Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Eur J Hum Genet. 2011 Feb;19(2):138-44. doi: 10.1038/ejhg.2010.171. Epub 2010 Nov 10.
Various syndromes of the Ras-mitogen-activated protein kinase (MAPK) pathway, including the Noonan, Cardio-Facio-Cutaneous, LEOPARD and Costello syndromes, share the common features of craniofacial dysmorphisms, heart defect and short stature. In a subgroup of patients, severe muscle hypotonia, central nervous system involvement and failure to thrive occur as well. In this study we report on five children diagnosed initially with classic metabolic and clinical symptoms of an oxidative phosphorylation disorder. Later in the course of the disease, the children presented with characteristic features of Ras-MAPK pathway-related syndromes, leading to the reevaluation of the initial diagnosis. In the five patients, in addition to the oxidative phosphorylation disorder, disease-causing mutations were detected in the Ras-MAPK pathway. Three of the patients also carried a second, mitochondrial genetic alteration, which was asymptomatically present in their healthy relatives. Did we miss the correct diagnosis in the first place or is mitochondrial dysfunction directly related to Ras-MAPK pathway defects? The Ras-MAPK pathway is known to have various targets, including proteins in the mitochondrial membrane influencing mitochondrial morphology and dynamics. Prospective screening of 18 patients with various Ras-MAPK pathway defects detected biochemical signs of disturbed oxidative phosphorylation in three additional children. We concluded that only a specific, metabolically vulnerable sub-population of patients with Ras-MAPK pathway mutations presents with mitochondrial dysfunction and a more severe, early-onset disease. We postulate that patients with Ras-MAPK mutations have an increased susceptibility, but a second metabolic hit is needed to cause the clinical manifestation of mitochondrial dysfunction.
多种 Ras-丝裂原活化蛋白激酶（MAPK）途径综合征，包括 Noonan、Cardio-Facio-Cutaneous、LEOPARD 和 Costello 综合征，具有颅面畸形、心脏缺陷和身材矮小的共同特征。在亚组患者中，还会出现严重的肌肉张力减退、中枢神经系统受累和生长不良。在这项研究中，我们报告了五名最初被诊断为经典代谢和临床症状的氧化磷酸化障碍患者。在疾病的后期，这些患儿表现出 Ras-MAPK 途径相关综合征的特征性表现，导致对初始诊断的重新评估。在这五名患者中，除了氧化磷酸化障碍外，还在 Ras-MAPK 途径中检测到致病突变。其中三名患者还携带第二种线粒体遗传改变，而他们健康的亲属则无症状携带这种改变。我们是否一开始就误诊了，还是线粒体功能障碍与 Ras-MAPK 途径缺陷直接相关？Ras-MAPK 途径已知有多种靶点，包括影响线粒体形态和动力学的线粒体膜蛋白。对 18 名患有各种 Ras-MAPK 途径缺陷的患者进行前瞻性筛查，在另外三名儿童中发现了氧化磷酸化紊乱的生化迹象。我们得出结论，只有 Ras-MAPK 途径突变患者中具有特定代谢脆弱性的亚群会出现线粒体功能障碍和更严重、早发性疾病。我们推测 Ras-MAPK 突变患者的易感性增加，但需要第二次代谢打击才能导致线粒体功能障碍的临床表现。
