scholarly journals Updates on the diagnosis and management of the most common hereditary porphyrias: AIP and EPP

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 400-410
Author(s):  
Michael Linenberger ◽  
Kleber Y. Fertrin
Keyword(s):  
Biosynthetic Pathway ◽  
Aminolevulinic Acid ◽  
Clinical Manifestations ◽  
Acute Intermittent Porphyria ◽  
High Plasma ◽  
Suppressive Therapy ◽  
Gene Encoding ◽  
Burning Pain ◽  
Recessive Mutations ◽  
Systemic Distribution

Abstract The porphyrias are a family of metabolic disorders caused by defects in the activity of one of the enzymes in the heme biosynthetic pathway. Acute intermittent porphyria (AIP), caused by autosomal dominant mutations in the gene encoding hydroxymethylbilane synthase, can lead to hepatocyte overaccumulation and systemic distribution of the proximal porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). ALA and PBG are toxic to neurons and extrahepatic tissue and cause the neurovisceral clinical manifestations of AIP. Management of AIP includes awareness and avoidance of triggering factors, infusions of hemin for severe acute attacks, and, if indicated for chronic suppressive therapy, maintenance treatment with hemin or givosiran, a small interfering RNA molecule that antagonizes ALA synthase 1 transcripts. Erythropoietic protoporphyria (EPP) is most commonly caused by autosomal recessive mutations in the gene encoding ferrochelatase (FECH), the heme pathway terminal enzyme. FECH deficiency leads to erythrocyte overaccumulation and high plasma levels of lipophilic protoporphyrins that photoactivate in the skin, causing burning pain and erythema. Protoporphyrins excreted in the bile can cause gallstones, cholestasis, fibrosis, and ultimately liver failure. Management of EPP includes skin protection and afamelanotide, an α-melanocyte stimulating hormone analog that increases melanin pigment and reduces photoactivation. Liver transplantation may be necessary for severe EPP-induced liver complications. Because AIP and EPP arise from defects in the heme biosynthetic pathway, hematologists are often consulted to evaluate and manage suspected or proven porphyrias. A working knowledge of these disorders increases our confidence and effectiveness as consultants and medical providers.

scholarly journals Molecular and Biochemical Studies of Acute Intermittent Porphyria in 196 Patients and Their Families

2002 ◽  
Vol 48 (11) ◽  
pp. 1891-1900 ◽  
Author(s):  
Raili Kauppinen ◽  
Mikael von und zu Fraunberg
Keyword(s):  
Diagnostic Accuracy ◽  
Aminolevulinic Acid ◽  
Clinical Manifestations ◽  
Acute Intermittent Porphyria ◽  
Reference Interval ◽  
Acute Attack ◽  
Fecal Excretion ◽  
Variant Form ◽  
Roc Curve Analysis ◽  
Biochemical Tests

Abstract Background: Acute intermittent porphyria (AIP) is a metabolic disease with clinical manifestations that mimic other abdominal, neurologic, or mental crises. We studied the diagnostic accuracy of current laboratory tests during an acute attack and in remission. Methods: Since 1966, we have studied all known Finnish AIP patients (n = 196) and their families (n = 45) and identified the porphobilinogen deaminase (PBGD) mutation in each family. Diagnoses or exclusions of AIP were based on clinical data (including family history), biochemical tests, and in 239 cases, mutation testing. We retrospectively evaluated the diagnostic accuracy of erythrocyte PBGD activity, urinary excretion of porphobilinogen (PBG) and δ-aminolevulinic acid, and urinary and fecal excretion of porphyrins in these patients. Results: Measurement of urinary PBG identified all 35 AIP patients studied during an acute attack. The mean excretion of PBG was 50-fold above the reference interval, although the intraindividual increases were modest (1.6- to 4.0-fold). In the mutation-screened population, urinary PBG analysis identified only 85% of 81 AIP patients studied during remission, but by ROC curve analysis it was nonetheless the best of the biochemical tests. It was increased ≤2-fold in 29% of healthy relatives. Erythrocyte PBGD activity was decreased in only 84% of AIP patients, with results within the reference interval mainly in the variant form of AIP; it was decreased in 23% of healthy relatives. Conclusions: Measurement of urinary PBG is the best biochemical test for AIP, although it is unspecific and does not distinguish AIP from other acute porphyrias. Because the acute increase in PBG is often modest, the medical history, signs, and symptoms must be evaluated carefully during an acute attack. In addition, because biochemical analyses often remain indeterminate in remission, mutation analysis is needed to exclude or confirm the diagnosis of AIP.

scholarly journals PILOT RESEARCH OF A GENETIC PREDISPOSITION FOR CLINICAL MANIFESTATIONS OF ACUTE INTERMITTENT PORPHYRIA

2019 ◽  
Vol 64 (2) ◽  
pp. 123-137
Author(s):  
O. S. Pshenichnikova ◽  
M. V. Goncharova ◽  
Y. S. Pustovoit ◽  
I. V. Karpova ◽  
V. L. Surin
Keyword(s):  
Aminolevulinic Acid ◽  
Clinical Manifestations ◽  
Acute Intermittent Porphyria ◽  
Severe Form ◽  
Heme Biosynthesis ◽  
Whole Exome ◽  
Number Of Patients ◽  
Detoxification Systems ◽  
Illumina Hiseq4000

Introduction. Acute intermittent porphyria (AIP) is the most common and severe form of acute hepatic porphyria. AIP is caused by a deficiency in the third enzyme of the heme biosynthesis system — hydroxymethylbilanine synthase (HMBS) — and has a dominant inheritance type. However, the probability of the clinical manifestation of this condition in carriers of the mutation in the HMBS gene constitutes only 10–20 %. Thi s suggests that the presence of such a mutation can be a necessary but not a sufficient condition for the development of the disease.Aim. To search for additional genetic factors, which determine the clinical penetrance of AIP using Whole-Exome Sequencing.Materials and methods. Sequencing of the whole exome was performed using a TruSeqExomeLibraryPrepkit (Illumina) kit by an Illumina HiSeq4000 instrument for 6 women with API with known mutations in the HMBS gene. All the patients suffered from a severe form of the disease. As a reference, a version of the hg19 human genome was used.Results. No common mutations were found in the examined patients. However, in each patient, functional variations were found in the genes related to detoxification systems, regulation of the heme biosynthesis cascade and expression of delta-aminolevulinic acid synthase (ALAS1) and in genes of proteins regulating nervous system. These variations require further study involving an extended number of patients with AIP manifestations and their relatives, who are asymptomatic carriers of disorders in the gene HMBS.Conclusions. The results obtained have allowed us to formulate a hypothesis about a possible role of genetic defects in the penetrance of AIP, which determine the development of other neurological pathologies. This is evidenced by the presence of gene pathogenic variations in 5 out of 6 examined patients, defects in which are associated with hereditary myasthenia and muscle atrophy.

The Porphyrias

2016 ◽  
Author(s):  
Karl E Anderson ◽  
Attallah Kappas
Keyword(s):  
Biosynthetic Pathway ◽  
Aminolevulinic Acid ◽  
Clinical Symptoms ◽  
Porphyria Cutanea Tarda ◽  
Acute Intermittent Porphyria ◽  
Genetic Traits ◽  
Molecular Defects ◽  
Clinical Presentations ◽  
Congenital Erythropoietic Porphyria ◽  
Hereditary Coproporphyria

The porphyrias are uncommon disorders caused by deficiencies in the activities of enzymes of the heme biosynthetic pathway. The enzymatic defects that cause porphyrias are inherited, with the exception of porphyria cutanea tarda, which is primarily acquired. In all porphyrias, there is significant interplay between genetic traits and acquired or environmental factors in the expression of clinical symptoms. This review discusses the classification, pathophysiology, and clinical presentations of the porphyrias. These include those associated with neurovisceral attacks (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and δ-aminolevulinic acid dehydratase [alad] deficiency porphyria) and the porphyrias associated with cutaneous photosensitivity (porphyria cutanea tarda, hepatoerythropoietic porphyria, erythropoietic protoporphyria, and congenital erythropoietic porphyria). Specific emphasis on the epidemiology, molecular defects and pathophysiology, clinical features, diagnosis, and treatment are discussed for each of these disorders. A table lists the safe and unsafe drugs for patients with porphyrias. Figures illustrate the genetic pathways of the disorders and the activities of enzymes of the heme biosynthetic pathway. This review contains 2 highly rendered figures, 1 table, and 96 references.

scholarly journals Genetic polymorphism for IFNγ +874T/A in patients with acute toxoplasmosis

2012 ◽  
Vol 45 (6) ◽  
pp. 757-760 ◽  
Author(s):  
Elizabeth de Souza Neves ◽  
André Luis Land Curi ◽  
Maira Cavalcanti de Albuquerque ◽  
Cassius Schnel Palhano-Silva ◽  
Laura Berriel da Silva ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Case Control Study ◽  
Severe Disease ◽  
Clinical Manifestations ◽  
Nucleotide Polymorphism ◽  
Gene Encoding ◽  
Single Nucleotide ◽  
Duration Of Disease ◽  
Acute Toxoplasmosis ◽  
Control Study

INTRODUCTION: A single nucleotide polymorphism (SNP) in the gene encoding gamma interferon influences its production and is associated with severity of infectious diseases. This study aimed to evaluate the association of IFNγ+874T/A SNP with duration of disease, morbidity, and development of retinochoroiditis in acute toxoplasmosis. METHODS: A case-control study was conducted among 30 patients and 90 controls. RESULTS: Although statistical associations were not confirmed, A-allele was more common among retinochoroiditis cases and prolonged illness, while T-allele was more frequent in severe disease. CONCLUSIONS: Despite few cases, the results could indicate a relation between IFNγ+874T/A single nucleotide polymorphism and clinical manifestations of toxoplasmosis.

scholarly journals Pregnancy-Induced High Plasma Levels of Soluble Endoglin in Mice Lead to Preeclampsia Symptoms and Placental Abnormalities

2020 ◽  
Vol 22 (1) ◽  
pp. 165
Author(s):  
Lucía Pérez-Roque ◽  
Elena Núñez-Gómez ◽  
Alicia Rodríguez-Barbero ◽  
Carmelo Bernabéu ◽  
José M. López-Novoa ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Ex Vivo ◽  
Clinical Manifestations ◽  
High Plasma ◽  
Trophoblast Invasion ◽  
Future Research ◽  
Soluble Factors ◽  
Human Trophoblast ◽  
Soluble Endoglin ◽  
Pregnant Mice

Preeclampsia is a pregnancy-specific disease of high prevalence characterized by the onset of hypertension, among other maternal or fetal signs. Its etiopathogenesis remains elusive, but it is widely accepted that abnormal placentation results in the release of soluble factors that cause the clinical manifestations of the disease. An increased level of soluble endoglin (sEng) in plasma has been proposed to be an early diagnostic and prognostic biomarker of this disease. A pathogenic function of sEng involving hypertension has also been reported in several animal models with high levels of plasma sEng not directly dependent on pregnancy. The aim of this work was to study the functional effect of high plasma levels of sEng in the pathophysiology of preeclampsia in a model of pregnant mice, in which the levels of sEng in the maternal blood during pregnancy replicate the conditions of human preeclampsia. Our results show that wild type pregnant mice carrying human sEng-expressing transgenic fetuses (fWT(hsEng+)) present high plasma levels of sEng with a timing profile similar to that of human preeclampsia. High plasma levels of human sEng (hsEng) are associated with hypertension, proteinuria, fetal growth restriction, and the release of soluble factors to maternal plasma. In addition, fWT(hsEng+) mice also present placental alterations comparable to those caused by the poor remodeling of the spiral arteries characteristic of preeclampsia. In vitro and ex vivo experiments, performed in a human trophoblast cell line and human placental explants, show that sEng interferes with trophoblast invasion and the associated pseudovasculogenesis, a process by which cytotrophoblasts switch from an epithelial to an endothelial phenotype, both events being related to remodeling of the spiral arteries. Our findings provide a novel and useful animal model for future research in preeclampsia and reveal a much more relevant role of sEng in preeclampsia than initially proposed.

scholarly journals Biosynthetic pathways and enzymes involved in the production of phosphonic acid natural products

2021 ◽  
Vol 85 (1) ◽  
pp. 42-52
Author(s):  
Taro Shiraishi ◽  
Tomohisa Kuzuyama
Keyword(s):  
Natural Products ◽  
Biosynthetic Pathway ◽  
Organophosphorus Compounds ◽  
Genome Mining ◽  
Biological Molecules ◽  
Antibacterial Drug ◽  
Gene Encoding ◽  
Quarter Century ◽  
Lead Compounds ◽  
Biosynthetic Machinery

Abstract Phosphonates are organophosphorus compounds possessing a characteristic C−P bond in which phosphorus is directly bonded to carbon. As phosphonates mimic the phosphates and carboxylates of biological molecules to potentially inhibit metabolic enzymes, they could be lead compounds for the development of a variety of drugs. Fosfomycin (FM) is a representative phosphonate natural product that is widely used as an antibacterial drug. Here, we review the biosynthesis of FM, which includes a recent breakthrough to find a missing link in the biosynthetic pathway that had been a mystery for a quarter-century. In addition, we describe the genome mining of phosphonate natural products using the biosynthetic gene encoding an enzyme that catalyzes C–P bond formation. We also introduce the chemoenzymatic synthesis of phosphonate derivatives. These studies expand the repertoires of phosphonates and the related biosynthetic machinery. This review mainly covers the years 2012-2020.

scholarly journals The Multifaceted Roles of MicroRNAs in Cystic Fibrosis

Diagnostics ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1102
Author(s):  
Fatima Domenica Elisa De Palma ◽  
Valeria Raia ◽  
Guido Kroemer ◽  
Maria Chiara Maiuri
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Infections ◽  
Current Knowledge ◽  
Pancreatic Insufficiency ◽  
Clinical Manifestations ◽  
Predictive Biomarkers ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Multisystemic Disease

Cystic fibrosis (CF) is a lifelong disorder affecting 1 in 3500 live births worldwide. It is a monogenetic autosomal recessive disease caused by loss-of-function mutations in the gene encoding the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR), the impairment of which leads to ionic disequilibria in exocrine organs. This translates into a chronic multisystemic disease characterized by airway obstruction, respiratory infections, and pancreatic insufficiency as well as hepatobiliary and gastrointestinal dysfunction. Molecular characterization of the mutational heterogeneity of CFTR (affected by more than 2000 variants) improved the understanding and management of CF. However, these CFTR variants are linked to different clinical manifestations and phenotypes, and they affect response to treatments. Expanding evidence suggests that multisystemic disease affects CF pathology via impairing either CFTR or proteins regulated by CFTR. Thus, altering the expression of miRNAs in vivo could constitute an appealing strategy for developing new CF therapies. In this review, we will first describe the pathophysiology and clinical management of CF. Then, we will summarize the current knowledge on altered miRNAs in CF patients, with a focus on the miRNAs involved in the deregulation of CFTR and in the modulation of inflammation. We will highlight recent findings on the potential utility of measuring circulating miRNAs in CF as diagnostic, prognostic, and predictive biomarkers. Finally, we will provide an overview on potential miRNA-based therapeutic approaches.

scholarly journals Biochemical and hematological analysis in acute intermittent porphyria (AIP): a case report

