RESUMEN
BACKGROUND: Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life-threatening acute neurovisceral attacks due to the induction of hepatic δ-aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. So far, the treatment of choice is hemin which represses ALAS1. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks. OBJECTIVE: The aim of this study was to determine whether chronic hemin administration contributes to the recurrence of acute attacks. METHODS: A follow-up study was conducted between 1974 and 2015 and included 602 French AIP patients, of whom 46 had recurrent AIP. Moreover, we studied the hepatic transcriptome, serum proteome, liver macrophage polarization and oxidative and inflammatory profiles of Hmbs-/- mice chronically treated by hemin and extended the investigations to five explanted livers from recurrent AIP patients. RESULTS: The introduction of hemin into the pharmacopeia has coincided with a 4.4-fold increase in the prevalence of chronic patients. Moreover, we showed that both in animal model and in human liver, frequent hemin infusions generate a chronic inflammatory hepatic disease which induces HO1 remotely to hemin treatment and maintains a high ALAS1 level responsible for recurrence. CONCLUSION: Altogether, this study has important impacts on AIP care underlying that hemin needs to be restricted to severe neurovisceral crisis and suggests that alternative treatment targeting the liver such as ALAS1 and HO1 inhibitors, and anti-inflammatory therapies should be considered in patients with recurrent AIP.
Asunto(s)
5-Aminolevulinato Sintetasa/sangre , Hidroximetilbilano Sintasa/fisiología , Hígado/fisiopatología , Porfiria Intermitente Aguda/fisiopatología , Enfermedad Aguda , Animales , Estudios de Cohortes , Estudios Transversales , Femenino , Estudios de Seguimiento , Hemo-Oxigenasa 1/metabolismo , Hemina/administración & dosificación , Hemina/efectos adversos , Humanos , Hígado/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Porfiria Intermitente Aguda/diagnóstico , Porfiria Intermitente Aguda/epidemiología , Porfiria Intermitente Aguda/terapia , Recurrencia , Factores de RiesgoRESUMEN
BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare metabolic disorder, characterized by photosensitivity, caused by errors of the haem biosynthetic pathway. Avoidance of sun exposure is recommended; however, some patients suggested a paradoxical improvement of symptoms when they move to sunny areas. OBJECTIVES: In a national French study, we sought to investigate the influence of sun exposure on EPP symptoms. MATERIALS AND METHODS: We used a national transversal observational study by questionnaire. Patients were selected from the national record of the Centre Français des Porphyries (French Porphyrias referral centre). Sun exposure level by geographic area was assessed using climate data provided by the French national meteorological service (Météo France). RESULTS: Eighty-nine patients were included. We notably observed that 40% of patients declared an improvement in their tolerance of sun exposure after repeated sun exposures. In the more sunny areas, the intensity of the pain was lower (r = -0·26) and the duration of the sun exposure responsible for flares was longer (r = 0·39) than in the areas that were less sunny (P < 0·05). CONCLUSIONS: This study proposes a benefit of natural progressive sun exposure for patients with EPP.
