Alternative titles; symbols
ORPHA: 35120; DO: 583;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p14.3 | Anemia, congenital, nonspherocytic hemolytic, 8 | 266120 | Autosomal recessive | 3 | NT5C3A | 606224 |
A number sign (#) is used with this entry because of evidence that congenital nonspherocytic hemolytic anemia-8 (CNSHA8) is caused by homozygous or compound heterozygous mutation in the UMPH1 gene (NT5C3A; 606224) on chromosome 7p14.
A deficiency of pyrimidine 5-prime nucleotidase (P5N), also called uridine 5-prime monophosphate hydrolase (UMPH1), causes congenital nonspherocytic hemolytic anemia-8 (CNSHA8), which is characterized by marked basophilic stippling and the accumulation of high concentrations of pyrimidine nucleotides within the erythrocyte. The enzyme is implicated in the anemia of lead poisoning and is possibly associated with learning difficulties. Hirono et al. (1988) suggested that this deficiency is the third most common RBC enzymopathy--after G6PD (300908) and pyruvate kinase (see 266200) deficiencies--causing hemolysis (summary by Marinaki et al., 2001).
Valentine et al. (1974) showed deficiency of pyrimidine 5-prime nucleotidase in 4 individuals with hereditary hemolytic anemia. Ribosephosphate pyrophosphokinase was severely reduced, probably as an epiphenomenon resulting from inhibition of its synthesis by high concentrations of pyrimidine.
Hansen et al. (1983) reported 2 affected Norwegian sibs, the first cases in Scandinavia. The parents were distantly related. The 2 children showed intravascular hemolysis with hemoglobinuria and loss of iron in the urine necessitating iron medication.
Ericson et al. (1983) reported 2 affected Norwegian children, a brother and sister, and noted that one of the first families of Valentine et al. (1974) was of Norwegian origin. The disease has, however, been described in many parts of the world. Disturbed synthesis of red cell membrane phospholipids was suggested as being partly responsible for intravascular hemolysis. Energy production was thought to be adequate.
Although not separable electrophoretically, 2 P5N isozymes with different substrate specificities are demonstrable by the fact that UMPH1 is lacking in patients with hemolytic anemia, whereas normal UMPH2 activity is retained in these patients; see 191720 (Swallow et al., 1983; Paglia et al., 1984). Hirono et al. (1987) separated the 2 isozymes of P5N chromatographically and studied their biochemical properties from 5 patients with P5N deficiency. They found that P5N-II had normal activity and other normal enzymologic properties, whereas P5N-I from these patients had abnormal properties including reduced activity. They suggested that the main cause of P5N deficiency may be an abnormality of P5N-I, probably arising from a structural gene mutation.
De Korte et al. (1989) concluded that analysis of ribonucleotide patterns, in combination with determination of P5N activity, improves the accuracy of diagnosis of heterozygosity. David et al. (1991) demonstrated inhibition of the hexose monophosphate shunt in young erythrocytes by pyrimidine nucleotides.
In patients with congenital nonspherocytic hemolytic anemia-8, Marinaki et al. (2001) identified mutations in the UMPH1 gene (606224.0001-606224.0003).
In Turkish patients with CNSHA8, Balta et al. (2003) identified homozygous mutations in the UMPH1 gene (606224.0004-606224.0005).
Anderson, J. E., Teng, Y.-S., Giblett, E. R. Stains for six enzymes potentially applicable to chromosomal assignment by cell hybridization. Birth Defects Orig. Art. Ser. 11: 295-299, 1975. [PubMed: 54198]
Balta, G., Gumruk, F., Akarsu, N., Gurgey, A., Altay, C. Molecular characterization of Turkish patients with pyrimidine 5-prime nucleotidase-I deficiency. Blood 102: 1900-1903, 2003. [PubMed: 12714505] [Full Text: https://doi.org/10.1182/blood-2003-02-0628]
Ben-Bassat, I., Brok-Simoni, F., Kende, G., Holtzmann, F., Ramot, B. A family with red cell pyrimidine 5-prime-nucleotidase deficiency. Blood 47: 919-922, 1976. [PubMed: 1276472]
Beutler, E., Baranko, P. V., Feagler, J., Matsumoto, F., Miro-Quesdada, M., Selby, G., Singh, P. Hemolytic anemia due to pyrimidine-5-prime-nucleotidase deficiency: report of eight cases in six families. Blood 56: 251-255, 1980. [PubMed: 6249430]
David, O., Ramenghi, U., Camaschella, C., Vota, M. G., Comino, L., Pescarmona, G. P., Nicola, P. Inhibition of hexose monophosphate shunt in young erythrocytes by pyrimidine nucleotides in hereditary pyrimidine 5-prime nucleotidase deficiency. Europ. J. Haemat. 47: 48-54, 1991. [PubMed: 1868914] [Full Text: https://doi.org/10.1111/j.1600-0609.1991.tb00560.x]
