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1.
Int J Mol Sci ; 22(2)2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33445793

RESUMO

Poisoning by high concentrations of dioxin and its related compounds manifests variable toxic symptoms such as general malaise, chloracne, hyperpigmentation, sputum and cough, paresthesia or numbness of the extremities, hypertriglyceridemia, perinatal abnormalities, and elevated risks of cancer-related mortality. Such health hazards are observed in patients with Yusho (oil disease in Japanese) who had consumed rice bran oil highly contaminated with 2,3,4,7,8-pentachlorodibenzofuran, polychlorinated biphenyls, and polychlorinated quaterphenyls in 1968. The blood concentrations of these congeners in patients with Yusho remain extremely elevated 50 years after onset. Dioxins exert their toxicity via aryl hydrocarbon receptor (AHR) through the generation of reactive oxygen species (ROS). In this review article, we discuss the pathogenic implication of AHR in dioxin-induced health hazards. We also mention the potential therapeutic use of herbal drugs targeting AHR and ROS in patients with Yusho.


Assuntos
Dioxinas/envenenamento , Porfirias/induzido quimicamente , Porfirias/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Humanos , Espécies Reativas de Oxigênio/metabolismo , Óleo de Farelo de Arroz/efeitos adversos
5.
Nat Commun ; 10(1): 5463, 2019 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784520

RESUMO

Iron Regulatory Protein 1 (IRP1) is a bifunctional cytosolic iron sensor. When iron levels are normal, IRP1 harbours an iron-sulphur cluster (holo-IRP1), an enzyme with aconitase activity. When iron levels fall, IRP1 loses the cluster (apo-IRP1) and binds to iron-responsive elements (IREs) in messenger RNAs (mRNAs) encoding proteins involved in cellular iron uptake, distribution, and storage. Here we show that mutations in the Drosophila 1,4-Alpha-Glucan Branching Enzyme (AGBE) gene cause porphyria. AGBE was hitherto only linked to glycogen metabolism and a fatal human disorder known as glycogen storage disease type IV. AGBE binds specifically to holo-IRP1 and to mitoNEET, a protein capable of repairing IRP1 iron-sulphur clusters. This interaction ensures nuclear translocation of holo-IRP1 and downregulation of iron-dependent processes, demonstrating that holo-IRP1 functions not just as an aconitase, but throttles target gene expression in anticipation of declining iron requirements.


Assuntos
Enzima Ramificadora de 1,4-alfa-Glucana/genética , Proteínas de Drosophila/genética , Regulação da Expressão Gênica/genética , Proteína 1 Reguladora do Ferro/genética , Ferro/metabolismo , Porfirias/genética , Enzima Ramificadora de 1,4-alfa-Glucana/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Regulação para Baixo , Drosophila , Proteínas de Drosophila/metabolismo , Ecdisteroides/biossíntese , Glândulas Endócrinas/metabolismo , Técnicas de Introdução de Genes , Técnicas de Inativação de Genes , Heme/metabolismo , Proteína 1 Reguladora do Ferro/metabolismo , Proteínas com Ferro-Enxofre/metabolismo , Larva/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Porfirias/metabolismo , RNA Mensageiro/metabolismo
6.
F1000Res ; 8: 1135, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824661

RESUMO

Background: Basic and clinical scientific research at the University of South Florida (USF) have intersected to support a multi-faceted approach around a common focus on rare iron-related diseases. We proposed a modified version of the National Center for Biotechnology Information's (NCBI) Hackathon-model to take full advantage of local expertise in building "Iron Hack", a rare disease-focused hackathon. As the collaborative, problem-solving nature of hackathons tends to attract participants of highly-diverse backgrounds, organizers facilitated a symposium on rare iron-related diseases, specifically porphyrias and Friedreich's ataxia, pitched at general audiences. Methods: The hackathon was structured to begin each day with presentations by expert clinicians, genetic counselors, researchers focused on molecular and cellular biology, public health/global health, genetics/genomics, computational biology, bioinformatics, biomolecular science, bioengineering, and computer science, as well as guest speakers from the American Porphyria Foundation (APF) and Friedreich's Ataxia Research Alliance (FARA) to inform participants as to the human impact of these diseases. Results: As a result of this hackathon, we developed resources that are relevant not only to these specific disease-models, but also to other rare diseases and general bioinformatics problems. Within two and a half days, "Iron Hack" participants successfully built collaborative projects to visualize data, build databases, improve rare disease diagnosis, and study rare-disease inheritance. Conclusions: The purpose of this manuscript is to demonstrate the utility of a hackathon model to generate prototypes of generalizable tools for a given disease and train clinicians and data scientists to interact more effectively.


Assuntos
Ataxia de Friedreich , Porfirias , Bases de Dados Factuais , Humanos , Ferro , Doenças Raras , Estados Unidos
7.
Mol Genet Metab ; 128(3): 163, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31704238
8.
Mol Genet Metab ; 128(3): 242-253, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31706631

RESUMO

BACKGROUND AND AIM: An association between neuropsychiatric manifestations and neuroimaging suggestive of posterior reversible encephalopathy syndrome (PRES) during porphyric attacks has been described in numerous case reports. We aimed to systematically review clinical-radiological features and likely pathogenic mechanisms of PRES in patients with acute hepatic porphyrias (AHP) and porphyric attacks. METHODS: PubMed, Scopus, Ovid MEDLINE, and Google Scholar were searched (July 30, 2019). We included articles describing patients with convincing evidence of an AHP, confirmed porphyric attacks, and PRES in neuroimaging. RESULTS: Forty-three out of 269 articles were included, which reported on 46 patients. Thirty-nine (84.8%) patients were women. The median age was 24 ±â€¯13.8 years. 52.2% had unspecified AHP, 41.3% acute intermittent porphyria, 4.3% hereditary coproporphyria, and 2.2% variegate porphyria. 70.2% had systemic arterial hypertension. Seizures, mental changes, arterial hypertension, and hyponatremia occurred more frequently than expected for porphyric attacks (p < .001). Seizures and hyponatremia were also more frequent than expected for PRES. The most common distributions of brain lesions were occipital (81.4%), parietal (65.1%), frontal (60.5%), subcortical (40%), and cortical (32.5%). Cerebral vasoconstriction was demonstrated in 41.7% of the patients who underwent angiography. 19.6% of the patients had ischemic lesions, and 4.3% developed long-term sequelae (cognitive decline and focal neurological deficits). CONCLUSIONS: Brain edema, vasoconstriction, and ischemia in the context of PRES likely account for central nervous symptoms in some porphyric attacks.


Assuntos
Sistema Nervoso Central/fisiopatologia , Porfirias/complicações , Porfirias/diagnóstico , Síndrome da Leucoencefalopatia Posterior/etiologia , Adolescente , Adulto , Encéfalo/patologia , Criança , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Neuroimagem , Adulto Jovem
9.
Semin Neurol ; 39(5): 620-639, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31639845

RESUMO

The inherited neuropathies are a common and heterogeneous group of slowly progressive disorders affecting motor, sensory, and autonomic nerves. These hereditary conditions can be confined to the peripheral nervous system, termed the primary hereditary neuropathies, or can occur as part of a multisystem disease. Identification of systemic involvement is necessary to distinguish the primary and secondary hereditary neuropathies to prevent the misdiagnosis of potentially treatable entities. Recent genetic and technological advances have dramatically improved our understanding of the underlying pathophysiology of these inherited neuropathies and hence provide the correct milieu for the future development of disease-modifying therapies. This review provides clinical, neurophysiological, genetic, pathophysiological, and treatment insights into the primary inherited neuropathies, and those associated with multisystem diseases, including porphyria and mitochondrial disorders.


