title: Acute hepatic and erythropoietic porphyrias: from ALA synthases 1 and 2 to new molecular bases and treatments.
abstract: OBJECTIVE
  Many studies over the past decade have together identified new genes including modifier genes and new regulation and pathophysiological mechanisms in inherited inborn diseases of the heme biosynthetic pathway. A new porphyria has been characterized: X-linked protoporphyria and the perspective to have innovative treatment at very short-term became a reality. We will summarize how recent data on both ALAS1 and ALAS2 have informed our understanding of disease pathogenesis with an emphasis on how this information may contribute to new therapeutic strategies.
  
  
  RESULTS
  The development of clinical and biological porphyria networks improved the long-term follow up of cohorts. The ageing of patients have allowed for the identification of novel recurrently mutated genes, and highlighted long-term complications in acute hepatic porphyrias. The treatment of hepatic porphyrias by an RNAi-targeting hepatic ALAS1 is actually tested and may lead to improve the management of acute attacks.In erythropoietic porphyrias, the key role of ALAS2 as a gate keeper of the heme and subsequently hemoglobin synthesis has been demonstrated. Its implication as a modifier gene in over erythroid disorders has also been documented.
  
  
  CONCLUSIONS
  The knowledge of both the genetic abnormalities and the regulation of heme biosynthesis has increased over the last 5 years and open new avenues in the management of erythropoietic and acute hepatic porphyrias.
authors.affiliation: aINSERM U1149 CNRS ERL 8252, Centre de Recherche sur l'inflammation, Université Paris Diderot, site Bichat, Sorbonne Paris Cité bLaboratory of excellence, GR-Ex, Paris cAP-HP, Centre Français des Porphyries, Hôpital Louis Mourier, Colombes dAP-HP, Hôpital Beaujon, Service de Biochimie Clinique, Clichy, France.
authors.forename: Hana
authors.initials: H
authors.lastname: Manceau
authors.forename: Laurent
authors.initials: L
authors.lastname: Gouya
authors.forename: Hervé
authors.initials: H
authors.lastname: Puy
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D000367:Age Factors; D000818:Animals; D015415:Biomarkers; D059350:Chronic Pain / Q000209:etiology; D004789:Enzyme Activation; D004912:Erythrocytes / Q000378:metabolism; D005786:Gene Expression Regulation; D050172:Genes, X-Linked; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006418:Heme / Q000096:biosynthesis; D006801:Humans; D009154:Mutation; D010641:Phenotype; D000623:Porphobilinogen Synthase / Q000172:deficiency* / Q000378:metabolism; D017092:Porphyria, Erythropoietic / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism* / Q000628:therapy; D017094:Porphyrias, Hepatic / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism* / Q000628:therapy; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D015415:Biomarkers; D034741:RNA, Small Interfering; D006418:Heme; D000624:5-Aminolevulinate Synthetase; C480079:ALAS2 protein, human; D000623:Porphobilinogen Synthase