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Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway
- Source :
- European Journal of Human Genetics, 19, 138-44, European Journal of Human Genetics, 19, 2, pp. 138-44
- Publication Year :
- 2011
-
Abstract
- Contains fulltext : 97118.pdf (Publisher’s version ) (Closed access) 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.
- Subjects :
- Heart Defects, Congenital
Mitochondrial encephalomyopathy
medicine.medical_specialty
Adolescent
Genomic disorders and inherited multi-system disorders Energy and redox metabolism [IGMD 3]
MAP Kinase Signaling System
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Biology
Bioinformatics
DNA, Mitochondrial
LEOPARD Syndrome
Renal disorder Energy and redox metabolism [IGMD 9]
Article
Craniofacial Abnormalities
Proto-Oncogene Proteins p21(ras)
Genomic disorders and inherited multi-system disorders [IGMD 3]
Mitochondrial Encephalomyopathies
Internal medicine
Genetics
medicine
Perception and Action [DCN 1]
Humans
Abnormalities, Multiple
HRAS
Multiple Acyl Coenzyme A Dehydrogenase Deficiency
Inner mitochondrial membrane
Genetics (clinical)
Renal disorder [IGMD 9]
Infant
Mitochondrial medicine Energy and redox metabolism [IGMD 8]
Barth syndrome
Middle Aged
3-Methylglutaconic Aciduria
Glycostation disorders [IGMD 4]
medicine.disease
PTPN11
Renal disorder Membrane transport and intracellular motility [IGMD 9]
Endocrinology
Mitochondrial medicine [IGMD 8]
Child, Preschool
Barth Syndrome
Mutation
Genetics and epigenetic pathways of disease Functional Neurogenomics [NCMLS 6]
Skin Abnormalities
ras Proteins
Female
Subjects
Details
- ISSN :
- 10184813
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- European Journal of Human Genetics
- Accession number :
- edsair.doi.dedup.....23d198fcb1a856576a63dd57f2676fac