RESUMO
Acute porphyrias are a group of rare inherited disorders causing acute neurovisceral attacks. Many terms used frequently in the literature and clinical practice are ambiguous, which can lead to confusion in the way patients are managed, studied, and reported in clinical studies. Agreed definitions are a necessary first step in developing management guidelines and will facilitate communication of results of future clinical research. The Delphi method was used to generate consensus on key terms and definitions in acute porphyria. The process started with a brainstorming phase offered to all members of the European Porphyria Network followed by two Delphi rounds among international experts in the field of porphyria (the Acute Porphyria Expert Panel). A consensus of 75% or more was defined as the agreement threshold. A total of 63 respondents from 26 countries participated in the brainstorming phase, leading to the choice of nine terms and definitions. A total of 34 experts were invited to take part in the Delphi rounds. Seven of the initial nine terms and definitions which entered the first Delphi round achieved the threshold for agreement. Following a second Delphi round, all nine definitions achieved agreement. Agreement on the definitions for nine important terms describing acute porphyrias represents a significant step forward for the porphyria community. It will facilitate more accurate comparison of outcomes among porphyria centres and in clinical trials and provide a strong framework for developing evidence-based clinical guidelines.
Assuntos
Porfiria Aguda Intermitente , Porfirias , Humanos , Porfiria Aguda Intermitente/diagnóstico , Porfiria Aguda Intermitente/terapia , Técnica Delphi , Consenso , Doenças RarasRESUMO
The acute hepatic porphyrias (AHP) are associated with long-term complications such as primary liver cancer, hypertension, and chronic kidney disease. Data on other related comorbidities are scarce. In this register-based, matched cohort study, we assessed the risks of nonhepatic cancers, cardiovascular diseases, renal diseases, psychiatric disorders, and mortality in relation to porphyria type, sex, and biochemical disease activity. All patients in the Swedish porphyria register with a verified AHP diagnosis during 1987-2015 were included. The biochemical activity of acute intermittent porphyria was assessed using recorded maximal urinary porphobilinogen (U-PBG). Data on incident comorbidities and mortality were collected from national health registries. Cumulative incidences, rates, and hazards were compared to reference individuals from the general population, matched 1:10 by age, sex, and county. We identified 1244 patients with AHP with a median follow-up of 19 years. Health registries identified 149 AHP-subjects (12.0%) with nonhepatic cancer, similar to 1601 (13.0%) in the matched reference population (n = 12 362). Patients with AHP had a higher risk of kidney cancer (0.8% vs. 0.2%, p < 0.001), hypertension, and chronic kidney disease but no increase in risk for cardiovascular disease, except for cerebrovascular disease in patients with elevated U-PBG, (aHR = 1.40 [95% CI:1.06-1.85]). Mortality risk during follow-up was higher among patients with AHP (21% vs. 18%, p = 0.001), and associated with primary liver cancer, female sex, and biochemical activity. In conclusion, AHP is associated with an increased risk of kidney cancer, hypertension, chronic kidney disease, and mortality but not with cardiovascular disease or other nonhepatic cancers.
Assuntos
Comorbidade , Neoplasias , Sintase do Porfobilinogênio , Porfirias Hepáticas , Estudos de Coortes , Neoplasias/epidemiologia , Humanos , Masculino , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Incidência , Medição de Risco , Suscetibilidade a Doenças , Insuficiência Renal Crônica/epidemiologia , Doenças Cardiovasculares/epidemiologia , Transtornos Mentais/epidemiologia , Doenças do Sistema Nervoso/epidemiologia , Porfirias Hepáticas/epidemiologia , Porfirias Hepáticas/mortalidade , Sintase do Porfobilinogênio/deficiência , Neoplasias Renais/epidemiologiaRESUMO
Variegate porphyria is caused by mutations in the protoporphyrinogen oxidase IX (PPOX, EC 1.3.3.4) gene, resulting in reduced overall enzymatic activity of PPOX in human tissues. Recently, we have identified the His333Arg mutation in the PPOX protein (PPOX(H333R)) as a putative founder mutation in the Moroccan Jewish population. Herein we report the molecular characterization of PPOX(H333R) in vitro and in cells. Purified recombinant PPOX(H333R) did not show any appreciable enzymatic activity in vitro, corroborating the clinical findings. Biophysical experiments and molecular modeling revealed that PPOX(H333R) is not folded properly and fails to adopt its native functional three-dimensional conformation due to steric clashes in the vicinity of the active site of the enzyme. On the other hand, PPOX(H333R) subcellular distribution, as evaluated by live-cell confocal microscopy, is unimpaired suggesting that the functional three-dimensional fold is not required for efficient transport of the polypeptide chain into mitochondria. Overall, the data presented here provide molecular underpinnings of the pathogenicity of PPOX(H333R) and might serve as a blueprint for deciphering whether a given PPOX variant represents a disease-causing mutation.
