Cardiofaciocutaneous (CFC) syndrome associated with muscular coenzyme Q₁₀ deficiency

Abstract

The cardiofaciocutaneous (CFC) syndrome is characterized by congenital heart defect, developmental delay, peculiar facial appearance with bitemporal constriction, prominent forehead, downslanting palpebral fissures, curly sparse hair and abnormalities of the skin. CFC syndrome phenotypically overlaps with Noonan and Costello syndromes. Mutations of several genes (PTPN11, HRAS, KRAS, BRAF, MEK1 and MEK2), involved in the mitogen-activated protein kinase (MAPK) pathway, have been identified in CFC-Costello-Noonan patients. Coenzyme Q10 (CoQ10), a lipophilic molecule present in all cell membranes, functions as an electron carrier in the mitochondrial respiratory chain, where it transports electrons from complexes I and II to complex III. CoQ10 deficiency is a rare treatable mitochondrial disorder with various neurological (cerebellar ataxia, myopathy, epilepsy, mental retardation) and extraneurological (cardiomyopathy, nephropathy) signs that are responsive to CoQ10 supplementation. We report the case of a 4-year-old girl who presented a CFC syndrome, confirmed by the presence of a pathogenic R257Q BRAF gene mutation, together with a muscular CoQ10 deficiency. Her psychomotor development was severely impaired, hindered by muscular hypotonia and ataxia, both improving remarkably after CoQ10 treatment. This case suggests that there is a functional connection between the MAPK pathway and the mitochondria. This could be through the phosphorylation of a nuclear receptor essential for CoQ10 biosynthesis. Another hypothesis is that K-Ras, one of the proteins composing the MAPK pathway, might be recruited into the mitochondria to promote apoptosis. This case highlights that CoQ10 might contribute to the pathogenesis of CFC syndrome.

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

“…6 Metabolic abnormalities, comparable to possible mitochondrial dysfunction, were detected in three out of 18 patients. Only one patient who was severely malnourished had an MDC score 46, indicating probable mitochondrial dysfunction.…”

“…Oxidation rates of [U-14 C]malate were measured in the presence of malonate (inhibitor of SDH) to prevent the oxidation of [2,[3][4][5][6][7][8][9][10][11][12][13][14] C]malate to proceed beyond one TCA cycle. ATP production was measured in incubations containing pyruvate, malate, creatine and ADP, in both the absence and presence (blank reaction) of arsenite.…”

“…This suggests a functional connection between the Ras-MAPK pathway and mitochondrial function. 6 Interestingly, the role of mitochondrial DNA (mtDNA) mutations has been implicated before in a patient with NS, carrying not PTPN11 mutations but a heterozygous 3-bp deletion in the beta myosin heavy chain gene associated with seven mtDNA alterations. Unfortunately, familiality and functional assays in that patient were not available.…”

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.…”

Clinical Presentations of Coenzyme Q10 Deficiency Syndrome

“…A single patient with cardiofaciocutaneous syndrome due to a BRAF gene mutation also had CoQ 10 deficiency and improved with CoQ 10 supplementation [Aeby et al, 2007].…”