The diagnostic odyssey, clinical burden, and natural history of Barth syndrome: an analysis of patient registry data

Barth syndrome registry and repository

The Barth Syndrome Registry and Repository (BRR)^[22], which is maintained by the BSF, stores detailed information about individuals diagnosed with BTHS, and was developed in conjunction with clinicians with expertise in the disease. The BRR acts as a platform to amass data about the natural history of BTHS. Individuals diagnosed with BTHS or their caregivers (if the affected individual is under 18 years of age or unable to provide consent) can participate by enrolling at the BRR website (http://barthsyndromeregistry.org). After providing consent or assent to participate, participants are asked to complete several surveys that focus on basic demographic information, medical history, heart transplant status, quality of life (fatigue), and other clinical information. Participants are requested to complete the clinical, heart transplant, and quality of life surveys annually. The self- and/or caregiver-reported data are entered into a secure password-protected, web-based database via the Invitae Patient Insights Network. Institutional Review Board approval of the BRR was obtained from North Star Review Board (IRB #: NB300158).

Participants

Only registry participants with a confirmed genetic test or clinical diagnosis of BTHS were included in this analysis (n = 115). The study population was categorized as probands (n = 90) or other family members. Non-probands (n = 10) were defined as participants who had a relative in the BRR diagnosed at an earlier time, as well as those who reported being diagnosed before manifestations appeared due to an affected relative. For the analysis of manifestations by age, all participants, both living and deceased, were included. However, for the analysis of medication usage by age and the analysis of specialist medical care, only living participants were included. Each individual was included once per age group, and was classified as having the clinical phenotype if they reported having it at any time period within that age group.

Medical history and clinical information

Medical history and clinical information were obtained via self- or caregiver report via a clinical survey. The questions covered the age at which the diagnosis was made, whether there was any family history of BTHS, what specialists the participant visited throughout a 12-month period and the frequency, their clinical manifestations and medications, transplantation status, and significant medical events. Individuals were defined as having a cardiac disorder if they reported cardiomyopathy, cardiac arrest, cardiac failure, or an implantable device.

Fatigue

Fatigue was evaluated via the clinical survey (“Has the participant experienced excessive fatigue in the past 12 months?” or report of a diagnosis of chronic fatigue in the clinical history questions). Additionally, the Patient-Reported Outcomes Measurement Information System Fatigue Short Form 8A (PROMIS-F SF-8A)^[24] was used to assess fatigue more comprehensively. The questionnaire contains 8 items with a 5-point Likert-rating scale (e.g., “Not at all,” “A little bit,” “Somewhat,” “Quite a bit,” “Very much”). Examples of items include: “During the past 7 days, I have trouble starting things because I am tired,” “In the past 7 days, to what degree did your fatigue interfere with your physical functioning?” A summative raw score was computed for each participant and then converted into the corresponding T-score based on the PROMIS scoring tables^[24].

Diagnostic odyssey

Our analysis showed similar results to previous studies of individuals with BTHS, wherein cardiomyopathy began in childhood, with the majority experiencing cardiomyopathy before the age of one year^[16,25]. Analysis of the registry data indicated that diagnostic odysseys were often long, with slightly less than half of participants receiving a diagnosis within one year of onset of manifestation(s). Although a range of diagnostic timespans was seen for all presentations, those who presented with cardiomyopathy/heart failure were the most likely to be diagnosed within one year of onset while those with less common presentations were most likely to have a diagnostic odyssey greater than five years. This stark contrast illustrates the need for further clinical and community awareness of the less prevalent manifestations of BTHS. Physician-targeted educational programs (e.g., continuing medical education courses) regarding early recognition of BTHS and testing of infants with the less prevalent manifestations of feeding challenges and failure to thrive could be helpful in shortening the diagnostic odyssey.

