RESUMEN
The inherited porphyrias are inborn errors of haem biosynthesis, each resulting from the deficient activity of a specific enzyme of the haem biosynthetic pathway. Porphyrias are divided into erythropoietic and hepatic according to the predominant porphyrin-accumulating tissue. Three different erythropoietic porphyrias (EP) have been described: erythropoietic protoporphyria (EPP, MIM 177000) the most frequent, congenital erythropoietic porphyria (CEP, MIM 263700), and the very rare hepatoerythropoietic porphyria (HEP, MIM 176100). Bone marrow transplantation is considered as the only curative treatment for severe cases of erythropoietic porphyria (especially CEP), if donors are available. Some EPP patients who undergo liver failure may require hepatic transplantation. Murine models of EPP and CEP have been developed and mimic most of the human disease features. These models allow a better understanding of the pathophysiological mechanisms involved in EP as well as the development of new therapeutic strategies. The restoration of deficient enzymatic activity in the bone marrow compartment following gene therapy has been extensively studied. Murine oncoretroviral, and recently, lentiviral vectors have been successfully used to transduce hematopoietic stem cells, allowing full metabolic and phenotypic correction of both EPP and CEP mice. In CEP, a selective survival advantage of corrected cells was demonstrated in mice, reinforcing the arguments for a gene therapy approach in the human disease. These successful results form the basis for gene therapy clinical trials in severe forms of erythropoietic porphyrias.
Asunto(s)
Terapia Genética/métodos , Porfiria Eritropoyética/terapia , Animales , Trasplante de Médula Ósea , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Noqueados , Ratones Mutantes , Porfiria Cutánea Tardía/genética , Porfiria Cutánea Tardía/terapia , Porfiria Eritropoyética/genética , Porfiria Hepatoeritropoyética/genética , Porfiria Hepatoeritropoyética/terapiaRESUMEN
Recent advances in the molecular understanding of the porphyrias now offer specific diagnosis and precise definition of the types of genetic mutations involved in the disease. Molecular diagnostic testing is powerful and very useful in kindred evaluation and genetic counselling when a disease-responsible mutation has been identified in the family. It is also the only way to properly screen asymptomatic gene carriers, facilitating correct treatment and appropriate genetic counselling of family members at risk. However, it should be noted that DNA-based testing is for the diagnosis of the gene carrier status, but not for the diagnosis of clinical syndrome or severity of the disease, e.g. an acute attack. For the diagnosis of clinically expressed porphyrias, a logical stepwise approach including the analysis of porphyrins and their precursors should not be underestimated, as it is still very useful, and is often the best from the cost-effective point of view.
Asunto(s)
Porfirias/diagnóstico , Enfermedad Aguda , Enfermedad Crónica , Coproporfiria Hereditaria/diagnóstico , Coproporfiria Hereditaria/terapia , Hemo/biosíntesis , Humanos , Porfobilinógeno Sintasa/metabolismo , Porfiria Cutánea Tardía/diagnóstico , Porfiria Cutánea Tardía/terapia , Porfiria Eritropoyética/diagnóstico , Porfiria Eritropoyética/terapia , Porfiria Hepatoeritropoyética/diagnóstico , Porfiria Hepatoeritropoyética/terapia , Porfiria Variegata/diagnóstico , Porfiria Variegata/terapia , Porfirias/clasificación , Porfirias/terapia , Porfirias Hepáticas/diagnóstico , Porfirias Hepáticas/terapia , Protoporfiria Eritropoyética/diagnóstico , Protoporfiria Eritropoyética/terapiaAsunto(s)
Trastornos por Fotosensibilidad/sangre , Porfiria Hepatoeritropoyética/sangre , Sangre/efectos de la radiación , Salud de la Familia , Femenino , Fluorescencia , Humanos , Trasplante de Hígado , Persona de Mediana Edad , Trastornos por Fotosensibilidad/patología , Trastornos por Fotosensibilidad/terapia , Plasmaféresis , Porfiria Hepatoeritropoyética/patología , Porfiria Hepatoeritropoyética/terapia , Rayos UltravioletaRESUMEN
BACKGROUND: Erythropoietic protoporphyria (EPP) is an inherited disease characterised by a ferrochelatase (FECH) deficiency, the latest enzyme of the heme biosynthetic pathway, leading to the accumulation of toxic protoporphyrin in the liver, bone marrow and spleen. We have previously shown that a successful gene therapy of a murine model of the disease was possible with lentiviral vectors even in the absence of preselection of corrected cells, but lethal irradiation of the recipient was necessary to obtain an efficient bone marrow engraftment. To overcome a preconditioning regimen, a selective growth advantage has to be conferred to the corrected cells. METHODS: We have developed a novel bicistronic lentiviral vector that contains the human alkylating drug resistance mutant O(6)-methylguanine DNA methyltransferase (MGMT G156A) and FECH cDNAs. We