Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Mol Genet Metab. 2019 Nov;128(3):358-362. doi: 10.1016/j.ymgme.2018.08.015. Epub 2018 Aug 31.
The erythropoietic porphyrias are inborn errors of heme biosynthesis with prominent cutaneous manifestations. They include autosomal recessive Congenital Erythropoietic Porphyria (CEP) due to loss-of-function (LOF) mutations in the Uroporphyrinogen III Synthase (UROS) gene, Erythropoietic Protoporphyria (EPP) due to LOF mutations in the ferrochelatase (FECH) gene, and X-Linked Protoporphyria (XLP) due to gain-of-function mutations in the terminal exon of the Aminolevulinic Acid Synthase 2 (ALAS2) gene. During the 11-year period from 01/01/2007 through 12/31/2017, the Mount Sinai Porphyrias Diagnostic Laboratory provided molecular diagnostic testing for one or more of these disorders in 628 individuals, including 413 unrelated individuals. Of these 628, 120 patients were tested for CEP, 483 for EPP, and 331 for XLP, for a total of 934 tests. For CEP, 24 of 78 (31%) unrelated individuals tested had UROS mutations, including seven novel mutations. For EPP, 239 of 362 (66%) unrelated individuals tested had pathogenic FECH mutations, including twenty novel mutations. The IVS3-48 T > C low-expression allele was present in 231 (97%) of 239 mutation-positive EPP probands with a pathogenic FECH mutation. In the remaining 3%, three patients with two different FECH mutations in trans were identified. For XLP, 24 of 250 (10%) unrelated individuals tested had ALAS2 exon 11 mutations. No novel ALAS2 mutations were identified. Among family members referred for testing, 33 of 42 (79%) CEP, 62 of 121 (51%) EPP, and 31 of 81 (38%) XLP family members had the respective family mutation. Mutation-positive CEP, EPP, and XLP patients who had been biochemically tested had marked elevations of the disease-appropriate porphyrin intermediates. These results expand the molecular heterogeneity of the erythropoietic porphyrias by adding a total of 27 novel mutations. The results document the usefulness of molecular testing to confirm the positive biochemical findings in these patients and to identify heterozygous family members.
红细胞生成性卟啉症是血红素生物合成的先天性错误，具有明显的皮肤表现。它们包括常染色体隐性先天性红细胞生成性卟啉症（CEP），是由于尿卟啉原 III 合酶（UROS）基因的功能丧失（LOF）突变引起的；红细胞生成性原卟啉症（EPP），是由于亚铁螯合酶（FECH）基因的 LOF 突变引起的；X 连锁原卟啉症（XLP），是由于氨基酮戊酸合成酶 2（ALAS2）基因末端外显子的获得性功能突变引起的。在 2007 年 1 月 1 日至 2017 年 12 月 31 日的 11 年期间，西奈山卟啉症诊断实验室为 628 个人中的一个或多个这些疾病提供了分子诊断检测，其中包括 413 个无关个体。在这 628 人中，有 120 名患者接受了 CEP 检测，483 名患者接受了 EPP 检测，331 名患者接受了 XLP 检测，共进行了 934 次检测。对于 CEP，在 78 个无关个体中，有 24 个（31%）进行了 UROS 突变检测，其中包括 7 个新突变。对于 EPP，在 362 个无关个体中，有 239 个（66%）进行了致病性 FECH 突变检测，其中包括 20 个新突变。在 239 个具有致病性 FECH 突变的 EPP 先证者中，231 个（97%）存在 IVS3-48T>C 低表达等位基因。在其余 3%的患者中，鉴定出了三个存在两个不同 FECH 突变的患者。对于 XLP，在 250 个无关个体中，有 24 个（10%）进行了 ALAS2 外显子 11 突变检测。没有发现新的 ALAS2 突变。在接受检测的家族成员中，42 个 CEP 家族成员中有 33 个（79%）、121 个 EPP 家族成员中有 62 个（51%）和 81 个 XLP 家族成员中有各自家族的突变。经过生化检测的 CEP、EPP 和 XLP 突变阳性患者的疾病相关卟啉中间产物显著升高。这些结果通过增加总共 27 个新突变，扩展了红细胞生成性卟啉症的分子异质性。结果证明了分子检测在确认这些患者的阳性生化结果和识别杂合家族成员方面的有用性。
