Left ventricular noncompaction (LVNC) and low mitochondrial membrane potential are specific for Barth syndrome

• Published in: Journal of inherited metabolic disease Vol. 36; no. 6; pp. 929 - 937
• Main Authors: Karkucinska-Wieckowska, Agnieszka, Trubicka, Joanna, Werner, Bozena, Kokoszynska, Katarzyna, Pajdowska, Magdalena, Pronicki, Maciej, Czarnowska, Elzbieta, Lebiedzinska, Magdalena, Sykut-Cegielska, Jolanta, Ziolkowska, Lidia, Jaron, Weronika, Dobrzanska, Anna, Ciara, Elzbieta, Wieckowski, Mariusz R., Pronicka, Ewa
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.11.2013; Springer; Blackwell Publishing Ltd
• Subjects: Barth Syndrome - complications; Barth Syndrome - diagnosis; Barth Syndrome - etiology; Barth Syndrome - physiopathology; Biochemistry; Biological and medical sciences; Cardiology. Vascular system; Cells, Cultured; Child; Child, Preschool; Congenital heart diseases. Malformations of the aorta, pulmonary vessels and vena cava; Heart; Human Genetics; Humans; Internal Medicine; Male; Medical genetics; Medical sciences; Medicine; Medicine & Public Health; Membrane Potential, Mitochondrial; Metabolic Diseases; Muscle, Skeletal - pathology; Original; Original Article; Pediatrics; Siblings; Mitochondrial Membrane Potential; Barth Syndrome; Severe Lactic Acidosis; Biotinidase; Endocardial Fibroelastosis; Nutrition; Electrophysiology; Cardiovascular disease; Metabolic diseases; Hemopathy; Left ventricle; Genetic disease; Striated muscle disease; Mitochondria; Barth syndrome; Low; Genetics; Membrane potential; Ventricular non compaction; Congenital cardiopathy
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1007/s10545-013-9584-4

Barth syndrome (BTHS) is an X-linked mitochondrial defect characterised by dilated cardiomyopathy, neutropaenia and 3-methylglutaconic aciduria (3-MGCA). We report on two affected brothers with c.646G > A (p.G216R) TAZ gene mutations. The pathogenicity of the mutation, as indicated by the structure-based functional analyses, was further confirmed by abnormal monolysocardiolipin/cardiolipin ratio in dry blood spots of the patients as well as the occurrence of this mutation in another reported BTHS proband. In both brothers, 2D-echocardiography revealed some features of left ventricular noncompaction (LVNC) despite marked differences in the course of the disease; the eldest child presented with isolated cardiomyopathy from late infancy, whereas the youngest showed severe lactic acidosis without 3-MGCA during the neonatal period. An examination of the patients’ fibroblast cultures revealed that extremely low mitochondrial membrane potentials (mtΔΨ about 50 % of the control value) dominated other unspecific mitochondrial changes detected (respiratory chain dysfunction, abnormal ROS production and depressed antioxidant defense). 1) Our studies confirm generalised mitochondrial dysfunction in the skeletal muscle and the fibroblasts of BTHS patients, especially a severe impairment in the mtΔΨ and the inhibition of complex V activity. It can be hypothesised that impaired mtΔΨ and mitochondrial ATP synthase activity may contribute to episodes of cardiac arrhythmia that occurred unexpectedly in BTHS patients. 2) Severe lactic acidosis without 3-methylglutaconic aciduria in male neonates as well as an asymptomatic mild left ventricular noncompaction may characterise the ranges of natural history of Barth syndrome.