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Blood Advances Feb 2022The Mendelian inheritance pattern of acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria is autosomal dominant, but the clinical phenotype...
The Mendelian inheritance pattern of acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria is autosomal dominant, but the clinical phenotype is heterogeneous. Within the general population, penetrance is low, but among first-degree relatives of a symptomatic proband, penetrance is higher. These observations suggest that genetic factors, in addition to mutation of the specific enzyme of the biosynthetic pathway of heme, contribute to the clinical phenotype. Recent studies by others suggested that the genotype of the transporter protein ABCB6 contribute to the porphyria phenotype. Identifying the molecule(s) that are transported by ABCB6 has been problematic and has led to uncertainty with respect to how or if variants/mutants contribute to phenotypic heterogeneity. Knockout mouse models of Abcb6 have not provided a direction for investigation as homozygous knockout animals do not have a discrete phenotype. To address the proposed link between ABC6 genotype and porphyria phenotype, a large cohort of patients with acute hepatic porphyria and erythropoietic protoporphyria was analyzed. Our studies showed that ABCB6 genotype did not correlate with disease severity. Therefore, genotyping of ABCB6 in patients with acute hepatic porphyria and erythropoietic protoporphyria is not warranted.
Topics: ATP-Binding Cassette Transporters; Animals; Humans; Mice; Mice, Knockout; Porphobilinogen Synthase; Porphyrias; Porphyrias, Hepatic; Protoporphyria, Erythropoietic
PubMed: 34724702
DOI: 10.1182/bloodadvances.2021005484 -
Molecular Genetics and Metabolism Nov 2019The inborn errors of heme biosynthesis, the Porphyrias, include eight major disorders resulting from loss-of-function (LOF) or gain-of-function (GOF) mutations in eight... (Review)
Review
The inborn errors of heme biosynthesis, the Porphyrias, include eight major disorders resulting from loss-of-function (LOF) or gain-of-function (GOF) mutations in eight of the nine heme biosynthetic genes. The major sites of heme biosynthesis are the liver and erythron, and the underlying pathophysiology of each of these disorders depends on the unique biochemistry, cell biology, and genetic mechanisms in these tissues. The porphyrias are classified into three major categories: 1) the acute hepatic porphyrias (AHPs), including Acute Intermittent Porphyria (AIP), Hereditary Coproporphyria (HCP), Variegate Porphyria (VP), and 5-Aminolevlulinic Acid Dehydratase Deficient Porphyria (ADP); 2) a hepatic cutaneous porphyria, Porphyria Cutanea Tarda (PCT); and 3) the cutaneous erythropoietic porphyrias, Congenital Erythropoietic Porphyria (CEP), Erythropoietic Protoporphyria (EPP), and X-Linked Protoporphyria (XLP). Their modes of inheritance include autosomal dominant with markedly decreased penetrance (AIP, VP, and HCP), autosomal recessive (ADP, CEP, and EPP), or X-linked (XLP), as well as an acquired sporadic form (PCT). There are severe homozygous dominant forms of the three AHPs. For each porphyria, its phenotype, inheritance pattern, unique genetic principles, and molecular genetic heterogeneity are presented. To date, >1000 mutations in the heme biosynthetic genes causing their respective porphyrias have been reported, including low expression alleles and genotype/phenotype correlations that predict severity for certain porphyrias. The tissue-specific regulation of heme biosynthesis and the unique genetic mechanisms for each porphyria are highlighted.
Topics: Biosynthetic Pathways; Gain of Function Mutation; Gene Expression Regulation; Heme; Humans; Loss of Function Mutation; Penetrance; Porphobilinogen Synthase; Porphyria, Acute Intermittent; Porphyrias; Porphyrias, Hepatic; Protoporphyria, Erythropoietic
PubMed: 30594473
DOI: 10.1016/j.ymgme.2018.11.012 -
Digestive and Liver Disease : Official... Apr 2022In erythropoietic protoporphyria (EPP), which presents with severe painful phototoxicity, progressive deposition of protoporphyrins in hepatocytes and bile canaliculi...
BACKGROUND
In erythropoietic protoporphyria (EPP), which presents with severe painful phototoxicity, progressive deposition of protoporphyrins in hepatocytes and bile canaliculi may result in liver disease. Clinically EPP related liver disease ranges from mildly elevated liver enzymes to cirrhosis and acute cholestatic hepatic failure. The prevalence of liver disease in EPP, and factors predicting the risk of developing liver disease, have not been defined in a large series of unselected EPP patients.
AIM
To determine the prevalence of liver disease in EPP-patients.
METHODS
A single-center prospective unselected cohort study of 114 adult EPP patients, who underwent routine laboratory testing, abdominal ultrasonography and transient elastography to assess the presence of steatosis (controlled attenuation parameter,dB/m) and liver stiffness (kPa).