Asunto(s)
Trastornos por Fotosensibilidad/epidemiología , Protoporfiria Eritropoyética/epidemiología , Luz Solar , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Vestuario , Exposición a Riesgos Ambientales/estadística & datos numéricos , Femenino , Francia/epidemiología , Helioterapia/métodos , Humanos , Masculino , Persona de Mediana Edad , Dolor/prevención & control , Trastornos por Fotosensibilidad/prevención & control , Protoporfiria Eritropoyética/prevención & control , Protectores Solares/uso terapéutico , Tiempo (Meteorología) , Adulto JovenRESUMEN
BACKGROUND: Porphyria cutanea tarda (PCT), the most frequent type of porphyria, results from decreased uroporphyrinogen decarboxylase (UROD) activity. Two forms of PCT have been described: a familial form (fPCT) characterized by the inherited decrease of UROD activity in all tissues and a sporadic form (sPCT) characterized by decreased UROD activity in the liver. Cytochrome P450 CYP1A2 plays a major role in triggering experimental uroporphyria in rodents. It has been suggested that the highly inducible -163A/A genotype of the CYP1A2 gene could confer a heightened risk of PCT in patients. OBJECTIVES: To examine the impact of CYP1A2 polymorphisms on the clinical course of PCT. METHODS: We performed an extensive CYP1A2 gene analysis in 96 (48 fPCT and 48 sPCT) unrelated French caucasian patients with PCT and in 99 healthy volunteers of similar ethnic origin. Results We did not observe any difference in CYP1A2 allele distribution, including a novel and rare CYP1A2 c.1063C>T (p.R355W) single nucleotide polymorphism. In addition, we compared the frequency of the -163A highly inducible allele both in patients with symptomatic fPCT (n = 48) and in asymptomatic UROD gene mutations carrier relatives (n=54). This variant was not over-represented in patients with PCT vs. either healthy volunteers or asymptomatic UROD gene mutation carriers. CONCLUSIONS: The CYP1A2 genotype does not appear to be a major susceptibility factor in the development of fPCT or sPCT in the French population.
Asunto(s)
Citocromo P-450 CYP1A2/genética , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Porfiria Cutánea Tardía/genética , Población Blanca/genética , Estudios de Casos y Controles , Francia , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Genotipo , Heterocigoto , HumanosRESUMEN
BACKGROUND: Congenital erythropoietic porphyria (CEP) is an autosomal recessive cutaneous porphyria caused by decreased activity of uroporphyrinogen III synthase (UROS). Its predominant characteristics include bullous cutaneous photosensitivity to visible light from early infancy, progressive photomutilation and chronic haemolytic anaemia. Due to its rarity and genetic heterogeneity, clinical phenotypes are unclear and its impact on health-related quality of life (HRQoL) has not been previously assessed. OBJECTIVES: To define comprehensively CEP phenotypes and assess their impact on HRQoL, and to correlate these factors with laboratory parameters. METHODS: A single observer assessed patients with CEP from four European countries. RESULTS: Twenty-seven unrelated patients with CEP, aged between 7.6 and 65 years, participated in the study. The patients came from the U.K. (17), France (4), Switzerland (4) and Germany (2). Additional data were obtained for two deceased patients. Newly characterized features of CEP include acute-onset cutaneous and noncutaneous symptoms immediately following sunlight exposure, and pink erythematous facial papules. There was a lack of consistent genotype-phenotype correlation in CEP. The main poor prognostic factors in CEP are the early age of disease onset and haematological complications. CONCLUSIONS: CEP is a multisystem disease; cutaneous, ocular, oral and skeletal manifestations also contribute to disease severity and impact on HRQoL, in addition to the haematological complications. The rarity of the disease can lead to delayed diagnosis. The lack of consistent genotype-phenotype correlation in CEP suggests a contribution to phenotype from other factors, such as environment, patients' photoprotective behaviour and genes other than UROS. There is currently an unmet need for multidisciplinary management of patients with CEP.
Asunto(s)
Porfiria Eritropoyética/genética , Uroporfirinógeno III Sintetasa/genética , Adolescente , Adulto , Niño , Estudios de Cohortes , Europa (Continente) , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Porfiria Eritropoyética/fisiopatología , Calidad de Vida , Adulto JovenRESUMEN
BACKGROUND: Congenital erythropoietic porphyria (CEP) is an autosomal recessive photomutilating porphyria with onset usually in childhood, where haematological complications determine prognosis. Due to its extreme rarity and clinical heterogeneity, management decisions in CEP are often difficult. OBJECTIVES: To develop a management algorithm for patients with CEP based on data from carefully characterized historical cases. METHODS: A single investigator collated data related to treatments and their outcomes in 29 patients with CEP from the U.K., France, Germany and Switzerland. RESULTS: Six children were treated with bone marrow transplantation (BMT); five have remained symptomatically cured up to 11.5 years post-transplantation. Treatments such as oral charcoal, splenectomy and chronic hypertransfusion were either of no benefit or were associated with complications and negative impact on health-related quality of life. Lack of consistent genotype-phenotype correlation meant that this could not be used to predict disease prognosis. The main poor prognostic factors were early age of disease onset and severity of haematological manifestations. CONCLUSIONS: A management algorithm is proposed where every patient, irrespective of disease severity at presentation, should receive a comprehensive, multidisciplinary clinical assessment and should then be reviewed at intervals based on their predicted prognosis, and the rate of onset of complications. A BMT should be considered in those with progressive, symptomatic haemolytic anaemia and/or thrombocytopenia. Uroporphyrinogen III synthase genotypes associated with poor prognosis would additionally justify consideration for a BMT. Rigorous photoprotection of the skin and eyes from visible light is essential in all patients.
