RESUMEN
Defects in hydroxymethylbilane synthase (HMBS) can cause acute intermittent porphyria (AIP), an acute neurological disease. Although sequencing-based diagnosis can be definitive, â¼â of clinical HMBS variants are missense variants, and most clinically reported HMBS missense variants are designated as "variants of uncertain significance" (VUSs). Using saturation mutagenesis, en masse selection, and sequencing, we applied a multiplexed validated assay to both the erythroid-specific and ubiquitous isoforms of HMBS, obtaining confident functional impact scores for >84% of all possible amino acid substitutions. The resulting variant effect maps generally agreed with biochemical expectations and provide further evidence that HMBS can function as a monomer. Additionally, the maps implicated specific residues as having roles in active site dynamics, which was further supported by molecular dynamics simulations. Most importantly, these maps can help discriminate pathogenic from benign HMBS variants, proactively providing evidence even for yet-to-be-observed clinical missense variants.
Asunto(s)
Hidroximetilbilano Sintasa , Porfiria Intermitente Aguda , Humanos , Hidroximetilbilano Sintasa/química , Hidroximetilbilano Sintasa/genética , Hidroximetilbilano Sintasa/metabolismo , Mutación Missense/genética , Porfiria Intermitente Aguda/diagnóstico , Porfiria Intermitente Aguda/genética , Sustitución de Aminoácidos , Simulación de Dinámica MolecularRESUMEN
New treatment options and low attack-related mortality have changed the life expectancy of patients with acute porphyria (AP) to that of the general population. Clinicians should therefore be aware of the long-term complications of AP, which typically include chronic neuropathy and encephalopathy, high blood pressure and porphyria-associated kidney disease. Patients have an increased risk of primary liver cancer (PLC), but no increased risk of non-hepatic cancers. Chronic pain occurs in patients with recurrent attacks, combined with chronic fatigue and nausea, leading to poor quality of life. Patients with sporadic attacks may also have chronic symptoms, which should be distinguished from mild recurrent attacks and treated appropriately. Sequels of acute polyneuropathy after an attack should be distinguished from ongoing chronic polyneuropathy, as the management is different. Overestimation of chronic neuropathy or encephalopathy caused by AP should be avoided, and other causes should be treated accordingly. Prevention of recurrent attacks is the best strategy for managing chronic comorbidities and should be actively accomplished. Hormonal interventions in female patients, or in severe cases, prophylactic givosiran or haematin, may be helpful before liver transplantation to prevent recurrent attacks. Regular monitoring can be personalised according to the patient's age, comorbidities and AP activity. Blood pressure, renal function and cardiovascular risk factors should be monitored annually in patients with previous symptoms. Appropriate medication and lifestyle management, including nutrition and hydration, are necessary to prevent complications. As PLC is common, especially in patients with acute intermittent porphyria, bi-annual surveillance after the age of 50 is important.
RESUMEN
BACKGROUND: Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months. The primary end point was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization, an urgent health care visit, or intravenous administration of hemin at home.) Key secondary end points were levels of ALA and porphobilinogen and the annualized attack rate among patients with acute hepatic porphyria, along with hemin use and daily worst pain scores in patients with acute intermittent porphyria. RESULTS: A total of 94 patients underwent randomization (48 in the givosiran group and 46 in the placebo group). Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001); the results were similar among the 94 patients with acute hepatic porphyria. Among the patients with acute intermittent porphyria, givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of hemin use, and better daily scores for pain than placebo. Key adverse events that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions. CONCLUSIONS: Among patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations than those who received placebo. The increased efficacy was accompanied by a higher frequency of hepatic and renal adverse events. (Funded by Alnylam Pharmaceuticals; ENVISION ClinicalTrials.gov number, NCT03338816.).