RESULTS
114 adult EPP patients were included. Elevated liver enzymes were found in 6.2% of the patients. Liver steatosis was detected in 29.0%, and significant fibrosis as assessed with liver stiffness measurements was present in 9.6% of patients. BMI positively predicted CAP-values (p = 0.026); and protoporphyrin IX levels (p = 0.043) positively predicted liver stiffness.
CONCLUSIONS
This study demonstrates a prevalence of hepatic steatosis and fibrosis in adult EPP-patients comparable to that found in the general population. Protoporphyrin IX levels correlate with increased liver stiffness in EPP.
Topics: Adult; Cohort Studies; Humans; Liver; Liver Diseases; Prospective Studies; Protoporphyria, Erythropoietic
PubMed: 34475006
DOI: 10.1016/j.dld.2021.08.007 -
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 -
Biomedicine & Pharmacotherapy =... Feb 2023Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by skin photosensitivity caused by accumulation of protoporphyrin IX. We aimed to... (Review)
Review
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by skin photosensitivity caused by accumulation of protoporphyrin IX. We aimed to review the clinical evidence of efficacy and safety of skin photosensitivity treatments in individuals with EPP or XLP. We systematically searched MEDLINE, Embase, the Cochrane Library, and ClinicalTrials.gov. A total of 40 studies with data on 18 treatment modalities were included. Comprehensive treatment safety data were obtained from the European Medicines Agency and the United States Food and Drug Administration. The studies used different outcome measures to evaluate the sensitivity without a generally accepted method to assess treatment effect on skin photosensitivity. Of the included studies, 13 were controlled trials. Gathered, the trials showed moderate positive effect of inorganic sunscreen application and subcutaneous implant of afamelanotide and no effect of organic sunscreen application, or oral treatment with beta-carotene, cysteine, N-acetylcysteine, vitamin C, or warfarin. Studies without control groups suggested treatment effect of foundation cream, dihydroxyacetone/lawsone cream, narrow-band ultraviolet B phototherapy, erythrocyte transfusion, extracorporeal erythrocyte photodynamic therapy, or oral treatment with zinc sulphate, terfenadine, cimetidine, or canthaxanthin, but the real effect is uncertain. Assessment of treatment effect on photosensitivity in patients with EPP or XLP carries a high risk of bias since experienced photosensitivity varies with both weather conditions, exposure pattern, and pigmentation. Controlled trials of promising treatment options are important although challenging in this small patient population.
Topics: United States; Humans; Protoporphyria, Erythropoietic; Sunscreening Agents; Photosensitivity Disorders; Genetic Diseases, X-Linked; Protoporphyrins
PubMed: 36525819
DOI: 10.1016/j.biopha.2022.114132 -
Hepatology Communications Oct 2023Bile, which contains bile acids, the natural ligands for farnesoid x receptor (FXR), moves from the liver to the intestine through bile ducts. Ductular reaction often...
BACKGROUND
Bile, which contains bile acids, the natural ligands for farnesoid x receptor (FXR), moves from the liver to the intestine through bile ducts. Ductular reaction often occurs during biliary obstruction. A subset of patients with erythropoietic protoporphyria, an inherited genetic mutation in heme biosynthetic enzyme ferrochelatase, accumulate porphyrin-containing bile plugs, leading to cholestasis. Here, we examined the link between FXR, bile plug formation, and how heme biosynthesis relates to this connection.
METHODS
We treated female and male wild-type and global and tissue-specific Fxr knockout mice with a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine, an inhibitor of ferrochelatase, and examined the expression of heme biosynthetic genes. We mined FXR mouse ChIP-Seq data, performed biochemical and histological analysis, and tested HepG2 and primary human hepatocytes after treatment with obeticholic acid, an FXR agonist.
RESULTS
We observed that hepatic but not intestinal Fxr loss resulted in reduced bile plugs and ductular reaction in the liver. Then, we examined if FXR plays a regulatory role in heme biosynthesis and found significantly lower porphyrin accumulation in 3,5-diethoxycarbonyl-1, 4-dihydrocollidine-fed Fxr knockout mice. Gene expression and FXR mouse ChIP-Seq atlas analysis revealed that FXR orchestrates the expression of multiple heme biosynthetic enzymes. Finally, human HepG2 cells and primary human hepatocytes treated with obeticholic acid, showed increased expression of several heme biosynthetic genes.
CONCLUSIONS
Overall, our data show that hepatic Fxr is necessary to maintain ductular reaction and accumulation of bile plugs. FXR can direct the expression of multiple heme biosynthetic genes. Thus, modulating FXR activity in EPP patients may help alleviate its associated liver disease.