Asunto(s)
Porfiria Eritropoyética/terapia , Índice de Severidad de la Enfermedad , Adolescente , Adulto , Algoritmos , Transfusión Sanguínea/métodos , Trasplante de Médula Ósea/métodos , Carbón Orgánico/administración & dosificación , Niño , Preescolar , Estudios de Cohortes , Europa (Continente) , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Porfiria Eritropoyética/genética , Ropa de Protección , Esplenectomía/métodos , Adulto Joven , beta Caroteno/administración & dosificaciónRESUMEN
Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis that results from an accumulation of protoporphyrin IX in erythroid cells, plasma, skin and liver. EPP leads to acute photosensitivity and, in about 2% of patients, liver disease. EPP is a complex syndrome in which two genes are independently involved: FECH and ALAS2. More than 96% of unrelated EPP patients have ferrochelatase (FECH) deficiency (MIM 177000). Four percent of them present with autosomal recessive inheritance with two mutated FECH alleles. In dominant cases (95%) the inheritance of a common hypomorphic IVS3-48C FECH allele trans to a deleterious FECH mutation reduces FECH activity below a critical threshold. The frequency of the IVS3-48C allele differs widely from the Japanese (45%), to Black West Africans (<1%) populations. These differences in the frequency of this single common SNP account for the prevalence of overt EPP in different countries and for the absence of EPP in Black Africans. The phylogenic origin of the IVS3-48C haplotypes strongly suggests that the IVS3-48C allele arose from a single recent mutational event that occurred 60 Kyears ago. Acquired somatic mutation of FECH secondary to myeloid disease may also exceptionally cause EPP (<1%). Finally, about 4% of unrelated EPP patients have X-linked dominant protoporphyria (XLDPP) (MIM 300752) caused by gain-of-function mutations in the ALAS2 gene leading to an increased erythroid heme biosynthesis and subsequently an accumulation of protoporphyrin without any FECH deficiency.
Asunto(s)
5-Aminolevulinato Sintetasa/genética , Ferroquelatasa/genética , Protoporfiria Eritropoyética/genética , Secuencia de Aminoácidos , Femenino , Genes Dominantes , Genes Recesivos , Genes Ligados a X , Enfermedades Genéticas Ligadas al Cromosoma X/epidemiología , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Genotipo , Humanos , Masculino , Datos de Secuencia Molecular , Mutación , Fenotipo , Protoporfiria Eritropoyética/epidemiología , Protoporfiria Eritropoyética/etnología , Grupos Raciales/genética , Terminología como AsuntoRESUMEN
BACKGROUND: Porphyria cutanea tarda (PCT) is rare in childhood and association with bone marrow transplant has occasionally been reported. PATIENTS AND METHODS: A 13-year-old boy was referred to our department for bullous lesions on sun-exposed areas. His past medical history revealed acute biphenotypic leukaemia with complete remission after allogeneic hematopoietic stem cell transplantation (unrelated donor). Complications of bone marrow transplant comprised anaemia (treated by blood transfusions), primary cytomegalovirus (CMV) infection, pulmonary aspergillosis and acute digestive graft-versus-host disease. The diagnosis of type I sporadic PCT was based on high levels of porphyria and normal erythrocytic uroporphyrinogen decarboxylase activity. The bullous lesions disappeared on bleeding, but the patient subsequently developed sclerodermiform lesions. DISCUSSION: An association between PCT and bone marrow transplant has been reported previously in two independent cases, of which one involved a child. The causative role of bone marrow transplantation in the development of PCT could be related to several triggering factors: primary CMV infection, hepatotoxic drugs, blood transfusion and possible chronic hepatic graft-versus-host disease. CONCLUSION: We report the second case in a child of type I PCT associated with bone marrow transplantation. This new case reinforces the hypothesis of a non-random relationship between the two conditions.