tested their capacity to protect hematopoietic cell lines efficiently from alkylating drug toxicity and correct enzymatic deficiency. RESULTS: EPP lymphoblastoid (LB) cell lines, K562 and cord-blood-derived CD34(+) cells were transduced at a low multiplicity of infection (MOI) with the bicistronic constructs. Resistance to O(6)-benzylguanine (BG)/N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) was clearly shown in transduced cells, leading to the survival and expansion of provirus-containing cells. Corrected EPP LB cells were selectively amplified, leading to complete restoration of enzymatic activity and the absence of protoporphyrin accumulation. CONCLUSIONS: This study demonstrates that a lentiviral vector including therapeutic and G156A MGMT genes followed by BG/BCNU exposure can lead to a full metabolic correction of deficient cells. This vector might form the basis of new EPP mouse gene therapy protocols without a preconditioning regimen followed by in vivo selection of corrected hematopoietic stem cells.
Asunto(s)
Terapia Genética , Vectores Genéticos , Lentivirus/genética , O(6)-Metilguanina-ADN Metiltransferasa/genética , Porfiria Hepatoeritropoyética/terapia , Animales , Antígenos CD34/inmunología , Antineoplásicos/farmacología , Carmustina/farmacología , Línea Celular , ADN Complementario/genética , ADN Complementario/metabolismo , Resistencia a Antineoplásicos , Ferroquelatasa/genética , Ferroquelatasa/metabolismo , Regulación de la Expresión Génica , Regulación Viral de la Expresión Génica , Proteínas Fluorescentes Verdes , Humanos , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Ratones , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , Mutación Puntual , Porfiria Hepatoeritropoyética/genética , Porfiria Hepatoeritropoyética/metabolismo , Regiones Promotoras Genéticas , Linfocitos T/inmunología , Factores de Tiempo , TransgenesRESUMEN
The breast cancer resistance protein (BCRPABCG2) is a member of the ATP-binding cassette family of drug transporters and confers resistance to various anticancer drugs. We show here that mice lacking Bcrp1Abcg2 become extremely sensitive to the dietary chlorophyll-breakdown product pheophorbide a, resulting in severe, sometimes lethal phototoxic lesions on light-exposed skin. Pheophorbide a occurs in various plant-derived foods and food supplements. Bcrp1 transports pheophorbide a and is highly efficient in limiting its uptake from ingested food. Bcrp1(-/-) mice also displayed a previously unknown type of protoporphyria. Erythrocyte levels of the heme precursor and phototoxin protoporphyrin IX, which is structurally related to pheophorbide a, were increased 10-fold. Transplantation with wild-type bone marrow cured the protoporphyria and reduced the phototoxin sensitivity of Bcrp1(-/-) mice. These results indicate that humans or animals with low or absent BCRP activity may be at increased risk for developing protoporphyria and diet-dependent phototoxicity and provide a striking illustration of the importance of drug transporters in protection from toxicity of normal food constituents.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/fisiología , Clorofila/análogos & derivados , Clorofila/toxicidad , Dermatitis Fototóxica/prevención & control , Resistencia a Medicamentos/genética , Proteínas de Neoplasias , Fármacos Fotosensibilizantes/toxicidad , Porfiria Hepatoeritropoyética/prevención & control , Porfirinas/metabolismo , Protoporfirinas/sangre , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/genética , Administración Oral , Animales , Trasplante de Médula Ósea , Línea Celular , Clorofila/administración & dosificación , Clorofila/farmacocinética , Cromatografía Líquida de Alta Presión , Dermatitis Fototóxica/etiología , Dieta/efectos adversos , Femenino , Feto/metabolismo , Fibroblastos/metabolismo , Predisposición Genética a la Enfermedad , Medicago sativa/efectos adversos , Ratones , Ratones Endogámicos , Ratones Noqueados , Estructura Molecular , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/farmacocinética , Porfiria Hepatoeritropoyética/genética , Porfiria Hepatoeritropoyética/terapia , Porfirinas/farmacocinética , Embarazo , Protoporfirinas/química , Quimera por Radiación , Topotecan/farmacocinética , Topotecan/toxicidadRESUMEN
Since Professor Magnus first defined erythropoietic protoporphyria (EPP) in 1961, there has been considerable progress in the understanding this disease. The past decade has been a period of spectacular progress in understanding the genetics and pathogenesis of the disease by molecular investigation. However, progress in therapy for EPP has been slower, and has been dogged by difficulty in assessing treatment efficacy in patients. We are now entering an era in which advances in molecular genetics are directly affecting patient management. This review summarises laboratory and clinical progress in EPP in the past 40 years, and assesses the potential impact of molecular biology on clinical practice.