Topics: Animals; Female; Humans; Male; Mice; Cholestasis; Ferrochelatase; Heme; Liver; Porphyrins
PubMed: 37695073
DOI: 10.1097/HC9.0000000000000213 -
ACG Case Reports Journal Feb 2023Erythropoietic protoporphyria (EPP) presents with nonblistering photosensitivity. Hepatobiliary manifestations are seen in around 5% cases and include cholelithiasis,...
Erythropoietic protoporphyria (EPP) presents with nonblistering photosensitivity. Hepatobiliary manifestations are seen in around 5% cases and include cholelithiasis, elevations in liver enzymes, progressive jaundice, and end-stage liver disease. The diagnosis is suspected based on clinical features and elevated erythrocyte metal-free protoporphyrin and confirmed by genetic analysis showing loss-of-function mutations in the ferrochelatase (FECH) gene. We present an adolescent boy who presented with jaundice and photosensitivity with the liver biopsy showing deposition of brown pigments within the canaliculi and hepatocytes. This pigment showed Maltese cross birefringence on polarizing microscopy and Medusa-head appearance on electron microscopy. Genetic analysis revealed loss-of-function mutations in FECH. Introduction of EPP is an inborn error of heme biosynthesis caused by mutations in FECH with a prevalence of 1:75,000 to 1:200,000. We present a case of a 16-year-old adolescent boy with photosensitivity, abdominal pain, and jaundice with protoporphyrin deposition in the liver who was ultimately diagnosed with EPP based on genetic analysis.
PubMed: 36891180
DOI: 10.14309/crj.0000000000000996 -
JAMA Dermatology Aug 2017Autosomal recessive erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare photodermatoses presenting with variable degrees of painful... (Observational Study)
Observational Study
IMPORTANCE
Autosomal recessive erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare photodermatoses presenting with variable degrees of painful phototoxicity that markedly affects quality of life. The clinical variability, determinants of severity, and genotype/phenotype correlations of these diseases are not well characterized.
OBJECTIVE
To describe the baseline clinical characteristics, genotypes, and determinants of disease severity in a large patient cohort with EPP or XLP.
DESIGN, SETTING, AND PARTICIPANTS
A prospective observational study was conducted among patients with confirmed diagnoses of EPP or XLP from November 1, 2010, to December 6, 2015, at 6 academic medical centers of the Porphyrias Consortium of the National Institutes of Health Rare Diseases Clinical Research Network. Detailed medical histories, including history of phototoxicity and treatment, were collected on standardized case report forms. Patients underwent baseline laboratory testing, total erythrocyte protoporphyrin (ePPIX) testing, and molecular genetic testing. Data were entered into a centralized database.
MAIN OUTCOMES AND MEASURES
Results of biochemical and genetic tests were explored for association with clinical phenotype in patients with EPP or XLP.
RESULTS
Of the 226 patients in the study (113 female and 113 male patients; mean [SD] age, 36.7 [17.0] years), 186 (82.3%) had EPP with a FECH (OMIM 612386) mutation and the common low-expression FECH allele IVS3-48T>C, and only 1 patient had 2 FECH mutations. Twenty-two patients had XLP (9.7%; 10 male and 12 female patients), and 9 patients (4.0%) had elevated ePPIX levels and symptoms consistent with protoporphyria but no detectable mutation in the FECH or ALAS2 (OMIM 301300) gene. Samples of DNA could not be obtained from 8 patients. Patients' mean (SD) age at symptom onset was 4.4 (4.4) years. Anemia (107 [47.3%]), history of liver dysfunction (62 [27.4%]), and gallstones (53 [23.5%]) were commonly reported. Higher ePPIX levels were associated with earlier age of symptom onset (median ePPIX levels for those who developed symptoms before vs after 1 year of age, 1744 vs 1567 µg/dL; P = .02), less sun tolerance (median ePPIX levels for those reporting symptoms before vs after 10 minutes of sun exposure, 2233 vs 1524 µg/dL; P ≤ .001), and increased risk of liver dysfunction (median ePPIX levels for those with liver dysfunction vs normal liver function, 2016 vs 1510 µg/dL; P = .003). Patients with EPP and FECH missense mutations had significantly lower ePPIX levels than those with other mutations (1462 vs 1702 µg/dL; P = .01). Male patients with XLP had significantly higher ePPIX levels, on average, than did patients with EPP (3574 vs 1669 µg/dL; P < .001). Marked clinical variability was seen in female patients with XLP owing to random X-chromosomal inactivation.
CONCLUSIONS AND RELEVANCE
These data suggest that higher ePPIX levels are a major determinant of disease severity and risk of liver dysfunction in patients with EPP or XLP. These findings provide a framework for clinical monitoring and management of these disorders.