It is currently still unclear whether the time from first manifestation to diagnosis has decreased over the years. Based on the raw data, there appears to be a shift toward faster diagnosis over time. However, patients diagnosed in the earlier decades may represent milder cases, as those surviving to adulthood were more likely to be entered into the registry. This is supported by the observation that a smaller percentage of patients diagnosed in the earlier time period had cardiac manifestation as their first manifestation compared to those born and diagnosed in the later decades. Since it is possible that milder cases may be more difficult to recognize and therefore take longer to diagnose, this may skew the results for the earlier time periods toward longer diagnostic odysseys. In addition, births in 2010-2019 may include children who have not yet been diagnosed, which may skew results for this time period toward shorter diagnostic odysseys. Thus, more studies are needed to assess whether or not the diagnostic journey has shortened over the years.

BTHS is not currently included in newborn screening tests, despite data demonstrating that early BTHS diagnosis is critical for favorable prognosis as mortality is especially high during infancy^[26]. Newborn screening in the United States is guided by the principles defined by Wilson and Jungner in 1968, which includes an acceptable screening test and consensus on how to treat patients with the disorder^[27]. For newborn screening to be conducted ethically without rigorous informed consent of the parents, it is necessary that the test and consequent follow-up offer clinical benefit to the child^[28]. However, in the past few decades, there has been increasing interest in population-based screening for disorders that do not meet the classic criteria, with emphasis on benefits beyond those to the child, such as avoidance of the diagnostic odyssey, provision of reproductive information to the family, and opportunities to study the impact of early treatment^[28,29]. It has been suggested that screening for disorders that do not meet the classic criteria be conducted after the newborn period and with explicit informed consent from the parents in a second tier of screening^[28], and this approach is currently being piloted in a research setting^[30]. As new technology and methods emerge with the potential for early detection of BTHS, adding BTHS to newborn screening panels should be considered.

Clinical manifestations

The prevalence of cardiomyopathy in individuals with BTHS has been reported to be about 90%-95%^[16,31,32]. In the present study, however, the frequency of individuals with BTHS who had a documented cardiac disorder was 80.7%. Three of the individuals in our analysis who did not have a cardiac disorder reported that they were genetically diagnosed after another family member was diagnosed with BTHS and two of the individuals were less than six months old. When these five individuals were excluded, the frequency of cardiac disorders increased to 84.5%, which is still lower than previous reports. Likewise, the frequency of neutropenia/frequent infections in our study (67.2%) is less than previous reports of 84%-86%^[17,31]. Steward et al. analyzed data from individuals who were diagnosed clinically, while Rigaud et al. included individuals who were diagnosed through family-based testing, as in our BRR data^[17,31]. The studies by Rigaud et al. and Kang et al., however, included clinical assessment of individuals, while our study is based on self-report^[31,25]. Lack of clinical assessment, inclusion of individuals diagnosed through family screening, and biases in self-reported data may explain the lower frequency of these manifestations in our analysis.

Because cardiomyopathy is a predominant clinical feature of BTHS, with >70% of affected individuals reporting cardiomyopathy as a manifestation in various reports^{[16,25,31-33]}, cardiologists may be more aware of BTHS than other specialists. In our analysis, cardiac disorders were the most common presenting manifestation for individuals with BTHS but accounted for 57% of individuals with BTHS. The second most common presenting manifestation was feeding difficulty, weight loss, and/or failure to thrive. Furthermore, two-thirds of registry participants reported a GI disorder, the most common being chronic constipation, chronic diarrhea, dysphagia, feeding difficulties, and GERD. The number of patients with chronic constipation or diarrhea is higher than expected based on general population data^[34]. Nutritional challenges and GI disorders in BTHS have not been thoroughly described in most previous natural history reports. In fact, our results support the elevation of nutritional and GI issues as cardinal characteristics of the disorder, as over half of BTHS-affected individuals report experiencing them at some point in life.

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^[35]. As more knowledge is gained on the GI aspects of BTHS, the development of additional 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%)^[17]. We found 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 worsening nature of fatigue in BTHS^[23]. Although early and chronic fatigue is common in disorders of mitochondrial energy metabolism^[36], the subjective impact of fatigue in BTHS is underappreciated. Fatigue 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^[18] and is significantly correlated with impaired health-related quality of life^[38]. 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), which may have significant implications on quality of life^[39]. 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 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, though previous studies did not identify any correlation^[33]. 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^[40], and gene therapies^[41,42]. As progress continues to be made in finding 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.