Asunto(s)
Porfiria Hepatoeritropoyética/genética , Animales , Ferroquelatasa/genética , Terapia Genética , Humanos , Ratones , Biología Molecular , Porfiria Hepatoeritropoyética/enzimología , Porfiria Hepatoeritropoyética/terapiaRESUMEN
Acute myelogenous leukemia occurred in a 47-year-old woman whose 25-year history of cutaneous photosensitivity had been undiagnosed until abnormally high erythrocyte, plasma, and fecal protoporphyrin levels were discovered during evaluation for her hematologic disorder. She was found to be heteroallelic for ferrochelatase gene mutations, bearing a novel missense mutation caused by a C185-->G (Pro62-->Arg) transversion in exon 2 of one allele, and a previously described g-->a transition at the +5 position of the exon 1 donor site of the other allele, confirming a diagnosis of erythropoietic protoporphyria. Successful bone marrow transplantation from her brother, who is a mildly affected bearer of the second mutation, resulted in remission of the leukemia and in conversion of the protoporphyria phenotype of the recipient to one resembling that of the donor.
Asunto(s)
Trasplante de Médula Ósea , Ferroquelatasa/genética , Leucemia Mielomonocítica Aguda/terapia , Porfiria Hepatoeritropoyética/diagnóstico , Porfiria Hepatoeritropoyética/terapia , Cartilla de ADN , Femenino , Humanos , Leucemia Mielomonocítica Aguda/complicaciones , Persona de Mediana Edad , Mutación , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Porfiria Hepatoeritropoyética/complicaciones , Porfiria Hepatoeritropoyética/genética , Porfiria Hepatoeritropoyética/patología , Porfirinas/sangre , Porfirinas/metabolismo , Porfirinas/orina , Protoporfirinas/sangre , Protoporfirinas/metabolismo , Protoporfirinas/orinaRESUMEN
Erythropoietic protoporphyria (EPP) is characterized by a deficiency of ferrochelatase the final enzyme of the heme biosynthetic pathway. Patients with EPP may overproduce protoporphyrin IX, chiefly in developing erythrocytes. In some, protoporphyrin accumulates and causes toxicity, particularly to the skin and liver. Orthotopic liver transplantation (OLT) treats the severe liver disease that sometimes occurs in EPP; however, it does not correct the underlying metabolic disorder. We recently reported a patient with EPP who was improved with plasmapheresis and i.v. heme-albumin before OLT. Subsequently he developed histological and biochemical evidence of recurrent hepatotoxicity from protoporphyrin in the graft liver. We now report successful treatment of the patient with additional plasmapheresis and heme-albumin with improvement of hepatic histological and biochemical abnormalities. We conclude that plasmapheresis and heme-albumin are of benefit in EPP complicated by hepatotoxicity before and after liver transplantation.
Asunto(s)
Albúminas/administración & dosificación , Hemo/administración & dosificación , Trasplante de Hígado/efectos adversos , Plasmaféresis , Porfiria Hepatoeritropoyética/terapia , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Porfiria Hepatoeritropoyética/etiologíaRESUMEN
Successful treatment of blood disorders by gene therapy has several complications, one of which is the frequent lack of selective advantage of genetically corrected cells. Erythropoietic protoporphyria (EPP), caused by a ferrochelatase deficiency, is a good model of hematological genetic disorders with a lack of spontaneous in vivo selection. This disease is characterized by accumulation of protoporphyrin in red blood cells, bone marrow, and other organs, resulting in severe skin photosensitivity. Here we develop a self-inactivating lentiviral vector containing human ferrochelatase cDNA driven by the human ankyrin-1/beta-globin HS-40 chimeric erythroid promoter/enhancer. We collected bone marrow cells from EPP male donor mice for lentiviral transduction and injected them into lethally irradiated female EPP recipient mice. We observed a high transduction efficiency of hematopoietic stem cells resulting in effective gene therapy of primary and secondary recipient EPP mice without any selectable system. Skin photosensitivity was corrected for all secondary engrafted mice and was associated with specific ferrochelatase expression in the erythroid lineage. An erythroid-specific expression was sufficient to reverse most of the clinical and biological manifestations of the disease. This improvement in the efficiency of gene transfer with lentiviruses may contribute to the development of successful clinical protocols for erythropoietic diseases.