2013 ◽  
Vol 85 (3) ◽  
pp. 1207-1214 ◽  
Author(s):  
ANNA R.R. DOS SANTOS ◽  
RAFAELA R. DE ALBUQUERQUE ◽  
MARIA J.R. DORIQUI ◽  
GRACIOMAR C. COSTA ◽  
ANA PAULA S.A. DOS SANTOS
Keyword(s):  
Biochemical Parameters ◽  
Contraceptive Use ◽  
Aminolevulinic Acid ◽  
Neuropsychiatric Symptoms ◽  
Acute Intermittent Porphyria ◽  
Signs And Symptoms ◽  
Acute Porphyria ◽  
Reactive Protein ◽  
Hematological Analysis ◽  
Hematological And Biochemical Parameters

Acute intermittent porphyria is the most common acute porphyria caused by a decrease in hepatic porphobilinogen deaminase activity, resulting in an accumulation of delta-aminolevulinic acid and porphobilinogen. This disease shows nonspecific signs and symptoms that can be confused with other diseases, thereby making the diagnosis difficult. We report a case of acute intermittent porphyria, reviewing clinical and laboratory aspects, highlighting the hematological and biochemical parameters during and after the crisis. A female patient, aged 28 years, suffered two crises, both presenting gastrointestinal disorders. The second presented neuropsychiatric symptoms. The analysis of hematological and biochemical parameters during the second crisis showed anemia, leukocytosis, hyponatremia, mild hypokalemia, uremia and elevated C-reactive protein. The initial treatment included glucose infusion, a diet rich in carbohydrates and interruption of porphyrinogenic drugs. Subsequently, treatment was maintained with oral contraceptive use. According to the observed data, signs and symptoms of gastrointestinal, neurological and psychiatric disorders, associated with laboratory results presented in this paper can be applied to screen acute porphyria, contributing to early diagnosis.

scholarly journals Pathogen and Pest Responses Are Altered Due to RNAi-Mediated Knockdown of GLYCOALKALOID METABOLISM 4 in Solanum tuberosum

2017 ◽  
Vol 30 (11) ◽  
pp. 876-885 ◽  
Author(s):  
Jamuna Risal Paudel ◽  
Charlotte Davidson ◽  
Jun Song ◽  
Itkin Maxim ◽  
Asaph Aharoni ◽  
...  
Keyword(s):  
Solanum Tuberosum ◽  
Biosynthetic Pathway ◽  
Plant Protection ◽  
Insect Pest ◽  
Metabolite Profile ◽  
Gene Encoding ◽  
Rnai Line ◽  
Leaf Consumption ◽  
Insect Mortality ◽  
Potato Growth

Steroidal glycoalkaloids (SGAs) are major secondary metabolites constitutively produced in cultivated potato Solanum tuberosum, and α-solanine and α-chaconine are the most abundant SGAs. SGAs are toxic to humans at high levels but their role in plant protection against pests and pathogens is yet to be established. In this study, levels of SGAs in potato were reduced by RNA interference (RNAi)-mediated silencing of GLYCOALKALOID METABOLISM 4 (GAME4)—a gene encoding cytochrome P450, involved in an oxidation step in the conversion of cholesterol to SGA aglycones. Two GAME4 RNAi lines, T8 and T9, were used to investigate the effects of manipulation of the SGA biosynthetic pathway in potato. Growth and development of an insect pest, Colorado potato beetle (CPB), were affected in these lines. While no effect on CPB leaf consumption or weight gain was observed, early instar larval death and accelerated development of the insect was found while feeding on leaves of GAME4 RNAi lines. Modulation of SGA biosynthetic pathway in GAME4 RNAi plants was associated with a larger alteration to the metabolite profile, including increased levels of one or both the steroidal saponins or phytoecdysteroids, which could affect insect mortality as well as development time. Colonization by Verticillium dahliae on GAME4 RNAi plants was also tested. There were increased pathogen levels in the T8 GAME4 RNAi line but not in the T9. Metabolite differences between T8 and T9 were found and may have contributed to differences in V. dahliae infection. Drought responses created by osmotic stress were not affected by modulation of SGA biosynthetic pathway in potato.

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