Bridging the clinical-research gap: Harnessing an electronic data capture, integration, and visualization platform to systematically assess prospective patient-reported outcomes in mitochondrial 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.

Early developmental delay in Leigh syndrome spectrum disorders is associated with poor clinical prognosis.

BACKGROUND: Leigh spectrum syndrome (LSS) is a primary mitochondrial disorder characterized by neurodevelopmental regression and metabolic stroke typically in early life. Developmental delay (DD) is known to follow episodes of neurologic regression in LSS, although primary developmental delay (pDD) has been rarely reported. We hypothesized that pDD precedes regression in a broader subset of LSS individuals and may associate with worse long-term educational outcomes. METHODS: From a retrospective cohort, subjects with pathogenic variant(s) in a nuclear or mitochondrial gene associated with LSS and consistent clinical manifestations and neuroradiological findings. Detailed developmental histories and neurologic outcomes were extracted. RESULTS: Of 69 LSS subjects, 47 (68.1%) had a history of pDD and 53 (76.8%) had neurodevelopmental regression. We identified 3 distinct developmental phenotypes: [1] pDD followed by regression (N = 31/69, 44.9%), [2] pDD without subsequent regression (16/69, 23.2%), [3] regression without pDD (N = 22/69, 31.9%). A history of pDD was associated with earlier disease onset (p = 0.0003) and worse educational outcomes (OR 22.14). CONCLUSION: LSS is associated with multiple developmental phenotypes and pDD is associated with negative educational outcomes. pDD occurring prior to neurologic regression suggests that mitochondrial energetics impact developmental trajectories prior to acute metabolic failure and regression, providing an opportunity for earlier diagnosis and/or therapeutic intervention.

Long-Term POTS Outcomes Survey: Diagnosis, Therapy, and Clinical Outcomes.

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.

Optimized Nutrition in Mitochondrial Disease Correlates to Improved Muscle Fatigue, Strength, and Quality of Life.

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 Mitochondrial Disease Activity Factors (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.

Development of a Mitochondrial Myopathy-Composite Assessment Tool.

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.