Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway

作者：Kleefstra Tjitske; Wortmann Saskia B; Rodenburg Richard J T; Bongers Ernie M H F; Hadzsiev Kinga; Noordam Cees; van den Heuvel Lambert P; Nillesen Willy M; Hollody Katalin; Gillessen Kae**ach Gabrielle; Lammens Martin; Smeitink Jan A M; van der Burgt Ineke; Morava Eva^*

来源：European Journal of Human Genetics, 2011, 19(2): 138-144.

DOI：10.1038/ejhg.2010.171

• Cardio-Facio-Cutaneous syndrome
• HRAS
• PTPN11
• mitochondrial encephalomyopathy
• 3-methylglutaconic aciduria
• ethylmalonic aciduria

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. European Journal of Human Genetics (2011) 19, 138-144; doi:10.1038/ejhg.2010.171; published online 10 November 2010

• 出版日期2011-2