Asunto(s)
Células de la Médula Ósea/metabolismo , Modelos Animales de Enfermedad , Terapia Genética/métodos , Lentivirus/genética , Porfiria Hepatoeritropoyética/genética , Porfiria Hepatoeritropoyética/terapia , Animales , Southern Blotting , Trasplante de Médula Ósea , Línea Celular , Elementos de Facilitación Genéticos/genética , Femenino , Ferroquelatasa/genética , Ferroquelatasa/metabolismo , Ferroquelatasa/uso terapéutico , Expresión Génica/genética , Vectores Genéticos/genética , Humanos , Lentivirus/fisiología , Masculino , Ratones , Especificidad de Órganos , Porfiria Hepatoeritropoyética/enzimología , Porfiria Hepatoeritropoyética/patología , Porfirinas/metabolismo , Regiones Promotoras Genéticas/genética , Protoporfiria Eritropoyética , Piel/patología , Transducción GenéticaRESUMEN
Erythropoietic protoporphyria is characterized clinically by skin photosensitivity and biochemically by a ferrochelatase deficiency resulting in an excessive accumulation of photoreactive protoporphyrin in erythrocytes, plasma and other organs. The availability of the Fech(m1Pas)/Fech(m1Pas) murine model allowed us to test a gene therapy protocol to correct the porphyric phenotype. Gene therapy was performed by ex vivo transfer of human ferrochelatase cDNA with a retroviral vector to deficient hematopoietic cells, followed by re-injection of the transduced cells with or without selection in the porphyric mouse. Genetically corrected cells were separated by FACS from deficient ones by the absence of fluorescence when illuminated under ultraviolet light. Five months after transplantation, the number of fluorescent erythrocytes decreased from 61% (EPP mice) to 19% for EPP mice engrafted with low fluorescent selected BM cells. Absence of skin photosensitivity was observed in mice with less than 20% of fluorescent RBC. A partial phenotypic correction was found for animals with 20 to 40% of fluorescent RBC. In conclusion, a partial correction of bone marrow cells is sufficient to reverse the porphyric phenotype and restore normal hematopoiesis. This selection system represents a rapid and efficient procedure and an excellent alternative to the use of potentially harmful gene markers in retroviral vectors.
Asunto(s)
Separación Celular/métodos , Terapia Genética/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Porfiria Hepatoeritropoyética/terapia , Animales , Línea Celular , ADN Complementario/genética , Modelos Animales de Enfermedad , Femenino , Ferroquelatasa/genética , Citometría de Flujo , Vectores Genéticos , Hematopoyesis , Interleucina-3/fisiología , Hepatopatías/terapia , Masculino , Ratones , Ratones Endogámicos BALB C , Fenotipo , Trastornos por Fotosensibilidad/terapia , Porfiria Hepatoeritropoyética/fisiopatología , Retroviridae/genéticaAsunto(s)
Antioxidantes/uso terapéutico , Ferroquelatasa/genética , Terapia Genética , Porfiria Hepatoeritropoyética/terapia , Animales , Trasplante de Médula Ósea , Carotenoides/uso terapéutico , Células Cultivadas , Femenino , Ferroquelatasa/metabolismo , Técnicas de Transferencia de Gen , Humanos , Masculino , Ratones , Ratones Pelados , Ratones Endogámicos BALB C , Oxígeno/fisiología , Fotoquímica , Porfiria Hepatoeritropoyética/tratamiento farmacológico , Oxígeno Singlete , Piel/efectos de los fármacos , Piel/efectos de la radiación , Luz Solar , Transfección , Rayos Ultravioleta , beta Caroteno/farmacologíaRESUMEN
In a five-year-old girl with photosensitivity (burning skin sensation after a sun bath) and purpura on the nose and the sides of the fingers erythropoietic protoporphyria was diagnosed, an autosomal dominant disease.