Assuntos
Flavoproteínas/genética , Proteínas Mitocondriais/genética , Mutação/genética , Protoporfirinogênio Oxidase/genética , Sequência de Aminoácidos , Fenômenos Biofísicos , Linhagem Celular , Estabilidade Enzimática , Flavoproteínas/química , Flavoproteínas/isolamento & purificação , Humanos , Cinética , Proteínas Mitocondriais/química , Proteínas Mitocondriais/isolamento & purificação , Modelos Moleculares , Multimerização Proteica , Protoporfirinogênio Oxidase/química , Protoporfirinogênio Oxidase/isolamento & purificação , Frações Subcelulares/metabolismo , TemperaturaRESUMO
PURPOSE OF REVIEW: Porphyrias constitute a group of rare metabolic disorders that result in a deficiency of the heme biosynthetic pathway and lead to the accumulation of metabolic intermediaries. Patients with porphyria can experience recurrent neurovisceral attacks which are characterized by neuropathic abdominal pain and acute gastrointestinal symptoms, including nausea, vomiting, and constipation. Depending on the type of porphyria, patients can present with cutaneous manifestations, such as severe skin photosensitivity, chronic hemolysis, or evidence of neurologic dysfunction, including alterations in consciousness, neurovascular involvement, seizures, transient sensor-motor symptoms, polyneuropathy, and behavioral abnormalities. RECENT FINDINGS: More recently, cases of posterior reversible encephalopathy syndrome, cerebral vasoconstriction, and acute flaccid paralysis have also been described. While the exact pathogenic mechanisms linking the accumulation of abnormal heme biosynthetic intermediaries to neurologic manifestations have not been completely elucidated, it has been proposed that these manifestations are more common than previously thought and can result in permanent neurologic injury. This article reviews the basic principles of heme synthesis as well as the pathogenic mechanism of disease, presentation, and treatment of acute hepatic porphyrias with emphasis on those with neurologic manifestations.
Assuntos
Neuralgia , Porfiria Aguda Intermitente , Porfirias Hepáticas , Porfirias , Síndrome da Leucoencefalopatia Posterior , Heme/metabolismo , Humanos , Porfiria Aguda Intermitente/complicações , Porfirias/complicações , Porfirias/diagnóstico , Porfirias/terapia , Porfirias Hepáticas/diagnósticoRESUMO
BACKGROUND AND PURPOSE: We hypothesized that upon sun exposure, a sub-population of primary skin-derived mesenchymal-like cells is deleteriously affected and thus contribute to the chronic inflammatory state in autosomal recessive variegate porphyria patients. The aim of this study was to isolate and characterize the mesenchymal-like stem cells from different areas of the skin in a porphyria patient (sun exposed, SE, and sun protected, SP) and to compare them with cells from a healthy individual. METHODS: The proliferation rate and the migration ability of SE and SP cells were evaluated in the presence of an antioxidant compound, N-acetylcysteine. A co-culture of SE-damaged cells with the conditioned medium from the enriched mesenchymal cell-like SP population was performed in order to regenerate the dermal injured tissue after sun exposure in patients. RESULTS: Results showed that the percentage of CD105+ cells varies between 3.9% in SP and 5% in SE of the healthy individual and between 3.6% and 1.4% in SP and SE in the porphyria patient, respectively. The osteogenic differentiation potential was lower in the porphyria patient when compared to the control. Furthermore, the expression of stem cell markers was more pronounced in SE than in SP cells of both control and porphyria. The use of N-acetyl cysteine did not show any beneficial effects on porphyria SE cells. Treatment with SP-conditioned medium slightly increased the expression of stem cell markers in SE of porphyria patient. CONCLUSION: In conclusion, the pool of mesenchymal stem-like SE cells is affected in variegate porphyria patient along with modification of their self-renewal and differentiation properties.