Assuntos
Doenças Mitocondriais/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Porfirias/tratamento farmacológico , Erros de Diagnóstico/prevenção & controle , Humanos , Doenças Mitocondriais/diagnóstico , Doenças do Sistema Nervoso Periférico/diagnóstico , Porfirias/diagnóstico
10.
Int J Neurosci ; 129(12): 1226-1233, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31402774

RESUMO

Porphyrias are inherited disorders of the heme biosynthetic pathway, usually characterized by dermatological changes due to the accumulation of byproducts in the pathway. Select porphyrias also affect the nervous system, namely hereditary coproporphyria, acute intermittent porphyria and variegate porphyria. Complications include paralysis, hyponatremia which can risk central pontine myelinolysis, seizures and coma. Neurological complications usually result from severe episodes of acute attacks. Acute attacks may also elicit neuropsychiatric symptoms such as confusion, hallucinations, anxiety and psychosis. However, these manifestations are generally self-limiting. Due to the generally low incidence of porphyria and full knowledge the associated neurological and psychiatric manifestations, we review the relevant porphyrias along with their clinical manifestations, evaluation, and management to raise its awareness in the clinical picture and to prevent misdiagnosis. Porphyria should be considered within the differential diagnosis for unexplained neurological symptoms.


Assuntos
Transtornos Mentais/etiologia , Doenças do Sistema Nervoso/etiologia , Porfirias/complicações , Heme/biossíntese , Humanos , Doenças do Sistema Nervoso Periférico/etiologia , Porfirias/diagnóstico , Porfirias/terapia
11.
Mol Genet Metab ; 128(3): 164-177, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31326287

RESUMO

Porphyrias, is a general term for a group of metabolic diseases that are genetic in nature. In each specific porphyria the activity of specific enzymes in the heme biosynthetic pathway is defective and leads to accumulation of pathway intermediates. Phenotypically, each disease leads to either neurologic and/or photocutaneous symptoms based on the metabolic intermediate that accumulates. In each porphyria the distinct patterns of these substances in plasma, erythrocytes, urine and feces are the basis for diagnostically defining the metabolic defect underlying the clinical observations. Porphyrias may also be classified as either erythropoietic or hepatic, depending on the principal site of accumulation of pathway intermediates. The erythropoietic porphyrias are congenital erythropoietic porphyria (CEP), and erythropoietic protoporphyria (EPP). The acute hepatic porphyrias include ALA dehydratase deficiency porphyria, acute intermittent porphyria (AIP), hereditary coproporphyria (HCP) and variegate porphyria (VP). Porphyria cutanea tarda (PCT) is the only porphyria that has both genetic and/or environmental factors that lead to reduced activity of uroporphyrinogen decarboxylase in the liver. Each of the 8 enzymes in the heme biosynthetic pathway have been associated with a specific porphyria (Table 1). Mutations affecting the erythroid form of ALA synthase (ALAS2) are most commonly associated with X-linked sideroblastic anemia, however, gain-of-function mutations of ALAS2 have also been associated with a variant form of EPP. This overview does not describe the full clinical spectrum of the porphyrias, but is meant to be an overview of the biochemical steps that are required to make heme in both erythroid and non-erythroid cells.


Assuntos
Heme/biossíntese , Porfirias/genética , Animais , Vias Biossintéticas , Meio Ambiente , Humanos , Fígado/fisiopatologia , Camundongos , Mutação , Sintase do Porfobilinogênio/deficiência , Porfiria Aguda Intermitente , Porfirias/classificação , Porfirias/congênito , Porfirias Hepáticas , Uroporfirinogênio Descarboxilase/metabolismo
12.
Eur J Intern Med ; 67: 24-29, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31257150

