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Molecular Genetics and Metabolism Nov 2019Each of the four acute hepatic porphyrias is due to mutation of an enzyme in the heme biosynthetic pathway. The accumulation of pathway intermediates that occur most... (Review)
Review
Each of the four acute hepatic porphyrias is due to mutation of an enzyme in the heme biosynthetic pathway. The accumulation of pathway intermediates that occur most notably when these diseases are active is the basis for screening and establishing a biochemical diagnosis of these rare disorders. Measurement of enzyme activities and especially DNA testing also are important for diagnosis. Suspicion of the diagnosis and specific testing, particularly measurement of urinary porphobilinogen, are often delayed because the symptoms are nonspecific, even when severe. Urinary porphyrins are also measured, but their elevation is much less specific. If porphobilinogen is elevated, second line testing will establish the type of acute porphyria. DNA testing identifies the familial mutation and enables screening of family members. Management includes removal of triggering factors whenever possible. Intravenous hemin is the most effective treatment for acute attacks. Carbohydrate loading is sometimes used for mild attacks. Cyclic attacks, if frequent, can be prevented by a GnRH analogue. Frequent noncyclic attacks are sometime preventable by scheduled (e.g. weekly) hemin infusions. Long term complications may include chronic pain, renal impairment and liver cancer. Other treatments, including RNA interference, are under development.
Topics: Animals; Biosynthetic Pathways; Clinical Trials as Topic; Disease Management; Heme; Hemin; Humans; Mice; Porphobilinogen; Porphobilinogen Synthase; Porphyrias, Hepatic
PubMed: 31311713
DOI: 10.1016/j.ymgme.2019.07.002 -
BMJ Case Reports Jun 2021Acute porphyrias are rarely reported in Southeast Asia. They may be underdiagnosed due to their clinical mimicry and lack of awareness among physicians. There is a...
Acute porphyrias are rarely reported in Southeast Asia. They may be underdiagnosed due to their clinical mimicry and lack of awareness among physicians. There is a common cognitive bias to gravitate towards common conditions. In this case report, a 28-year-old woman, who presented with seizures, rhabdomyolysis hyponatraemia and altered mental state, was initially diagnosed as amphetamine overdose. She had presented 3 days prior with abdominal pain, treated for acute cystitis and discharged. On readmission for seizures a day later, she was extensively worked up for altered mental state. Despite normalisation of serum sodium concentration and control of her seizures, she remained unwell. Further investigations later confirmed a diagnosis of acute porphyria. The aim of this case report is to highlight the non-specific nature of presentation of acute porphyria and the importance of considering it as a differential diagnosis in cases of abdominal pain with neuropsychiatric features.
Topics: Abdominal Pain; Adult; Diagnosis, Differential; Female; Humans; Porphyria, Acute Intermittent; Porphyrias; Rhabdomyolysis; Seizures
PubMed: 34187794
DOI: 10.1136/bcr-2021-241580 -
Annals of Translational Medicine Sep 2020Hyponatremia is a common feature during the neurovisceral acute attacks which characterize hepatic porphyrias, as well as a sign of its severity. Therapeutic options for... (Review)
Review
Hyponatremia is a common feature during the neurovisceral acute attacks which characterize hepatic porphyrias, as well as a sign of its severity. Therapeutic options for first-line acute attacks are intravenous administration of glucose and/or exogenous heme. The former treatment can aggravate hyponatremia by dilution and cause seizures; thus, the correction of hyponatremia must be carried out with extreme caution. This review summarizes recommendations for the management of hyponatremia during acute episodes of porphyria. Hyponatremia should be corrected slowly and seizures treated with medications in order to not exacerbate motor and sensory axonal neuropathy. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is considered a frequent cause of hyponatremia in acute porphyrias and must be identified as a symptom of an acute porphyria attack. Tolvaptan produces aquaresis and is considered a safe drug in porphyria. However, its use has only been reported in isolated cases during a porphyria attack. The convenience and usefulness of this drug in acute porphyria are discussed.
