Wolfe Rachel, Heiman Paige, D'Annibale Olivia, Karunanidhi Anuradha, Powers Alyssa, Mcguire Marianne, Seminotti Bianca, Dobrowolski Steven F, Reyes-Múgica Miguel, Torok Kathryn S, Mohsen Al-Walid, Vockley Jerry, Ghaloul-Gonzalez Lina
Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
University of Pittsburgh, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Mol Genet Metab Rep. 2022 Oct 29;33:100932. doi: 10.1016/j.ymgmr.2022.100932. eCollection 2022 Dec.
Autoimmune Disease, Multisystem, with Facial Dysmorphism (ADMFD) is an autosomal recessive disorder due to pathogenic variants in the gene. It is characterized by failure to thrive, dysmorphic facial features, developmental delay, and systemic autoimmunity that can manifest variably with autoimmune hepatitis, thyroiditis, and enteropathy, among other organ manifestations. It was originally described in 10 consanguineous Old Order Amish patients, and more recently in two patients of White British and Black German ethnicities. While the role of ITCH protein in apoptosis and inflammation has previously been characterized, a defect in cellular bioenergetics has not yet been reported in ITCH deficiency. Here we present a Caucasian female originally evaluated for possible mitochondrial respiratory chain deficiency, who ultimately was found to have two novel variants in with absence of ITCH protein in patient derived fibroblasts. Clinical studies of patient muscle showed mitochondrial DNA copy number of 57% compared to controls. Functional studies in skin fibroblasts revealed decreased activity of mitochondrial fatty acid oxidation and oxidative phosphorylation, and decreased overall ATP production. Our findings confirm mitochondrial energy dysfunction in a patient with ITCH deficiency offering the opportunity to assess alternative therapeutic options.
伴有面部畸形的多系统自身免疫性疾病（ADMFD）是一种常染色体隐性疾病，由该基因的致病变异引起。其特征包括生长发育迟缓、面部畸形、发育延迟以及系统性自身免疫，可表现为自身免疫性肝炎、甲状腺炎和肠病等多种器官表现，且症状各异。该病最初在10名有血缘关系的旧秩序阿米什患者中被描述，最近在两名英国白人及德国黑人患者中也有报道。虽然ITCH蛋白在细胞凋亡和炎症中的作用此前已得到描述，但细胞生物能量学缺陷在ITCH缺乏症中尚未见报道。在此，我们介绍一名最初因可能存在线粒体呼吸链缺陷而接受评估的白种女性，最终发现其该基因存在两个新变异，且患者来源的成纤维细胞中不存在ITCH蛋白。对患者肌肉的临床研究显示，与对照组相比，线粒体DNA拷贝数为57%。对皮肤成纤维细胞的功能研究表明，线粒体脂肪酸氧化和氧化磷酸化活性降低，ATP总产量下降。我们的研究结果证实了一名ITCH缺乏症患者存在线粒体能量功能障碍，为评估替代治疗方案提供了机会。
