ERYTHROPOIETIC PROTOPORPHYRIA - MECHANISMS OF DISEASES

DESCRIPTION: (Adapted from investigator's abstract) Erythropoietic protoporphyria (EPP) arises from genetically determined partially deficient activity of the heme synthetic enzyme ferrochelatase (FC) that causes accumulation of protoporphyrin (PP) in rbc, plasma, liver and feces. PP causespainful cutaneous photosensitivity and may lead to fatal hepatotoxicity. Much remains unknown about the natural course of EPP, its pathogenetic mechanisms and inheritance patterns. Continuation of ongoing longitudinal investigations of an established EPP study population with a standardized protocol, and an existing data base built over 10 years in 24 subjects of diverse ethnic backgrounds, will further elucidate the natural course of the disease. Individual patients may benefit from early detection of adverse changes in hepatic function. Factors leading to development of fatal hepatotoxicity may be learned from retrospective analysis of the data base for patients who develop liver dysfunction when compared with the data of the population as a whole. Information about the variance in defective activity of FC in a diverse United States EPP population will be gained by measuring its levels in leukocytes of patients, family members and controls. This information will also aid in establishing the inheritance pattern(s) of the disease, which may be complex. Molecular genetic studies (restriction fragment length polymorphisms, detection and description of gene mutations) will be continued in genetic material isolated from blood of patients, family members and controls to further define the genetic heterogeneity of EPP, and will be correlated with clinical symptomatology, porphyrin burden and metabolic balance in blood and fecal distribution compartments, and FC activity in this diverse EPP population. Clinical and laboratory evaluations of unusual cases of several related forms of porphyria will be continued as a national resource function of the laboratory. Immunomapping of the microanatomical level of the epidermal-dermal separation and direct immunoelectron microscopic localization of immune reactants in blistering forms of porphyrias and "pseudoporphyrias" will be performed in skin biopsy specimens of patients with these disorders, to examine similarities or differences among them, and to target appropriate biomolecular components of the basement membrane zone for further study. The prevalence of the association of hepatitis B and C viral exposure and sporadic vs. familial porphyria cutanea tarda (PCT) in the United States will be determined by a multicenter study of blood specimens from PCT patients examining evidence of viral infection, levels of porphyrin accumulation and uroporphyrinogen decarboxylase activity. This information, and relevant historical, physical examination, and clinical laboratory data will be analyzed for statistically significant correlations.