Asunto(s)
Trasplante de Médula Ósea/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Bifenotípica Aguda/terapia , Porfiria Cutánea Tardía/diagnóstico , Porfiria Cutánea Tardía/terapia , Adolescente , Humanos , Masculino , Inducción de RemisiónRESUMEN
OBJECTIVE: Acute intermittent porphyria (AIP) is caused by a deficiency of hydroxymethylbilane synthase. Clinical manifestations are abdominal pain and neurovisceral symptoms, accompanied by overproduction of heme-precursors in the liver, which frequently remains long-lasting in AIP patients. We tested the hypothesis that this condition may be associated with alterations of hepatic proteins known to be either increased or decreased in serum according to diverse pathological conditions including malnutrition, inflammation or liver disease. DESIGN: Serum proteins were analyzed in 26 biochemically active AIP patients that were classified according to the EPI (European Porphyria Initiative) guidelines as follows: (i) patients who presented a single acute attack having remained so far free of clinical symptoms; (ii) patients who present recurrent attacks or chronic symptoms associated with exacerbations of AIP. RESULTS: Most of the serum proteins were within normal limits, however insulin-like growth factor 1 (IGF-1) was decreased in 53.8% of AIP patients (z-score = -2.86 +/- 0.37) and transthyretin (prealbumin) was found significantly decreased in 38.5% of them. The IGF-1 z-score was lower in group B versus group A patients (-2.66 vs. -1.43; P = 0.024). The coincident decrease of both IGF-1 and transthyretin was associated with worsening of the clinical condition. CONCLUSIONS: This first study in humans suggests that the clinical expression AIP is associated with a state of under-nutrition and/or with hepatic inflammation due to the sustained accumulation of heme-precursors. We propose the use of both IGF-1 and transthyretin as biomarkers of disease morbidity/severity for the clinical follow-up of AIP patients.
Asunto(s)
Factor I del Crecimiento Similar a la Insulina/análisis , Porfiria Intermitente Aguda/sangre , Prealbúmina/análisis , Adulto , Biomarcadores/sangre , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Morbilidad , Estadísticas no ParamétricasRESUMEN
Partial deficiency of the last enzyme of the heme biosynthetic pathway (namely ferrochelatase, FECH) in humans is responsible for erythropoietic protoporphyria (EPP). This disorder is characterised by painful photosensitivity, due to excessive production of protoporphyrin IX (PPIX) by erythrocytes. Controversial hypotheses have been proposed to explain the hematologic and iron status of EPP patients. In the present work, we explored these parameters in 55 patients with dominant EPP recruited at the French Center of Porphyrias (Colombes, France) and confirmed by molecular analysis. Our data show that erythrocyte accumulation of PPIX in EPP patients influences hematologic and iron status. Patients studied had a mild anemia and thrombocytopenia, as shown by the downward shift of hematologic parameters, which positively correlated with the amount of erythrocyte PPIX. Interestingly, erythropoiesis did not seem to be limited by iron supply in patients, since serum iron and soluble transferring (Tf) receptor (sTfR) were normal. However, iron and Tf saturation negatively correlated with erythrocyte PPIX. Moreover, and as previously described in a mouse model of EPP, we noted a positive correlation between erythrocyte PPIX and Tf levels. Altogether, these results suggest a positive effect of PPIX on the synthesis on Tf, which could facilitate the mobilization of tissue iron stores to meet erythropoiesis requirement. Based on these observations and previous results in EPP mouse model, we propose that the PPIX-liver transferrin pathway plays a role in the orchestration of iron distribution between peripheral iron stores, the spleen and the bone marrow.