Asunto(s)
Acetilgalactosamina/análogos & derivados , Ácido Aminolevulínico/orina , Porfobilinógeno/orina , Porfiria Intermitente Aguda/tratamiento farmacológico , Pirrolidinas/uso terapéutico , Tratamiento con ARN de Interferencia , Acetilgalactosamina/efectos adversos , Acetilgalactosamina/uso terapéutico , Adulto , Método Doble Ciego , Fatiga/etiología , Femenino , Humanos , Inyecciones Subcutáneas , Análisis de los Mínimos Cuadrados , Hígado/efectos de los fármacos , Masculino , Náusea/etiología , Dolor/etiología , Evaluación del Resultado de la Atención al Paciente , Porfiria Intermitente Aguda/complicaciones , Porfiria Intermitente Aguda/orina , Pirrolidinas/efectos adversos , Insuficiencia Renal Crónica/inducido químicamente , Transaminasas/sangreRESUMEN
One-year data from EXPLORE Part A showed high disease burden and impaired quality of life (QOL) in patients with acute hepatic porphyria (AHP) with recurrent attacks. We report baseline data of patients who enrolled in EXPLORE Part B for up to an additional 3 years of follow-up. EXPLORE B is a long-term, prospective study evaluating disease activity, pain intensity, and QOL in patients with AHP with ≥1 attack in the 12 months before enrollment or receiving hemin or gonadotropin-releasing hormone prophylaxis. Data were evaluated in patients with more (≥3 attacks or on prophylaxis treatment) or fewer (<3 attacks and no prophylaxis treatment) attacks. Patients in the total population (N = 136), and more (n = 110) and fewer (n = 26) attack subgroups, reported a median (range) of 3 (0-52), 4 (0-52), and 1 (0-2) acute attacks, respectively, in the 12 months prior to the baseline visit. Pain, mood/sleep, digestive/bladder, and nervous system symptoms were each experienced by ≥80% of patients; most received hemin during attacks. Almost three-quarters of patients reported chronic symptoms between attacks, including 85% of patients with fewer attacks. Pain intensity was comparable among both attack subgroups; most patients required pain medication. All groups had diminished QOL on the EuroQol visual analog scale and the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 versus population norms. Patients with AHP with recurrent attacks, even those having fewer attacks, experience a high disease burden, as evidenced by chronic symptoms between attacks and impaired QOL.
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Porfiria Intermitente Aguda , Porfirias Hepáticas , Humanos , Estudios Prospectivos , Calidad de Vida , Hemina/uso terapéutico , Porfirias Hepáticas/tratamiento farmacológico , Dolor , Porfiria Intermitente Aguda/complicaciones , Porfiria Intermitente Aguda/tratamiento farmacológicoRESUMEN
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.
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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.
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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
BACKGROUND: Erythropoietic protoporphyria is a severe photodermatosis that is associated with acute phototoxicity. Patients with this condition have excruciating pain and a markedly reduced quality of life. We evaluated the safety and efficacy of an α-melanocyte-stimulating hormone analogue, afamelanotide, to decrease pain and improve quality of life. METHODS: We conducted two multicenter, randomized, double-blind, placebo-controlled trials of subcutaneous implants containing 16 mg of afamelanotide. Patients in the European Union (74 patients) and the United States (94 patients) were randomly assigned, in a 1:1 ratio, to receive a subcutaneous implant containing either afamelanotide or placebo every 60 days (a total of five implants in the European Union study and three in the U.S study). The type and duration of sun exposure, number and severity of phototoxic reactions, and adverse events were recorded over the respective 180-day and 270-day study periods. Quality of life was assessed with the use of validated questionnaires. A subgroup of U.S. patients underwent photoprovocation testing. The primary efficacy end point was the number of hours of direct exposure to sunlight without pain. RESULTS: In the U.S. study, the duration of pain-free time after 6 months was longer in the afamelanotide group (median, 69.4 hours, vs. 40.8 hours in the placebo group; P=0.04). In the European Union study, the duration of pain-free time after 9 months was also longer in the afamelanotide group than in the placebo group (median, 6.0 hours vs. 0.8 hours; P=0.005), and the number of phototoxic reactions was lower in the the afamelanotide group (77 vs. 146, P=0.04). In both trials, quality of life improved with afamelanotide therapy. Adverse events were mostly mild; serious adverse events were not thought to be related to the study drug. CONCLUSIONS: Afamelanotide had an acceptable side-effect and adverse-event profile and was associated with an increased duration of sun exposure without pain and improved quality of life in patients with erythropoietic protoporphyria. (Funded by Clinuvel Pharmaceuticals and others; ClinicalTrials.gov numbers, NCT01605136 and NCT00979745.).
