RESUMEN
We describe developments in understanding of the porphyrias associated with each step in the haem biosynthesis pathway and the role of individuals whose contributions led to major advances over the past 150 years. The first case of erythropoietic porphyria was reported in 1870, and the first with acute porphyria in 1889. Photosensitisation by porphyrin was confirmed by Meyer-Betz, who self-injected haematoporphyrin. Günther classified porphyrias into haematoporphyria acuta, acuta toxica, congenita and chronica. This was revised by Waldenström into porphyria congenita, acuta and cutanea tarda, with the latter describing those with late-onset skin lesions. Waldenström was the first to recognise porphobilinogen's association with acute porphyria, although its structure was not solved until 1953. Hans Fischer was awarded the Nobel prize in 1930 for solving the structure of porphyrins and the synthesis of haemin. After 1945, research by several groups elucidated the pathway of haem biosynthesis and its negative feedback regulation by haem. By 1961, following the work of Watson, Schmid, Rimington, Goldberg, Dean, Magnus and others, aided by the availability of modern techniques of porphyrin separation, six of the porphyrias were identified and classified as erythropoietic or hepatic. The seventh, 5-aminolaevulinate dehydratase deficiency porphyria, was described by Doss in 1979. The discovery of increased hepatic 5-aminolaevulinate synthase activity in acute porphyria led to development of haematin as a treatment for acute attacks. By 2000, all the haem biosynthesis genes were cloned, sequenced and assigned to chromosomes and disease-specific mutations identified in all inherited porphyrias. These advances have allowed definitive family studies and development of new treatments.
Asunto(s)
Genómica , Hemo , Porfirias , Historia del Siglo XX , Humanos , Porfirias/genética , Porfirias/historia , Historia del Siglo XIX , Hemo/biosíntesis , Hemo/metabolismo , Historia del Siglo XXI , 5-Aminolevulinato Sintetasa/genética , 5-Aminolevulinato Sintetasa/metabolismoRESUMEN
BACKGROUND AND AIMS: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.
Asunto(s)
Porfobilinógeno Sintasa/deficiencia , Porfirias Hepáticas/tratamiento farmacológico , Porfirias Hepáticas/fisiopatología , Adulto , Anciano , Biomarcadores/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Porfobilinógeno Sintasa/orina , Porfirias Hepáticas/orina , Estudios Prospectivos , Recurrencia , Adulto JovenRESUMEN
With the advent of precision and genomic medicine, a critical issue is whether a disease gene variant is pathogenic or benign. Such is the case for the three autosomal dominant acute hepatic porphyrias (AHPs), including acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, each resulting from the half-normal enzymatic activities of hydroxymethylbilane synthase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase, respectively. To date, there is no public database that documents the likely pathogenicity of variants causing the porphyrias, and more specifically, the AHPs with biochemically and clinically verified information. Therefore, an international collaborative with the European Porphyria Network and the National Institutes of Health/National Center for Advancing Translational Sciences/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NCATS/NIDDK)-sponsored Porphyrias Consortium of porphyria diagnostic experts is establishing an online database that will collate biochemical and clinical evidence verifying the pathogenicity of the published and newly identified variants in the AHP-causing genes. The overall goal of the International Porphyria Molecular Diagnostic Collaborative is to determine the pathogenic and benign variants for all eight porphyrias. Here we describe the overall objectives and the initial efforts to validate pathogenic and benign variants in the respective heme biosynthetic genes causing the AHPs.
Asunto(s)
Porfirias/genética , Porfirias/fisiopatología , Virulencia/genética , Curaduría de Datos/métodos , Bases de Datos Factuales , Femenino , Humanos , Masculino , Patología Molecular , Porfobilinógeno Sintasa/deficiencia , Porfobilinógeno Sintasa/genética , Porfiria Intermitente Aguda/genética , Porfiria Intermitente Aguda/fisiopatología , Porfirias Hepáticas/genética , Porfirias Hepáticas/fisiopatología , Estados UnidosRESUMEN
Severe recurrent acute attacks of porphyria have traditionally been treated with either prophylactic human haemin or gonadorelin analogues (GnA) in females. Evidence on the most effective treatment for this patient subgroup is lacking. This audit surveyed the use of prophylactic GnA in the UK.Twenty female patients (who experienced between 2 and 45 acute attacks of porphyria requiring hospitalisation and treatment with human haemin prior to GnA prophylaxis) were included in the audit. Data was retrospectively collected based on patient history and case review.Twenty three treatment courses were given lasting a median period of 12 months. Monthly subcutaneous Goserelin was most commonly used. In three patients in whom timing with the menstrual cycle was not considered, an acute attack occurred after initiation of the first dose. The majority of patients experienced oestrogen deficiency symptoms during treatment. Fifty percent of the prescribed courses of GnA resulted in a degree of clinical benefit. This successfully treated group experienced between 3 and 20 acute attacks prior to and between 0 and 6 acute attacks during GnA treatment.The audit revealed large variation in practice in the United Kingdom regarding indication, duration of treatment, specific drug used and management of side effects. In view of the limited treatment options available for this cohort and the mixed outcome successes reported, we believe it is reasonable for porphyria specialists to continue offering GnA treatment to women with severe recurrent debilitating acute attacks of porphyria associated with the menstrual cycle, and we propose best practice guidelines to standardise management.
