Hemolytic anemia due to pyrimidine-5'-nucleotidase deficiency: report of eight cases in six families

Abstract

We describe the clinical. hematologic. and biochemical findings in eight patients with pyrimidine-5'-nucleotidase deficiency occurring in six unrelated families. In most cases, a profound lowering of red cell pyrimidine-5'-nucleotidase activity. associated with the characteristic change in the u.v. spectrum brought about by increased levels of pyrimidine nucleotides was observed. One patient had an atypical presentation in that no stippled cells were apparent in the peripheral blood film. and the u.v. spectrum of red cell extracts was normal or nearly so. In addition, the one parent of this patient whose red cells were tested was not pyrimidine-5'-nucleotidase deficient. This patient may be a heterozygote for pyrimidine-5'-nucleotidase deficiency with hemolysis due to this or another cause. Several of the patients were found to be mentally retarded, and in one family in which several sibs. two with and one without pyrimidine-5'-nucleotidase deficiency. could be studied. the low IQ values were found only in the enzyme-deficient subjects. A pyrimidine-5'-nucleotidase activity is found in normal fibroblasts and. to the same extent. in the fibroblast of patients with pyrimidine-5'-nucleotidase deficiency. This activity is largely membrane bound. however. and is inhibited by the 5'-nucleotidase inhibitor, a-$-methylene ADP. Accordingly. it appears that fibroblasts are devoid of the type of specific pyrimidine-5'-nucleotidase activity found in normal erythrocytes. We suggest that pyrimidine-5'-nucleotidase deficiency is one of the more common recognized causes of nonspherocytic hemolytic anemia and that in some cases it may produce, in addition to hemolysis, mental retardation.

Molecular basis of Japanese variants of pyrimidine 5′‐nucleotidase deficiency

“…Severe deficiency of P5N‐I in RBC results in the accumulation of pyrimidine nucleotides. Increased levels of pyrimidine di‐ or triphosphates, such as cytidine diphosphate (CDP), uridine diphosphate (UDP), CTP or UTP, may interfere with reactions that require either ADP or ATP, resulting in impaired glycolysis (Beutler et al , 1980). In addition, CTP is a competitive inhibitor of glucose‐6‐phosphate and a non‐competitive inhibitor of NADP, with the result that hexose monophosphate shunt activity is suppressed by the pathological concentration of CTP and UTP because of P5N‐I deficiency (Tomoda et al , 1982).…”

Pyrimidine 5′‐nucleotidase activity in normal and deficient human lymphoblastoid cells

“…Little is known about the tissue distribution of UMPH1 except that it was reported not to occur in fibroblasts (Beutler et al, 1980), but it is likely that UMPH1 does occur in other tissues since in rodents the homologous enzyme has a wide tissue distribution (Swallow et al, 1983a). Furthermore, in man a pyrimidine nucleotidase of mobility comparable with UMPH 1 and UMPH2 is seen in most tissues (Swallow et al, 1983a) but because these two isozymes have a very similar electrophoretic mobility it is not entirely clear whether one or both are present in any particular tissue.…”

Hereditary pyrimidine 5′‐nucleotidase deficiency: from genetics to clinical manifestations

“…Delayed development and learning difficulties of variable degree were reported in seven patients, which was not related to the severity of haemolysis (Torrance et al , 1977b; Beutler et al , 1980; Li et al , 1991; Balta et al , 2003). Database searches have shown the presence of P5′N‐1 cDNA libraries in brain tissue (Marinaki et al , 2001); however, the significance of the association between mental retardation and P5′N deficiency is hard to assess; possible confounding factors include kernicterus or concomitance of other genetic defects in consanguineous families.…”

“…Aplastic crisis following parvovirus B19 infection (Rechavi et al , 1989) and chronic ankle ulcers (Beutler et al , 1980) were rare.…”

“…The blood film is mainly characterised by red cell basophilic stippling (2–12% of erythrocytes) (Ben‐Bassat et al , 1976; Marinaki et al , 2001; Bianchi et al , 2003) due to intracellular precipitation of undegraded RNA (Ericson et al , 1983); 5–10% of spherocytes, mostly spiculated, were detected at peripheral blood smear examination in two cases described by Valentine et al (1974) and Beutler et al (1980) and in the six patients reported by Bianchi et al (2003). Red cell osmotic fragility is usually normal with few exceptions (Buc et al , 1979; Paglia et al , 1980; Bianchi et al , 2003).…”