BACKGROUND:Limited data exist on long-term outcomes associated with postural orthostatic tachycardia syndrome (POTS). We designed an online questionnaire to assess outcomes for patients formerly managed in a single-center pediatric POTS program. Here, we report the educational, economic, and social long-term impacts of pediatric POTS. METHODS:In part, the Long-Term POTS Outcomes Survey (LT-POTS) sought to evaluate education, employment, and social impact of POTS. Patients aged ≤18 years at the time of POTS diagnosis were included. The survey was emailed to patients diagnosed or managed in the Children's Hospital of Philadelphia POTS Program. RESULTS:Of 862 patients surveyed, 227 returned questionnaires with enough data for interpretation. Respondents were predominantly women (85%) and White individuals (97%). Half of patients missed >100 days of school, and 20% temporarily dropped out of school. More than 90% of patients graduated high school, and <50% graduated college. Only 26% of patients were able to work >40 hours/week, with 35% having reduced hours due to POTS symptoms. Significant loss of income and financial expenditures were associated with POTS. Loss of social relationships and inability to live independently were additional associated social impacts. CONCLUSIONS:POTS is a long-term disorder associated with significant physical disability as well as adverse educational, economic, and social impacts. Although certain accommodations may mitigate the impact of the disease on education and employment, POTS poses significant educational, economic, and socioemotional risks, requiring further understanding of its pathophysiology and optimization of its management to reduce individual and societal impact.

Purpose: Single large-scale mtDNA deletions (SLSMD) result in single large-scale deletion syndromes (SLSMDS). SLSMDS presentations have classically been recognized to encompass at least 3 distinct clinical phenotypes: Pearson syndrome (PS), Kearns-Sayre syndrome (KSS), and chronic progressive ophthalmoplegia. Methods: A facilitated review of electronic medical records, manual charts, and Research Electronic Data Capture research databases was performed to complete a retrospective natural history study of 30 participants with SLSMDS in a single health system between 2002 and 2020. The evaluated characteristics included genetic and clinical laboratory test values, growth parameters, signs and symptoms, demographics, and patient-reported outcome measures of fatigue, quality of life, and overall function. Results: Detailed cohort characterization highlighted that a recurrent deleted region involving MT-ND5 (HGNC:7641) occurs in 96% of participants with SLSMDS regardless of the clinical phenotype, which tends to evolve over time. Higher blood heteroplasmy correlated with an earlier age of onset. Growth differentiation factor 15 levels were elevated in all participants with SLSMDS. A history of PS was associated with poor survival prognosis. Furthermore, increased fatigue and decreased quality of life have been reported in patients with SLSMD with advanced age. Conclusion: A retrospective natural history study of patients with SLSMDS demonstrated the evolution of classically considered PS, Kearns-Sayre syndrome, and chronic progressive ophthalmoplegia clinical presentations in affected individuals, which may inform future clinical trial developments. (c) 2025 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

ABSTRACT Purpose To describe a novel data integration workflow developed to automate clinical and research electronic health system data integration and harmonization from siloed sources for centralized access, visualization and analysis by clinicians and researchers in an end user-friendly customized analytic platform. Methods A centralized, semi-automated framework provides data provenance and user access to integrated data sources. Data models are implemented leveraging a centralized server (Alteryx) for high-level analytics including scheduling, integration and modeling. A secure Tableau instance hosts end-user visualizations, with minimal software development required. Results MMFP-Tableau, named for its origin in the Mitochondrial Medicine Frontier Program (MMFP) at Children’s Hospital of Philadelphia, facilitates direct access to integrated, highly robust health system datasets. This scalable data solution enables integration of clinical and research parameters with research samples; enhances external biopharma collaborations for clinical trial design, subject recruitment and data tracking; accelerates retrospective clinical cohort data analysis; and improves complex data visualization for clinicians and researchers. Conclusion MMFP-Tableau promotes complex data integration, visibility, and advanced analytic capabilities to facilitate seamless multidisciplinary research, benefitting clinical care and research in rare disease patients and cohorts. This approach represents a generalizable workflow concept readily adaptable to implement across diverse fields of medicine