RESUMEN
Acute porphyrias are rare inherited disorders due to deficiencies of haem synthesis enzymes. To date, all UK cases have been one of the three autosomal dominant forms, although penetrance is low and most gene carriers remain asymptomatic. Clinical presentation is typically with acute neurovisceral attacks characterised by severe abdominal pain, vomiting, tachycardia and hypertension. Severe attacks may be complicated by hyponatraemia, peripheral neuropathy sometimes causing paralysis, seizures and psychiatric features. Attacks are triggered by prescribed drugs, alcohol, hormonal changes, fasting or stress. The diagnosis is made by finding increased porphobilinogen excretion in a light-protected random urine sample. Management includes administration of intravenous human haemin and supportive treatment with non-porphyrinogenic drugs. A few patients develop recurrent attacks, a chronic illness requiring specialist management. Late complications include chronic pain, hepatocellular carcinoma, chronic renal failure and hypertension. In the UK, the National Acute Porphyria Service provides clinical advice and supplies haemin when indicated.
Asunto(s)
Porfiria Intermitente Aguda , Enfermedad Crónica , Manejo de la Enfermedad , Humanos , Porfiria Intermitente Aguda/diagnóstico , Porfiria Intermitente Aguda/patología , Porfiria Intermitente Aguda/terapiaRESUMEN
The porphyrias are disorders of haem biosynthesis which present with acute neurovisceral attacks or disorders of sun-exposed skin. Acute attacks occur mainly in adults and comprise severe abdominal pain, nausea, vomiting, autonomic disturbance, central nervous system involvement and peripheral motor neuropathy. Cutaneous porphyrias can be acute or chronic presenting at various ages. Timely diagnosis depends on clinical suspicion leading to referral of appropriate samples for screening by reliable biochemical methods. All samples should be protected from light. Investigation for an acute attack: ⢠Porphobilinogen (PBG) quantitation in a random urine sample collected during symptoms. Urine concentration must be assessed by measuring creatinine, and a repeat requested if urine creatinine <2 mmol/L. ⢠Urgent porphobilinogen testing should be available within 24 h of sample receipt at the local laboratory. Urine porphyrin excretion (TUP) should subsequently be measured on this urine. ⢠Urine porphobilinogen should be measured using a validated quantitative ion-exchange resin-based method or LC-MS. ⢠Increased urine porphobilinogen excretion requires confirmatory testing and clinical advice from the National Acute Porphyria Service. ⢠Identification of individual acute porphyrias requires analysis of urine, plasma and faecal porphyrins. Investigation for cutaneous porphyria: ⢠An EDTA blood sample for plasma porphyrin fluorescence emission spectroscopy and random urine sample for TUP. ⢠Whole blood for porphyrin analysis is essential to identify protoporphyria. ⢠Faeces need only be collected, if first-line tests are positive or if clinical symptoms persist. Investigation for latent porphyria or family history: ⢠Contact a specialist porphyria laboratory for advice. Clinical, family details are usually required.
Asunto(s)
Porfobilinógeno/orina , Porfirias/diagnóstico , Porfirinas , Piel/metabolismo , Enfermedad Aguda , Algoritmos , Cromatografía Liquida , Enfermedad Crónica , Colorimetría , Heces/química , Fluorometría , Humanos , Espectrometría de Masas , Porfirias/sangre , Porfirias/clasificación , Porfirias/orina , Porfirinas/sangre , Porfirinas/orina , Control de Calidad , Piel/patología , Factores de TiempoRESUMEN
An unusual case of an 11-month-old, black Limousin-cross heifer, with an 8-month history of episodic seizures and photosensitisation, was referred by a veterinary practitioner to the Farm Animal Section of the UCD Veterinary Hospital, School of Veterinary Medicine, University College Dublin, Ireland, in August 2014. Following an investigation, a diagnosis of Bovine Congenital Erythropoietic Protoporphyria (BCEPP) was made. To the authors' knowledge this is the first report of such a case in Ireland. BCEPP should be considered as a differential diagnosis in young animals displaying periodic seizures and/or photosensitisation.
