Echocardiographic Variables Predict Outcome in Children, Adolescents, and Adults with Barth Syndrome: A Longitudinal Observational Study

Background Barth Syndrome (BTHS) is an X-linked mitochondrial cardio-skeletal myopathy caused by defects in TAFAZZIN, the gene responsible for the final remodeling step to produce mature cardiolipin. Critical for mitochondrial function, lack of cardiolipin leads to clinical manifestations including cardiomyopathy (typically dilated and/or noncompaction), muscle weakness, fatigue, neutropenia, and growth abnormalities. Cardiac disease primarily drives outcome in BTHS. Natural history data, especially outcomes outside of infancy, are poorly understood. Hypothesis Risk factors predicting outcome of cardiac death or transplant (CD/TX) in BTHS can be identified by systematic longitudinal cardiac evaluation, leading to enhanced screening and potential therapies. Methods Male subjects with BTHS and at least 2 cardiac evaluations (or one evaluation followed by an outcome of death or transplant) were included. Echocardiographic and outcome data were collected at 6 time points from 2002-2018. In addition to baseline and continuous variables to predict CD/TX, analysis of categorical variables included RV or LV noncompaction, RV dysfunction, and restrictive phenotype as potential risk factors. Differences between patients who survived versus those who had CD/TX were assessed. Results Median age at enrollment was 7 years (range: 0.5-22 years; n=44). There was 74.4% transplant-free survival at 15 years from first evaluation with a median time 12 years between first and last evaluation (IQR 9, 17). In the whole cohort, there was no significant change in end-diastolic or end-systolic volume z-scores over time, but there was a significant decline in stroke-volume z-score (p=0.002), FS (p=0.0045), EF (p= 0.0001) and worsening global longitudinal strain (p=0.0035) with advancing age. Excluding 2 infectious deaths, significant differences in changes over time were seen between subjects progressing to CD/TX (n=9) and subjects with transplant-free survival (n=33), including worsening of LV dilation (p=0.021), global longitudinal strain (0.031), FS (p=0.032) and EF (p=0.057) in those with CD/TX outcome compared to relative stability in transplant-free survival. Having 2 or more cardiac risk factors significantly predicted an outcome of CD/TX (p=0.0073). Of baseline variables, only global longitudinal strain was independently associated with progression to CD/TX (p=0.014). Conclusions While most subjects (nearly 75%) did not progress to CD/TX, high risk patients with BTHS can be identified. In addition to progressive LV enlargement and dysfunction, high risk cardiac morphologies may warrant more frequent surveillance and intense therapy. Barth Syndrome (BTHS) is an X-linked mitochondrial cardio-skeletal myopathy caused by defects in TAFAZZIN, the gene responsible for the final remodeling step to produce mature cardiolipin. Critical for mitochondrial function, lack of cardiolipin leads to clinical manifestations including cardiomyopathy (typically dilated and/or noncompaction), muscle weakness, fatigue, neutropenia, and growth abnormalities. Cardiac disease primarily drives outcome in BTHS. Natural history data, especially outcomes outside of infancy, are poorly understood. Risk factors predicting outcome of cardiac death or transplant (CD/TX) in BTHS can be identified by systematic longitudinal cardiac evaluation, leading to enhanced screening and potential therapies. Male subjects with BTHS and at least 2 cardiac evaluations (or one evaluation followed by an outcome of death or transplant) were included. Echocardiographic and outcome data were collected at 6 time points from 2002-2018. In addition to baseline and continuous variables to predict CD/TX, analysis of categorical variables included RV or LV noncompaction, RV dysfunction, and restrictive phenotype as potential risk factors. Differences between patients who survived versus those who had CD/TX were assessed. Median age at enrollment was 7 years (range: 0.5-22 years; n=44). There was 74.4% transplant-free survival at 15 years from first evaluation with a median time 12 years between first and last evaluation (IQR 9, 17). In the whole cohort, there was no significant change in end-diastolic or end-systolic volume z-scores over time, but there was a significant decline in stroke-volume z-score (p=0.002), FS (p=0.0045), EF (p= 0.0001) and worsening global longitudinal strain (p=0.0035) with advancing age. Excluding 2 infectious deaths, significant differences in changes over time were seen between subjects progressing to CD/TX (n=9) and subjects with transplant-free survival (n=33), including worsening of LV dilation (p=0.021), global longitudinal strain (0.031), FS (p=0.032) and EF (p=0.057) in those with CD/TX outcome compared to relative stability in transplant-free survival. Having 2 or more cardiac risk factors significantly predicted an outcome of CD/TX (p=0.0073). Of baseline variables, only global longitudinal strain was independently associated with progression to CD/TX (p=0.014). While most subjects (nearly 75%) did not progress to CD/TX, high risk patients with BTHS can be identified. In addition to progressive LV enlargement and dysfunction, high risk cardiac morphologies may warrant more frequent surveillance and intense therapy.