Asunto(s)
Dolor/prevención & control , Protoporfiria Eritropoyética/tratamiento farmacológico , Luz Solar/efectos adversos , alfa-MSH/análogos & derivados , Adulto , Método Doble Ciego , Implantes de Medicamentos , Humanos , Persona de Mediana Edad , Dolor/etiología , Protoporfiria Eritropoyética/complicaciones , alfa-MSH/efectos adversos , alfa-MSH/uso terapéuticoRESUMEN
Acute encephalopathy (AE) can be a manifestation of an acute porphyric attack. Clinical data were studied in 32 patients during AE with or without polyneuropathy (PNP) together with 12 subjects with PNP but no AE, and 17 with dysautonomia solely. Brain neuroimaging was done in 20 attacks during AE, and PEPT2 polymorphisms were studied in 56 subjects, 24 with AE. AE manifested as a triad of seizures, confusion and/or blurred vision. Symptoms lasting 1-5 days manifested 3-19 days from the onset of an attack. 55% of these patients had acute PNP independent of AE. Posterior reversible encephalopathy syndrome (PRES) was detected in 42% of the attacks. These patients were severely affected and hyponatremic (88%). Reversible segmental vasoconstriction was rare. There was no statistical difference in hypertension or urinary excretion of porphyrin precursors among the patients with or without AE. In 94% of the attacks with AE, liver transaminases were elevated significantly (1.5 to fivefold, P = 0.034) compared to a normal level in 87% of the attacks with dysautonomia, or in 25% of patients with PNP solely. PEPT2*2/2 haplotype was less common among patients with AE than without (8.3% vs. 25.8%, P = 0.159) and in patients with PNP than without (9.5% vs. 22.9%, P = 0.207), suggesting a minor role, if any, in acute neurotoxicity. In contrast, PEPT2*2/2 haplotype was commoner among patients with chronic kidney disease (P = 0.192). Acute endothelial dysfunction in porphyric encephalopathy could be explained by a combination of abrupt hypertension, SIADH, and acute metabolic and inflammatory factors of hepatic origin.
Asunto(s)
Encefalopatías , Hipertensión , Polineuropatías , Porfirias Hepáticas , Síndrome de Leucoencefalopatía Posterior , Disautonomías Primarias , Humanos , Síndrome de Leucoencefalopatía Posterior/diagnóstico , Encefalopatías/diagnóstico , Imagen por Resonancia MagnéticaRESUMEN
Pregnane X receptor (PXR) is known to stimulate haem synthesis, but detailed knowledge on the effects of PXR activation on porphyrin metabolism in humans is lacking. We utilized a randomized, crossover, open (blinded laboratory) and placebo-controlled trial with 600-mg rifampicin or placebo dosed for a week to investigate the effects of PXR activation on erythrocyte, plasma, faecal and urine porphyrins. Sixteen healthy volunteers participated on the trial, but the number of volunteers for blood and urine porphyrin analyses was 15 while the number of samples for faecal analyses was 14. Rifampicin increased urine pentaporphyrin concentration 3.7-fold (mean 1.80 ± 0.6 vs. 6.73 ± 4.4 nmol/L, p = 0.003) in comparison with placebo. Urine coproporphyrin I increased 23% (p = 0.036). Faecal protoporphyrin IX decreased (mean 31.6 ± 23.5 vs. 19.2 ± 27.8 nmol/g, p = 0.023). The number of blood erythrocytes was slightly elevated, and plasma bilirubin, catabolic metabolite of haem, was decreased. In conclusion, rifampicin dosing elevated the excretion of certain urinary porphyrin metabolites and decreased faecal protoporphyrin IX excretion. As urine pentaporphyrin and coproporphyrin I are not precursors in haem biosynthesis, increased excretion may serve as a hepatoprotective shunt when haem synthesis or porphyrin levels are increased.
Asunto(s)
Porfirinas , Rifampin , Humanos , Eritrocitos , Voluntarios Sanos , Hemo/metabolismo , Porfirinas/metabolismo , Porfirinas/orina , Rifampin/farmacología , Receptor X de Pregnano/efectos de los fármacos , Receptor X de Pregnano/metabolismoRESUMEN
Defects in hydroxymethylbilane synthase (HMBS) can cause Acute Intermittent Porphyria (AIP), an acute neurological disease. Although sequencing-based diagnosis can be definitive, ~â of clinical HMBS variants are missense variants, and most clinically-reported HMBS missense variants are designated as "variants of uncertain significance" (VUS). Using saturation mutagenesis, en masse selection, and sequencing, we applied a multiplexed validated assay to both the erythroid-specific and ubiquitous isoforms of HMBS, obtaining confident functional impact scores for >84% of all possible amino-acid substitutions. The resulting variant effect maps generally agreed with biochemical expectation. However, the maps showed variants at the dimerization interface to be unexpectedly well tolerated, and suggested residue roles in active site dynamics that were supported by molecular dynamics simulations. Most importantly, these HMBS variant effect maps can help discriminate pathogenic from benign variants, proactively providing evidence even for yet-to-be-observed clinical missense variants.
