Case Of Erythropoietic Protoporphyria Research Articles

When the diagnosis is written in the DNA: a case of erythropoietic protoporphyria in a patient with a chromosome-18 deletion.

In this case study, we describe a 21-year-old man with erythropoietic protoporphyria who sought medical attention in April 2022 for diffuse edema and erythema of the hands. These symptoms had been present since childhood and usually occurred soon after sun exposure. The patient's medical history showed that chromosome 18's long arm had partially deleted. We performed a number of tests, including measuring total erythrocyte protoporphyrin levels and utilizing a spectrofluorometer to assess the fluorometric emission peak of plasma porphyrins, based on the patient's medical history and clinical symptoms. Furthermore, a genetic analysis identified an intronic variant on one allele, c.315-48T>C (IVS3-48T>C), which is categorized as a susceptibility polymorphism, and a complete deletion of the ferrochelatase gene on the other allele. The patient's clinical condition improved following the June 2022 afamelanotide implant procedure.

Two Novel FECH Mutations in a Patient with Erythropoietic Protoporphyria

Introduction: Erythropoietic protoporphyria (EPP) is a rare photodermatosis mainly caused by deficiency of the enzyme ferrochelatase (FECH). We herein report a case of EPP associated with two novel mutations in FECH. Case presentation: A 15-year-old boy experienced pain and pruritus after sunlight exposure. He had occasional claret-red urine, hepatomegaly with increased alanine aminotransferase and aspartate aminotransferase levels, and an elevated free erythrocyte protoporphyrin level. He was treated with oral β-carotene and cholestyramine and avoidance of sunlight as much as possible. Discussion: Genome sequencing revealed two novel FECH mutations that had been inherited from his healthy parents. Pathogenicity analysis involving prediction using PolyPhen-2, SIFT, and Mutation Taster revealed that the two novel mutations were likely pathogenic. Although the patient’s parents were healthy, they each had one of these two mutations. This finding is consistent with previous reports stating that individuals carrying low-expression alleles can be asymptomatic. The pathogenesis of the disease caused by these two mutations requires verification by larger and more detailed studies. Conclusion: Although the precise role of these mutations in EPP is not clear, the findings in the present case expand the genotypic spectrum of the disease.

Liver involvement in patients with erythropoietic protoporphyria: retrospective analysis of clinicopathological features of 5 cases

Erythropoietic protoporphyria (EPP) is a rare inherited disease whose morbidity is about 1:75,000 to 1:200,000. It is caused by the deficiency of porphyrin ferrochelatase (FECH). Liver involvement in EPP is even rarer. The diagnosis of EPP with liver involvement mainly relies on clinical manifestations, laboratory examinations, histopathological examinations and genetic testing, which is still a huge challenge for both clinicians and pathologists. Here, 5 cases of EPP with liver injury were collected, and the clinicopathological features of these patients were analyzed. The clinical manifestations and laboratory examinations varied from person to person, whereas the liver biopsies showed that there were dark brown deposits within the hepatocytes, Kupffer cells, bile canaliculi and the lumen of bile ducts, which was a constant finding by histopathological examination. Gene tests were conducted in two of the five cases, and the results confirmed the diagnosis. Fully understanding of the diseases can help us reduce the rate of missed diagnosis and provide proper treatment as early as possible.

肝障害を契機に遺伝子学的に診断され，肝生検で経時的な線維化の進行を確認できた骨髄性プロトポルフィリン症の1例

肝障害を契機に遺伝子学的に診断され，肝生検で経時的な線維化の進行を確認できた骨髄性プロトポルフィリン症の1例

重篤な肝障害を来した骨髄性プロトポルフィリン症の1例

症例は42歳男性．10歳時に近医で骨髄性プロトポルフィリン症（Erythropoietic protoporphyria：EPP）と診断され，20歳，40歳時にEPPによる肝障害，腹痛で入院歴あり，安静で改善した．2014年6月に腹痛，便秘，黄疸が出現し，EPP急性発作の診断で入院となった．遮光下で安静，緩下剤の投与を行うも改善せず，T-Bilの上昇（17.1 mg/dL）を認めた．入院5日目からHeminの投与を行い，投与終了後より徐々にT-Bilは低下，腹痛は改善傾向となった．以降は増悪なく入院30日目に退院となり，退院2カ月後の採血では肝機能，T-Bilは正常化していた．肝障害を伴う急性発作が出現し，治療に難渋したEPPの1例を経験したので報告する．

Oocyte Cryopreservation and Delayed Pre-Implantation Genetic Diagnosis in the Setting of Erythropoietic Protoporphyria (EPP): A Case Report