Purpose. Optimizing individualized clinical care in heterogeneous rare disorders, such as primary mitochondrial disease (PMD), will require gaining more comprehensive and objective understanding of the patient experience by longitudinally tracking quantifiable patient-specific outcomes and integrating subjective data with clinical data to monitor disease progression and targeted therapeutic effects.Methods. Electronic surveys of patient (and caregiver) reported outcome (PRO) measures were administered in REDCap within clinical domains commonly impaired in patients with PMD in the context of their ongoing routine care, including quality of life, fatigue, and functional performance. Descriptive statistics, group comparisons, and inter-measure correlations were used to evaluate system feasibility, utility of PRO results, and consistency across outcome measure domains. Real-time tracking and visualization of longitudinal individual-level and cohort-level data were facilitated by a customized data integration and visualization system, MMFP-Tableau. Results. An efficient PRO electronic capture and analysis system was successfully implemented within a clinically and genetically heterogeneous rare disease clinical population spanning all ages. Preliminary data analyses demonstrated the flexibility of this approach for a range of PROs, as well as the value of selected PRO scales to objectively capture qualitative functional impairment in four key clinical domains. High inter-measure reliability and correlation were observed. Between-group analyses revealed that adults with PMD reported significantly worse quality of life and greater fatigue than did affected children, while PMD patients with nuclear gene disorders reported lower functioning relative to those with an mtDNA gene disorder in several clinical domains.Conclusion. Incorporation of routine electronic data collection, integration, visualization, and analysis of relevant PROs for rare disease patients seen in the clinical setting was demonstrated to be feasible, providing prospective and quantitative data on key clinical domains relevant to the patient experience. Further work is needed to validate specific PROs in diverse PMD patients and cohorts, and to formally evaluate the clinical impact and utility of harnessing integrated data systems to objectively track and integrate quantifiable PROs in the context of rare disease patient clinical care.

Background Limited data exist on long‐term outcomes in individuals with postural orthostatic tachycardia syndrome (POTS). We designed an electronic questionnaire assessing various aspects of outcomes among patients diagnosed and treated in a single‐center pediatric POTS clinical program. Methods and Results The LT‐POTS (Long Term POTS Outcomes Survey) included questions about quality of life, symptoms, therapies, education, employment, and social impact of disease. Patients age≤18 years at POTS diagnosis who were managed in the Children's Hospital of Philadelphia POTS Program were included. A total of 227 patients with POTS responded with sufficient data for interpretation. The mean age of respondents was 21.8±3.5 years. The median age of symptom onset was 13 (interquartile range 11–14) years, with mean 9.6±3.4 years symptom duration. Multiple cardiovascular, neurologic, and gastrointestinal symptoms were reported. Symptom prevalence and severity were worse for female patients, with 99% of patients reporting ongoing symptoms. Quality of life showed moderate function and limitation, with more severe limitations in energy/fatigue and general health. Nearly three quarters of patients had diagnostic delays, and over half were told that their symptoms were “in their head.” Multiple medications were used and were felt to be effective, whereas fewer nonpharmacologic interventions demonstrated efficacy. Nearly 90% of patients required continued nonpharmacologic therapy to control symptoms. Conclusions POTS is a chronic disorder leading to significant disability with a range of multisystem problems. Although symptoms can be modifiable, it rarely spontaneously resolves. Improved understanding of POTS presentation and therapeutic approaches may inform provider education, improve diagnostic success, and help patients self‐advocate for appropriate medical management approaches.