Asunto(s)
Eritrocitos/metabolismo , Hierro/metabolismo , Protoporfiria Eritropoyética/sangre , Protoporfiria Eritropoyética/metabolismo , Protoporfirinas/metabolismo , Adolescente , Adulto , Niño , Eritropoyesis/fisiología , Femenino , Humanos , Lípidos/sangre , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Porfirinas/metabolismo , Protoporfiria Eritropoyética/genética , Adulto JovenRESUMEN
Erythropoietic protoporphyria (EPP) is a syndrome in which accumulation of protoporphyrin IX in erythroid cells, plasma, skin and liver leads to acute photosensitivity and, in about 2% of patients, liver disease. More than 95% of unrelated patients have ferrochelatase (FECH) deficiency (MIM 177000) while about 2% have X-linked dominant protoporphyria (XLDPP) (MIM 300752) caused by gain-of-function mutations in the ALAS2 gene. Most FECH-deficient patients are compound heterozygotes for a hypomorphic allele (FECH IVS3-48C) and a deleterious FECH mutation that together lower FECH activity to around 30% of normal. The frequency of the IVS3-48C allele varies between populations, ranging from less than 1% to 45%. About 4% of unrelated FECH-deficient patients are compound heterozygotes or homozygotes for rare FECH mutations and have lower enzyme activities. Acquired somatic mutation of FECH secondary to myeloid disease may rarely cause EPP. The risk of liver disease is increased in XLDPP and in FECH-deficient patients who are hetero- or homoallelic for rare FECH mutations. Inherited FECH-deficient EPP is an autosomal recessive disorder with some families showing pseudodominant inheritance; the proportion of such families being determined by the population frequency of the IVS3-48C allele.
Asunto(s)
Protoporfiria Eritropoyética/genética , 5-Aminolevulinato Sintetasa/genética , 5-Aminolevulinato Sintetasa/metabolismo , Alelos , Ferroquelatasa/genética , Ferroquelatasa/metabolismo , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Polimorfismo de Nucleótido Simple , Protoporfiria Eritropoyética/enzimología , Factores de RiesgoRESUMEN
Tryptophan (TRP) is the precursor of melatonin, the primary secretory product of the pineal gland. Hepatic heme deficiency decreases the activity of liver tryptophan pyrrolase, leading to increased plasma TRP and serotonin. As a paradox, patients with attacks of acute intermittent porphyria (AIP), exhibit low nocturnal plasma melatonin levels. This study using a rat experimental model was designed to produce a pattern of TRP and melatonin production similar to that in AIP patients. Pineal melatonin production was measured in response to: (a) a heme synthesis inhibitor, succinylacetone, (b) a heme precursor, delta-aminolevulinic acid (Ala), (c) a structural analogue of Ala, gamma-aminobutyric acid. Studies were performed in intact rats, perifused pineal glands, and pinealocyte cultures. Ala, succinylacetone, and gamma-aminobutyric acid significantly decreased plasma melatonin levels independently of blood TRP concentration. In the pineal gland, the key enzyme activities of melatonin synthesis were unchanged for hydroxyindole-O-methyltransferase and decreased for N-acetyltransferase. Our results strongly suggest that Ala overproduced by the liver acts by mimicking the effect of gamma-aminobutyric acid on pineal melatonin in AIP. They also support the view that Ala acts as a toxic element in the pathophysiology of AIP.