PubMed: 33145317
DOI: 10.21037/atm-20-1529 -
Molecular Genetics and Metabolism Nov 2019Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare, genetic photodermatoses resulting from defects in enzymes of the heme-biosynthetic... (Review)
Review
Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare, genetic photodermatoses resulting from defects in enzymes of the heme-biosynthetic pathway. EPP results from the partial deficiency of ferrochelatase, and XLP results from gain-of-function mutations in erythroid specific ALAS2. Both disorders result in the accumulation of erythrocyte protoporphyrin, which is released in the plasma and taken up by the liver and vascular endothelium. The accumulated protoporphyrin is activated by sunlight exposure, generating singlet oxygen radical reactions leading to tissue damage and excruciating pain. About 2-5% of patients develop clinically significant liver dysfunction due to protoporphyrin deposition in bile and/or hepatocytes which can advance to cholestatic liver failure requiring transplantation. Clinically these patients present with acute, severe, non-blistering phototoxicity within minutes of sun-exposure. Anemia is seen in about 47% of patients and about 27% of patients will develop abnormal serum aminotransferases. The diagnosis of EPP and XLP is made by detection of markedly increased erythrocyte protoporphyrin levels with a predominance of metal-free protoporphyrin. Genetic testing by sequencing the FECH or ALAS2 gene confirms the diagnosis. Treatment is limited to sun-protection and there are no currently available FDA-approved therapies for these disorders. Afamelanotide, a synthetic analogue of α-melanocyte stimulating hormone was found to increase pain-free sun exposure and improve quality of life in adults with EPP. It has been approved for use in the European Union since 2014 and is not available in the U.S. In addition to the development of effective therapeutics, future studies are needed to establish the role of iron and the risks related to the development of hepatopathy in these patients.
Topics: 5-Aminolevulinate Synthetase; Anemia; Clinical Trials as Topic; Dermatitis, Phototoxic; Disease Management; Genes, X-Linked; Heme; Humans; Liver Diseases; Porphyrias, Hepatic; Protoporphyria, Erythropoietic
PubMed: 30704898
DOI: 10.1016/j.ymgme.2019.01.020 -
Rambam Maimonides Medical Journal Apr 2018The porphyrias are a group of rare metabolic disorders, inherited or acquired, along the heme biosynthetic pathway, which could manifest with neurovisceral and/or...
The porphyrias are a group of rare metabolic disorders, inherited or acquired, along the heme biosynthetic pathway, which could manifest with neurovisceral and/or cutaneous symptoms, depending on the defective enzyme. Neurovisceral porphyrias are characterized by acute attacks, in which excessive heme production is induced following exposure to a trigger. An acute attack usually presents with severe abdominal pain, vomiting, and tachycardia. Other symptoms which could appear include hypertension, hyponatremia, peripheral neuropathy, and mild mental symptoms. In severe attacks there could be severe symptoms including seizures and psychosis. If untreated, the attack might become very severe, affecting the peripheral, central, and autonomic nervous system, leading to paralysis, respiratory failure, hyponatremia, coma, and even death. From the biochemical point of view, acute attacks are involved with increased levels of precursors in the heme biosynthetic pathway, up to the deficient step. Of these precursors, aminolevulinic acid (ALA) is considered to be neurotoxic. Treatment is directed to reduce ALA production by reducing the activity of the enzyme aminolevulinate synthase (ALAS)-most effectively by heme therapy. Cutaneous symptoms are a consequence of elevated porphyrins in the blood stream. These porphyrins react to light; therefore sun-exposed areas are affected, producing fragile erosive skin lesions in porphyria cutanea tarda (PCT) or non-scarring stinging and burning symptoms in erythropoietic protoporphyria (EPP). Unlike the most common neurovisceral porphyria, acute intermittent porphyria (AIP), variegate porphyria (VP), and hereditary coproporphyria (HCP) can have cutaneous symptoms as well. Differentiating them from other cutaneous porphyrias is essential for accurate diagnosis, treatment, and patient recommendations.