RESUMEN
The National Acute Porphyria Service (NAPS) provides acute care support and clinical advice for patients in England with active acute porphyria requiring haem arginate treatment and patients with recurrent acute attacks.This audit examined the benefits and complications of regular haem arginate treatment started with prophylactic intent to reduce the frequency of recurrent acute attacks in a group of patients managed through NAPS. We included 22 patients (21 female and 1 male) and returned information on diagnosis, indications for prophylactic infusions, frequency and dose, analgesia, activity and employment and complications including thromboembolic disease and iron overload.The median age at presentation with porphyria was 21 years (range 9-44), with acute abdominal pain as the predominant symptom. Patients had a median of 12 (1-400) attacks before starting prophylaxis and had received a median of 52 (0-1,350) doses of haem arginate. The median age at starting prophylaxis was 28 years (13-58) with a median delay of 4 years (0.5-37) between presentation and prophylaxis. The frequency of prophylactic haem arginate varied from 1 to 8 per month, and 67% patients were documented as having a reduction in pain frequency on prophylaxis. Only one patient developed clinically significant iron overload and required iron chelation, but the number of venous access devices required varied from 1 to 15, with each device lasting a median of 1.2 years before requiring replacement. Six patients stopped haem arginate and in three this was because their symptoms had improved. Prophylactic haem arginate appears to be beneficial in patients with recurrent acute porphyria symptoms, but maintaining central venous access may prove challenging.
RESUMEN
The porphyrias are a group of mainly inherited disorders of heme biosynthesis where accumulation of porphyrins and/or porphyrin precursors gives rise to 2 types of clinical presentation: cutaneous photosensitivity and/or acute neurovisceral attacks. The cutaneous porphyrias present with either bullous skin fragility or nonbullous acute photosensitivity. This review discusses the epidemiology, pathogenesis, clinical presentation, laboratory diagnosis, complications, and current approach to porphyria management. Although focusing mainly on their dermatological aspects, the article also covers the management of acute porphyria, which by virtue of its association with variegate porphyria and hereditary coproporphyria, may become the responsibility of the clinical dermatologist.
Asunto(s)
Porfirias , Porfirinas/metabolismo , Enfermedades de la Piel , Piel/metabolismo , Luz Solar/efectos adversos , Protectores Solares/uso terapéutico , Diagnóstico Diferencial , Humanos , Porfirias/diagnóstico , Porfirias/metabolismo , Porfirias/prevención & control , Ropa de Protección , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/metabolismo , Enfermedades de la Piel/prevención & controlAsunto(s)
Hidroximetilbilano Sintasa/genética , Porfiria Intermitente Aguda/genética , Adulto , Exones , Femenino , HumanosRESUMEN
Retrospective estimates of the prevalence of porphyrias have been reported but there has been no large scale prospective study of their incidence. The European Porphyria Network collected information prospectively over a 3 year period about the number of newly diagnosed symptomatic patients with an inherited porphyria (335 patients from 11 countries). Prevalence was calculated from the incidence and mean disease duration. The incidence of hepato-cellular carcinoma (HCC) in acute hepatic porphyria and the prevalence of patients with recurrent acute attacks of porphyria were also investigated. The incidence of symptomatic acute intermittent porphyria (AIP) was similar in all countries (0.13 per million per year; 95 % CI: 0.10 - 0.14) except Sweden (0.51; 95 % CI: 0.28-0.86). The incidence ratio for symptomatic AIP: variegate porphyria: hereditary coproporphyria was 1.00:0.62: 0.15. The prevalence of AIP (5.4 per million; 95 % CI: 4.5-6.3) was about half that previously reported. The prevalence of erythropoietic protoporphyria (EPP) was less uniform between countries and, in some countries, exceeded previous estimates. Fourteen new cases of HCC (11 from Sweden) were reported in patients with acute porphyria. Sixty seven patients (3 VP; 64 AIP: 53 females, 11 males) with recurrent attacks of acute porphyria were identified. The estimated percentage of patients with AIP that will develop recurrent acute attacks was 3-5 %. In conclusion, the prevalence of symptomatic acute porphyria may be decreasing, possibly due to improved management, whereas the prevalence of EPP may be increasing due to improved diagnosis and its greater recognition as a cause of photosensitivity.
