Barth syndrome: Natural history in infants and young children

Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder caused by pathogenic variants in TAFAZZIN. It is characterized by cardiomyopathy, neutropenia, growth delay, skeletal myopathy, and developmental concerns. Advances in genetic testing have enabled earlier diagnoses, creating opportunities to better define the natural history of disease in infancy and early childhood. We conducted a longitudinal, observational study of 21 male patients (ages 0-48 months) with genetically confirmed BTHS evaluated at the Barth Syndrome Interdisciplinary Clinic at Kennedy Krieger Institute. Data collected included perinatal history, growth, feeding, cardiac function, hematologic findings, gross motor development, quality of life, and pain assessment. Gross motor skills were assessed via milestone acquisition and the Peabody Developmental Motor Scales (PDMS-2/3). Quality of life was evaluated using the PedsQL™ parent-proxy questionnaire. The most common presenting features were cardiomyopathy (n = 10) and failure to thrive (n = 6), with an average age at diagnosis of 5.5 months, which was significantly earlier than historical cohorts. Eighteen patients developed cardiac dysfunction, 25 % required heart transplantation, and one death occurred due to cardiopulmonary arrest. Feeding difficulties were frequent, with 16 patients affected and 7 requiring gastrostomy tubes. Growth delay was common, though height/weight ratios were often preserved. Neutropenia was present in 19 patients, with variable severity and infection risk. Gross motor development was delayed, particularly for standing and walking, with progressive deficits on PDMS subtests. Quality of life scores indicated substantial impairment, especially in fatigue and general functioning domains. Pain was rarely reported. We conclude that infants and toddlers with BTHS present with significant cardiac, growth, and developmental abnormalities. Earlier diagnosis facilitated by genetic testing allows for earlier intervention and monitoring. These findings highlight the need for proactive cardiac surveillance, nutritional support, and early therapeutic interventions to optimize outcomes, and they provide critical endpoints for future clinical trials in this young age group.