Assuntos
Células-Tronco Mesenquimais , Porfiria Variegada , Porfirias , Dermatopatias , Meios de Cultivo Condicionados , Humanos , OsteogêneseRESUMO
OBJECTIVE: Penetrance, predictive value and female patients' perspectives on genetic testing were evaluated among Finnish patients with acute porphyria. We conducted a retrospective study to evaluate prognosis among at-risk female family members depending on the primary method of diagnosis. METHODS: The penetrance was calculated among 23 genetically heterogeneous families selected from the Finnish porphyria registry (n = 515, AIP 333; VP 182). We included kindreds with ≥9 patients in a family (range 9-23 patients, total 216 AIP; 129 VP). In 2015, the registry included 164 living female subjects between 14 and 85 years of age. A questionnaire was sent to 143 women, of whom 107 (75%, AIP 67; VP 40) replied. Female at-risk relatives (AIP 54; VP 30) were divided into two groups based on the primary method of diagnosis: mutation analysis (Group A, n = 40) or biochemical analysis (Group B, n = 44). RESULTS: Mean penetrance for all acute symptoms was 35% among AIP and 40% among VP families. In both study groups, the penetrance was higher among female (AIP 50%; VP 44%) than male patients (AIP 17%; VP 33%). Penetrance for hospitalized attacks was 30% among AIP families (range 10-80%, for women 41%) and 25% in VP (range 0-50%, for women 27%) demonstrating wide variations among families even with the similar genotype. Acute porphyria was diagnosed at the median age of 26 years (range 0-76 years) among female patients, commonly after the onset of acute symptoms. Diagnostic delay was an average of 7.4 years (range 1-30 years). Acute symptoms occurred at the median age of 24 years (range 10-57 years) and the first hospitalization at the median age of 26.5 years (range 15-57 years). At the onset of symptoms, 38% of the women were ≤ 20 years of age. According to the life table analysis, acute attacks occurred mainly during the following five years after the diagnosis and the attack risk diminished after 35 years of age. The annual risk for hospitalization due to an acute attack during fertile years was lower in Group A than Group B (0.002 vs. 0.010, p = .018), but the risk of all subsequent acute symptoms did not diminish (Group A 0.017 vs. Group B 0.019, p = .640). The cumulative risk of acute symptoms among asymptomatic patients at the time of diagnosis was 26.7% for Group A and 58.3% for Group B. The cumulative risk of the first subsequent attack requiring hospitalization after the diagnosis among all at-risk relatives was similarly less frequent in Group A than in Group B (OR 0.180; 95% CI 0.041-0.789, p = .041). If attacks were followed among symptomatic patients only, attack-free years were more frequent in Group A than in Group B. Patients preferred genetic screening before puberty to minimize the risk of acute symptoms and genetic discrimination was rare. 44% of the patients reported social, psychological or physical impairment due to acute hepatic porphyria, emphasizing the importance of supporting patients' emotional and resilience capacity. CONCLUSIONS: Among female at-risk relatives the annual risk for hospitalization due to an acute attack is <1% and for acute symptoms <2% during the fertile years. Genetic testing of relatives diminishes the risk of acute attacks. Diagnosis before symptom onset is key for subjects to remain asymptomatic during follow-up, and genetic screening should be done earlier than currently.
Assuntos
Diagnóstico Tardio/estatística & dados numéricos , Porfiria Aguda Intermitente/diagnóstico , Porfiria Aguda Intermitente/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Assintomáticas , Análise Mutacional de DNA , Feminino , Testes Genéticos , Genótipo , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Penetrância , Porfiria Aguda Intermitente/fisiopatologia , Porfiria Aguda Intermitente/psicologia , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Inquéritos e QuestionáriosRESUMO
The acute hepatic porphyrias (AHPs) are inborn errors of heme biosynthesis, which include three autosomal dominant porphyrias, Acute Intermittent Porphyria (AIP), Hereditary Coproporphyria (HCP), and Variegate Porphyria (VP), and the ultra-rare autosomal recessive porphyria, δ-Aminolevulinic Acid Dehydratase Deficiency Porphyria (ADP). AIP, HCP, VP, and ADP each results from loss-of-function (LOF) mutations in their disease-causing genes: hydroxymethylbilane synthase (HMBS); coproporphyrinogen oxidase (CPOX); protoporphyrinogen oxidase (PPOX), and δ-aminolevulinic acid dehydratase (ALAD), respectively. During the 11-year period from January 1, 2007 through December 31, 2017, the Mount Sinai Porphyrias Diagnostic Laboratory diagnosed 315 unrelated AIP individuals with HMBS mutations, including 46 previously unreported mutations, 29 unrelated HCP individuals with CPOX mutations, including 11 previously unreported mutations, and 54 unrelated VP individuals with PPOX mutations, including 20 previously unreported mutations. Overall, of the 1692 unrelated individuals referred for AHP molecular diagnostic testing, 398 (23.5%) had an AHP mutation. Of the 650 family members of mutation-positive individuals tested for an autosomal dominant AHP, 304 (46.8%) had their respective family mutation. These data expand the molecular genetic heterogeneity of the AHPs and document the usefulness of molecular testing to confirm the positive biochemical findings in symptomatic patients and identify at-risk asymptomatic family members.