Topics: 5-Aminolevulinate Synthetase; Adolescent; Adult; Aged; Child; Child, Preschool; Female; Ferrochelatase; Genetic Diseases, X-Linked; Genotype; Humans; Liver Diseases; Male; Middle Aged; Mutation; Phenotype; Prospective Studies; Protoporphyria, Erythropoietic; Quality of Life; Severity of Illness Index; Young Adult
PubMed: 28614581
DOI: 10.1001/jamadermatol.2017.1557 -
Frontiers in Molecular Biosciences 20225-Aminolevulinate synthase (ALAS; E.C. 2.3.1.37) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the key regulatory step of porphyrin biosynthesis in... (Review)
Review
5-Aminolevulinate synthase (ALAS; E.C. 2.3.1.37) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the key regulatory step of porphyrin biosynthesis in metazoa, fungi, and α-proteobacteria. ALAS is evolutionarily related to transaminases and is therefore classified as a fold type I PLP-dependent enzyme. As an enzyme controlling the key committed and rate-determining step of a crucial biochemical pathway ALAS is ideally positioned to be subject to allosteric feedback inhibition. Extensive kinetic and mutational studies demonstrated that the overall enzyme reaction is limited by subtle conformational changes of a hairpin loop gating the active site. These findings, coupled with structural information, facilitated early prediction of allosteric regulation of activity via an extended C-terminal tail unique to eukaryotic forms of the enzyme. This prediction was subsequently supported by the discoveries that mutations in the extended C-terminus of the erythroid ALAS isoform (ALAS2) cause a metabolic disorder known as X-linked protoporphyria not by diminishing activity, but by enhancing it. Furthermore, kinetic, structural, and molecular modeling studies demonstrated that the extended C-terminal tail controls the catalytic rate by modulating conformational flexibility of the active site loop. However, the precise identity of any such molecule remains to be defined. Here we discuss the most plausible allosteric regulators of ALAS activity based on divergences in AlphaFold-predicted ALAS structures and suggest how the mystery of the mechanism whereby the extended C-terminus of mammalian ALASs allosterically controls the rate of porphyrin biosynthesis might be unraveled.
PubMed: 35911972
DOI: 10.3389/fmolb.2022.920668 -
Journal of the American Veterinary... Dec 2020A 6-month-old sexually intact male Clumber Spaniel was evaluated because of small stature, recurrent dermatitis of the head, and progressive pigmentary hepatopathy.
CASE DESCRIPTION
A 6-month-old sexually intact male Clumber Spaniel was evaluated because of small stature, recurrent dermatitis of the head, and progressive pigmentary hepatopathy.
CLINICAL FINDINGS
Clinicopathologic findings included nonanemic hypochromic microcytosis, hypocholesterolemia, persistently high serum liver enzyme activities, and anicteric hyperbilirubinemia. Histologic examination of liver biopsy specimens collected when the dog was 6 months and 2 years of age revealed expansion and bridging of portal tracts, occasional centrilobular parenchymal collapse, scattered lymphoplasmacytic infiltrates, and dark red to brown pigment within large aggregates of macrophages, engorged bile canaliculi, and hepatocytes. The pigment failed to stain for the presence of iron, copper, bile, and glycoprotein and, when examined with polarized microscopy, emitted a yellow to green birefringence with occasional Maltese cross configurations. Further analyses confirmed marked porphyrin accumulation in blood, urine, feces, and liver tissue; protoporphyrin accumulation in RBCs and liver tissue; and a signature porphyrin profile and fluorescence peak consistent with erythropoietic protoporphyria. Advanced protoporphyric hepatopathy was diagnosed. The chronic dermatopathy was presumed to reflect protoporphyric photosensitivity.
TREATMENT AND OUTCOME
Management was focused on avoiding conditions known to induce heme synthesis and catabolism, administrating ursodeoxycholic acid and antioxidants -adenosylmethionine and vitamin E, and avoiding sunlight exposure. At follow-up at 4 years of age, the dog was stable without evidence of jaundice but with probable persistent erythropoietic protoporphyria-related solar dermatopathy.
CLINICAL RELEVANCE
Clinical and histologic features of congenital erythropoietic protoporphyria and resultant protoporphyric hepatopathy, the diagnosis, and the successful management of a dog with these conditions over 4 years were described. Veterinarians should consider porphyric syndromes when unusual pigmentary hepatopathies are encountered.
Topics: Animals; Bile; Dog Diseases; Dogs; Liver; Liver Diseases; Male; Protoporphyria, Erythropoietic; Ursodeoxycholic Acid
PubMed: 33226294
DOI: 10.2460/javma.2020.257.11.1148