Fertility preservation (FP) has received considerable focus for cancer patients facing gonadotoxic therapy. A host of patients with hematologic and rheumatologic disorders may also benefit from FP. Porphyria constitutes a spectrum of disorders involving inborn errors of heme synthesis. Erythropoietic protoporphyria (EPP) can vary in severity, and liver and bone marrow transplantation have been recommended in severe cases of EPP.1 In addition numerous hematologic disorders, like EPP, are the result of specific gene disorders and are thus amenable to FP combined with pre-implantation genetic diagnosis (PGD). To describe a case in which fertility preservation was performed in a patient with EPP prior to bone marrow transplant. A 22 year-old G0 presented to a university-based infertility clinic for FP prior to bone marrow transplantation (BMT). Her hematology team had recommended a BMT due to worsening liver function. Genetic testing revealed this patient's EPP resulted from a single allele mutation of ALAS2, making her a heterozygote for X-linked porphyria (XLP). The patient was offered expectant management, ovarian suppression with GnRH agonist, oocyte and embryo banking, and ovarian tissue banking by our FP team. Fertility preservation with oocyte cryopreservation was pursued due to the high risk of post-treatment amenorrhea after bone-marrow transplantation (risk of ovarian failure is 80-100%). Basal ovarian reserve markers were within normal limits (FSH 6.6 mIU/ml with an estradiol of 70 pg/dl; AFC of 15 follicles each side). An antagonist protocol was used for controlled ovarian hyperstimulation, with dosing of 150 units each of recombinant follicle stimulating hormone and human menopausal gonadotropins daily. A peak estradiol of 3771 pg/dl was noted on cycle day 9, and human chorionic gonadotropin 10,000 units was administered on the same day. Oocyte retrieval was performed 36 hours later, and 21 MII oocytes were retrieved and cryopreserved. Preimplantation genetic diagnosis (PGD) is planned when fertility is desired to screen for embryos aff5cted with EPP. Erythropoietic protoporphyria represents one of many disorders that may require bone marrow transplant (BMT). BMT and the associated medications used to control recipient response are strongly associated with subsequent amenorrhea and ovarian failure. Our case highlights the need to discuss fertility preservation with all patients undergoing BMT and the potential to combine fertility preservation with future PGD. 1.Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Blood. 2012 Nov;120(23):4496-504.2.Meirow, D, Biederman, H, Anderson, R A, Wallace, W, Hamish B. Toxicity of Chemotherapy and Radiation on Female Reproduction. Clin Obstet Gynecol. 2010 Dec: 53(4): 727-39.3.Jadoul P, Donnez J. How does bone marrow transplantation affect ovarian function and fertility? Curr Opin Obstet Gynecol. 2012.

A case of erythropoietic protoporphyria with severe liver dysfunction

A case of erythropoietic protoporphyria with severe liver dysfunction

Erythropoietic protoporphyria

Erythropoietic protoporphyria (EPP) is an inherited disorder of the haem metabolic pathway characterised by accumulation of protoporphyrin in blood, erythrocytes and tissues, and cutaneous manifestations of photosensitivity. EPP has been reported worldwide, with prevalence between 1:75,000 and 1:200,000. It usually manifests in early infancy upon the first sun exposures. EPP is characterised by cutaneous manifestations of acute painful photosensitivity with erythema and oedema, sometimes with petechiae, together with stinging and burning sensations upon exposure to sunlight, without blisters. These episodes have a variable severity depending on the exposure duration and may result in chronic permanent lesions on exposed skin. As protoporphyrin is a lipophilic molecule that is excreted by the liver, EPP patients are at risk of cholelithiasis with obstructive episodes, and chronic liver disease that might evolve to rapid acute liver failure. In most patients, EPP results from a partial deficiency of the last enzyme of the haem biosynthetic pathway, ferrochelatase, EC 4.99.1.1/FECH (encoded by the FECH gene). EPP appears to be inherited as an autosomal dominant disease, the clinical expression of which is modulated by the presence of the hypomorphic FECH IVS3-48C allele trans, but recessive inheritance with two mutated FECH alleles has also been described. In about 2% of patients, overt disease was recently shown to be caused by gain-of-function mutations in the erythroid-specific aminolevulinic acid synthase 2 (ALAS2/ALAS, EC 2.3.1.27) gene and named X-linked dominant protoporphyria. Diagnosis is established by finding increased levels of protoporphyrin in plasma and red blood cells, and detection of a plasma fluorescence peak at 634 nm. Investigations for hepatic involvement, ferrochelatase activity level, genetic analysis (FECH mutations, presence of the hypomorphic FECH IVS3-48C allele trans and ALAS2 mutations) and family studies are advisable. Differential diagnosis includes phototoxic drug reactions, hydroa vacciniforme, solar urticaria, contact dermatitis, angio-oedema and, in some cases, other types of porphyria. Management includes avoidance of exposure to light, reduction of protoporphyrin levels and prevention of progression of possible liver disease to liver failure. As the major risk in EPP patients is liver disease, a regular follow-up of hepatic involvement is essential. Sequential hepatic and bone marrow transplantation should be considered as a suitable treatment for most severe cases of EPP with hepatic involvement. EPP is a lifelong disorder whose prognosis depends on the evolution of the hepatic disease. However, photosensitivity may have a significant impact on quality of life of EPP patients.