RESUMEN
Human acute intermittent porphyria (AIP), the most common acute hepatic porphyria, is an autosomal dominant inborn error of heme biosynthesis due to the half-normal activity of hydroxymethylbilane synthase (HMB-synthase). Here, we describe the first naturally occurring animal model of AIP in four unrelated cat lines who presented phenotypically as congenital erythropoietic porphyria (CEP). Affected cats had erythrodontia, brownish urine, fluorescent bones, and markedly elevated urinary uroporphyrin (URO) and coproporphyrin (COPRO) consistent with CEP. However, their uroporphyrinogen-III-synthase (URO-synthase) activities (deficient in CEP) were normal. Notably, affected cats had half-normal HMB-synthase activities and elevated urinary 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), the deficient enzyme and accumulated metabolites in human AIP. Sequencing the feline HMB-synthase gene revealed different mutations in each line: a duplication (c.189dupT), an in-frame 3 bp deletion (c.842_844delGAG) identical to that causing human AIP and two missense mutations, c.250G>A (p.A84T) and c.445C>T (p.R149W). Prokaryotic expression of mutations c.842_844delGAG and c.445C>T resulted in mutant enzymes with <1% wild-type activity, whereas c.250G>A expressed a stable enzyme with approximately 35% of wild-type activity. The discolored teeth from the affected cats contained markedly elevated URO I and III, accounting for the CEP-like phenocopy. In three lines, the phenotype was an autosomal dominant trait, while affected cats with the c.250G>A (p.A84T) mutation were homozygous, a unique recessive form of AIP. These animal models may permit further investigation of the pathogenesis of the acute, life-threatening neurological attacks in human AIP and the evaluation of therapeutic strategies. GenBank Accession Numbers: GQ850461-GQ850464.
Asunto(s)
Enfermedades de los Gatos/enzimología , Gatos/genética , Modelos Animales de Enfermedad , Hidroximetilbilano Sintasa/genética , Mutación , Porfiria Intermitente Aguda/enzimología , Porfiria Eritropoyética/enzimología , Animales , Huesos/metabolismo , Enfermedades de los Gatos/genética , Enfermedades de los Gatos/metabolismo , Gatos/metabolismo , Coproporfirinas/orina , Femenino , Humanos , Hidroximetilbilano Sintasa/química , Hidroximetilbilano Sintasa/metabolismo , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Porfiria Intermitente Aguda/genética , Porfiria Intermitente Aguda/metabolismo , Porfiria Eritropoyética/genética , Porfiria Eritropoyética/metabolismo , Porfirinas/metabolismo , Diente/metabolismo , Uroporfirinas/orinaRESUMEN
Erythropoietic, i.e., myelogenous porphyrias include erythropoietic protoporphyria and the very rare congenital protoporphyria and X-linked protoporphyria. Of these, in Finland only erythropoietic protoporphyria has been diagnosed, in which pain and swelling in the skin upon sunlight exposure are the most typical symptoms. A high protoporphyrin level in erythrocytes and a typical peak in the plasma porphyrin spectrum lead to diagnosis.
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Trastornos por Fotosensibilidad/etiología , Porfiria Eritropoyética/diagnóstico , Porfiria Eritropoyética/etiología , Porfirinas/sangre , Luz Solar/efectos adversos , Diagnóstico Diferencial , Recuento de Eritrocitos , Finlandia/epidemiología , Humanos , Trastornos por Fotosensibilidad/diagnóstico , Trastornos por Fotosensibilidad/epidemiología , Porfiria Eritropoyética/epidemiología , Protoporfirinas/sangre , Factores de RiesgoRESUMEN
BACKGROUND: Acute hepatic porphyria includes four inherited disorders caused by partial deficiencies of enzymes related to the heme biosynthesis. Clinical manifestations include acute attacks, occurring mainly among female patients. This study describes the diversity of acute symptoms, changes in triggering factors and life expectancy among female patients during the past five decades. METHODS: 107 Finnish female patients were enrolled into a retrospective, longitudinal study during 2015. Clinical, biochemical and genetic data was obtained from the medical reports, registry data and a questionnaire designed for the study. Causes of death were studied in additional 32 female patients. RESULTS: Of the 43 patients with hospitalization, 33% had non-complicated, 35% prolonged and 28% severe attacks with no correlation with the disease-causing mutation. Of the deceased patients, 31% died of an acute attack during 1957-1979. Thereafter the incidence and severity of acute attacks have decreased substantially. 55% of the subjects reported acute symptoms (dysautonomia and mental symptoms) without hospitalization, 29% had porphyria symptoms >10 times, and 23% within the last year. Despite 22% of the female patients had died of primary liver cancer, the life expectancy increased more than 10 years during the follow-up, and did not differ from the normal population at present. CONCLUSIONS: The incidence of acute attacks requiring hospitalization has decreased, but more than half of the female patients reported acute symptoms affecting their well-being. Symptoms are currently triggered by hormonal changes and weight loss emphasizing the importance of early recognition and active management to avoid disease exacerbation. Death due to primary liver cancer is common and should be screened regularly.
