RESUMEN
RESUMEN Las porfirias constituyen un grupo de trastornos, causados por defectos en la vía de síntesis del grupo hemo. En la porfiriaeritropoyética congénita, existe deficiencia de la uroporfirinógenosintetasa, lo que a su vez provoca acumulación de grandes cantidades de uroporfirina I en todos los tejidos, dando lugar a fotosensibilidad con lesiones mutilantes de la piel,eritrodoncia, anemia hemolítica, esplenomegalia y fragilidad ósea. El diagnóstico definitivo se fundamenta en la demostración de la actividad deficiente de la uroporfirinógenosintetasa o la determinación de mutaciones específicas en el gen respectivo;su tratamiento requiere colaboración multidisciplinaria. En el presente artículo se describe un caso de porfiriaeritropoyética, con la presentación clínica dermatológica muy característica.
SUMMARY Porphyrias are a group of disorders caused by defects in the synthesis pathway of heme. Congenital erythropoietic porphyria is characterized by uroporphyrinogen synthase deficiency, which causes accumulation of large amounts of uroporphyrin Iin all tissues; resulting in photosensitivity with mutilating skin lesions, erythrodontia, hemolytic anemia, splenomegaly, and bone fragility. Definitive diagnosis is based on demonstrating poor uroporphyrinogen synthase activity or determination of specific mutations in the respective gene; treatment requires multidisciplinary collaboration. A case of erythropoietic porphyria, with classical dermatological clinical presentation is reported.
RESUMEN
Hemoglobin is an essential biological component of human physiology and its production in red blood cells relies upon proper biosynthesis of heme and globin protein. Disruption in the synthesis of these precursors accounts for a number of human blood disorders found in patients. Mutations in genes encoding heme biosynthesis enzymes are associated with a broad class of metabolic disorders called porphyrias. In particular, one subtype - erythropoietic protoporphyria - is caused by the accumulation of protoporphyrin IX. Erythropoietic protoporphyria patients suffer from photosensitivity and a higher risk of liver failure, which is the principle cause of morbidity and mortality. Approximately 90% of these patients carry loss-of-function mutations in the enzyme ferrochelatase (FECH), while 5% of cases are associated with activating mutations in the C-terminus of ALAS2. Recent work has begun to uncover novel mechanisms of heme regulation that may account for the remaining 5% of cases with previously unknown genetic basis. One erythropoietic protoporphyria family has been identified with inherited mutations in the AAA+ protease ClpXP that regulates ALAS activity. In this review article, recent findings on the role of ClpXP as both an activating unfoldase and degrading protease and its impact on heme synthesis will be discussed. This review will also highlight the role of ClpX dysfunction in erythropoietic protoporphyria.
RESUMEN
ABSTRACT Hemoglobin is an essential biological component of human physiology and its production in red blood cells relies upon proper biosynthesis of heme and globin protein. Disruption in the synthesis of these precursors accounts for a number of human blood disorders found in patients. Mutations in genes encoding heme biosynthesis enzymes are associated with a broad class of metabolic disorders called porphyrias. In particular, one subtype - erythropoietic protoporphyria - is caused by the accumulation of protoporphyrin IX. Erythropoietic protoporphyria patients suffer from photosensitivity and a higher risk of liver failure, which is the principle cause of morbidity and mortality. Approximately 90% of these patients carry loss-of-function mutations in the enzyme ferrochelatase (FECH), while 5% of cases are associated with activating mutations in the C-terminus of ALAS2. Recent work has begun to uncover novel mechanisms of heme regulation that may account for the remaining 5% of cases with previously unknown genetic basis. One erythropoietic protoporphyria family has been identified with inherited mutations in the AAA+ protease ClpXP that regulates ALAS activity. In this review article, recent findings on the role of ClpXP as both an activating unfoldase and degrading protease and its impact on heme synthesis will be discussed. This review will also highlight the role of ClpX dysfunction in erythropoietic protoporphyria.