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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. [ABSTRACT FROM AUTHOR]

Congenital cutis laxa is a genetically heterogeneous condition presenting with loose and redundant skin folds, decreased elasticity of the skin, connective tissue involvement and a highly variable spectrum of associated features. The most common forms are inherited in an autosomal recessive or dominant fashion. Fibulin 5 and elastin mutations were detected in a limited number of patients, but in most cases the etiology is not known. Based on a previous observation of an abnormal transferrin isoelectric focusing pattern in a patient with cutis laxa indicating an N-glycosylation defect, we performed a screening for disorders of protein glycosylation in unrelated children with cutis laxa syndrome, including a recently developed test for defective O-glycosylation. Here, we describe five patients from consanguineous marriages with a cutis laxa syndrome with skeletal and joint involvement, developmental delay and neurological findings. Three of these five children have an inborn error of glycan biosynthesis affecting the synthesis of both N- and O-linked glycans. Two patients had normal glycosylation patterns. All known causes of secondary glycosylation disorders were excluded in the children. No mutations were found in the FBLN5 gene. In conclusion, we have identified a new combined glycosylation defect with a distinct clinical phenotype. Our results suggest that a combined defect of glycosylation might be a causative factor in congenital cutis laxa. This is the first report where abnormal N- and O-linked glycosylation is implicated in the etiology of cutis laxa syndrome.European Journal of Human Genetics (2005) 13, 414-421. doi:10.1038/sj.ejhg.5201361 Published online 19 January 2005 [ABSTRACT FROM AUTHOR]