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Page 286 Kenneson et al. J Transl Genet Genom 2024;8:285-97 https://dx.doi.org/10.20517/jtgg.2024.22

previous year, with cardiologists (97.9%) and hematologists (58.2%) being the most commonly seen specialists.

Conclusion: The data suggest that cardiac disorders are the most common manifestations of BTHS, but also reveal
a high frequency of feeding and GI-related issues that previous reports have not captured. Physician-targeted
education on the lesser-known symptoms and population-based screening for BTHS may aid in timely diagnosis
and improved clinical management.

Keywords: Barth syndrome, natural history, diagnostic odyssey, cardiomyopathy, neutropenia, gastrointestinal,
fatigue

INTRODUCTION
Barth syndrome (BTHS; OMIM 302060) is a complex, multi-system disorder that arises from pathogenic
[1,2]
variants in the gene TAFAZZIN (formerly TAZ; OMIM 300394) . Discovered in 1996 by Bione et al.,
TAFAZZIN is located on the distal portion of Xq28, a locus originally termed the G4.5 gene . As an X-
[3]
[4,5]
linked disorder, BTHS primarily affects males, but female cases have also been reported .
TAFAZZIN is a mitochondrial transacylase that remodels monolysocardiolipin (MLCL) into mature
cardiolipin (CL) . Pathogenic mutations in TAFAZZIN result in aberrant accumulation of MLCL in the
[6]
mitochondrial inner membrane and a reduction in the total abundance and composition of CL molecular
species . Accumulation of MLCL in the inner mitochondrial membrane promotes interactions with
[7]
cytochrome c that cause subsequent peroxidation of phospholipids . Because cardiolipin accounts for up to
[8]
20% of phospholipids in the mitochondrial membrane, the cellular and organismal implications of this
imbalance impact mitochondrial function at a structural and functional level, resulting in aberrant
mitochondrial morphology and impaired metabolism [9-11] . The resulting imbalance of CL (decreased levels)
and MLCL (increased levels) has been leveraged into a highly specific and sensitive mass spectrometry
blood spot assay (MLCL:CL ratio) to diagnose individuals affected by BTHS .
[12]

The cardinal manifestations of BTHS of cardiomyopathy, skeletal myopathy, and neutropenia were
comprehensively described in a pedigree published in 1983 by the eponymous Dr. Peter Barth . In
[13]
subsequent case reports of seven patients, Dr. Richard Kelley et al. similarly noted dilated cardiomyopathy,
[14]
growth delay, neutropenia, and 3-methylglutaconic aciduria . Longitudinal clinical and patient registry
research has further broadened the spectrum of BTHS natural history. The cardiomyopathy observed in
BTHS now includes a description of an undulating cardiomyopathy, which may be dilated, hypertrophic,
involve left-ventricular non-compaction (LVNC), or a mixed phenotype . Beyond the burden of cardiac
[15]
manifestations, heart monitoring, and transplantations, patients frequently demonstrate growth and
developmental delays, and report failure to thrive alongside the need for gastrostomy or nasogastric tube
[16]
feedings . In BTHS patients, the pattern of neutropenia was either intermittent and unpredictable, chronic
[17]
and severe, or cyclical with regular oscillations . These reported clinical and survey findings were reflected
in the BTHS Patient-focused Drug Development (PFDD) meeting, wherein these challenges were
contextualized into daily challenges and impact on the quality of life for affected individuals and served as
[18]
guidance for priorities in therapeutic development.

Tracking and treating the multi-system and heterogeneous manifestations of BTHS involves a
multidisciplinary clinical approach . This may include medical, pharmacological, and surgical
[19]
management of cardiac disorders and neutropenia, dietary interventions and feeding aids, and
[20]
rehabilitative, educational, and psychological services . Thus, individuals with BTHS may require visits
with cardiologists, hematologists, metabolic specialists, endocrinologists, neurologists, geneticists,