RESUMEN
Acute porphyrias are a group of inherited metabolic disorders representing overproduction syndromes with the formation of neurotoxic haem precursors. Clinical manifestations consist of acute attacks, which include abdominal pain, dysautonomia, mental symptoms, polyneuropathy and seizures mimicking many other acute neurological disorders.Porphyrin metabolites were screened in 108 patients with acute polyneuropathy or encephalopathy associated with pain and/or dysautonomia, who attended neurological wards, in order to evaluate the number of patients with acute porphyria.Urinary porphyrins and their precursors were increased in 21% of the cases. Surprisingly many patients (11%) had previously undiagnosed acute porphyria. Half of these patients had had mild to moderate symptoms of acute porphyria previously. Secondary porphyrinuria, which was mainly transient coproporphyrinuria because of hepatopathy, was also common (10%). Of the 108 patients studied, the levels of urinary porphyrins or their precursors were normal in the majority (79%) of the cases, who commonly had Guillain-Barré syndrome (40%). Epileptic seizures were also frequent (18%), but none of the patients with acute porphyria had solely epileptic seizures without prolonged confusion (>or= 1 day).Based on our findings, acute inherited porphyria is not infrequent among the selected group of neurological patients and screening of urinary PBG is cost-beneficial. Since the correct diagnosis of a hereditary disease is essential, genetic screening should be performed whenever possible for patients with clinically and biochemically confirmed acute porphyria.
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Encefalopatías/diagnóstico , Encefalopatías/orina , Polineuropatías/diagnóstico , Polineuropatías/orina , Porfobilinógeno/orina , Adolescente , Adulto , Femenino , Humanos , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Seven different porphyrias form a group of inherited metabolic disorders, each resulting from a partial deficiency of a specific enzyme in the haem biosynthesis pathway. Clinically, the three most important entities are an acute porphyric attack and acute and chronic skin symptoms. Porphyrias are rare and sometimes misdiagnosed, because various symptoms and signs mimic other diseases. Once porphyria is suspected, biochemical analyses easily detect porphyrins and their precursors from blood, urine, or faeces. Mutation screening can be done at the quiescent phase of the disease. Pathogenetic mechanisms and clinical manifestations differ in individual porphyrias and most of them require a specific treatment. Early diagnosis and information about precipitating factors can diminish mortality and prevent subsequent attacks among patients with acute porphyrias, so mutation screening is recommended for family members.
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Porfirias , Humanos , Porfiria Intermitente Aguda/diagnóstico , Porfiria Intermitente Aguda/terapia , Porfirias/complicaciones , Porfirias/diagnóstico , Porfirias/fisiopatología , Porfirias/terapia , Pronóstico , Enfermedades de la Piel/complicaciones , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/terapiaRESUMEN
Acute intermittent porphyria (AIP) is a metabolic disease due to a partial deficiency of hydroxymethylbilane synthase (HMBS) in heme biosynthesis. Direct sequencing of genomic DNA samples of 11 unrelated Russian AIP patients, 32 of their relatives and 50 healthy controls from northwestern Russia including Saint Petersburg revealed nine mutations in the HMBS gene. Three novel mutations, c.825+5G>C, c.825+3_825+6del, and c.770T>C, resulted in varying amounts of abnormal transcripts, r.822_825del and [r.770U>C, r.652_771del, r.613_771del]. Six mutations, c.77G>A (p.R26H), c.517C>T (p.R173W), c.583C>T (p.R195C), c.673C>T (p.R225X), c.739T>C (p.C247R), and c.748G>C (p.E250A), have previously been identified in AIP patients from Western and other Eastern European populations. All mutations expressed in COS-1 cells demonstrated low residual activities (0.1-1%). The majority of the mutations were family-specific and also confirmed allelic heterogeneity among Russian AIP patients. The diversity of mutations may reflect the old international history of Saint Petersburg and immigration of people from other parts of Europe.