Assuntos
Coproporfirinogênio Oxidase/genética , Hidroximetilbilano Sintase/genética , Mutação , Porfiria Aguda Intermitente/genética , Protoporfirinogênio Oxidase/genética , Doenças Assintomáticas , Família , Heterogeneidade Genética , Heme/biossíntese , Humanos , Técnicas de Diagnóstico Molecular , Porfiria Aguda Intermitente/diagnósticoRESUMO
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.
Assuntos
Porfiria Aguda Intermitente , Doença Crônica , Gerenciamento Clínico , Humanos , Porfiria Aguda Intermitente/diagnóstico , Porfiria Aguda Intermitente/patologia , Porfiria Aguda Intermitente/terapiaRESUMO
BACKGROUND: Acute hepatic porphyria (AHP) is considered to be a risk factor for primary liver cancer (PLC), but varying risk estimates have been published. OBJECTIVES: Our aim was to investigate the risk of PLC and other cancers in persons with AHP using a nationwide cohort design. Given that greater numbers of women than men tend to have manifest and more severe AHP, a further aim was to investigate sex differences in this risk. METHODS: The study sample consisted of all Norwegian residents aged 18 years or older during the period 2000-2011. Persons with AHP (n = 251) were identified through the Norwegian Porphyria Centre, and patients with a cancer diagnosis were identified by linkage to the Cancer Registry of Norway. RESULTS: For persons with AHP, the annual incidence rate of PLC was 0.35%. PLC risk was substantially higher for individuals with an AHP diagnosis compared to the reference population [adjusted hazard ratio (aHR) 108, 95% confidence interval (CI) 56-207]. In a meta-analysis of published studies on PLC and AHP, including ours, women had a higher risk than men. In addition, our results suggested that persons with AHP may have increased risks of kidney (aHR 7.4, 95% CI 2.4-23.1) and endometrial cancers (aHR 6.2, 95% CI 2.0-19.3). CONCLUSIONS: Our findings confirmed a substantially higher risk of PLC associated with AHP compared to the general population. In a meta-analysis, the risk was shown to be greater for women than men. The novel findings of a moderate to substantial association between AHP and kidney and endometrial cancers should be investigated further.
Assuntos
Neoplasias do Endométrio/epidemiologia , Neoplasias Renais/epidemiologia , Neoplasias Hepáticas/epidemiologia , Sintase do Porfobilinogênio/deficiência , Porfirias Hepáticas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Comorbidade , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Fatores de Risco , Distribuição por Sexo , Fatores Sexuais , Adulto JovemRESUMO
Porphyrias comprise a heterogeneous group of predominantly genetically determined metabolic diseases which are due to a dysfunction in heme biosynthesis. Variegate porphyria and hereditary coproporphyria are referred to as neurocutaneous porphyrias because affected patients can develop both cutaneous symptoms on light-exposed body sites and potentially life-threatening acute neurovisceral symptoms, thereby mimicking several other diseases. In this overview, we provide an update on pathogenesis, clinical manifestation, diagnosis, and therapy of these two types of porphyria.
Assuntos
Coproporfiria Hereditária/diagnóstico , Coproporfiria Hereditária/terapia , Síndromes Neurocutâneas/diagnóstico , Síndromes Neurocutâneas/terapia , Porfiria Variegada/diagnóstico , Porfiria Variegada/terapia , Diagnóstico Diferencial , Medicina Baseada em Evidências , Humanos , Resultado do TratamentoRESUMO
Variegate porphyria (VP) and acute intermittent porphyria (AIP), the two most common types of acute porphyrias (AHPs), result from a partial deficiency of protoporphyrinogen oxidase (PPOX) and hydroxymethylbilane synthase (HMBS), respectively. A rare but serious complication in the AHPs is hepatocellular carcinoma (HCC). However, the underlying pathomechanisms are yet unknown. We performed DNA sequence analysis in cancerous and non-cancerous liver tissue of a VP and an AIP patient, both with HCC. In samples of both cancerous and non-cancerous liver tissues from the patients, we identified the underlying PPOX and HMBS germline mutations, c.1082dupC and p.G111R, respectively. Additionally, we detected a second somatic mutation, only in the cancer tissue i.e., p.L416X in the PPOX gene of the VP patient and p.L220X in the HMBS gene of the AIP patient, both located in trans to the respective germline mutations. Both somatic mutations were not detected in 10 non-porphyria-associated HCCs. Our data demonstrate that in the hepatic cancer tissue of AHP patients, somatic second-hit mutations result in nearly complete inactivation of the enzymes catalyzing major steps in the heme biosynthetic pathway. Both PPOX and HMBS, which might act as tumor suppressors, play a crucial role in the development of HCC in these individuals.