Asunto(s)
Cromosomas Humanos Par 18 , Porfiria Hepatoeritropoyética/diagnóstico , Púrpura/etiología , Enfermedades Cutáneas Vesiculoampollosas/genética , Preescolar , Diagnóstico Diferencial , Femenino , Predisposición Genética a la Enfermedad , Humanos , Porfiria Hepatoeritropoyética/complicaciones , Porfiria Hepatoeritropoyética/genética , Porfiria Hepatoeritropoyética/terapia , Púrpura/patología , Enfermedades Cutáneas Vesiculoampollosas/etiologíaRESUMEN
An extremely painful cutaneous condition with no or only slight visible skin changes, presenting in a child or an adult as an acute reaction to sun light, is probably a manifestation of the porphyrin metabolic disorder erythropoietic protoporphyria (EPP). The disease is the result of a genetically determined condition where a mutation in the gene for the final enzyme in the haem synthetic chain, ferrochelatase, results in impaired activity of the enzyme. In some predisposed individuals, the condition is accompanied by heavy accumulation of the substrate for the deficient enzyme, i.e. of protoporphyrin. Distributing to the skin, and there absorbing light of certain wavelengths, the metabolite generates free radicals that give rise to photodynamic cell injury. The primary event takes place in the endothelial cells of the superficial skin capillaries, but complement activation and mast cell degranulation in the surrounding tissue follow in the process. Even if the disease is primarily dermatological the hepatic and psychosocial complications are features requiring close attention by the physician. In order to provide a basis for suggestions regarding lege artis protocols for the diagnosis, treatment and monitoring of the patient with EPP, the pathophysiology of the cutaneous and hepatic manifestations are discussed in some detail in the article.
Asunto(s)
Porfiria Hepatoeritropoyética/diagnóstico , Porfiria Hepatoeritropoyética/terapia , Porfirinas/metabolismo , Humanos , Porfiria Hepatoeritropoyética/fisiopatologíaRESUMEN
A 33-year-old woman with a history of photosensitivity, persistent abdominal pain, and liver dysfunction was admitted to our department because of abdominal pain and progression of liver dysfunction. On admission, levels of protoporphyrin and coproporphyrin within erythrocytes were markedly increased. Autofluorescent erythrocytes were also detected, leading to a diagnosis of erythropoietic protoporphyria. A liver biopsy specimen revealed cirrhosis with dark brown granules filling hepatocytes, bile canaliculi, and bile ductules. Transfusion of washed erythrocytes, hemodialysis, and administration of cholestyramine and beta-carotene transiently improved levels of porphyrins and liver function. The patient died of rupture of esophageal varices followed by multiple organ failure. However, the treatments were believed to have extended survival.
Asunto(s)
Cirrosis Hepática/etiología , Fallo Hepático/etiología , Insuficiencia Multiorgánica/etiología , Porfiria Hepatoeritropoyética/complicaciones , Porfiria Hepatoeritropoyética/terapia , Adulto , Autopsia , Biopsia con Aguja , Progresión de la Enfermedad , Quimioterapia Combinada , Várices Esofágicas y Gástricas/etiología , Resultado Fatal , Femenino , Humanos , Cirrosis Hepática/patología , Cirrosis Hepática/terapia , Fallo Hepático/patología , Pruebas de Función Hepática , Porfiria Hepatoeritropoyética/patología , Diálisis Renal , Rotura EspontáneaRESUMEN
Caso
Asunto(s)
Informes de Casos , Humanos , Masculino , Niño , Agaricus muscarius/uso terapéutico , Porfiria Hepatoeritropoyética/terapiaRESUMEN
Hepatoerythropoietic porphyria (HEP) is an inherited metabolic disorder characterized by the accumulation of porphyrins resulting from a deficiency in uroporphyrinogen decarboxylase (UROD). This autosomal recessive disorder is severe, starting early in infancy with no specific treatment. Gene therapy would represent a great therapeutic improvement. Because hematopoietic cells are the target for somatic gene therapy in this porphyria, Epstein-Barr virus-transformed B-cell lines from patients with HEP provide a model system for the disease. Thus, retrovirus-mediated expression of UROD was used to restore enzymatic activity in B-cell lines from 3 HEP patients. The potential of gene therapy for the metabolic correction of the disease was demonstrated by a reduction of porphyrin accumulation to the normal level in deficient transduced cells. Mixed culture experiments demonstrated that there is no metabolic cross-correction of deficient cells by normal cells. However, the observation of cellular expansion in vitro and in vivo in immunodeficient mice suggested that genetically corrected cells have a competitive advantage. Finally, to facilitate future human gene therapy trials, we have developed a selection system based on the expression of the therapeutic gene. Genetically corrected cells are easily separated from deficient ones by the absence of fluorescence when illuminated under UV light.
