Survival and Clinical Progression in Barth Syndrome: Insights From the Barth Syndrome Foundation's Database of 502 Affected Individuals.

Barth syndrome (BTHS; OMIM 302060) is an ultra-rare, life-limiting genetic disorder characterized by cardiomyopathy, skeletal muscle myopathy, neutropenia, gastrointestinal issues, and fatigue. Formal analyses of survival and clinical progression remain limited. Barth Syndrome Foundation has maintained an intake database (n = 502), representing > 80% of the known global population, as well as a patient-inputted registry for a subset of individuals (n = 162) with up to 11 years of longitudinal outcome data. We estimate the survival curve, identify factors associated with mortality, characterize clinical manifestations over time, and evaluate causes of death. Death disproportionately affected young children, with a 59% transplant-free survival rate for those age < 5. The risk of death plateaued between ages 5-25 before rising again. Heart transplantation (HR = 0.316, 95% CI: 0.162-0.619, p < 0.001) and living in a developed country (HR = 0.109, 95% CI: 0.018-0.659, p < 0.05) were associated with reduced risk of death. Clinical manifestations increased with age, with musculoskeletal/fatigue (66%) being most frequent. Top causes of death were cardiac-related complications, with cardiomyopathy/heart failure (51.3%), mostly in young children < 5, and arrhythmia/cardiac arrest (15%). This is the most comprehensive longitudinal assessment of BTHS survival, mortality risk, and clinical manifestation progression. Early childhood is a period of high mortality risk, driven in large part by heart failure. Although risk of death and hospitalizations plateaued between ages 5-25, the clinical burden of BTHS increases throughout the lifespan. Our results may guide clinical care, identify time windows for optimal intervention, and help clinicians better recognize BTHS clinical features.