Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway
until further notice
SourceEuropean Journal of Human Genetics, 19, 2, (2011), pp. 138-44
Article / Letter to editor
Display more detailsDisplay less details
Paediatrics - OUD tm 2017
Laboratory of Genetic, Endocrine and Metabolic Diseases
European Journal of Human Genetics
SubjectDCN 1: Perception and Action; IGMD 3: Genomic disorders and inherited multi-system disorders; IGMD 3: Genomic disorders and inherited multi-system disorders NCMLS 4: Energy and redox metabolism; IGMD 4: Glycostation disorders; IGMD 8: Mitochondrial medicine; IGMD 8: Mitochondrial medicine NCMLS 4: Energy and redox metabolism; IGMD 9: Renal disorder; IGMD 9: Renal disorder NCMLS 4: Energy and redox metabolism; IGMD 9: Renal disorder NCMLS 5: Membrane transport and intracellular motility; NCMLS 6: Genetics and epigenetic pathways of disease DCN 2: Functional Neurogenomics
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.
This item appears in the following Collection(s)
- Academic publications 
- Electronic publications 
- Faculty of Medical Sciences 
Upload full text
Use your RU credentials (u/z-number and password) to log in with SURFconext to upload a file for processing by the repository team.