New targets for monitoring and therapy in Barth syndrome

Purpose: Barth syndrome (BTHS), an X-linked disorder caused by defects in TAZ , is the only known single-gene disorder of cardiolipin remodeling. We hypothesized that through analysis of affected individuals, we would gain a better understanding of the range of clinical features and identify targets for monitoring and therapy. Methods: We conducted a multidisciplinary investigation involving 42 patients with BTHS, including echocardiograms, muscle strength testing, functional exercise capacity testing, physical activity assessments, cardiolipin analysis, 3-methylglutaconic acid analysis, and review of genotype data. We analyzed data points to provide a quantitative spectrum of disease characteristics and to identify relationships among phenotype, genotype, and relevant metabolites. Results: Echocardiography revealed considerable variability in cardiac features. By contrast, almost all patients had significantly reduced functional exercise capacity. Multivariate analysis revealed significant relationships between cardiolipin ratio and left ventricular mass and between cardiolipin ratio and functional exercise capacity. We additionally identified genotypes associated with a less severe metabolic and clinical profile. Conclusion: We defined previously unrecognized metabolite/phenotype/genotype relationships, established targets for therapeutic monitoring, and validated avenues for clinical assessment. In addition to providing insight into BTHS, these studies also provide insight into the myriad of multifactorial disorders that converge on the cardiolipin pathway. Genet Med 18 10, 1001–1010.