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Hidroximetilbilano Sintasa/genética , Mutación , Porfiria Intermitente Aguda/genética , Animales , Células COS , Chlorocebus aethiops , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Humanos , Hidroximetilbilano Sintasa/metabolismo , Masculino , Polimorfismo Genético , Porfiria Intermitente Aguda/diagnóstico , Empalme del ARN/fisiología , ARN Mensajero/metabolismo , Federación de Rusia/etnologíaRESUMEN
Acute intermittent porphyria (AIP), resulting from a deficiency of porphobilinogen deaminase (PBGD) in heme biosynthesis, is genetically heterogeneous and manifests with variable penetrance. The clinical outcome, prognosis, and correlation between PBGD genotype and phenotype were investigated in 143 Finnish and Russian AIP patients with 10 mutations (33G-->T, 97delA, InsAlu333, R149X, R167W, R173W, R173Q, R225G, R225X, 1073delA). Thirty-eight percent of the patients had experienced 1 or more acute attacks during their lives. The proportion of symptomatic patients has decreased dramatically from 49% to 17% among patients diagnosed before and after 1980, respectively. Patients with the R167W and R225G mutations showed lower penetrance (19% and 11%, respectively) and recurrence rate (33% and 0%, respectively) than patients with other mutations (range, 36%-67% and 0%-66%, respectively). Moreover, urinary excretions of porphyrins and their precursors were significantly lower in these patients (porphobilinogen [PBG], 47 +/- 10 vs. 163 +/- 21 micromol/L, p < 0.001; uroporphyrin, 130 +/- 40 vs. 942 +/- 183 nmol/d, p < 0.001). Erythrocyte PBGD activity did not correlate with PBG excretion in remission or with the clinical severity of the disease. Mutations R167W and R225G resulted in milder biochemical abnormalities and clinical symptoms indicating a milder form of AIP in these patients. In all AIP patients, normal PBG excretion predicted freedom from acute attacks. The risk of symptoms was highest for female patients with markedly increased PBG excretion (>100 micromol/L). Proper counseling contributed to the prevention of subsequent attacks in 60% of previously symptomatic and in 95% of previously symptom-free patients.
Asunto(s)
Hidroximetilbilano Sintasa/orina , Porfiria Intermitente Aguda/genética , Dolor Abdominal/etiología , Adolescente , Adulto , Análisis de Varianza , Eritrocitos/metabolismo , Femenino , Genotipo , Humanos , Hidroximetilbilano Sintasa/metabolismo , Modelos Logísticos , Masculino , Persona de Mediana Edad , Fenotipo , Porfiria Intermitente Aguda/complicaciones , Porfiria Intermitente Aguda/metabolismo , Factores Desencadenantes , Estadísticas no ParamétricasRESUMEN
Acute intermittent porphyria (AIP) is due to a deficiency of the third enzyme, the hydroxymethylbilane synthase, in heme biosynthesis. It manifests with occasional neuropsychiatric crises associated with overproduction of porphyrin precursors, aminolevulinic acid and porphobilinogen. The clinical criteria of an acute attack include the paroxysmal nature and various combinations of symptoms, such as abdominal pain, autonomic dysfunction, hyponatremia, muscle weakness, or mental symptoms, in the absence of other obvious causes. Intensive abdominal pain without peritoneal signs, acute peripheral neuropathy, and encephalopathy usually with seizures or psychosis are the key symptoms indicating possible acute porphyria. More than fivefold elevation of urinary porphobilinogen excretion together with typical symptoms of an acute attack is sufficient to start a treatment. Currently, the prognosis of the patients with AIP is good, but physicians should be aware of a potentially fatal outcome of the disease. Mutation screening and identification of type of acute porphyria can be done at the quiescent phase of the disease. The management of patients with AIP include following strategies: A, during an acute attack: 1) treatment with heme preparations, if an acute attack is severe or moderate; 2) symptomatic treatment of autonomic dysfunctions, polyneuropathy and encephalopathy; 3) exclusion of precipitating factors; and 4) adequate nutrition and fluid therapy. B, during remission: 1) exclusion of precipitating factors (education of patients and family doctors), 2) information about on-line drug lists, and 3) mutation screening for family members and education about precipitating factors in mutation-positive family members. C, management of patients with recurrent attacks: 1) evaluation of the lifestyle, 2) evaluation of hormonal therapy in women, 3) prophylactic heme therapy, and 4) liver transplantation in patients with severe recurrent attacks. D, follow-up of the AIP patients for long-term complications: chronic hypertension, chronic kidney insufficiency, chronic pain syndrome, and hepatocellular carcinoma.
