Prolidase deficiency

Prolidase deficiency (also known as peptidase D deficiency or imidodipeptidase deficiency) is a rare autosomal recessive metabolic disorder caused by mutations in the PEPD gene, which encodes the enzyme prolidase. This enzyme is essential for the final step in the degradation of imidodipeptides containing proline or hydroxyproline, particularly those derived from collagen breakdown. When prolidase is deficient, these dipeptides accumulate in body fluids and are excreted in massive amounts in the urine (iminodipeptiduria). Because collagen is a major structural protein throughout the body, the disorder affects multiple organ systems. The hallmark clinical feature is chronic, recalcitrant skin ulceration, predominantly affecting the lower extremities, which is often severe and resistant to conventional wound care. Other key manifestations include recurrent respiratory infections, splenomegaly, intellectual disability of variable severity, and characteristic facial features. Patients may also develop autoimmune phenomena, including systemic lupus erythematosus-like features, as well as chronic lung disease, anemia, thrombocytopenia, and hypergammaglobulinemia. The clinical presentation is highly variable, even among affected siblings, ranging from asymptomatic individuals to those with severe, debilitating disease. There is no definitive cure for prolidase deficiency. Treatment is largely supportive and symptomatic, focusing on wound management for skin ulcers, treatment of infections, and management of autoimmune complications. Various therapeutic approaches have been attempted, including topical and systemic proline and glycine supplementation, blood transfusions with erythrocytes containing functional prolidase (enzyme replacement via carrier erythrocytes), ascorbic acid, manganese supplementation, and growth hormone therapy, with variable and often limited success. Early diagnosis through measurement of prolidase enzyme activity in leukocytes or fibroblasts and identification of PEPD gene mutations is important for appropriate management and genetic counseling.

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