Asunto(s)
Linfocitos B/enzimología , Terapia Genética , Porfiria Hepatoeritropoyética/enzimología , Uroporfirinógeno Descarboxilasa/deficiencia , Animales , Linfocitos B/trasplante , Línea Celular Transformada , Transformación Celular Viral , Técnicas de Cocultivo , Citometría de Flujo , Herpesvirus Humano 4 , Humanos , Masculino , Ratones , Ratones Mutantes , Microscopía Fluorescente , Porfiria Hepatoeritropoyética/genética , Porfiria Hepatoeritropoyética/terapia , Selección Genética , Transfección , Rayos Ultravioleta , Uroporfirinógeno Descarboxilasa/genéticaRESUMEN
Definitive cure of an animal model of a human disease by gene transfer into hematopoietic stem cells has not yet been accomplished in the absence of spontaneous in vivo selection for transduced cells. Erythropoietic protoporphyria is a genetic disease in which ferrochelatase is defective. Protoporphyrin accumulates in erythrocytes, leaks into the plasma and results in severe skin photosensitivity. Using a mouse model of erythropoietic protoporphyria, we demonstrate here that ex vivo preselection of hematopoietic stem cells transduced with a polycistronic retrovirus expressing both human ferrochelatase and green fluorescent protein results in complete and long-term correction of skin photosensitivity in all transplanted mice.
Asunto(s)
Trasplante de Médula Ósea , Ferroquelatasa/genética , Terapia Genética , Trastornos por Fotosensibilidad/terapia , Porfiria Hepatoeritropoyética/terapia , Animales , Eritrocitos/metabolismo , Ferroquelatasa/biosíntesis , Técnicas de Transferencia de Gen , Proteínas Fluorescentes Verdes , Células Madre Hematopoyéticas , Humanos , Proteínas Luminiscentes/biosíntesis , Proteínas Luminiscentes/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Trastornos por Fotosensibilidad/sangre , Trastornos por Fotosensibilidad/patología , Porfiria Hepatoeritropoyética/sangre , Porfiria Hepatoeritropoyética/genética , Protoporfiria Eritropoyética , Protoporfirinas/sangre , Piel/patología , Trasplante IsogénicoRESUMEN
Many patients with cutaneous porphyria have curable or controllable disease; untreated porphyria may prove fatal. The genetic defects and mechanisms underlying porphyria are steadily being delineated, treatments have become more appropriate and genetic counselling is now more accurate. A summary of the basic diagnostic features, management and recent advances in the cutaneous porphyrias is presented, based on a workshop held by the British Photodermatology Group.
Asunto(s)
Porfirias/diagnóstico , Humanos , Porfiria Cutánea Tardía/diagnóstico , Porfiria Cutánea Tardía/genética , Porfiria Cutánea Tardía/terapia , Porfiria Eritropoyética/diagnóstico , Porfiria Eritropoyética/genética , Porfiria Eritropoyética/terapia , Porfiria Hepatoeritropoyética/diagnóstico , Porfiria Hepatoeritropoyética/genética , Porfiria Hepatoeritropoyética/terapia , Porfirias/genética , Porfirias/terapiaRESUMEN
Defects in the enzymes involved in the haem biosynthetic pathway can lead to a group of human diseases known as the porphyrias. yquem (yqe(tp61)) is a zebrafish mutant with a photosensitive porphyria syndrome. Here we show that the porphyric phenotype is due to an inherited homozygous mutation in the gene encoding uroporphyrinogen decarboxylase (UROD); a homozygous deficiency of this enzyme causes hepatoerythropoietic porphyria (HEP) in humans. The zebrafish mutant represents the first genetically 'accurate' animal model of HEP, and should be useful for studying the pathogenesis of UROD deficiency and evaluating gene therapy vectors. We rescued the mutant phenotype by transient and germline expression of the wild-type allele.