PubMed: 29553924
DOI: 10.5041/RMMJ.10333 -
Molecular Genetics and Metabolism Nov 20195-Aminolevulinate (ALA) synthase (ALAS), a homodimeric pyridoxal-5'-phosphate (PLP)-dependent enzyme, catalyzes the first step of heme biosynthesis in metazoa, fungi and... (Review)
Review
5-Aminolevulinate (ALA) synthase (ALAS), a homodimeric pyridoxal-5'-phosphate (PLP)-dependent enzyme, catalyzes the first step of heme biosynthesis in metazoa, fungi and α-proteobacteria. In this review, we focus on the advances made in unraveling the mechanism of the ALAS-catalyzed reaction during the past decade. The interplay between the PLP cofactor and the protein moiety determines and modulates the multi-intermediate reaction cycle of ALAS, which involves the decarboxylative condensation of two substrates, glycine and succinyl-CoA. Substrate binding and catalysis are rapid, and product (ALA) release dominates the overall ALAS kinetic mechanism. Interconversion between a catalytically incompetent, open conformation and a catalytically competent, closed conformation is linked to ALAS catalysis. Reversion to the open conformation, coincident with ALA dissociation, defines the slowest step of the reaction cycle. These findings were further substantiated by introducing seven mutations in the16-amino acid loop that gates the active site, yielding an ALAS variant with a greatly increased rate of catalytic turnover and heightened specificity constants for both substrates. Recently, molecular dynamics (MD) simulation analysis of various dimeric ALAS forms revealed that the seven active site loop mutations caused the proteins to adopt different conformations. In particular, the emergence of a β-strand in the mutated loop, which interacted with two preexisting β-strands to form an anti-parallel three-stranded β-sheet, conferred the murine heptavariant with a more stable open conformation and prompted faster product release than wild-type mALAS2. Moreover, the dynamics of the mALAS2 active site loop anti-correlated with that of the 35 amino acid C-terminal sequence. This led us to propose that this C-terminal extension, which is absent in prokaryotic ALASs, finely tunes mammalian ALAS activity. Based on the above results, we extend our previous proposal to include that discovery of a ligand inducing the mammalian C-terminal extension to fold offers a good prospect for the development of a new drug for X-linked protoporphyria and/or other porphyrias associated with enhanced ALAS activity and/or porphyrin accumulation.
Topics: 5-Aminolevulinate Synthetase; Biosynthetic Pathways; Catalysis; Heme; Humans; Kinetics; Molecular Dynamics Simulation; Protein Conformation; Pyridoxal Phosphate; Substrate Specificity
PubMed: 31345668
DOI: 10.1016/j.ymgme.2019.06.003 -
Acta Dermato-venereologica Jun 2019Erythropoietic protoporphyria is caused by a partial deficiency of ferrochelatase, which is the last enzyme in the heme biosynthesis pathway. In a typical erythropoietic... (Review)
Review
Erythropoietic protoporphyria is caused by a partial deficiency of ferrochelatase, which is the last enzyme in the heme biosynthesis pathway. In a typical erythropoietic protoporphyria, photosensitivity initially appears, following the first exposure to the sun in early infancy or childhood. Erythropoietic protoporphyria has been reported worldwide, but there is a regional variation in its epidemiology. Approximately 20% of the Japanese patients were recognized to have symptoms of erythropoietic protoporphyria after 10 years of age. Physicians occasionally encounter Japanese patients with erythropoietic protoporphyria, mild symptoms and no FECH gene mutations. The homozygous IVS3-48C polymorphism may cause a mild phenotype of the erythropoietic protoporphyria via a slight increase in protoporphyrin. The frequency of the homozygous IVS3-48C polymorphism in the Japanese population is higher than that observed in European countries. Japanese type of erythropoietic protopor-phyria shows a characteristic phenotype of the late onset and mild symptoms compared to the Caucasian erythropoietic protoporphyria. This review describes the characteristics of erythropoietic protoporphyria in Japanese patients.