Purpose: Barth syndrome (BTHS; OMIM #302060) is a rare disease characterized by cardiolipin abnormalities and cardiomyopathy, intermittent neutropenia and skeletal myopathy among other defects. Elamipretide is an investigational drug that binds to cardiolipin, resulting in improved membrane stability, cellular respiration, and adenosine triphosphate production. This case report seeks to provide guidance to clinicians for the effective use of elamipretide when managing BTHS patients. Methods: Here, we report an 11-month-old male requiring cardiopulmonary resuscitation and intubation on initial presentation. Echocardiogram showed a dilated left ventricle (LV) with severely diminished systolic LV function. The patient was placed on venoarterial extracorporeal membrane oxygenation (ECMO) due to a low cardiac output state. Within about two weeks of hospitalization, a diagnosis of BTHS was confirmed on rapid exome sequencing; daily elamipretide therapy (5 mg) was initiated. Results: The patient was decannulated from ECMO. Due to failing extubation, a Berlin Heart EXCOR left ventricular assist device (LVAD) was placed on hospital-day 29. Approximately five months later, echocardiogram demonstrated a marked improvement in LVEF (18% to 54%), with cardiac catheterization during pause of LVAD support indicating hemodynamic parameters favorable for LVAD explantation. He underwent successful LVAD explantation and was removed from the cardiac transplant list. The patient was discharged from the hospital and has remained stable on daily elamipretide therapy. Conclusion: In previous studies, elamipretide therapy has demonstrated normalization of mitochondrial function alongside improvement in LV function. Observations made in our case support these findings and emphasize the need for readily available, targeted therapies in BTHS patients.

We sought to prospectively characterize the nutritional status of adults ≥ 19 years (n = 22, 27% males) and children (n = 38, 61% male) with genetically-confirmed primary mitochondrial disease (PMD) to guide development of precision nutritional support strategies to be tested in future clinical trials. We excluded subjects who were exclusively tube-fed. Daily caloric requirements were estimated using World Health Organization (WHO) equations to predict resting energy expenditure (REE) multiplied by an activity factor (AF) based on individual activity levels. We developed a M itoch o ndrial Disease Ac tiv ity F a c tor s (MOTIVATOR) score to encompass the impact of muscle fatigue typical of PMD on physical activity levels. PMD cohort daily diet intake was estimated to be 1,143 ± 104.1 kcal in adults (mean ± SEM, 76.2% of WHO-MOTIVATOR predicted requirement), and 1,114 ± 62.3 kcal in children (86.4% predicted). A total of 11/22 (50%) adults and 18/38 (47.4%) children with PMD consumed ≤ 75% predicted daily Kcal needs. Malnutrition was identified in 16/60 (26.7%) PMD subjects. Increased protein and fat intake correlated with improved muscle strength in those with insufficient daily Kcal intake (≤ 75% predicted); higher protein and fat intake correlated with decreased muscle fatigue; and higher protein, fat, and carbohydrate intake correlated with improved quality of life (QoL). These data demonstrate the frequent occurrence of malnutrition in PMD and emphasize the critical need to devise nutritional interventions to optimize clinical outcomes.

In this retrospective cohort study of 193 consecutive subjects with primary mitochondrial disease (PMD) seen at the Children's Hospital of Philadelphia Mitochondrial Medicine Frontier Program, we assessed prevalence, severity, and time of onset of sensorineural hearing loss (SNHL) for PMD cases with different genetic etiologies. Subjects were grouped by genetic diagnosis: mitochondrial DNA (mtDNA) pathogenic variants, single large-scale mtDNA deletions (SLSMD), or nuclear DNA (nDNA) pathogenic variants. SNHL was audiometrically confirmed in 27% of PMD subjects (20% in mtDNA pathogenic variants, 58% in SLSMD and 25% in nDNA pathogenic variants). SLSMD had the highest odds ratio for SNHL. SNHL onset was post-lingual in 79% of PMD cases, interestingly including all cases with mtDNA pathogenic variants and SLSMD, which was significantly different from PMD cases caused by nDNA pathogenic variants. SNHL onset during school age was predominant in this patient population. Regular audiologic assessment is important for PMD patients, and PMD of mtDNA etiology should be considered as a differential diagnosis in pediatric patients and young adults with post-lingual SNHL onset, particularly in the setting of multi-system clinical involvement. Pathogenic mtDNA variants and SLSMD are less likely etiologies in subjects with congenital, pre-lingual onset SNHL.

Background: Impulsivity and sleep and circadian rhythm disturbance are core features of bipolar spectrum disorders (BSDs) that are antecedents to onset and persist even between mood episodes; their pervasive presence in BSD suggests that they may be particularly relevant to understanding BSD onset and course. Considerable research demonstrates bidirectional associations between impulsivity and sleep disturbance in healthy individuals; thus, it is important to examine how these features interact to impact BSD symptomatology. Methods: Young adults (N = 107, 55% female, M age = 21.82 years) at high risk for developing BSD (based on high self-reported reward sensitivity) or with recent-onset BSD participated in ecological momentary assessment (EMA) to examine relationships between impulsivity, sleep and circadian rhythm alterations, and mood symptoms in everyday life. Impulsivity was measured via self-report/behavioral task, sleep was measured via actigraphy, circadian rhythms were measured via dim light melatonin onset (DLMO) time, and mood symptoms were measured three times daily via self-report. Results: Multi-level modeling revealed that less total sleep time predicted increased next-day mood symptoms. Moreover, DLMO, total sleep time, and sleep onset latency moderated the relationship between impulsivity and EMA-assessed mood symptoms. Fewer minutes of sleep and later DLMO strengthened the positive relationship between impulsivity and mood symptoms. Limitations: Mood symptoms in our sample were mild; future studies should replicate findings in populations with more severe mood symptoms. Conclusions: This multi-method assessment of dynamic relationships revealed novel associations between impulsivity, sleep and circadian rhythm disturbance, and symptoms within individuals at high-risk for or with recent-onset BSD.

Primary mitochondrial diseases (PMD) are genetic disorders with extensive clinical and molecular heterogeneity where therapeutic development efforts have faced multiple challenges. Clinical trial design, outcome measure selection, lack of reliable biomarkers, and deficiencies in long-term natural history data sets remain substantial challenges in the increasingly active PMD therapeutic development space. Developing “FAIR” (findable, accessible, interoperable, reusable) data standards to make data sharable and building a more transparent community data sharing paradigm to access clinical research metadata are the first steps to address these challenges. This collaborative community effort describes the current landscape of PMD clinical research data resources available for sharing, obstacles, and opportunities, including ways to incentivize and encourage data sharing among diverse stakeholders. This work highlights the importance of, and challenges to, developing a unified system that enables clinical research structured data sharing and supports harmonized data deposition standards across clinical consortia and research groups. The goal of these efforts is to improve the efficiency and effectiveness of drug development and improve understanding of the natural history of PMD. This initiative aims to maximize the benefit for PMD patients, research, industry, and other stakeholders while acknowledging challenges related to differing needs and international policies on data privacy, security, management, and oversight.

Cortisol and C-reactive protein (CRP) typically change during total sleep deprivation (TSD) and psychological stress; however, it remains unknown whether these biological markers can differentiate robust individual differences in neurobehavioral performance and self-rated sleepiness resulting from these stressors. Additionally, little is known about cortisol and CRP recovery after TSD. In our study, 32 healthy adults (ages 27–53; mean ± SD, 35.1 ± 7.1 years; 14 females) participated in a highly controlled 5-day experiment in the Human Exploration Research Analog (HERA), a high-fidelity National Aeronautics and Space Administration (NASA) space analog isolation facility, consisting of two baseline nights, 39 h TSD, and two recovery nights. Psychological stress was induced by a modified Trier Social Stress Test (TSST) on the afternoon of TSD. Salivary cortisol and plasma CRP were obtained at six time points, before (pre-study), during [baseline, the morning of TSD (TSD AM), the afternoon of TSD (TSD PM), and recovery], and after (post-study) the experiment. A neurobehavioral test battery, including measures of behavioral attention and cognitive throughput, and a self-report measure of sleepiness, was administered 11 times. Resilient and vulnerable groups were defined by a median split on the average TSD performance or sleepiness score. Low and high pre-study cortisol and CRP were defined by a median split on respective values at pre-study. Cortisol and CRP both changed significantly across the study, with cortisol, but not CRP, increasing during TSD. During recovery, cortisol levels did not return to pre-TSD levels, whereas CRP levels did not differ from baseline. When sex was added as a between-subject factor, the time × sex interaction was significant for cortisol. Resilient and vulnerable groups did not differ in cortisol and CRP, and low and high pre-study cortisol/CRP groups did not differ on performance tasks or self-reported sleepiness. Thus, both cortisol and CRP reliably changed in a normal, healthy population as a result of sleep loss; however, cortisol and CRP were not markers of neurobehavioral resilience to TSD and stress in this study.