Asunto(s)
Ácido Aminolevulínico/metabolismo , Melatonina/biosíntesis , Glándula Pineal/metabolismo , Porfiria Intermitente Aguda/metabolismo , Acetilserotonina O-Metiltransferasa/metabolismo , Agonistas alfa-Adrenérgicos/farmacología , Agonistas Adrenérgicos beta/farmacología , Ácido Aminolevulínico/farmacología , Animales , Arilamina N-Acetiltransferasa/metabolismo , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Hemo/biosíntesis , Heptanoatos/farmacología , Técnicas In Vitro , Isoproterenol/farmacología , Masculino , Melatonina/sangre , Norepinefrina/farmacología , Fotoperiodo , Glándula Pineal/citología , Glándula Pineal/efectos de los fármacos , Glándula Pineal/enzimología , Porfobilinógeno Sintasa/antagonistas & inhibidores , Ratas , Ratas Wistar , Triptófano/sangre , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
A viable autosomal recessive mutation (named fch, or ferrochelatase deficiency) causing jaundice and anemia in mice arose in a mutagenesis experiment using ethylnitrosourea. Homozygotes (fch/fch) display a hemolytic anemia, photosensitivity, cholestasis, and severe hepatic dysfunction. Protoporphyrin is found at high concentration in erythrocytes, serum, and liver. Ferrochelatase activity in various tissues is 2.7-6.3% of normal. Heterozygotes (+/fch) are not anemic and have normal liver function; they are not sensitive to light exposure; ferrochelatase activity is 45-65% of normal. Southern blot analysis using a ferrochelatase cDNA probe reveals no gross deletion of the ferrochelatase gene. This is the first spontaneous form of erythropoietic protoporphyria in the house mouse. Despite the presence in the mouse of clinical and biochemical features infrequent in the human, this mutation may represent a model for the human disease, especially in its severe form.
Asunto(s)
Anemia Hemolítica/etiología , Eritrocitos/metabolismo , Hepatopatías/etiología , Porfirias/genética , Protoporfiria Eritropoyética , Protoporfirinas/metabolismo , Animales , Modelos Animales de Enfermedad , Globinas/genética , Ratones , Ratones Endogámicos BALB C , Mutación , Trastornos por Fotosensibilidad/complicaciones , Porfirias/enzimología , Porfirias/patologíaRESUMEN
Two mutations of the porphobilinogen (PBG) deaminase gene resulting in cross-reacting immunological material (CRIM) positive forms of acute intermittent porphyria (AIP) have been identified by in vitro amplification of cDNA and cloning of the amplified products in a bacterial expression vector. Both mutations resulted from G to A transitions in exon 10 of the gene and produced arginine to glutamine substitutions in the abnormal protein. Expression of mutant cDNA in Escherichia coli reveals that one but not the other of these amino acid changes results in a striking decrease of the optimal pH of the mutated enzyme. One or the other of these two mutations accounted for the defect causing AIP in six unrelated patients among the eight patients evaluated with the CRIM positive subtype of this disorder.
Asunto(s)
Exones , Hidroximetilbilano Sintasa/genética , Mutación , Porfirias/genética , Enfermedad Aguda , Secuencia de Aminoácidos , Secuencia de Bases , Western Blotting , Clonación Molecular , Escherichia coli/genética , Genes , Humanos , Concentración de Iones de Hidrógeno , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Porfirias/enzimologíaRESUMEN
INTRODUCTION: In mammals, iron balance is maintained by regulating intestinal iron absorption and iron recycling by macrophages. EXEGESIS: The central role of hepcidin in the establishment of iron deficiency or overload has been revealed by the study of murine models. CONCLUSION: Many hopes have emerged from the discovery of hepcidin, pointing to potential treatments for hemochromatosis and anemia of inflammation (anemia of chronic disease).
