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.
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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
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
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.
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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
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
Iron deficiency is the most frequent cause of hypochromic microcytic anemia in children, but other causes, some of them requiring specific management, may be involved. Checking the iron-status is absolutely mandatory. When iron-status parameters are low, inadequate intake, malabsorption, blood loss, and abnormal iron utilization must be tested. In absence of iron deficiency, α- and ß-globin and heme biosynthetic gene status must be checked. Assessing the iron stock level is difficult, because there is an overlap between the values observed in iron-replete and iron-deprived patients, so that at least 2 iron-status parameters must be below normal for diagnosing iron deficiency. Furthermore, inflammation may also mimic some characteristics of iron deficiency. Diagnosing iron deficiency leads to prescribing iron supplementation with follow-up at the end and 3 months after cessation of treatment. When iron stores are not replete at the end of treatment, compliance and dosage must be reevaluated and occult bleeding sought. The latter is also required when the iron store decreases 3 months after cessation of iron replacement.
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Anemia Hipocrómica/diagnóstico , Adolescente , Anemia Hipocrómica/etiología , Anemia Hipocrómica/terapia , Anemia Ferropénica/diagnóstico , Anemia Ferropénica/etiología , Anemia Ferropénica/terapia , Niño , Preescolar , Femenino , Estudios de Seguimiento , Hemo/genética , Humanos , Lactante , Hierro/administración & dosificación , Hierro/sangre , Masculino , Globinas alfa/genética , Globinas beta/genéticaRESUMEN
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
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: Erythropoietic protoporphyria (EPP) is a hereditary disorder caused by the deficiency of ferrochelatase (FECH) in the haem biosynthetic pathway. In the majority of families, EPP is transmitted as a pseudodominant trait. Autosomal recessive form of EPP is found in only about 3% of the families. OBJECTIVES: In this study, we describe a 6-year-old boy who suffered from both EPP and palmar keratoderma. METHODS AND RESULTS: A novel homoallelic missense mutation (p.Ser318Tyr) was identified in the FECH gene. In addition, a region of homozygosity of approximately 6.8 Mb was observed in chromosome 18 of the patient by both microsatellite and SNP array. The parents of the patient, both of Palestinian (Jordanian) origin, were heterozygous for the S318Y mutation, although no history of consanguinity was known. Microsatellite genotyping identified a partial haplotype from each parent that corresponds to the region of homozygosity in the patient. Assuming S318Y is a founder mutation, the number of generations separating the two parents from their common ancestor from whom they inherited S318Y was estimated as 21.7 (95% CI 3.4269.7). CONCLUSION: EPP was therefore inherited as an autosomal recessive trait in the family. This study confirms the association between palmar keratoderma and autosomal recessive EPP.
Asunto(s)
Ferroquelatasa/genética , Queratodermia Palmoplantar/complicaciones , Queratodermia Palmoplantar/genética , Protoporfiria Eritropoyética/complicaciones , Protoporfiria Eritropoyética/genética , Niño , Salud de la Familia , Genes Recesivos , Haplotipos , Homocigoto , Humanos , Masculino , Modelos Genéticos , Mutación MissenseRESUMEN
The rodent Harderian glands (HGs) are large paired orbital organs with highest porphyrinogenic rates. We have previously shown that continuous light exposure abolished the day/night variations of the delta-aminolevulinate synthase (ALA-S; the rate-limiting enzyme for porphyrin biosynthesis) gene expression observed under standard light: dark cycles (LD 12:12) in the rat HGs. This study was designed to examine whether the ALA-S changes were actually associated directly with light. The response of ferrochelatase (enzyme that converts protoporphyrin IX into heme) to light was also examined. Male Wistar rats were acclimatized to light: dark cycles regimen of 12:12 for 2 weeks. At the end of the 2 weeks, a 1 h-light pulse was applied in the middle of the dark phase. Animals were sacrificed immediately after the end of the light pulse. HGs were collected and stored at -80 degrees C until processed for quantitative RT-PCR. A 1 h-light pulse applied during mid-dark caused a significant increase of ALA-S gene expression (3-fold higher than in controls), whereas it was without effect on ferrochelatase gene expression. Our results suggest that light per se may regulate ALA-S gene expression in the rat HGs, and reveal that the ALA-S gene expression, and so heme biosynthesis, is under a photodynamic control.
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5-Aminolevulinato Sintetasa/biosíntesis , 5-Aminolevulinato Sintetasa/efectos de la radiación , Regulación Enzimológica de la Expresión Génica/efectos de la radiación , Glándula de Harder/enzimología , Glándula de Harder/efectos de la radiación , Luz , 5-Aminolevulinato Sintetasa/genética , Animales , Inducción Enzimática/genética , Inducción Enzimática/efectos de la radiación , Masculino , Ratas , Ratas WistarRESUMEN
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
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.
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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.
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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
The biochemical and the molecular diagnoses of an inherited porphyria require experience. False positive or negative screening tests and the low penetrance of the disease make a correct diagnosis difficult.The biochemical and the molecular procedures for the diagnosis of acute intermittent porphyria were applied to five unrelated patients suffering from acute intermittent porphyria. All patients were shown to be gene carriers of acute intermittent porphyria by both methods. The two different possibilities of the diagnosis corresponded well. In a family definitively identified by molecular diagnosis of one of the patients and his relatives, the patient's two children were asymptomatic. His son was shown to be a gene carrier of the father's deficiency by biochemical as well as molecular analysis, whereas his daughter was not affected by acute intermittent porphyria.