RESUMO

BACKGROUND: Porphyrias are a group of metabolic diseases, individually rare but with an important combined prevalence. Because of their pathological complexity and clinical heterogeneity, they present a challenging diagnosis. The present review aims to provide a clinically based approach to the recognition and treatment of these disorders. METHODS: We carried out a search in PubMed, with the keyword "porphyria", for reviews published in English from 2010 until 2017. RESULTS: The research yielded 196 papers, of which 64 were included in the final narrative review. CONCLUSIONS: Porphyrias can be divided based on clinical presentation in acute neurovisceral, chronic cutaneous bullous, chronic cutaneous non-bullous and acute neurovisceral/chronic cutaneous bullous. Each individual porphyria presents a characteristic pattern of porphyrins in plasma, urine, stool and red blood cells. As such, diagnosis is easily obtained by following a simple diagnostic algorithm. Early recognition is key in managing these diseases. Neurovisceral porphyrias require acute support therapy and chronic eviction of precipitating factors. Cutaneous prophyrias, as photosensitivity disorders, rely on sunlight avoidance and, in some cases, specific therapeutic interventions. Given the rarity of these conditions, physician awareness is crucial.


Assuntos
Porfirias/diagnóstico , Porfirias/terapia , Algoritmos , Humanos
14.
Isr Med Assoc J ; 21(6): 429-430, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31280520

Assuntos
Porfirias , Humanos
16.
Cell Mol Gastroenterol Hepatol ; 8(4): 535-548, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31233899

RESUMO

Genetic porphyrias comprise eight diseases caused by defects in the heme biosynthetic pathway that lead to accumulation of heme precursors. Consequences of porphyria include photosensitivity, liver damage and increased risk of hepatocellular carcinoma, and neurovisceral involvement, including seizures. Fluorescent porphyrins that include protoporphyrin-IX, uroporphyrin and coproporphyrin, are photo-reactive; they absorb light energy and are excited to high-energy singlet and triplet states. Decay of the porphyrin excited to ground state releases energy and generates singlet oxygen. Porphyrin-induced oxidative stress is thought to be the major mechanism of porphyrin-mediated tissue damage. Although this explains the acute photosensitivity in most porphyrias, light-induced porphyrin-mediated oxidative stress does not account for the effect of porphyrins on internal organs. Recent findings demonstrate the unique role of fluorescent porphyrins in causing subcellular compartment-selective protein aggregation. Porphyrin-mediated protein aggregation associates with nuclear deformation, cytoplasmic vacuole formation and endoplasmic reticulum dilation. Porphyrin-triggered proteotoxicity is compounded by inhibition of the proteasome due to aggregation of some of its subunits. The ensuing disruption in proteostasis also manifests in cell cycle arrest coupled with aggregation of cell proliferation-related proteins, including PCNA, cdk4 and cyclin B1. Porphyrins bind to native proteins and, in presence of light and oxygen, oxidize several amino acids, particularly methionine. Noncovalent interaction of oxidized proteins with porphyrins leads to formation of protein aggregates. In internal organs, particularly the liver, light-independent porphyrin-mediated protein aggregation occurs after secondary triggers of oxidative stress. Thus, porphyrin-induced protein aggregation provides a novel mechanism for external and internal tissue damage in porphyrias that involve fluorescent porphyrin accumulation.


Assuntos
Porfirias/genética , Porfirias/metabolismo , Porfirias/fisiopatologia , Animais , Carcinoma Hepatocelular/metabolismo , Dermatite Fototóxica/metabolismo , Dermatite Fototóxica/fisiopatologia , Heme/metabolismo , Humanos , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Camundongos , Oxirredução , Estresse Oxidativo/fisiologia , Transtornos de Fotossensibilidade , Porfirinas/metabolismo , Agregados Proteicos , Protoporfirinas , Uroporfirinas , Peixe-Zebra
17.
Hautarzt ; 70(7): 481-489, 2019 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-31197392

RESUMO

Syndromic disorders with skin fragility belong to different groups of genodermatoses: epidermolysis bullosa (EB), Ehlers-Danlos syndrome and porphyria. The genetic defects mainly concern structural proteins which assure the mechanical stability of the skin and other tissues. Depending on the expression pattern of the affected protein in the skin, cutaneous fragility may manifest as superficial erosions, blisters, wounds, wound healing defects or scars. Extracutaneous manifestations are manifold and involve the heart, skeletal muscles, intestine, kidneys, blood vessels or the skeleton. Syndromic types of EB include in addition to skin blistering: (i) cardiomyopathy in case of desmoplakin, plakoglobin, or kelch-like protein mutations; (ii) muscular dystrophy in case of plektin mutations; (iii) pyloric atresia in case of integrin α6ß4 or plectin mutations; (iv) nephrotic syndrome in case of CD151 or integrin α3 mutations. Lysyl hydroxylase 3 mutations affect posttranslational modifications of collagens and lead to a dystrophic epidermolysis bullosa-like multisystemic disorder. Ehlers-Danlos syndromes are due to defects of dermal collagens or their processing and affect the skin, joints and blood vessels. Finally porphyrias are complex metabolic disorders with photosensitivity and sometimes skin fragility, liver or neurologic problems. Their pathogenesis relies on the accumulation of precursors in the tissues. Although these syndromes are rare in clinical practice, knowledge of the syndromic constellation contributes to early diagnosis and detection of complications.


Assuntos
Síndrome de Ehlers-Danlos/patologia , Epidermólise Bolhosa/patologia , Porfirias/patologia , Dermatopatias Vesiculobolhosas/patologia , Síndrome de Ehlers-Danlos/genética , Epidermólise Bolhosa/genética , Humanos , Mutação , Porfirias/genética , Dermatopatias Vesiculobolhosas/genética , Síndrome
18.
Cell Mol Gastroenterol Hepatol ; 8(4): 659-682.e1, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31173894

RESUMO

BACKGROUND & AIMS: Porphyrias are caused by porphyrin accumulation resulting from defects in the heme biosynthetic pathway that typically lead to photosensitivity and possible end-stage liver disease with an increased risk of hepatocellular carcinoma. Our aims were to study the mechanism of porphyrin-induced cell damage and protein aggregation, including liver injury, where light exposure is absent. METHODS: Porphyria was induced in vivo in mice using 3,5-diethoxycarbonyl-1,4-dihydrocollidine or in vitro by exposing human liver Huh7 cells and keratinocytes, or their lysates, to protoporphyrin-IX, other porphyrins, or to δ-aminolevulinic acid plus deferoxamine. The livers, cultured cells, or porphyrin exposed purified proteins were analyzed for protein aggregation and oxidation using immunoblotting, mass spectrometry, and electron paramagnetic resonance spectroscopy. Consequences on cell-cycle progression were assessed. RESULTS: Porphyrin-mediated protein aggregation required porphyrin-photosensitized singlet oxygen and porphyrin carboxylate side-chain deprotonation, and occurred with site-selective native protein methionine oxidation. Noncovalent interaction of protoporphyrin-IX with oxidized proteins led to protein aggregation that was reversed by incubation with acidified n-butanol or high-salt buffer. Phototoxicity and the ensuing proteotoxicity, mimicking porphyria photosensitivity conditions, were validated in cultured keratinocytes. Protoporphyrin-IX inhibited proteasome function by aggregating several proteasomal subunits, and caused cell growth arrest and aggregation of key cell proliferation proteins. Light-independent synergy of protein aggregation was observed when porphyrin was applied together with glucose oxidase as a secondary peroxide source. CONCLUSIONS: Photo-excitable porphyrins with deprotonated carboxylates mediate protein aggregation. Porphyrin-mediated proteotoxicity in the absence of light, as in the liver, requires porphyrin accumulation coupled with a second tissue oxidative injury. These findings provide a potential mechanism for internal organ damage and photosensitivity in porphyrias.