Asunto(s)
Péptidos Catiónicos Antimicrobianos/metabolismo , Hierro/metabolismo , Animales , Péptidos Catiónicos Antimicrobianos/sangre , Hepcidinas , Homeostasis , Humanos , Absorción Intestinal , Hierro/sangre , Macrófagos/metabolismo , MamíferosRESUMEN
The hereditary porphyrias comprise a group of eight metabolic disorders of the haem biosynthesis pathway characterised by acute neurovisceral symptoms, skin lesions or both. Each porphyria is caused by abnormal function of a separate enzymatic step resulting in a specific accumulation of haem precursors. Seven porphyrias are the consequence of a partial enzyme deficiency while a gain of function mechanism has been recently characterised in a novel porphyria. Acute porphyrias present with severe abdominal pain, nausea, constipation, confusion and seizure, which may be life threatening. Cutaneous porphyrias can be present with either acute painful photosensitivity or skin fragility and blisters. Rare recessive porphyrias usually manifest in early childhood with either severe chronic neurological symptoms or chronic haemolysis and severe cutaneous photosensitivity. Porphyrias are still underdiagnosed, but once they are suspected, and depending on the clinical presentation, a specific and simple front line test allows the diagnosis in all symptomatic patients. Diagnosis is essential to institute as soon as possible a specific treatment. Screening families to identify presymptomatic carriers is crucial to prevent chronic complications and overt disease by counselling on avoiding potential precipitants.
Asunto(s)
Enfermedades Genéticas Congénitas , Enfermedades Hematológicas , Hemo/metabolismo , Porfirias , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/terapia , Enfermedades Hematológicas/diagnóstico , Enfermedades Hematológicas/genética , Enfermedades Hematológicas/metabolismo , Enfermedades Hematológicas/terapia , Hemo/genética , Humanos , Porfiria Intermitente Aguda/diagnóstico , Porfiria Intermitente Aguda/genética , Porfiria Intermitente Aguda/metabolismo , Porfiria Intermitente Aguda/terapia , Porfirias/diagnóstico , Porfirias/epidemiología , Porfirias/genética , Porfirias/terapiaRESUMEN
Partial deficiencies in enzymes activity of the heme biosynthesis pathway have been demonstrated in cultured skin fibroblasts and other tissues from patients suffering from congenital erythropoietic porphyria and hereditary coproporphyria. Using a new fluorimetric method, we have assessed quantitatively porphyrin biosynthesis from added delta-aminolevulinic acid in cultured fibroblasts of two congenital erythropoietic porphyria patients and one homozygous case of hereditary corproporphyria. The results were compared with those of the patients' parents and those of normal controls. All the porphyrins synthesized remained within the cells of normal subjects and of patients with congenital erythropoietic porphyria; these porphyrins were mostly (95%) protoporphyrin. The fibroblasts of the patient with homozygous hereditary coproporphyria synthesized the same amount of porphyrins, but only 25% were found within the cells, whereas 75% were found in the medium. The porphyrins found within the cells were coproporphyrin (25%) and protoporphyrin (75%); in the medium, only coproporphyrin was identified.
Asunto(s)
Fibroblastos/metabolismo , Porfirias/metabolismo , Porfirinas/biosíntesis , Células Cultivadas , Niño , Coproporfirinas/biosíntesis , Homocigoto , Humanos , Porfirias/congénito , Porfirias/genética , Protoporfirinas/biosíntesis , Piel/metabolismo , Uroporfirinas/biosíntesisRESUMEN
Defects in the human ferrochelatase gene lead to the hereditary disorder of erythropoietic protoporphyria. The clinical expression of this autosomal dominant disorder requires an allelic combination of a disabled mutant allele and a low-expressed nonmutant allele. Unlike most other erythropoietic protoporphyria populations, mutations identified among Swiss erythropoietic protoporphyria families to date have been relatively homogeneous. In this study, genotype analysis was conducted in seven Swiss erythropoietic protoporphyria families, three carrying mutation Q59X, two carrying mutation insT213, and two carrying mutation delTACAG(580-584). Three different haplotypes of five known intragenic single nucleotide polymorphisms, namely -251 A/G, IVS1-23C/T, 798 G/C, 921 A/G, and 1520C/T, were identified. Each haplotype was shared by families carrying an identical mutation in the ferrochelatase gene indicating a single mutation event for each of the three mutations. These mutations have been present in the Swiss erythropoietic protoporphyria population for a relatively long time as no common haplotypes of microsatellite markers flanking the ferrochelatase gene were found, except of two conserved regions, telomeric of the insT213 allele and centromeric of the delTACAG(580-584)allele, each with a size > 3 cM. Among the nonmutant ferrochelatase alleles, patients from six erythropoietic protoporphyria families shared a common haplotype [-251G; IVS1-23T] of the first two single nucleotide polymorphisms. An exception was the haplotype [-251 A; IVS1-23C] identified in the index patient of one erythropoietic protoporphyria family. These results supported the recent findings that the low expressed allele is tightly linked to a haplotype [-251G; IVS1-23T] of two intragenic single nucleotide polymorphisms in the ferrochelatase gene.