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Porfiria Intermitente Aguda/diagnóstico , Porfiria Intermitente Aguda/genética , Adolescente , Adulto , Niño , Reacciones Falso Positivas , Salud de la Familia , Femenino , Pruebas Genéticas/métodos , Heterocigoto , Humanos , Masculino , LinajeRESUMEN
Type B natriuretic peptide (BNP) versus n-terminal type B natriuretic propeptide in the diagnosis of cardiac failure in the elderly over 75 population The value of BNP is well established in the diagnosis of cardiac failure in cases of dyspnoea in the emergency room in young and, more and more, in elderly subjects. However, there are few studies comparing the diagnostic value of BNP and of the n-terminal pro-BNP in patients over 75 years of age. The aim of this study was to compare the diagnostic value of BNP and NT-pro BNP in dyspnoea of the elderly patient. One hundred and three consecutive patients over 75 years of age admitted to the emergency unit for dyspnoea were included. A blood sample for measuring the BNP (Biosite) and the NT-proBNP (Roche Diagnostic) was taken in the admission unit in addition to the standard blood workup. The final reference diagnosis was established by two independent cardiologists. Of the 103 patients, 61 were women and the average age was 84.9 +/- 6.2 years. The final diagnosis was cardiac failure in 49 patients (48%), pulmonary embolism in 6 patients, an acute exacerbation of chronic obstructive airways disease in 36 patients and an acute bronchitis in 30 patients. In 9 cases, the dyspnoea was considered to result from mixed cardiac and pulmonary disease. Renal function was assessed by calculating the creatinine clearance by Cockcroft and Gault's formula. The average value of the creatinine clearance was 41.7 +/- 16.4 ml/min indicating that mild renal failure was relatively common. The diagnostic value, assessed by the area under the ROC curve, was similar for the BNP (0.79; CI: 0.70-0.88) and NT-proBNP (0.80; CI: 0.71-0.89). A BNP value of 300 pg/ml had the same sensitivity and specificity as an NT-proBNP of less than 1 500 pg/ml. A BNP of less than 200 pg/ml and an NT-proBNP of less than 1 000 pg/ml had excellent negative predictive values for excluding the diagnosis of cardiac failure. The authors conclude that the BNP and NT-proBNP are useful for the diagnosis of cardiac failure in acute dyspnoea of the elderly and seem to have a comparable diagnostic value.
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Insuficiencia Cardíaca/diagnóstico , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Anciano , Anciano de 80 o más Años , Disnea/etiología , Femenino , Insuficiencia Cardíaca/sangre , Humanos , Masculino , Valor Predictivo de las Pruebas , Curva ROC , Sensibilidad y EspecificidadRESUMEN
Acute intermittent porphyria (AIP) is an autosomal dominant disorder of heme biosynthesis caused by molecular defects in the porphobilinogen deaminase (PBGD) gene. This paper reviews published mutations, their types, and polymorphisms within the PBGD gene. To date, 301 different mutations and 21 polymorphisms have been identified in the PBGD gene in AIP patients and individuals from various countries and ethnic groups. During the search for mutations identified among Slavic AIP patients we found 65 such mutations and concluded that there is not a distinct predominance of certain mutations in Slavs.
Asunto(s)
Hidroximetilbilano Sintasa/genética , Mutación , Polimorfismo Genético , Porfiria Intermitente Aguda/genética , Población Blanca/genética , Humanos , Porfiria Intermitente Aguda/epidemiologíaRESUMEN
Porphyrias are uncommon inherited diseases of haem biosynthesis for which the diagnosis and treatment varies in individual countries. Despite the existence of guidelines recommended by porphyria experts concerning the diagnosis and management of the acute porphyrias, and of specialist centres in most European countries, many clinicians still do not apply these guidelines. The European Porphyia Initiative (EPI) network was formed in 2001 in order to compare experience among countries to attempt to develop a common approach to the management of the porphyrias, particularly concerning recommendation of safe and unsafe drugs, and to facilitate international collaborative clinical and biological research. The main achievements of EPI during this period have been: * Drafting and agreeing to consensus protocols for the diagnosis and management of acute hepatic porphyrias. * Creation of a multilingual website, particularly focusing on guidelines for common prescribing problems in acute porphyria and on providing information for patients that is now available in 10 languages: (www.porphyria-europe.org). EPI's current objectives are to develop the EPI platform, expand to new countries, extend to non-acute porphyrias and design European research and clinical trials in porphyria. The project will focus on: 1. Setting up a European laboratory external quality assurance scheme (EQAS) for biochemical and molecular investigations and their interpretation 2. Establishing a consensus drug list in collaboration with the Nordic porphyria network 3. Improving patient counseling 4. Developing large multi-centre, multi-national research projects. Due to the rarity of the porphyrias, it would be very difficult for any one country to provide this data with a sufficient number of patients and within a reasonable timescale. The progress achieved will facilitate improvements in the treatment and development of new therapeutic strategies. It will set a pattern for establishing, and subsequently harmonising, between countries best clinical practice for a rare but important group of diseases, and will help to develop the optimal therapy and ensure its cost effectiveness.