in the milk that are 4 to 12 times normal (Shanks et al., 1984). Longevity and milk production are not affected. Cattle homozygotes are stillborn or die shortly after birth. Harden and Robinson (1987) reported new findings in cattle heterozygous for UMP synthase deficiency. Deficiency of UMP synthase (DUMPS) in cattle results in early embryonic death of homozygotes. Schwenger et al. (1993) demonstrated a C-to-T transition that converted codon 405 from CGA (arg) to TGA (stop). The loss of an AvaI site permitted development of a direct DNA test, which was applied to 102 animals. Complete concordance between DUMPS and the presence of the point mutation in heterozygous animals was observed.
Bailey, C. J. Orotic aciduria and uridine monophosphate synthase: a reappraisal. J. Inherit. Metab. Dis. 32 Suppl. 1: S227-S233, 2009. [PubMed: 19562503] [Full Text: https://doi.org/10.1007/s10545-009-1176-y]
Becroft, D. M. O., Phillips, L. I., Simmonds, A. Hereditary orotic aciduria: long-term therapy with uridine and a trial of uracil. J. Pediat. 75: 885-891, 1969. [PubMed: 5347440] [Full Text: https://doi.org/10.1016/s0022-3476(69)80318-5]
Becroft, D. M. O., Phillips, L. I., Webster, D. R., Wilson, J. D. Absence of immune deficiency in hereditary orotic aciduria. (Letter) New Eng. J. Med. 310: 1333 only, 1984. [PubMed: 6717503] [Full Text: https://doi.org/10.1056/NEJM198405173102021]
Bensen, J. T., Nelson, L. H., Pettenati, M. J., Block, S. M., Brusilow, S. W., Livingstone, L. R., Burton, B. K. First report of management and outcome of pregnancies associated with hereditary orotic aciduria. Am. J. Med. Genet. 41: 426-431, 1991. [PubMed: 1776631] [Full Text: https://doi.org/10.1002/ajmg.1320410408]
Bensen, J. T., Pettenati, M. J., Nelson, L. H., Brusilow, S. W., Burton, B. K. Hereditary orotic aciduria: an association with an 11:22 balanced translocation and familial inversion of chromosome 4. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A39 only, 1989.
Fallon, H. J., Smith, L. H., Jr., Graham, J. B., Burnett, C. H. A genetic study of hereditary orotic aciduria. New Eng. J. Med. 270: 878-881, 1964. [PubMed: 14110033] [Full Text: https://doi.org/10.1056/NEJM196404232701705]
Fox, R. M., O'Sullivan, W. J., Firkin, B. G. Orotic aciduria: differing enzyme patterns. Am. J. Med. 47: 332-336, 1969. [PubMed: 5808247] [Full Text: https://doi.org/10.1016/0002-9343(69)90160-0]
Fox, R. M., Wood, M. J., Royse-Smith, D., O'Sullivan, W. J. Hereditary orotic aciduria: type I and II. Am. J. Med. 55: 791-798, 1973. [PubMed: 4753642] [Full Text: https://doi.org/10.1016/0002-9343(73)90260-x]
Girot, R., Hamet, M., Perignon, J.-L., Guesnu, M., Fox, R. M., Cartier, P., Durandy, A., Griscelli, C. Cellular immune deficiency in two siblings with hereditary orotic aciduria. New Eng. J. Med. 308: 700-704, 1983. [PubMed: 6828110] [Full Text: https://doi.org/10.1056/NEJM198303243081207]
Haggard, M. E., Lockhart, L. H. Hereditary orotic aciduria, a disorder of pyrimidine metabolism responsive to uridine therapy. (Abstract) J. Pediat. 67: 906 only, 1965.
Harden, K. K., Robinson, J. L. Deficiency of UMP synthase in dairy cattle: a model for hereditary orotic aciduria. J. Inherit. Metab. Dis. 10: 201-209, 1987. [PubMed: 2448544] [Full Text: https://doi.org/10.1007/BF01800062]
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Morishita, H., Kokubo, M., Sumi, S., Suchi, M., Wada, Y. The first case of hereditary orotic aciduria in Japan. J. Jpn. Pediat. Soc. 90: 2775-2778, 1986.
Robinson, J. L., Drabik, M. R., Dombrowski, D. B., Clark, J. H. Consequences of UMP synthase deficiency in cattle. Proc. Nat. Acad. Sci. 80: 321-323, 1983. [PubMed: 6572893] [Full Text: https://doi.org/10.1073/pnas.80.2.321]
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Schwenger, B., Schober, S., Simon, D. DUMPS cattle carry a point mutation in the uridine monophosphate synthase gene. Genomics 16: 241-244, 1993. [PubMed: 8486364] [Full Text: https://doi.org/10.1006/geno.1993.1165]
Shanks, R. D., Dombrowski, D. B., Harpestad, G. W., Robinson, J. L. Inheritance of UMP synthase in dairy cattle. J. Hered. 75: 337-340, 1984. [PubMed: 6548235] [Full Text: https://doi.org/10.1093/oxfordjournals.jhered.a109951]
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Suchi, M., Mizuno, H., Kawai, Y., Tsuboi, T., Sumi, S., Okajima, K., Hodgson, M. E., Ogawa, H., Wada, Y. Molecular cloning of the human UMP synthase gene and characterization of point mutations in two hereditary orotic aciduria families. Am. J. Hum. Genet. 60: 525-539, 1997. [PubMed: 9042911]
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Winkler, J. K., Suttle, D. P. Analysis of UMP synthase gene and mRNA structure in hereditary orotic aciduria fibroblasts. Am. J. Hum. Genet. 43: 86-94, 1988. [PubMed: 2837086]
Worthy, T. E., Grobner, W., Kelley, W. N. Hereditary orotic aciduria: evidence for a structural gene mutation. Proc. Nat. Acad. Sci. 71: 3031-3035, 1974. [PubMed: 4528586] [Full Text: https://doi.org/10.1073/pnas.71.8.3031]