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. 2011 Feb;19(2):138-44.
doi: 10.1038/ejhg.2010.171. Epub 2010 Nov 10.

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

Tjitske Kleefstra  1 , Saskia B Wortmann, Richard J T Rodenburg, Ernie M H F Bongers, Kinga Hadzsiev, Cees Noordam, Lambert P van den Heuvel, Willy M Nillesen, Katalin Hollody, Gabrielle Gillessen-Kaesbach, Martin Lammens, Jan A M Smeitink, Ineke van der Burgt, Eva Morava
Affiliations

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

Tjitske Kleefstra et al. Eur J Hum Genet. 2011 Feb.

Abstract

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.

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Figures

Figure 1
Figure 1
Clinical images of patient 2 (a, b; aged 3 years), patient 3 (c, d; aged 3 years), patient 4 (f; aged 3.5 years) and patient 5 (g, h; aged 1.5 years). In patient 1 (e; aged 14 years), note multiple lentiges in the clavicular region.
Figure 2
Figure 2
Wrinkled skin of the hands in patients 2 (a), 4 (b) and 5 (c). Wrinkled, loose skin in the nuchal region in patient 3 (d). Note dry, ichthyosiform skin abnormalities in patients 3 (d) and 5 (c). Skin histology in patients 3 and 5 showed no histological alterations of the elastin fibers.
Figure 3
Figure 3
Mild abnormalities on MRI imaging of three patients. Cerebral MRI of patient 3 shows mild white matter changes on T1-weighed images (a; aged 4 years). Cerebral MRI of patient 5 shows delayed myelinization (b; aged 19 months) on T1-weighed images. Cerebral MRI of patients 4 (c; aged 2 years) and 5 (d; aged 15 months) shows hypoplasia of the corpus callosum and frontal atrophy on T2-weighed images.
See this image and copyright information in PMC

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References

    1. Gelb BD, Tartaglia M. Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction. Hum Mol Genet. 2006;15:R220–R226. - PubMed
    1. Sarkozy A, Carta C, Moretti S, et al. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat. 2009;30:695–702. - PMC - PubMed
    1. Morava E, van den Heuvel L, Hol F, et al. Mitochondrial disease criteria: diagnostic applications in children. Neurology. 2006;67:1823–1826. - PubMed
    1. Janssen A J, Trijbels FJ, Sengers RC, et al. Measurement of the energy-generating capacity of human muscle mitochondria: diagnostic procedure and application to human pathology. Clin Chem. 2006;52:860–871. - PubMed
    1. Van der Burgt I, Kupsky W, Stassou S, et al. Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive HRas activation. J Med Genet. 2007;44:459–462. - PMC - PubMed

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