We describe a patient in whom chronic leg ulceration was due to prolidase deficiency. The clinical features of this condition are described and we discuss the metabolic abnormality and the treatment regimes which have been employed. We also report the further finding of erosive cystitis, which we consider should be added to the list of clinical features of prolidase deficiency.
Prolidase (EC3.4.3.7) is an enzyme hydrolysing dipeptides containing C-terminal proline or hydroxyproline. A deficiency in this enzyme (McKusick 26413) produces an iminodipeptiduria and is reported to be associated with leg ulceration, unusual facies, mental retardation, hepatosplenomegaly, skeletal abnormalities and a lowered resistance to infection. There have been sporadic reports of elevated immunoglobulins and thrombocytopenia and it has been suggested that, in view of its collagen-like amino-acid sequences, complement factor Clq might be affected (Rosenberg and Scriver, 1980). We report full biochemical and immunological studies on a family with this disorder. CASE REPORTSThe index case was a 40-year-old woman (B.S.) who had a history of intractable leg ulcerations from the age of 17. Both legs showed atrophy and telangiectasia up to the waist with a complete absence of valves in the large communicating veins. She had a 'bird-like' facial appearance with slight webbing of the neck, although her karyotype was normal. There was no evidence of hepatosplenomegaly, skeletal abnormalities or a lowered resistance to infection and she was of normal intelligence.Subsequently it was found that her brother (M.S.) was prolidase deficient. He developed leg ulcerations for one month following an injury to his leg. He has a history of an undiagnosed liver disorder associated with mild jaundice, pyrexia and abnormal liver-function tests. His serum ferritin level was grossly elevated (50rag/l) suggesting haemochromatosis.There is one other brother (P.S.) and one sister (J.S.) who both appear clinically normal, as does their mother (W.S.). The father is deceased-cause of death unknown. METHODSUrinary amino acids were quantitated using an amino acid analyser before and after hydrolysis with 6M HC1 at 110°C for 24 h. Prolidase and prolinase were assayed in dialysed erythrocyte lysates and cell-free fibroblast extracts (Isemura et al., 1979). Immunoglobulins and Clq were measured by radial immunodiffusion (Ward, 1981), as were immune complexes after precipitation by polyethylene glycol (Haeney, 1981). RESULTSHigh voltage electrophoresis of urinary amino acids from B.S. and M.S. revealed a continuous band from glycine to glutamic acid. Quantitative analysis showed low levels of ~11 urinary amino acids with several unidentified peaks consistent with peptides. After hydrolysis these peaks disappeared and the levels of all amino acids rose, especially proline, hydroxyproline, glycine and aspartic acid. Prolidase activity, was undetectable (< 7 % normal mean) in erythrocytes from B.S, and M.S. and in fibroblasts from B.S. One brother P.S. had a level of prolidase activity consistent with the heterozygous state whilst the mother and remaining sister were within the normal range. Erythrocyte prolinase activity was normal in both patients and relatives. Although Clq was normal in all members of the family there were consistent elevations of IgG and IgA in plasma from the patients (Table 1) and circulating immune complexes were detect...
An 18-year-old West Indian male presented with severe sternal pain and an exacerbation of facial acne. Radiographs of the sternum revealed several lytic lesions which appeared as hot areas on successive technetium bone scans. Painful areas over the right iliac crest and left greater trochanter likewise appeared as transient hot areas on successive scans. Histology of affected bone revealed reactive changes only. High dose prednisolone provided rapid alleviation of pain, which recurred on reducing the dose to less than 10 mg daily. Auto-immune complex disease has been considered the most likely aetiological mechanism of systemic acne (acne fulminans), but lytic lesions of bone have never previously been reported in auto-immune disorders.
Clofazimine, at concentrations within the therapeutic range (0.01–5 μg/ml), stimulated human polymorphonuclear leucocytes (PMNL) to generate increased amounts of reactive oxidants (RO) when activated with the tripeptide leucoattractant N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP), calcium ionophore, phorbol myristate acetate and opsonised zymosan. Clofazimine per se did not activate the membrane-associated oxidative metabolism of PMNL, but rather primed these cells to hyperreact to the various stimuli. To investigate the therapeutic significance of these observations clofazimine was administered to patients with various chronic inflammatory diseases (lichen planus, discoid lupus erythematosus and rheumatoid arthritis) and generation of RO by FMLP-activated phagocytes was measured before and during clofazimine administration. A statistically significant potentiation of RO generation by FMLP-activated phagocytes was observed during clofazimine administration. Since RO are immunosuppressive and antimicrobial the therapeutic mechanisms of clofazimine may be related to pro-oxidative interactions of this agent with phagocytes.
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