ERYTHROPOIETIC PROTOPORPHYRIA--MECHANISMS OF DISEASE

描述：(改编自研究人员摘要)红系 原卟啉症(EPP)是由部分基因决定的 血红素合成酶铁络合酶(Fc)活性不足 引起原卟啉(PP)在红细胞、血浆、肝脏和 粪便。PP会引起疼痛的皮肤光敏反应，并可能导致致命 肝脏毒性。关于EPP的自然进程仍有许多未知之处， 其致病机制和遗传方式。延续 一项既定的资源增值研究的持续纵向调查 具有标准化协议的人口，以及建立的现有数据库 在10年内，在24个不同种族背景的学科中，将进一步 阐明这种疾病的自然病程。个别患者可能 从及早发现肝功能不良变化中受益。 可了解导致致命性肝毒性发生的因素 从对数据库的回顾分析中发现 肝功能障碍与人群数据的比较 完整的。有关FC的缺陷活动的差异的信息 多样化的美国EPP人口将通过衡量其 患者、家属和对照组的白细胞水平。这 信息也将有助于建立(S)的继承模式 疾病，这可能是复杂的。分子遗传学研究 (限制片段长度多态、检测和描述 基因突变)将在分离自 患者、家属和对照的血液，以进一步定义 EPP的遗传异质性，并将与临床相关 症状学，血和血液中的卟啉负荷和代谢平衡 粪便分配区段，以及不同EPP中的FC活性 人口。少见病例的临床和实验室评价 几种相关形式的卟啉症将继续作为国家 实验室的资源功能。免疫标记法 显微解剖层面的表皮-真皮分离和直接 水泡中免疫反应物的免疫电子显微镜定位 各种类型的卟啉症和假性卟啉症将在皮肤上进行。 这些疾病患者的活检标本，以检查 他们之间的相似或不同之处，并以适当的目标 基底膜带的生物分子组成有待进一步研究。 乙型和丙型肝炎病毒暴露的流行率与 美国散发性与家族性迟发性皮肤卟啉病(PCT) 将通过对PCT血液样本的多中心研究来确定 患者检查病毒感染的证据，卟啉水平 积累量和尿卟啉原脱羧酶活性。这 信息，以及相关的病史、体检和临床 将对实验室数据进行统计意义上的分析 关联性。

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.