RESUMEN
Variegate porphyria (VP) is an inherited metabolic disease resulting from the partial deficiency of protoporphyrinogen oxidase, the penultimate enzyme in the heme biosynthetic pathway. We have evaluated the clinical and biochemical outcome of 103 Finnish VP patients diagnosed between 1966 and 2001. Fifty-two per cent of patients had experienced clinical symptoms: 40% had photosensitivity, 27% acute attacks and 14% both manifestations. The proportion of patients with acute attacks has decreased dramatically from 38 to 14% in patients diagnosed before and after 1980, whereas the prevalence of skin symptoms had decreased only subtly from 45 to 34%. We have studied the correlation between PPOX genotype and clinical outcome of 90 patients with the three most common Finnish mutations I12T, R152C and 338G-->C. The patients with the I12T mutation experienced no photosensitivity and acute attacks were rare (8%). Therefore, the occurrence of photosensitivity was lower in the I12T group compared to the R152C group (P=0.001), whereas no significant differences between the R152C and 338G-->C groups could be observed. Biochemical abnormalities were significantly milder suggesting a milder form of the disease in patients with the I12T mutation. In all VP patients, normal excretion of protoporphyrin in faeces in adulthood predicted freedom from both skin symptoms and acute attacks. The most valuable test predicting an increased risk of symptoms was urinary coproporphyrin, but only a substantially increased excretion exceeding 1,000 nmol/day was associated with an increased risk of both skin symptoms and acute attacks. All patients with an excretion of more than 1,000 nmol/day experienced either skin symptoms, acute attacks, or both.
Asunto(s)
Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Oxidorreductasas/genética , Porfirias Hepáticas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Coproporfirinas/metabolismo , Coproporfirinas/orina , Heces/química , Femenino , Finlandia , Flavoproteínas , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Proteínas Mitocondriales , Oxidorreductasas/metabolismo , Fenotipo , Porfirias Hepáticas/metabolismo , Protoporfirinógeno-Oxidasa , Protoporfirinas/metabolismo , Relación Estructura-Actividad , Uroporfirinas/orinaRESUMEN
Acute intermittent porphyria (AIP) is an inherited metabolic disease with an autosomal dominant pattern of inheritance. The disease is caused by a partial deficiency of porphobilinogen deaminase (PBGD) in heme biosynthesis. Since biochemical measurements of patients and their healthy relatives overlap, the diagnosis of AIP may remain undetermined at the symptom-free phase. Mutation detection in AIP, which provides 95% sensitivity and around 100% specificity, has quickly been incorporated into good clinical practice. During an acute attack, which includes various neurovisceral symptoms, measurement of urinary porphobilinogen (PBG) is a method of choice to confirm diagnosis, and DNA testing is unnecessary at that stage. DNA testing has revealed many new patients and excluded AIP from many healthy relatives despite slightly increased excretions of porphyrin precursors and erythrocyte PBGD in the low or borderline zone. Thus, quality-assured DNA testing is accurate enough to confirm or exclude the diagnosis of AIP. The clinical utility of DNA testing is limited for those individuals whose mutation is currently unknown, in which biochemical analyses are essential and the majority of the patients can be identified using urinary PBG and erythrocyte PBGD measurements. The measurement of urinary PBG can be used to evaluate the prognosis for symptom-free individuals. Currently, DNA testing of AIP at the population level is not recommended unless the frequency of gene carriers is locally very high and large-scale population-based mutation screening is reasonable. In the future, the knowledge of gene-gene and gene-environment interactions and protein networks using gene array and proteomics technologies may provide more precise information about pathogenetic mechanisms and novel therapeutic strategies for an acute attack and the long-term complications of AIP. Increasing knowledge of pharmacogenetics may identify the patients who are at high risk for clinical manifestations.