Asunto(s)
Porfirias/epidemiología , Porfirias/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/epidemiología , Niño , Preescolar , Coproporfiria Hereditaria/epidemiología , Europa (Continente)/epidemiología , Femenino , Humanos , Incidencia , Lactante , Neoplasias Hepáticas/epidemiología , Masculino , Persona de Mediana Edad , Porfobilinógeno Sintasa/deficiencia , Porfiria Intermitente Aguda/epidemiología , Porfiria Variegata/epidemiología , Porfirias Hepáticas/epidemiología , Estudios Prospectivos , Protoporfiria Eritropoyética/epidemiología , Adulto JovenAsunto(s)
Síndromes Mielodisplásicos/genética , Porfiria Eritropoyética/genética , Anciano , Exones , Genes Recesivos , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/patología , Polimorfismo de Nucleótido Simple , Porfiria Eritropoyética/patología , Porfirinas/sangre , Porfirinas/orina , Enfermedades Cutáneas Vesiculoampollosas/genética , Uroporfirinas/genéticaRESUMEN
BACKGROUND: Clinically indistinguishable attacks of acute porphyria occur in acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). There are few evidence-based diagnostic strategies for these disorders. METHODS: The diagnostic sensitivity of mutation detection was determined by sequencing and gene-dosage analysis to search for mutations in 467 sequentially referred, unrelated patients. The diagnostic accuracy of plasma fluorescence scanning, fecal porphyrin analysis, and porphobilinogen deaminase (PBGD) assay was assessed in mutation-positive patients (AIP, 260 patients; VP, 152 patients; HCP, 31 patients). RESULTS: Sensitivities (95% CI) for mutation detection were as follows: AIP, 98.1% (95.6%-99.2%); HCP, 96.9% (84.3%-99.5%); VP, 100% (95.7%-100%). We identified 5 large deletions in the HMBS gene (hydroxymethylbilane synthase) and one in the CPOX gene (coproporphyrinogen oxidase). The plasma fluorescence scan was positive more often in VP (99% of patients) than in AIP (68%) or HCP (29%). The wavelength of the fluorescence emission peak and the fecal coproporphyrin isomer ratio had high diagnostic specificity and sensitivity for differentiating between AIP, HCP, and VP. DNA analysis followed by PBGD assay in mutation-negative patients had greater diagnostic accuracy for AIP than either test alone. CONCLUSIONS: When PBG excretion is increased, 2 investigations (plasma fluorescence scanning, the coproporphyrin isomer ratio) are sufficient, with rare exceptions, to identify the type of acute porphyria. When the results of PBG, 5-aminolevulinate, and porphyrin analyses are within reference intervals and clinical suspicion that a past illness was caused by an acute porphyria remains high, mutation analysis of the HMBS gene followed by PBGD assay is an effective strategy for diagnosis or exclusion of AIP.
Asunto(s)
Coproporfirinógeno Oxidasa/genética , Análisis Mutacional de ADN , Genes Dominantes , Hidroximetilbilano Sintasa/genética , Mutación , Porfirias/diagnóstico , Protoporfirinógeno-Oxidasa/genética , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Niño , Cartilla de ADN , Diagnóstico Diferencial , Humanos , Persona de Mediana Edad , Porfirias/genética , Estudios Retrospectivos , Sensibilidad y Especificidad , Adulto JovenRESUMEN
Erythropoietic protoporphyria (EPP) is an inherited disorder that results from partial deficiency of ferrochelatase (FECH). It is characterized clinically by acute photosensitivity and, in 2% of patients, liver disease. Inheritance is usually autosomal dominant with low penetrance but is recessive in about 4% of families. A cross-sectional study of 223 patients with EPP in the United Kingdom identified six individuals with palmar keratoderma. We now show that these and three additional patients, from six families, have an inherited subtype of EPP which is characterized by seasonal palmar keratoderma, relatively low erythrocyte protoporphyrin concentrations, and recessive inheritance. No patient had evidence of liver dysfunction; four patients had neurological abnormalities. Patients were hetero- or homoallelic for nine different FECH mutations; four of which were previously unreported. Prokaryotic expression predicted that FECH activities were 2.7-25% (mean 10.6%) of normal. Neither mutation type nor FECH activity provided an explanation for the unusual phenotype. Our findings show that palmar keratoderma is a clinical indicator of recessive EPP, identify a phenotype that occurs in 38% of reported families with recessive EPP that to our knowledge is previously unreported, and suggest that patients with this phenotype may carry a lower risk of liver disease than other patients with recessive EPP.
