JIMD Rep. 2025 Jul 7;66(4):e70034. doi: 10.1002/jmd2.70034. eCollection 2025 Jul.ABSTRACTBarth syndrome (BTHS) is a rare X-linked recessive disorder characterized by mutations in the TAFAZZIN gene, leading to mitochondrial dysfunction, cardioskeletal myopathy, neutropenia, exercise intolerance, and growth delay. While cardiac transplantation can improve heart function in BTHS patients, the metabolic effects of this procedure remain poorly understood. This study aimed to compare skeletal muscle morphology, substrate metabolism, energetics, and exercise tolerance in individuals with BTHS who had undergone cardiac transplantation (BTHS-T) versus BTHS patients without transplantation (BTHS-noT) and healthy controls. Six (n = 6) BTHS-T participants (3 adolescents, 3 adults) were compared with n = 29 BTHS-noT and n = 28 healthy controls. All participants underwent graded exercise testing, echocardiography, body composition analysis, and clinical metabolism studies, including 31P-MRS to assess mitochondrial energetics. No significant differences were observed in fat-free mass between BTHS-T participants and BTHS-noT. Exercise capacity (V̇O2peak) was significantly lower in both BTHS groups compared to controls, with lower heart rate responses during peak exercise. In addition, plasma lactate was higher in both BTHS groups compared to healthy controls. Skeletal muscle energetics showed slower phosphocreatine recovery and reduced ATP production in BTHS participants, regardless of cardiac transplantation status. Findings suggest while cardiac transplantation in BTHS may improve heart function, it may not normalize skeletal muscle mass and energetics, metabolic abnormalities, and exercise intolerance. The study enhances our understanding of long-term metabolic consequences of BTHS and potential limitations of cardiac transplantation in ameliorating these dysfunctions. Further research is needed to explore targeted therapies to address underlying metabolic abnormalities in BTHS patients.PMID:40626056 | PMC:PMC12230623 | DOI:10.1002/jmd2.70034