Asunto(s)
Polimorfismo de Nucleótido Simple , Porfiria Hepatoeritropoyética/genética , Salud de la Familia , Femenino , Ferroquelatasa/genética , Efecto Fundador , Haplotipos , Humanos , Masculino , Repeticiones de Microsatélite , Linaje , Penetrancia , SuizaRESUMEN
Erythropoietic protoporphyria is a hereditary disorder of porphyrin metabolism caused by mutations in the ferrochelatase gene. Ferrochelatase catalyzes the chelation of ferrous iron into protoporphyrin IX to form heme. Mutation analysis was performed in four Spanish erythropoietic protoporphyria families resulting in the identification of four different mutations in the ferrochelatase gene. Two of them were novel mutations, a missense mutation (1157 A-->C, H386P) and a frameshift mutation (843delC) found in two Spanish families, respectively. The third and the forth Spanish patients carried already published ferrochelatase gene mutations, a nonsense mutation (343C-->T, R115X) and a missense mutation (557T-->C, I186T), respectively. The newly described frameshift mutation (843delC) predicted formation of an abrupt mRNA. The deleterious effect of His386 to Pro substitution as a result of mutation 1157 A-->C on the ferrochelatase activity was investigated by expressing the mutant ferrochelatase in Escherichia coli. The mutant ferrochelatase exhibited only 0.8% of the wild-type ferrochelatase activity. Prediction of the secondary structure of ferrochelatase suggested that the H386P mutation disrupted the original alpha-helical structure by way of introducing a turn, a rather drastic structural change of the enzyme sufficient to cause activity loss.
Asunto(s)
Ferroquelatasa/genética , Porfiria Hepatoeritropoyética/genética , Electroforesis en Gel de Poliacrilamida , Femenino , Mutación del Sistema de Lectura , Humanos , Masculino , Mutación , Linaje , Porfiria Hepatoeritropoyética/enzimología , Análisis de Secuencia de ADN , EspañaRESUMEN
Effects of some anaesthetic drugs on the activity of delta-aminolevulinate synthetase and on the formation of porphyrins and cytochrome P-450 were studied in 18-day-old chick embryo livers in ovo. The drugs were either tested alone or with a small dose of 1,4-dihydro-3,5-dicarbethoxycollidine, which reproduces in the embryo liver a partial block in the heme biosynthesis pathway similar to that found in cells of human patients with porphyrias. Two series of local anaesthetics were tested: procaine and its derivatives (proxymetacaine, oxybuprocaine, butacaine and tetracaine) had no (or very slight) porphyrogenic effects. In contrast, lidocaine and its derivatives (bupivacaine, mepivacaine, etidocaine, pyrrocaine and prilocaine) were found to induce delta-aminolevulinate synthetase and to cause accumulation of porphyrins and cytochrome P-450. Some other drugs used in anaesthesiology were tested: fentanyl, morphine, sodium oxybate, pancuronium, pethidine and phenoperidine were found to be non-porphyrogenic; alcuronium was a slight inducer. It is suggested that the inducing drugs should be avoided in patients with hepatic porphyrias.