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Kenneson et al. J Transl Genet Genom 2024;8:285-97 https://dx.doi.org/10.20517/jtgg.2024.22 Page 295

disciplines could lead to a more holistic understanding of the affected individual’s condition and multiple
facets of the disease.

Strengths and limitations
One of the strengths of this study was including a relatively large sample size for an ultra-rare disease,
accounting for approximately one-third of the known BTHS patients globally. In addition, many of the
registry participants completed surveys multiple times, as often as yearly, resulting in longitudinal data. To
our knowledge, this is the first study that reported on the diagnostic odyssey, medical provider utilization in
BTHS, and manifestations across various age groups, including older adults. There are also several caveats
to consider. Limitations include biases associated with retrospectively collected self- or caregiver-reported
data, and the fact that follow-up intervals across participants may not have been equal. That is, not all
participants completed the surveys each year, so some participants are represented to a greater extent in the
data than others. Ascertainment bias should also be considered, as those with increased severity of
manifestations are more likely to receive a diagnosis or seek medical care. This may lead to potential
mismatches between the registry data and current clinical practice, as the registry cohort may not be fully
representative of all those with BTHS.

Conclusion
Taken together, this study provides valuable insights into the natural history of BTHS. Our findings
corroborate previous work that characterized cardiac manifestations and neutropenia as the most common
clinical presentations in BTHS. Interestingly, we also found that GI and feeding challenges affected over half
of the study population and that fatigue was even more frequent and severe than previously reported. Our
analysis further illustrates the shared manifestations, medications, and healthcare needs reported by affected
individuals and their caregivers. Additionally, we revealed that timely diagnosis remains a challenge,
particularly for less common manifestations. Looking forward, a more detailed analysis of longitudinal data
such as a survival analysis would be useful to study the potential impact of early diagnosis and management
on outcomes, which could support the inclusion of BTHS in newborn screening programs in the future.
Similarly, data from the BRR can be utilized to undertake a more rigorous genotype-phenotype analysis to
determine if there is any correlation between the TAFAZZIN genotype and the corresponding phenotype,
[33]
though previous studies did not identify any correlation . Although there are currently no specific
treatments approved for BTHS, natural history registries like the BRR will further inform unmet needs and
may contribute to the development of emerging therapies including but not limited to small molecules,
enzyme replacement therapy , and gene therapies [41,42] . As progress continues to be made in finding
[40]
treatments for BTHS, the goal of the BRR is to be a meaningful resource for scientists, clinicians, and
affected families alike. In addition to the research findings we have highlighted, we hope that the shared
data will be useful for affected individuals and their families in navigating what to expect in terms of
manifestations experienced, alongside medical and healthcare utilization across the lifespan of BTHS.

DECLARATIONS
Acknowledgments
We would like to thank the affected individuals and their families who participated in the Barth Syndrome
Foundation’s BTHS Registry and Repository. The data that they entered into the registry made this analysis
possible. Special thanks to JW, KB, and RH for their perspectives as BTHS-affected individuals and their
invaluable input in this manuscript. We also thank Chelsea Cole for assistance with data analysis.

Authors’ contributions
The conceptualization of the project and development of the data analysis plan: Kenneson A, Huang Y,
Lontok E