Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway.
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.
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Tjitske
T
Kleefstra
Saskia B
SB
Wortmann
Richard J T
RJ
Rodenburg
Ernie M H F
EM
Bongers
Kinga
K
Hadzsiev
Cees
C
Noordam
Lambert P
LP
van den Heuvel
Willy M
WM
Nillesen
Katalin
K
Hollody
Gabrielle
G
Gillessen-Kaesbach
Martin
M
Lammens
Jan A M
JA
Smeitink
Ineke
I
van der Burgt
Eva
E
Morava
D000015:Abnormalities, Multiple / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000293:Adolescent; D056889:Barth Syndrome / Q000235:genetics*; D002675:Child, Preschool; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000473:pathology; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D006330:Heart Defects, Congenital / Q000235:genetics / Q000473:pathology; D006801:Humans; D007223:Infant; D044542:LEOPARD Syndrome / Q000235:genetics / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008875:Middle Aged; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics* / Q000473:pathology; D054069:Multiple Acyl Coenzyme A Dehydrogenase Deficiency / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012868:Skin Abnormalities / Q000235:genetics / Q000473:pathology; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
D004272:DNA, Mitochondrial; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins