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Page 294 Kenneson et al. J Transl Genet Genom 2024;8:285-97 https://dx.doi.org/10.20517/jtgg.2024.22

Moreover, we found that cardiac disorders, neutropenia or frequent infections, and GI manifestations all
decreased in frequency after ~25 years of age. This decrease could be due to increased mortality in
childhood and early adulthood for those with more severe manifestations. Under 20 years of age, cardiac
disorders were the most reported manifestation of BTHS, with neutropenia/frequent infections and GI
disorders being reported with equal frequencies in the older age groups. Thus, GI disorders occur with
similar frequencies and in a similar age profile to cardiac and hematological manifestations. Medication use
for cardiac and neutropenia manifestations largely mirrored the frequency of manifestations across ages. In
contrast, GI manifestations and medication use did not follow this pattern of results, which may be driven
by different clinical care approaches to GI issues, since there is a general lack of knowledge about GI
involvement in relation to BTHS and may represent an area for improved care management. Cardiac- and
neutropenia-related medication use correlated with the frequency of manifestations by age, as expected.
Interestingly, usage of GI medications was less frequent from ages 6-20, although GI disorders were higher
in those age groups. Available from the BSF website is educational material on the management of
diarrhea . As more knowledge is gained on the GI aspects of BTHS, the development of additional
[35]
educational resources with expert input on other GI manifestations may be helpful for the patients and
providers.

Fatigue
Fatigue was reported more frequently in our study (60.9%) than in a previous report (53%) . We found
[17]
that excessive fatigue did not decrease in frequency as individuals aged, suggesting that fatigue is chronic
and persists throughout life. This observation is consistent with prior qualitative reports of the enduring and
[23]
worsening nature of fatigue in BTHS . Although early and chronic fatigue is common in disorders of
mitochondrial energy metabolism , the subjective impact of fatigue in BTHS is underappreciated. Fatigue
[36]
in BTHS is postulated to be intertwined with, but distinct from, skeletal myopathy and muscle weakness .
[37]
Unlike cardiac, neutropenia, and GI manifestations which have medications available for their management
and/or supportive care, supportive measures currently do not exist for fatigue. Despite this lack of available
care, BTHS-affected individuals and families have voiced that fatigue is the manifestation that causes the
most profound impact in their daily lives and is significantly correlated with impaired health-related
[18]
[38]
quality of life . Recent qualitative investigations to better understand fatigue have revealed that it can
manifest in a variety of ways: physically (e.g., muscle soreness, overall weakness, muscle endurance),
cognitively (e.g., slowed thinking, trouble focusing), and psychosocially (e.g., self-care, emotion regulation),
[39]
which may have significant implications on quality of life . Although our results largely echo prior reports
on the high prevalence of fatigue in BTHS, this analysis is the largest cohort analyzed to date. Fatigue in
BTHS is debilitating and remains an unmet need that urgently warrants further research and the
development of appropriate therapies.

Healthcare utilization
In addition to manifestations, we also documented the healthcare utilization of individuals with BTHS. A
variety of medical specialists were involved in managing the care of patients with BTHS. Participants saw,
on average, 3.6 different specialists, with cardiologists and hematologists being the most commonly seen
specialists. Only 28% of participants reported having seen a gastroenterologist in the previous year, despite
the high frequency of individuals who reported GI disorders. However, 59% reported seeing a nutritionist/
dietitian in the previous year, so it is possible that GI manifestations are being addressed by these providers.
The heterogeneity of BTHS and varied specialists involved in the care of patients highlight the need for
interdisciplinary clinics dedicated to BTHS diagnosis and care management. To date, two interdisciplinary
centers of clinical expertise for BTHS exist: one in the United States at the Kennedy Krieger Institute and
the second at the University Hospitals Bristol in the United Kingdom. Our data illustrate the need for
additional centers across the globe that specialize in BTHS. Combining perspectives across different