Asunto(s)
Ferroquelatasa/genética , Genes Recesivos , Queratodermia Palmoplantar/complicaciones , Queratodermia Palmoplantar/genética , Protoporfiria Eritropoyética/complicaciones , Protoporfiria Eritropoyética/genética , Adolescente , Adulto , Niño , Femenino , Ferroquelatasa/fisiología , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Estaciones del AñoRESUMEN
All reported mutations in ALAS2, which encodes the rate-regulating enzyme of erythroid heme biosynthesis, cause X-linked sideroblastic anemia. We describe eight families with ALAS2 deletions, either c.1706-1709 delAGTG (p.E569GfsX24) or c.1699-1700 delAT (p.M567EfsX2), resulting in frameshifts that lead to replacement or deletion of the 19-20 C-terminal residues of the enzyme. Prokaryotic expression studies show that both mutations markedly increase ALAS2 activity. These gain-of-function mutations cause a previously unrecognized form of porphyria, X-linked dominant protoporphyria, characterized biochemically by a high proportion of zinc-protoporphyrin in erythrocytes, in which a mismatch between protoporphyrin production and the heme requirement of differentiating erythroid cells leads to overproduction of protoporphyrin in amounts sufficient to cause photosensitivity and liver disease.
Asunto(s)
5-Aminolevulinato Sintetasa/genética , Cromosomas Humanos X/genética , Porfirias Hepáticas/patología , Eritrocitos/metabolismo , Femenino , Hemo/metabolismo , Humanos , Masculino , Mutación , Porfirias Hepáticas/genética , Protoporfirinas/sangreRESUMEN
Porphyrias are a heterogenous group of diseases that may result in disabling or life threatening neurovisceral symptoms and/or cutaneous photosensitivity. In acute intermittent porphyria, the clinical features, particularly neurological symptoms, may be life-threatening and disabling. Conventional treatment with human hemin, though effective in reducing symptoms, does not reverse neuropathy when structural nerve damage has occurred and may cause intense phlebitis. Liver transplantation (LT) may be considered as treatment for those with repeated life-threatening acute attacks resulting in poor quality of life, requirement of ventilatory support, and progressive loss of venous access due to hemin infusion. Patients with variegate porphyria (VP) present after puberty with neurovisceral symptoms and skin manifestations. LT resolved VP in the 1 patient reported in the literature. Aminolaevulinic acid dehydratase deficient porphyria is a rare autosomal recessive disorder and a child who presented with failure to thrive and required transfusions and parenteral nutrition did not improve with LT. In erythropoietic protoporphyria (EPP), there is excessive production of protoporphyrin in the bone marrow. Protoporphyrin is hepatotoxic and pigment loading of hepatocytes and bile canalicular sludging may result in progressive cholestasis and cirrhosis. LT is beneficial for such patients with end-stage liver disease. Perioperative management includes use of filters on operative lights to prevent skin burns and intestinal perforation. Other concerns include development of neuropathy, biliary complications, and recurrent liver disease. This review addresses the rationale, patient selection, evaluation, management issues, and technique of performing LT in various types of porphyria.
Asunto(s)
Trasplante de Hígado , Porfirias Hepáticas/cirugía , Carcinoma Hepatocelular/cirugía , Supervivencia de Injerto , Hemina/uso terapéutico , Humanos , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/mortalidad , Trasplante de Hígado/fisiología , Porfirias Hepáticas/tratamiento farmacológico , Porfirias Hepáticas/enzimología , Porfirias Hepáticas/patología , Estudios Retrospectivos , Seguridad , Análisis de SupervivenciaRESUMEN
Erythropoietic protoporphyria (EPP) results from deficiency of ferrochelatase (FECH). Accumulation of protoporphyrin IX causes life-long acute photosensitivity. Microcytic anemia occurs in 20% to 60% of patients. We investigated 178 patients with dominant EPP confirmed by molecular analysis. Erythropoiesis was impaired in all patients; all had a downward shift in hemoglobin (Hb), and the mean decreased in males by 12 g/L (1.2 g/dL). By World Health Organization criteria, 48% of women and 33% of men were anemic. Iron stores, assessed by serum ferritin (sFn), were decreased by two-thirds, but normal serum soluble transferrin receptor-1 and iron concentrations suggested that erythropoiesis was not limited by iron supply. FECH deficiency in EPP appears to lead to a steady state in which decreased erythropoiesis is matched by reduced iron absorption and supply. This response may in part be mediated by protoporphyrin, but we found no correlation between erythrocyte protoporphyrin and Hb, sFn, total iron-binding capacity, or transferrin saturation.