Erythropoietic protoporphyria with eye complications

We herein report a case of erythropoietic protoporphyria (EPP) complicated by a decrease in eyesight that occurred in a Japanese male. An ophthalmologist initially thought that the eyesight loss might be the result of idiopathic optic nerve atrophy due to a vascular obstruction in the fundus. There are no previous reports of EPP cases with eye complications. However, an eye abnormality has been reported in an animal model of protoporphyria after long-term, low-level exposure to blue light. As a result, in our case, it is therefore possible that a relationship may have existed between EPP and the onset of eye complications.

Clinical, Biochemical, and Genetic Study of 11 Patients With Erythropoietic Protoporphyria Including One With Homozygous Disease

To study the mutations in the ferrochelatase gene (FECH) and the phenotypic expression of erythropoietic protoporphyria (EPP) in a group of Spanish patients. Case series. University-based hospital. Eleven unrelated patients with EPP and 19 asymptomatic relatives from 10 families. Measurement of protoporphyrin concentration in red blood cells and feces by fluorometry and chromatography. Analysis of the mutations of the FECH gene by single-strand conformation analysis. Expression of mutations in Escherichia coli. FECH gene mutations were found in all 11 patients. Ten were heterozygous and carried the IVS3-48C low-expression allele. Three novel mutations were found: IVS4 + 1delG, 347-351delC, and 130_147dupl 18. One patient did not present the IVS3-48C polymorphism and was found to harbor a novel A185T missense mutation in both alleles. The familial study confirmed a recessive mode of inheritance of the disease. The A185T mutation showed a residual activity 4% of normal when expressed in E coli. This patient presented cutaneous photosensitivity similar to the heterozygous cases, but a higher protoporphyrin accumulation in erythrocytes, microcytic anemia, and early signs of liver engagement. FECH mutations were found in 10 healthy relatives, none of whom carried the low-expression allele. The frequency of the IVS3-48C allele among 180 nonporphyric Spanish individuals was 5.2%. These findings confirm, among a group of Spanish patients, that most cases of EPP result from the coinheritance of IVS3-48C and a mutation in the FECH gene, and also document the existence of patients with mutations in homozygosity that may present a more severe form of the disease.

A Case of Erythropoietic Protoporphyria with Severe Liver Dysfunction and Neurological Symptoms

A Case of Erythropoietic Protoporphyria with Severe Liver Dysfunction and Neurological Symptoms

Protoporfiria eritropoyética: Estudio de cuatro casos y revisión de la literatura

Erythropoietic protoporphyria (EPP) is an inherited inborn error of porphyrin metabolism caused by decreased activity of the enzyme ferrochelatase. It is a rare disease, characterized clinically by photosensitivity. Otherwise, the patients often refer only itching and swelling in photoexposed areas, without visible lesions. This often hampers the diagnosis of EPP. We describe four cases of EPP that we saw in our Photobiology Department and review the most important features of the disease.

A case of erythropoietic protoporphyria with liver cirrhosis suggesting a therapeutic value of supplementation with α-tocopherol

Erythropoietic protoporphyria (EPP) was diagnosed in a 27-year-old man based on a typical clinical history, and a marked increase in erythrocyte and fecal protoporphyrin concentrations. Although liver disease is not a common feature in EPP, he had slight liver dysfunction. A percutaneous liver biopsy was performed and it showed minimal hepatocellular damage and many reddish brown pigment deposits in hepatocytes, Kupffer cells, portal histiocytes, bile canaliculi and small biliary radicles. Electron microscopic findings confirmed that these deposits were composed of protoporphyrin crystals. Liver biochemistry remained well for >2 years, but deteriorated rapidly and second liver biopsy obtained 28 months after the first biopsy revealed the development of liver cirrhosis. We treated the patient with intravenous administration of dl-a-tocopherol acetate (vitamin E; 500 IU/body/day). Following the administration of vitamin E, the concentration of protoporphyrin in erythrocytes decreased significantly and the liver function tests were improved. Sixteen weeks later he showed the full clinical and biochemical recovery suggesting that vitamin E supplementation might be useful in treating patients with EPP who developed liver damage.

Structure and function of ferrochelatase.