Abstract Background ‘Mitochondrial Myopathy’ (MM) refers to genetically‐confirmed Primary Mitochondrial Disease (PMD) that predominantly impairs skeletal muscle function. Validated outcome measures encompassing core MM domains of muscle weakness, muscle fatigue, imbalance, impaired dexterity, and exercise intolerance do not exist. The goal of this study was to validate clinically‐meaningful, quantitative outcome measures specific to MM. Methods This was a single centre study. Objective measures evaluated included hand‐held dynamometry, balance assessments, Nine Hole Peg Test (9HPT), Functional Dexterity Test (FDT), 30 second Sit to Stand (30s STS), and 6‐minute walk test (6MWT). Results were assessed as z‐scores, with < −2 standard deviations considered abnormal. Performance relative to the North Star Ambulatory Assessment (NSAA) of functional mobility was assessed by Pearson's correlation. Results In genetically‐confirmed MM participants [n = 59, mean age 21.6 ± 13.9 (range 7 – 64.6 years), 44.1% male], with nuclear gene aetiologies, n = 18/59, or mitochondrial (mtDNA) aetiologies, n = 41/59, dynamometry measurements demonstrated both proximal [dominant elbow flexion (−2.6 ± 2.1, mean z‐score ± standard deviation, SD), hip flexion (−2.5 ± 2.3), and knee flexion (−2.8 ± 1.3)] and distal muscle weakness [wrist extension (−3.4 ± 1.7), palmar pinch (−2.5 ± 2.8), and ankle dorsiflexion (−2.4 ± 2.5)]. Balance [Tandem Stance (TS) Eyes Open (−3.2 ± 8.8, n = 53) and TS Eyes Closed (−2.6 ± 2.7, n = 52)] and dexterity [FDT (−5.9 ± 6.0, n = 44) and 9HPT (−8.3 ± 11.2, n = 53)] assessments also revealed impairment. Exercise intolerance was confirmed by strength‐based 30s STS test (−2.0 ± 0.8, n = 38) and mobility‐based 6MWT mean z‐score (−2.9 ± 1.3, n = 46) with significant decline in minute distances (slope −0.9, p = 0.03, n = 46). Muscle fatigue was quantified by dynamometry repetitions with strength decrement noted between first and sixth repetitions at dominant elbow flexors (−14.7 ± 2.2%, mean ± standard error, SEM, n = 21). All assessments were incorporated in the MM‐Composite Assessment Tool (MM‐COAST). MM‐COAST composite score for MM participants was 1.3 ± 0.1 (n = 53) with a higher score indicating greater MM disease severity, and correlated to NSAA (r = −0.64, p < 0.0001, n = 52) to indicate clinical meaning. Test–retest reliability of MM‐COAST assessments in an MM subset (n = 14) revealed an intraclass correlation coefficient (ICC) of 0.81 (95% confidence interval: 0.59–0.92) indicating good reliability. Conclusions We have developed and successfully validated a MM‐specific Composite Assessment Tool to quantify the key domains of MM, shown to be abnormal in a Definite MM cohort. MM‐COAST may hold particular utility as a meaningful outcome measure in future MM intervention trials.

There is a need to better understand key factors that impact sleep and circadian function for young adults of differing races and sexes. Sex and race are common factors contributing to disparities in health outcomes; however, the influence of these variables on sleep and circadian patterns for young adults are not well known. Multiple objective and self-report facets of sleep and circadian function were assessed (melatonin onset, actigraphy, and sleep diaries) in an ecological momentary assessment study of 150 emerging adults (M-age=21.8 years; 58.7% female; 56% White, 22.7% Black, 21.3% Other ethnicity) at high or low risk for bipolar spectrum disorder (BSD). Controlling for BSD risk status, sex and race were significant predictors of objective and self-reported sleep and circadian rhythm measures. Males self-reported better sleep efficiency and exhibited later dim light melatonin onset phase than females, whereas females exhibited more actigraphy-measured sleep periods. White participants exhibited more actigraphy-measured total sleep time (TST), better sleep efficiency, and fewer sleep periods, and more self-reported TST and better sleep efficiency than Black participants. Our findings enhance the literature by utilizing robust measurement of sleep and circadian parameters to extend previous findings to a young adult sample at high or low risk for BSD.