Immunochemical analyses of prolidase deficiency sera

Sera of a 30-year-old Italian female and a 32-year-old Japanese female with prolidase deficiency were analysed by two-dimensional immunoelectrophoresis, rocket immunoelectrophoresis, and single radial immunodiffusion (SRID). In both patients, amounts of transferrin, albumin and IgM were significantly low, while concentrations of α1-acid glycoprotein, α1-antitrypsin, α1-antichymotrypsin, ceruloplasmin, IgA and Clq were elevated in comparison with levels of these proteins in sera of healthy Italian and Japanese female adults (as normal controls). The amount of haptoglobin was conspicuously high in the Italian patient but remarkably low in the Japanese patient.     

Characterization of fibroblast-derived prolidase. The presence of two forms of prolidase

Crude enzyme solutions of prolidase were extracted from cultured human skin fibroblasts derived from control and prolidase-deficient sisters. Two forms of prolidases (prolidase-I and II) were partially purified by high performance liquid chromatography equipped with an ion exchange column. On gel filtration, the relative molecular weights of prolidase-I and II were estimated to be MW = 105,000 and 151,000, respectively. The substrate specificity of partially purified prolidase-I and II in control fibroblasts was estimated against Gly-Pro, Ala-Pro, Met-Pro. Each form of prolidase differed in its substrate specificity. In prolidase-deficient sisters, the elder with typical clinical manifestations and the younger with only slight clinical manifestations, the activity of prolidase-I was absent. However, the activity of prolidase-II was sufficiently present in both sisters. The substrate specificity of prolidase-II in the patients was similar to that of control. No difference in substrate specificity was found between these two patients.     

Therapeutic apheresis exchange in two patients with prolidase deficiency

BACKGROUND: Prolidase deficiency is a rare genetic disorder for which a cure has not yet been found. OBJECTIVES: To assess the effectiveness of apheresis exchange as a new therapeutic approach. METHODS: Apheresis exchanges were repeated monthly for four consecutive months, in parallel, on two patients, replacing prolidase-deficient red blood cells with normal filtered cells. Prolidase activity and urinary dipeptides were determined at regular intervals. RESULTS: The constant presence of active prolidase inside cells allowed a continuous, although partial, degradation of imidodipeptides, with a concomitant improvement of skin ulceration. CONCLUSIONS: Apheresis exchange could be a reasonable way of obtaining a clinical improvement in these patients.     

Hereditary prolidase deficiency in 2 sisters with therapy-resistant leg ulcers

Two sisters with hereditary prolidase deficiency are presented. Recurrent and painful leg ulcers are the predominant feature.     

Blood transfusions in the therapy of a case of prolidase deficiency

A case is reported of a 15-year-old boy with prolidase deficiency and marked urinary excretion of the iminodipeptide gly-pro. Prolidase activity of erythrocytes against substrate glycyl-proline was deficient, but after blood transfusions this was increased to 15.7% of donor activity and declined to 12% and 3.4% of normal activity after 8 and 45 days, respectively. Urinary iminodipeptide levels following transfusion remained unaltered.     

Prolidase deficiency in two siblings with chronic leg ulcerations. Clinical, biochemical, and morphologic aspects

Prolidase deficiency occurred in two sisters suffering from recurrent leg ulcers that appeared in early childhood. The patients presented the typical clinical symptoms of the disease, including characteristic facies, dermatologic manifestations of the lower extremities, splenomegaly, and hematologic anomalies. Large amounts of iminodipeptides were excreted into the urine, and prolidase activity in their erythrocytes was virtually absent. Changes associated with a connective-tissue disorder were demonstrated by light and electron microscopic studies of the patients' apparently normal skin. Collagen fibers were smaller than in controls and were irregularly packed; the fibrils had normal aspect but were significantly smaller than in one age-matched control. Elastin fibers appeared altered both in size and structure.     

Corticosteroid treatment of prolidase deficiency skin lesions by inhibiting iminodipeptide-primed neutrophil superoxide generation

We studied the pathogenetic role of iminodipeptides, and the effects of corticosteroids on the skin lesions of two adult female siblings with prolidase deficiency. The elder sister had had severe skin ulcers and mental retardation since childhood, while the younger sister had shown milder clinical manifestations since late adolescence. The ulcers showed vascular wall thickening and neutrophil infiltration. Oral prednisolone at moderate doses was not effective, but corticosteroid pulse therapy followed by a moderate dose of prednisolone improved the preulcerative indurated lesions and ulcers. A 2-year follow-up of the younger patient indicated that N-formyl methionyl leucyl phenylalanine-induced neutrophil superoxide generation was elevated, in parallel with an increase in the serum iminodipeptide level, when the skin ulcers and preulcerative indurated lesions were most active. Corticosteroid pulse therapy downregulated the superoxide generation by neutrophils. The serum iminodipeptide level, however, did not decrease during 25 days after pulse therapy. These findings suggest that iminodipeptides may play an important part in aggravating the skin lesions by priming neutrophil superoxide generation, and that high-dose corticosteroids improve the skin lesions, probably by inhibiting the infiltration, and superoxide generation by, neutrophils. Neutrophil superoxide generation was more prominent in the elder sister, suggesting that clinical severity may depend on the response of neutrophils to the iminodipeptides. Chronic stimulation by superoxide may cause thickening of cerebral blood vessels and eventual mental retardation.