Cardiofaciocutaneous (CFC) syndrome associated with muscular coenzyme Q₁₀ deficiency

• Published in: Journal of inherited metabolic disease Vol. 30; no. 5; p. 827
• Main Authors: Aeby, A, Sznajer, Y, Cavé, H, Rebuffat, E, Van Coster, R, Rigal, O, Van Bogaert, P
• Format: Journal Article
• Language: English
• Published: Dordrecht Dordrecht : Springer Netherlands 01.10.2007; Springer Netherlands; Springer; Blackwell Publishing Ltd
• Subjects: Abnormalities, Multiple - enzymology; Biological and medical sciences; Child, Preschool; Coenzymes - deficiency; Coenzymes - therapeutic use; Craniofacial Abnormalities - complications; Craniofacial Abnormalities - enzymology; Female; Heart Defects, Congenital - complications; Heart Defects, Congenital - enzymology; Humans; MAP Kinase Signaling System; Medical genetics; Medical sciences; Metabolic diseases; Mitochondria - enzymology; Mitochondrial Diseases - complications; Mitochondrial Diseases - drug therapy; Mitochondrial Diseases - enzymology; Muscle, Skeletal - enzymology; Skin Abnormalities - complications; Skin Abnormalities - enzymology; Syndrome; Treatment Outcome; Ubiquinone - analogs & derivatives; Ubiquinone - deficiency; Ubiquinone - therapeutic use; Skin disease; Association; Nutrition; Cardio facio cutaneous syndrome; Deficiency; Cardiovascular disease; Genetics; Metabolic diseases; Coenzyme; Genetic disease
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1007/s10545-007-0612-0

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.