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

Eva Morava (1) , Tjitske Kleefstra (1) , Saskia Wortmann (1) , Richard Rodenburg (1) , Ernie Mhf Bongers (1) , Kinga Hadzsiev (1) , Lambert van den Heuvel (1) , Willy M Nillessen (1) , Katalin Hollody (1) , Martin Lammens (1) , Jan Smeitink (1) , Ineke van Der Burgt (1) , Gabriele Gillessen-Kaesbach (1) , Cees Noordam (1)

1 Nijmegen Center for Mitochondrial Disorders at the Department of Pediatrics and the Institute for Genetic and Metabolic Disease (IGMD)

Various syndromes of the Ras-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 the patients severe muscle hypotonia, central nervous system involvement and failure to thrive occur as well. Here 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 re-evaluation of the initial diagnosis. In the five patients, additional to the oxidative phosphorylation disorder, disease causing mutations were detected in the Ras-MAPK pathway. Three of the patients also carried a second, mitochondrial-related genetic alteration which was asymptomatically present in their healthy relatives. Did we miss the correct diagnosis at 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 eighteen 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 subpopulation of patients with Ras-MAPK pathway mutations present 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.

Mots clés: Cardio-Facio-Cutaneous syndrome; HRAS; 3-methylglutaconic aciduria

Eva Morava, Tjitske Kleefstra, Saskia Wortmann, Richard Rodenburg, Ernie Mhf Bongers, et al.. Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway. European Journal of Human Genetics, 2010, ⟨10.1038/ejhg.2010.171⟩. ⟨hal-00591692⟩