coenzyme-q10 and Heart-Defects--Congenital

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.

Topics: Abnormalities, Multiple; Child, Preschool; Coenzymes; Craniofacial Abnormalities; Female; Heart Defects, Congenital; Humans; MAP Kinase Signaling System; Mitochondria; Mitochondrial Diseases; Muscle, Skeletal; Skin Abnormalities; Syndrome; Treatment Outcome; Ubiquinone

Adriamycin (2.5-10.0 micrograms) was administered to 4 1/2 and 5 day embryonic chicks (Hamburger-Hamilton developmental stages 24-26) to investigate the effect of the drug on cardiovascular morphogenesis. The drug produced dose-related increases in both mortality rate and malformation frequency with a maximum incidence of 82% cardiovascular anomalies following a dose of 10.0 micrograms/egg (P less than .001 relative to saline controls). Frequencies of embryos with ventricular septal defect (P less than .005), dextroposition of the aorta (P less than .005), or aortic arch anomalies (P less than .05) were significantly higher than among controls. In a second study, embryos were pretreated with ouabain (12.2 micrograms), verapamil (0.5 micrograms), coenzyme Q10 (100 micrograms, 200 micrograms), or vitamin E (1.0 mg, 5.0 mg)--agents previously shown to protect against adriamycin-induced cardiotoxicity. Pretreatment of embryos with ouabain significantly reduced the incidence of cardiovascular malformations induced by adriamycin from 55 to 21% (P less than .05). A major protective effect was observed relative to the induction of ventricular septal defect, the frequency of which was reduced from 45 to 14% (P less than .05). However, administration of verapamil, coenzyme Q10, or vitamin E did not have an appreciable effect on adriamycin-induced frequencies of cardiovascular malformations. Negative inotropism is suggested as a mechanism for adriamycin-induced cardiac anomalies but warrants further study.

Topics: Animals; Chick Embryo; Coenzymes; Dose-Response Relationship, Drug; Doxorubicin; Heart; Heart Defects, Congenital; Morphogenesis; Ouabain; Ubiquinone; Verapamil; Vitamin E