Assuntos
Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/genética , Flavoproteínas/genética , Hidroximetilbilano Sintase/genética , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/genética , Proteínas Mitocondriais/deficiência , Proteínas Mitocondriais/genética , Mutação , Porfiria Aguda Intermitente/complicações , Porfiria Aguda Intermitente/genética , Porfiria Variegada/complicações , Porfiria Variegada/genética , Protoporfirinogênio Oxidase/genética , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/enzimologia , Feminino , Mutação em Linhagem Germinativa , Humanos , Neoplasias Hepáticas/enzimologia , Porfiria Aguda Intermitente/enzimologia , Porfiria Variegada/enzimologia , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/genéticaRESUMO
Recent studies have shown that the claim that King George III suffered from acute porphyria is seriously at fault. This article explores some of the causes of this misdiagnosis and the consequences of the misleading claims, also reporting on the nature of the king's recurrent mental illness according to computer diagnostics. In addition, techniques of cognitive archaeology are used to investigate the nature of the king's final decade of mental illness, which resulted in the appointment of the Prince of Wales as Prince Regent. The results of this analysis confirm that the king suffered from bipolar disorder type I, with a final decade of dementia, due, in part, to the neurotoxicity of his recurrent episodes of acute mania.
Assuntos
Transtorno Bipolar/diagnóstico , Transtorno Bipolar/história , Demência/diagnóstico , Demência/história , Pessoas Famosas , Porfirias/diagnóstico , Porfirias/história , Diagnóstico por Computador , Inglaterra , Escrita Manual , História do Século XVIII , História do Século XIX , Humanos , MasculinoRESUMO
Porphyrias are predominantly genetic metabolic disorders caused by dysregulation of specific enzymes in porphyrin-heme biosynthesis. The enzymatic dysfunction leads to formation and excretion of intermediate metabolic products in the form of porphyrins and/or their precursors δaminolevulinic acid and porphobilinogen, which have cyto- and tissue-toxic properties. Clinically, porphyrias are extremely diverse, with symptoms ranging from skin changes on light-exposed areas of the body to potentially life-threatening neurovisceral attacks. Biochemical tests in urine, blood and stool are used for diagnosis, which can be supplemented by molecular genetic analyses. Treatment of the various forms of porphyria is complex and often requires close interdisciplinary cooperation between different medical specialties.
Assuntos
Porfirias , Humanos , Porfirias/diagnóstico , Porfirias/terapia , Porfirias/genética , Porfirinas/urina , Porfirinas/metabolismoRESUMO
BACKGROUND: Variegate porphyria is caused by mutations in the PPOX gene; it usually presents in adolescents and adults as an autosomal dominant condition, with cutaneous features or acute peripheral and/or central nervous system crises. A rarer variant, homozygous variegate porphyria, presents in childhood with cutaneous manifestations as well as neurophenotypes. This study sought to further characterize the homozygous PPOX-related neuroendocrine phenotype. METHODS: This study is a retrospective review of the patients' charts, including their clinical evaluation and molecular genetics, neurodiagnostic, and neuroradiological investigations. RESULTS: We describe here three children from a consanguineous family who presented with nystagmus, developmental delay and ataxia, photosensitive skin manifestations, and adrenal insufficiency. Analysis of porphyrins in plasma, urine, and stool together with a genetic study of the PPOX gene confirmed the diagnosis. Interestingly, brain MRI showed severe hypomyelination, a finding rarely reported in variegate porphyria, together with adrenal insufficiency. CONCLUSION: We recommend analysis of porphyrins in unexplained hypomyelination disorders. Patients with variegate porphyria should be tested for adrenal insufficiency.
Assuntos
Insuficiência Adrenal , Porfiria Variegada , Porfirinas , Criança , Humanos , Insuficiência Adrenal/complicações , Flavoproteínas/genética , Proteínas Mitocondriais/genética , Fenótipo , Porfiria Variegada/genética , Porfiria Variegada/complicações , Protoporfirinogênio Oxidase/genéticaRESUMO
Background and aims: Porphyrias constitute a group of rare genetic diseases due to various, mostly autosomal dominant mutations, causing enzymatic deficiency in heme biosynthesis. As a result, neurotoxic porphyrin precursors and light-sensitive porphyrins accumulate, while dysfunction in their targets determines the disease symptoms. Variegate porphyria (VP), one of the acute hepatic porphyrias, is caused by a protoporphyrinogen oxidase (PPOX) mutation. During acute attacks, among other factors, triggered by drugs, stressors, or fasting, an increase in urinary and fecal porphobilinogen (PBG), aminolevulinic acid (ALA), and porphyrins occurs, damaging the autonomous, peripheral, or central nervous system. The disease remains often latent or displays minimal symptoms usually overlooked, exposing undiagnosed patients to potentially serious complications in the presence of the aforementioned triggers. Case report: This 46-year-old woman presented, some days after a bariatric surgery, with severe flaccid tetraparesis and neuropathic pain, initially misdiagnosed as a functional neurological disorder. The severe axonal sensorimotor polyneuropathy led to further investigations, disclosing high urinary porphobilinogen, ALA, and porphyrin levels due to a new PPOX mutation. Retrospectively, it appeared that the patient had had typical VP symptoms (abdominal pain, fragile skin, and dark urine episodes) for years prior to the surgery. Treated with carbohydrate load, neurorehabilitation, and analgesics, she slowly recovered to full mobility, with partial autonomy in her daily life activities, although fatigue and severe pain persisted, preventing her from returning to work. Conclusion: This case documents gastric bypass surgery as a trigger of severe VP invalidating neurological symptoms and illustrates how the delayed diagnosis and post-interventional complications could have been prevented by screening for porphyria cardinal symptoms prior to the intervention. Likewise, this cost-effective screening should be performed before any treatment influencing the diet, which would dramatically improve the porphyria diagnosis rate and outcome.
RESUMO
Variegate Porphyria (VP) is an inherited rare disorder that is caused by mutations in the protoporphyrinogen oxidase (PPOX) gene. This deficiency is associated with the accumulation of porphyrins and porphyrin precursors in the body, which, in turn, can potentially result in a variety of skin and neurological symptoms. Here, we reported a 7-year-old boy with homozygous VP and novel mutation on PPOX gene. He was admitted with three episodes of generalized tonic-clonic seizure in the last 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin. The weakness of limbs and brachydactyly were observed. In the follow-up, he had aggressive behavior, learning disability and abdominal pain, particularly around the navel. Eventually, the whole exome sequencing (WES) result reported a novel homozygous pathogenic variant (c.1072G > A p.G358R) in PPOX gene which confirmed the VP. He had been advised to be away from the sun and use sunscreen regularly.
Assuntos
Porfiria Variegada , Criança , Dedos , Flavoproteínas/genética , Humanos , Irã (Geográfico) , Masculino , Proteínas Mitocondriais/genética , Mutação , Porfiria Variegada/diagnóstico , Porfiria Variegada/genética , Protoporfirinogênio Oxidase/genéticaRESUMO
Heme, iron protoporphyrin IX, is one of life's most central molecules. Hence, availability of the enzymatic machinery necessary for its synthesis is crucial for every cell. Consequently, inborn errors of porphyrin metabolism that compromise normal synthesis, namely the family of porphyrias, undermine normal cellular metabolism given that heme has functions in catalytic centers, signal transduction and functional regulation and its synthesis is fully integrated into the center of intermediary metabolism. Very often, diagnosis of porphyrias is difficult and therefore delayed. Therapy can be as complicated. Over the last 50 years, several strategies have been developed: because of its integration with other parts of intermediary metabolism, the infusion of glucose (glucose effect) was one of the first attempts to counterbalance the dysregulation of porphyrin synthesis in porphyrias. Since heme synthesis is impaired, infusional replacement of heme was the next important therapeutic step. Recently, siRNA technology has been introduced in order to downregulate 5-ALA-synthase 1, which contributes to the patho-physiology of these diseases. Moreover, other novel therapies using enzyme protein replacement, mRNA techniques or proteostasis regulators are being developed.
RESUMO
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.