Topics: Age of Onset; Anemia; Cholelithiasis; Europe; Ferrochelatase; Homozygote; Humans; Japan; Liver Diseases; Mutation; North America; Phenotype; Polymorphism, Genetic; Prevalence; Protoporphyria, Erythropoietic
PubMed: 30938825
DOI: 10.2340/00015555-3184 -
The Journal of Pediatrics Nov 2018Erythropoietic protoporphyria is a photodermatosis presenting in childhood with severe pain on sun exposure. The diagnosis is often delayed because of the lack of... (Review)
Review
Erythropoietic protoporphyria is a photodermatosis presenting in childhood with severe pain on sun exposure. The diagnosis is often delayed because of the lack of awareness among pediatricians. We describe the diagnostic odyssey of 2 children presenting with symptoms of erythropoietic protoporphyria and report results of a survey of 129 affected individuals.
Topics: Child, Preschool; Delayed Diagnosis; Diagnosis, Differential; Female; Humans; Hypersensitivity; Male; Photosensitivity Disorders; Prognosis; Protective Clothing; Protoporphyria, Erythropoietic; Recurrence; Risk Assessment; Severity of Illness Index; Sunlight
PubMed: 30041937
DOI: 10.1016/j.jpeds.2018.06.001 -
Molecules (Basel, Switzerland) Mar 2018This review summarizes recent knowledge about the use of the amino acid l-Cysteine (l-Cys) through diet, nutritional supplements or drugs with the aim to improve human... (Review)
Review
This review summarizes recent knowledge about the use of the amino acid l-Cysteine (l-Cys) through diet, nutritional supplements or drugs with the aim to improve human health or treat certain diseases. Three databases (PubMed, Scopus, and Web of Science) and different keywords have been used to create a database of documents published between 1950 and 2017 in scientific journals in English or Spanish. A total of 60,885 primary publications were ultimately selected to compile accurate information about the use of l-Cys in medicine and nutritional therapies and to identify the reported benefits of l-Cys on human health. The number of publications about the use of l-Cys for these purposes has increased significantly during the last two decades. This increase seems to be closely related to the rise of nutraceutical industries and personalized medicine. The main evidence reporting benefits of l-Cys usage is summarized. However, the lack of accurate information and studies based on clinical trials hampers consensus among authors. Thus, the debate about the role and effectiveness of supplements/drugs containing l-Cys is still open.
Topics: Alopecia; Bibliometrics; Clinical Trials as Topic; Cysteine; Diabetes Mellitus, Type 2; Diet; Dietary Supplements; Feeding Behavior; Humans; Porphyria, Erythropoietic; Precision Medicine
PubMed: 29510494
DOI: 10.3390/molecules23030575 -
Journal of Postgraduate Medicine 2023Porphyrias are a rare group of inborn errors of metabolism due to defects in the heme biosynthetic pathway. The biochemical hallmark is the overproduction of porphyrin...
Porphyrias are a rare group of inborn errors of metabolism due to defects in the heme biosynthetic pathway. The biochemical hallmark is the overproduction of porphyrin precursors and porphyrin species. Afflicted patients present with a myriad of symptoms causing a diagnostic odyssey. Symptoms often overlap with those of common diseases and may be overlooked unless there is heightened clinical suspicion. We are reporting clinical features and diagnostic challenges in four pediatric patients having variegate porphyria, congenital erythropoietic porphyria, acute intermittent porphyria, and erythropoietic protoporphyria (EPP), who presented with diverse multisystem manifestations. This case series illustrates a logical analysis of symptoms and judicious selection of investigations and the role of genotyping in successfully diagnosing porphyrias.
Topics: Child; Humans; Porphyrias; Porphyria, Acute Intermittent; Porphyrins
PubMed: 37082991
DOI: 10.4103/jpgm.jpgm_698_22