Ferrochelatase is the terminal enzyme of the heme biosynthetic pathway in all cells. It catalyzes the insertion of ferrous iron into protoporphyrin IX, yielding heme. In eukaryotic cells, ferrochelatase is a mitochondrial inner membrane-associated protein with the active site facing the matrix. Decreased values of ferrochelatase activity in all tissues are a characteristic of patients with protoporphyria. Point-mutations in the ferrochelatase gene have been recently found to be associated with certain cases of erythropoietic protoporphyria. During the past four years, there have been considerable advances in different aspects related to structure and function of ferrochelatase. Genomic and cDNA clones for bacteria, yeast, barley, mouse, and human ferrochelatase have been isolated and sequenced. Functional expression of yeast ferrochelatase in yeast strains deficient in this enzyme, and expression in Escherichia coli and in baculovirus-infected insect cells of different ferrochelatase cDNAs have been accomplished. A recently identified (2Fe-2S) cluster appears to be a structural feature shared among mammalian ferrochelatases. Finally, functional studies of ferrochelatase site-directed mutants, in which key amino acids were replaced with residues identified in some cases of protoporphyria, will be summarized in the context of protein structure.

A Case of Erythropoietic Protoporphyria with Severe Liver Dysfunction Suggesting a Close Relationship between Erythrocyte Protoporphyrin Levels and Those of γ‐GTP

A case of erythropoietic protoporphyria (EPP) with severe acute abdominal pain and jaundice was reported. Erythrocyte protoporphyrin (PP) levels were constantly high, and liver histology showed a slight fibrosis with inflammatory infiltration. During the investigation period of 18 months, erythrocyte PP levels closely paralleled those of serum gamma-GTP.

Relief of the photosensitivity of erythropoietic protoporphyria by pyridoxine

Twenty-five years ago the use of pyridoxine was described for the treatment of photosensitivity eruptions. We report two cases of erythropoietic protoporphyria, which were only moderately responsive to β-carotene and sunscreens, whereas the use of pyridoxine has been associated with a marked reduction in photosensitivity without evidence of adverse effects. Regarding the mechanism of action, we can only speculate that pyridoxine could be mediated by increased endogenous nicotinamide production. We believe that our results warrant therapeutic trial of oral pyridoxine in patients with unrelieved photosensitivity as a result of erythropoietic protoporphyria.

Urinary porphyrin excretion in various types of porphyria. Thin-layer chromatographic study.

A new method of thin-layer chromatography was used for the study of urinary porphyrins in 42 porphyric patients (27 cases of porphyria cutanea tarda (PCT), 5 cases of porphyria variegata, 4 cases of acute intermittent porphyria, 2 cases of hereditary coproporphyria and 4 cases of erythropoietic protoporphyria), 21 of their clinically normal relatives and 5 controls. The results are compared to previously published data and discussed for the diagnosis of the porphyrias. If urinary porphyrin pattern seems sufficiently pathognomonic for PCT, it appears often unable to allow exact diagnosis of the acute porphyrias; faecal studies and sometimes enzymatic determinations are necessary.

Erythropoietic protoporphyria: Evidence that it is due to a variant ferrochelatase

Erythroid ferrochelatase activity was measured at different pH and temperature values in normal subjects and patients with porphyria variegate (PV) and erythropoietic protoporphyria (EPP). The pH activity curves were similar but whereas in PV patients and normal subjects the plots of ferrochelatase activity vs temperature were monophasic in EPP they were truncated. In addition zinc did not form a zinc protoporphyrin complex in fibroblasts from cases of EPP. These findings support the concept that erythropoietic protoporphyria is due to a genetic mutation resulting in a variant ferrochelatase.

Faecal porphyrin excretion in various types of porphyria

A new method of thin layer chromatography was used for the study of faecal porphyrins in 31 porphyric patients (20 cases of porphyria cutanea tarda, 5 cases of porphyria variegata, 2 cases of hereditary coproporphyria, 1 case of acute intermittent porphyria and 3 cases of erythropoietic protoporphyria), 14 of their clinically normal relatives and 5 controls. The pattern obtained was characteristic of each type of porphyria and compared to previously published data.

The detection of porphyria in photosensitive patients

The biochemical diversity of the various porphyris often leads to incomplete investigation of photosensitive patients and porphyria may be excluded wrongly on the basis of normal urinary porphyrins alone. Establishing a biochemical referral centre for photosensitive patients suspected of having porphyria led to the diagnosis of 5 cases of porphyria cutanea tarda (PCT) and 2 cases of erythropoietic protoporphyria (EPP) among 34 patients referred by dermatologists over a period of 12 months. Iron overload was conformed in 3 the PCT patients by plasma ferritin assay. Studies on the available families of the two EPP patients revealed elevated red cell protoporphyrin levels in several clinically asymptomatic relatives.