Uridine 5-Prime Monophosphate Hydrolase Deficiency, Hemolytic Anemia Due To

A number sign (#) is used with this entry because hemolytic anemia due to uridine 5-prime monophosphate hydrolase deficiency is caused by homozygous or compound heterozygous mutation in the NT5C3A gene (606224) on chromosome 7p14.

Description

Deficiency of pyrimidine 5-prime nucleotidase, also called uridine 5-prime monophosphate hydrolase, causes an autosomal recessive hemolytic anemia 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).

Clinical Features

Valentine et al. (1974) showed deficiency of this enzyme in 4 subjects 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.

Molecular Genetics

In patients with hemolytic anemia due to deficiency of P5N, Marinaki et al. (2001) identified mutations in the UMPH1 gene (606224.0001-606224.0003).

In Turkish patients with pyrimidine 5-prime nucleotidase deficiency (266120), Balta et al. (2003) identified homozygous mutations in the UMPH1 gene (606224.0004-606224.0005).