Acta Dermato-Venereologica 99-7CompleteContent | 页面 6

634 REVIEW ARTICLE Erythropoietic Protoporphyria in a Japanese Population Megumi MIZAWA 1 , Teruhiko MAKINO 1 , Hajime NAKANO 2 , Daisuke SAWAMURA 2 and Tadamichi SHIMIZU 1 Department of Dermatology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Toyama, and Department of Dermatology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan 1 2 Erythropoietic protoporphyria is caused by a parti- al deficiency of ferrochelatase, which is the last en- zyme in the heme biosynthesis pathway. In a typical erythro­poietic protoporphyria, photosensitivity initi- ally appears, following the first exposure to the sun in early infancy or childhood. Erythropoietic proto- porphyria has been reported worldwide, but there is a regional variation in its epidemiology. Approxima- tely 20% of the Japanese patients were recognized to have symptoms of erythropoietic protoporphyria after 10 years of age. Physicians occasionally encounter Ja- panese patients with erythropoietic protoporphyria, mild symptoms and no FECH gene mutations. The ho- mozygous 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. Key words: erythropoietic protoporphyria; ferrochelatase; pho- tosensitivity. Accepted Apr 2, 2019; E-published Apr 2, 2019 Acta Derm Venereol 2019; 99: 634–639. Corr: Megumi Mizawa, M.D., Ph.D., Department of Dermatology, Gradu- ate School of Medicine and Pharmaceutical Sciences, University of Toya- ma, Sugitani, Toyama 930-0194, Japan. E-mail: [email protected] ma.ac.jp E rythropoietic protoporphyria (EPP; OMIM #177000) is an inherited cutaneous porphyria caused by mutations in the ferrochelatase gene (FECH), which codes for an enzyme that catalyses iron insertion into protoporphyrin (PP) to form heme. A partial decrease in FECH activity results in the accumulation of PP in the skin, blood cells and skin blood vessels. The accumula- tion of PP in the skin causes painful photosensitivity in patients, which begins in early childhood. In less than 10% of patients, the accumulation of PP in the liver can lead to hepatic injury (1, 2). The disease is considered to occur across races and ethnic groups. However, we often note differences between Japanese patients and those from other countries with regard to the clinical symptoms of EPP. doi: 10.2340/00015555-3184 Acta Derm Venereol 2019; 99: 634–639 SIGNIFICANCE Erythropoietic protoporphyria (EPP) is a rare autosomal do- minant disorder of heme biosynthesis, which results from a decrease in ferrochelatase activity, leading to an excess accumulation of protoporphyrin. EPP is characterized by painful photosensitivity, which begins in early childhood. The time of onset in Japanese patients may be later than in patients of other ethnicities. The homozygous IVS3-48C polymorphism may cause a mild phenotype of EPP via a slight increase in protoporphyrin. Japanese EPP shows a characteristic phenotype, such as the late onset and mild symptoms compared to Caucasian EPP. We reviewed the clinical and genetic findings of EPP patients in the Japanese population. PATHOGENESIS AND CLINICAL FINDINGS OF TYPICAL ERYTHROPOIETIC PROTOPORPHYRIA EPP is an autosomal-dominant inherited disorder. More than 175 different mutations of the FECH gene have been reported (3). However, EPP has a low clinical penetrance, with less than 10% of mutation carriers developing overt clinical symptoms (4). Gouya et al. (2, 5, 6) revealed that the single intronic nucleotide polymorphism (SNP) (rs: 2272783) of C at IVS3-48 in trans to a mutated FECH allele results in the development of the EPP phenotype via the low expression of FECH. At present, 12 SNPs in the coding region of FECH gene have been indicated, 4 of which are synonymous (3). It has been shown that the c.68–23C > T variant located in intron 1 (rs: 2269219) alters the secondary structure of the mRNA (7). In ad- dition, the functional significance of c.1-251A>G (rs: 17063905) on the transcriptional activity of the FECH gene lies in decreasing the promoter activity (8). The accumulation of phototoxic PP in the superficial vessels is activated by blue light (400 to 410 nm), trig- gering singlet oxygen free radical reactions that lead to severe neuropathic pain, which lasts hours to days. PP is released from erythroid cells into the circulation; gains access to the vascular endothelium and liver, and is then excreted through the biliary system. Laboratory investi- gations have revealed an increased PP concentration. A large number of fluorocytes are observed in the peripheral blood (Fig. 1B). The characteristics of photosensitivity in EPP are first a burning, stinging sensation, appearing This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica.