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

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.

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

“…32 In five children with progeroid skin anomalies and/or syndromal presentation associated with wrinkled skin, a MAPK pathway-related defect has been considered and confirmed. In one patient, a HRAS mutation was found, in two patients BRAF missense mutations were found, already described in association with CL 29 and in two patients the common missense mutation in the SHOC2 gene 33 was confirmed. This led us to a cohort of 26 patients meeting the criteria for suspected autosomal recessive inheritance non-type 1 (see Supplementary Figure 1).…”

“…CL has been recently described in patients with both BRAF and PNTP11 mutations (causing cardiofaciocutaneous syndrome (CFC; MIM 115150) and Noonan syndrome (NS; MIM 163950), respectively, Figure 1a. The typical features diagnostic for the syndromes were not apparent at birth 29 and patients could be Other syndromes with neurological symptoms include, for example, Keutel syndrome, a disorder with hearing loss, cartilaginous ossification and intellectual disability and mild CL (MIM 245150); Sotos syndrome, an overgrowth syndrome with spasticity and developmental delay (MIM 117550); and Cantu syndrome, a syndrome of hypertrichosis, skeletal dysplasia, cardiomyopathy and intellectual disability (MIM 114620). 30 In this article, we evaluate a large cohort of patients suspected with ARCL based on the clinical phenotype and the presence of neurological features.…”

Cardio-Facio-Cutaneous Syndrome: Clinical Features, Diagnosis, and Management Guidelines

“…67 In addition, some preliminary observations have described individuals with CFC with oxidative phosphorylation dysfunction and muscular coenzyme Q10 deficiency. 68,69 Orthopedic conditions in CFC (Table 3) occur with high frequency and cause significant disability, 65 so referral to an orthopedist is recommended at diagnosis. Individuals may have scoliosis and/or kyphosis, pectus excavatum and/ or carinatum, joint hyperextensibility, joint contractures, pes planus, and dysfunctional gait.…”

Co‐occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death

“…To the best of our knowledge, 22 patients with NS with p.Thr42Ala have been reported in literature (Table 1). 12, 13, 15, 17, 21, 25, 26, 27, 28, 29, 30, 31, 32 However, data were limited because of the lack of a detailed description of their clinical features (Table 1). Among these reported patients with NS with p.Thr42Ala mutation in PTPN11 , ASD or atrioventricular canal defect (AVCD) were reported in six patients (Table 1).…”