Assuntos
Oxigênio/metabolismo , Porfirias/metabolismo , Ácido Aminolevulínico , Animais , Carcinoma Hepatocelular/metabolismo , Linhagem Celular , Desferroxamina , Heme/metabolismo , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transtornos de Fotossensibilidade , Fármacos Fotossensibilizantes , Porfirias/fisiopatologia , Porfirinas/metabolismo , Agregados Proteicos , Conformação Proteica , Protoporfirinas
19.
J Coll Physicians Surg Pak ; 29(6): S23-S25, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31142411

RESUMO

Congenital erythropoietic porphyria, also called Gunther's disease, is a very rare genetic autosomal recessive diseaseaffecting less than 1 per 1,000,000 children. Pathogenesis involves genetic mutation encoding uroporphyrinogen-III cosynthase which leads to accumulation of porphyrin in many tissues, leading to extreme skin photosensitivity, red cell lysis, splenomegaly and reduced life expectancy. Herein, we report a 12-year mentally challenged girl with multiple blisters and scars on sun exposed sites since birth. She had hepatomegaly, erythrodontia, severe anaemia with haemolytic blood picture and mildly elevated liver enzymes. Skin biopsy showed deposition of amorphous eosinophilic porphyrins in the dermis, thus confirming a diagnosis of congenital erythropoietic porphyria.


Assuntos
Anemia Hemolítica/diagnóstico , Deficiência Intelectual , Transtornos de Fotossensibilidade/diagnóstico , Porfiria Eritropoética/diagnóstico , Porfirias/congênito , Biópsia , Criança , Feminino , Hepatomegalia , Humanos , Transtornos de Fotossensibilidade/metabolismo , Transtornos de Fotossensibilidade/patologia , Porfiria Eritropoética/complicações , Porfiria Eritropoética/metabolismo , Porfirias/metabolismo , Porfirias/patologia
20.
Gastroenterology ; 157(2): 365-381.e4, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31085196

RESUMO

Physicians should be aware of porphyrias, which could be responsible for unexplained gastrointestinal, neurologic, or skin disorders. Despite their relative rarity and complexity, most porphyrias can be easily defined and diagnosed. They are caused by well-characterized enzyme defects in the complex heme biosynthetic pathway and are divided into categories of acute vs non-acute or hepatic vs erythropoietic porphyrias. Acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and aminolevulinic acid dehydratase deficient porphyria) manifest in attacks and are characterized by overproduction of porphyrin precursors, producing often serious abdominal, psychiatric, neurologic, or cardiovascular symptoms. Patients with variegate porphyria and hereditary coproporphyria can present with skin photosensitivity. Diagnosis relies on measurement of increased urinary 5-aminolevulinic acid (in patients with aminolevulinic acid dehydratase deficient porphyria) or increased 5-aminolevulinic acid and porphobilinogen (in patients with other acute porphyrias). Management of attacks requires intensive care, strict avoidance of porphyrinogenic drugs and other precipitating factors, caloric support, and often heme therapy. The non-acute porphyrias are porphyria cutanea tarda, erythropoietic protoporphyria, X-linked protoporphyria, and the rare congenital erythropoietic porphyria. They lead to the accumulation of porphyrins that cause skin photosensitivity and occasionally severe liver damage. Secondary elevated urinary or blood porphyrins can occur in patients without porphyria, for example, in liver diseases, or iron deficiency. Increases in porphyrin precursors and porphyrins are also found in patients with lead intoxication. Patients with porphyria cutanea tarda benefit from iron depletion, hydroxychloroquine therapy, and, if applicable, elimination of the hepatitis C virus. An α-melanocyte-stimulating hormone analogue can reduce sunlight sensitivity in patients with erythropoietic protoporphyria or X-linked protoporphyria. Strategies to address dysregulated or dysfunctional steps within the heme biosynthetic pathway are in development.


Assuntos
Gastroenteropatias/diagnóstico , Doenças do Sistema Nervoso/diagnóstico , Porfirias/diagnóstico , Guias de Prática Clínica como Assunto , Dermatopatias/diagnóstico , Ácido Aminolevulínico/urina , Gastroenterologia/normas , Gastroenteropatias/etiologia , Gastroenteropatias/terapia , Gastroenteropatias/urina , Humanos , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/terapia , Doenças do Sistema Nervoso/urina , Porfobilinogênio/urina , Porfirias/complicações , Porfirias/terapia , Porfirias/urina , Porfirinas/biossíntese , Dermatopatias/etiologia , Dermatopatias/terapia , Dermatopatias/urina
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