Pyrimidine 5nucleotidase deficiency

Pyrimidine 5'-nucleotidase deficiency is not uncommon, although only some 40 or 50 families have been reported in the literature. It is probably the third most common enzyme deficiency causing haemolytic anaemia, perhaps equal to GPI deficiency. Nearly all reported cases have shown homozygosity for the mutation, and the mutation has been specific for individual families. There is, however, a suggestion that certain mutations (Del G576 and INS GG743) might be more prevalent in southern Italy or southern Mediterranean regions. One compound heterozygote was found in this region.

Deficiency of P5N1 is associated with a recessively inherited haemolytic anaemia characterized by marked basophilic stippling in the red cells (Figure 9.16) and accumulation of high concentrations of pyrimidine nucleotides. The haemolysis is usually mild to moderate, although more severe cases have been reported. Splenectomy is usually of little value, though benefit has been reported in some cases. The appearance of the blood film is similar to that seen in lead poisoning, and the mechanism of the anaemia in lead poisoning certainly involves the inhibition of pyrimidine 5'-nucleotidase.

General and reviews

Arya R, Layton DM, Bellingham AJ (1995) Hereditary red cell enzymopathies. Blood Reviews 9:165-75.

Beutler E, Blume KG, Kaplan JC et al. (1979) International Committee for Standardization in Haematology: recommended screening test for glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. British Journal of Haematology 43:465-7.

Dacie JV (1999) The Haemolytic Anaemias, Vol. 1, 3rd edn. Churchill Livingstone, London.

Miwa S, Fujii H (1996) Molecular basis of erythroenzymopathies associated with hereditary haemolytic anaemia: tabulation of mutant enzymes. American Journal of Hematology 51:122-32.

OMIM. Online Mendelian Inheritance in Man (www.ncbi.nih.gov/ entrez/query).

Roper D, Layton M, Lewis SM (2001) Investigation ofthe hereditary haemolytic anaemias: membrane and enzyme abnormalities. In: Dacie and Lewis, Practical Haematology (SM Lewis, BJ Bain, I Bates, eds), 9th edn, pp. 167-98. Churchill Livingstone, London.

Enzyme deficiencies of the Embden-Meyerhof pathway

Pyruvate kinase deficiency

Baronciani L, Bianchi P, Zanella A (1996) Hematologically important mutations: red cell pyruvate kinase. Blood Cells Molecules and Diseases 22: 85-9.

Beutler E, Baronciani L (1996) Mutations in pyruvate kinase. Human Mutation 7:1-6 .

Beutler E, Gelbart T (2000) PK deficiency prevalence and the limitations of a population-based survey [Letter]. Blood96:4005-6.

Bianchi P, Zappa M, Bredi E et al. (1999) A case of complete adenylate kinase deficiency due to a nonsense mutation in AK-1 gene (Arg 107^Stop, CGA^TGA) associated with chronic haemolytic anaemia. British Journal of Haematology 105: 75-9.

Carey PJ, Chandler J, Hendrick A et al. (2000) Prevalence of pyru-vate kinase deficiency in a northern European population in the north of England [Letter]. Blood96:4005.

Gilsanz F, Vega MA, Gomez-Castillo E etal. (1993) Fetal anemia due to pyruvate kinase deficiency. Archive of Diseases of Childhood 69: 523-4.

Kugler W, Laspe P, Stahl M etal. (1999) Identification of a novel promoter mutation in the human pyruvate kinase (PK) LR gene of a patient with severe haemolytic anaemia. British Journal of Haematology 105: 596-8.

Manco L, Bento C, Ribeiro ML etal. (2002) Consequences at mRNA level ofthe PKLR gene splicing mutations IVS10(+1)G^C and IVS8(+2)T^G causing pyruvate kinase deficiency. British Journal of Haematology 118: 927-8.

Marshall SR, Saunders PWG, Hamilton PJ et al. (2000) The dangers of iron overload in pyruvate kinase deficiency. British Journal of Haematology 120:1090-1.

Miwa S, Fujii H (1996) Molecular basis of erythroenzymopathies associated with hereditary hemolytic anemia: tabulation of mutant enzymes. American Journal of Hematology 51:122-32.

Zanella A, Bianchi P, Fermo E etal. (2001) Molecular characterization of the PK-LR gene in sixteen pyruvate kinase-deficient patients. British Journal of Haematology 113:43-8.

Other enzymes of the Embden-Meyerhof pathway

Beutler E, West C, Britton HA etal. (1997) Glucose phosphate isomerase (GPI) deficiency mutations associated with hereditary nonspherocytic haemolytic anemia (HNSHA). Blood cells, Molecules and Diseases 23:402-9.

Kreuder J, Borkhardt A, Repp R et al. (1996) Brief report: inherited metabolic myopathy and hemolysis due to a mutation in aldolase A. New England Journal of Medicine 334:1101-4.

McCann SR, Finkel B, Cadman S etal. (1976) Study of a kindred with hereditary spherocytosis and glyceraldehyde-3-phosphate dehydrogenase deficiency. Blood 47:171-81.

Morimoto A, Ueda I, Hirashima Y etal. (2003) A novel missense mutation (1060G^C) in the phosphoglycerate kinase gene in a Japanese boy with chronic haemolytic anaemia, developmental delay and rhadomyolysis. British Journal of Haematology 122: 1009-13.

Murakmi K, Kanno H, Tancabelic J etal. (2002) Gene expression and biological significance of hexokinase in erythroid cells. Acta Haematologica 108: 204-9.

Tani K, Fujii H, Takegawa S etal. (1983) Two cases of phosphofruc-tokinase deficiency associated with congenital hemolytic anaemia found in Japan. American Journal of Hematology 14:165-79.

Valentin C, Pissard S, Martin J etal. (2000) Triose phosphate isomerase deficiency in three French families: two novel null alleles, a frameshift mutation (TPI Alfortville), and an alteration in the initiation codon (TPI Paris). Blood 96:1130-5.

Vora S, Corash L, Engel WK etal. (1980) The molecular mechanisms of the inherited phosphofructokinase deficiency associated with haemolysis and myopathy. Blood 69: 629-35.

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