de Korte, D., Sijstermans, J. M., Seip, M., van Doorn, C. C. H., van Gennip, A. H., Roos, D. Pyrimidine 5-prime-nucleotidase deficiency: improved detection of carriers. Clin. Chim. Acta 184: 175-180, 1989. [PubMed: 2557985] [Full Text: https://doi.org/10.1016/0009-8981(89)90287-8]
Ericson, A., de Verdier, C.-H., Hansen, T. W. R., Seip, M. Erythrocyte nucleotide pattern in two children in a Norwegian family with pyrimidine 5-prime-nucleotidase deficiency. Clin. Chim. Acta 134: 25-33, 1983. [PubMed: 6317231] [Full Text: https://doi.org/10.1016/0009-8981(83)90181-x]
Hansen, T. W. R., Seip, M., de Verdier, C.-H., Ericson, A. Erythrocyte pyrimidine 5-prime-nucleotidase deficiency: report of 2 new cases, with a review of the literature. Scand. J. Haemat. 31: 122-128, 1983. [PubMed: 6310729]
Harley, E. H., Heaton, A., Wicomb, W. Pyrimidine metabolism in hereditary erythrocyte pyrimidine 5-prime-nucleotidase deficiency. Metabolism 27: 1743-1754, 1978. [PubMed: 723629] [Full Text: https://doi.org/10.1016/0026-0495(78)90260-3]
Hirono, A., Forman, L., Beutler, E. Enzymatic diagnosis in non-spherocytic hemolytic anemia. Medicine 67: 110-117, 1988. [PubMed: 3352512] [Full Text: https://doi.org/10.1097/00005792-198803000-00004]
Hirono, A., Fujii, H., Miyajima, H., Kawakatsu, T., Hiyoshi, Y., Miwa, S. Three families with hereditary hemolytic anemia and pyrimidine 5-prime-nucleotidase deficiency: electrophoretic and kinetic studies. Clin. Chim. Acta 130: 189-197, 1983. [PubMed: 6307548] [Full Text: https://doi.org/10.1016/0009-8981(83)90116-x]
Hirono, A., Fujii, H., Natori, H., Kurokawa, I., Miwa, S. Chromatographic analysis of human erythrocyte pyrimidine 5-prime-nucleotidase from five patients with pyrimidine 5-prime-nucleotidase deficiency. Brit. J. Haemat. 65: 35-41, 1987. [PubMed: 3028466] [Full Text: https://doi.org/10.1111/j.1365-2141.1987.tb06132.x]
Marinaki, A. M., Escuredo, E., Duley, J. A., Simmonds, H. A., Amici, A., Naponelli, V., Magni, G., Seip, M., Ben-Bassat, I., Harley, E. H., Thein, S. L., Rees, D. C. Genetic basis of hemolytic anemia caused by pyrimidine 5-prime-nucleotidase deficiency. Blood 97: 3327-3332, 2001. [PubMed: 11369620] [Full Text: https://doi.org/10.1182/blood.v97.11.3327]
Oda, E., Oda, S., Tomoda, A., Lachant, N. A., Tanaka, K. R. Hemolytic anemia in hereditary pyrimidine 5-prime-nucleotidase deficiency. II. Effect of pyrimidine nucleotides and their derivatives on glycolytic and pentose phosphate shunt enzyme activity. Clin. Chim. Acta 141: 93-100, 1984. [PubMed: 6091951] [Full Text: https://doi.org/10.1016/0009-8981(84)90001-9]
Ozsoylu, S., Gurgey, A. A case of hemolytic anemia due to erythrocyte pyrimidine 5-prime-nucleotidase deficiency. Acta Haemat. 66: 56-58, 1981. [PubMed: 6270945] [Full Text: https://doi.org/10.1159/000207094]
Paglia, D. E., Fink, K., Valentine, W. N. Additional data from two kindreds with genetically induced deficiencies of erythrocyte pyrimidine nucleotidase. Acta Haemat. 63: 262-267, 1980. [PubMed: 6251690] [Full Text: https://doi.org/10.1159/000207413]
Paglia, D. E., Valentine, W. N., Brockway, R. A. Identification of thymidine nucleotidase and deoxyribonucleotidase activities among normal isozymes of 5-prime-nucleotidase in human erythrocytes. Proc. Nat. Acad. Sci. 81: 588-592, 1984. [PubMed: 6320196] [Full Text: https://doi.org/10.1073/pnas.81.2.588]
Paglia, D. E., Valentine, W. N., Keitt, A. S., Brockway, R. A., Nakatani, M. Pyrimidine nucleotidase deficiency with active dephosphorylation of dTMP: evidence for existence of thymidine nucleotidase in human erythrocytes. Blood 62: 1147-1149, 1983. [PubMed: 6313098]
Paglia, D. E., Valentine, W. N. Hereditary and acquired defects in the pyrimidine nucleotidase of human erythrocytes. Curr. Top. Hemat. 3: 75-109, 1980. [PubMed: 6276103]
Swallow, D. M., Turner, V. S., Hopkinson, D. A. Isozymes of rodent 5-prime-nucleotidase: evidence for two independent structural loci UMPH-1 and UMPH-2. Ann. Hum. Genet. 47: 9-17, 1983. [PubMed: 6301357] [Full Text: https://doi.org/10.1111/j.1469-1809.1983.tb00965.x]
Torrance, J. D., Karabus, C. D., Shnier, M., Meltzer, M., Katz, J., Jenkins, T. Haemolytic anaemia due to erythrocyte pyrimidine 5-prime-nucleotidase deficiency: report of the first South African family. S. Afr. Med. J. 52: 671-672, 1977. [PubMed: 601633]
Valentine, W. N., Fink, K., Paglia, D. E., Harris, S. R., Adams, W. S. Hereditary hemolytic anemia with human erythrocyte pyrimidine 5-prime-nucleotidase deficiency. J. Clin. Invest. 54: 866-879, 1974. [PubMed: 4372252] [Full Text: https://doi.org/10.1172/JCI107826]
Vives-Corrons, J. L., Montserrat-Costa, E., Rozman, C. Hereditary hemolytic anemia with erythrocyte pyrimidine 5-prime-nucleotidase deficiency in Spain. Clinical, biological and familial studies. Hum. Genet. 34: 285-292, 1976. [PubMed: 187542] [Full Text: https://doi.org/10.1007/BF00295292]