Clinical Features, Disease Burden and Impact on Quality of Life in Patients with Mitochondrial Encephalomyopathy

Clinical Features, Disease Burden and Impact on Quality of Life in Patients with Mitochondrial Encephalomyopathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical Features, Disease Burden and Impact on Quality of Life in Patients with Mitochondrial Encephalomyopathy John Sieh Dumbuya, Chuan Tian, Lin Deng, Bashir Ahmad, Xiuling Chen, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5916685/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Mitochondrial encephalomyopathy (ME) significantly impacts patient quality of life (QoL) and imposes burdens on caregivers. This study examined disease burden, financial strain, QoL, disability levels, and caregiver burden among patients with ME to identify critical relationships. Methods A cross-sectional study was conducted on ME patients and caregivers at Haikou Affiliated Hospital of Xiangya Medical College, Central South University, utilising validated scales including CHU-9D, PedsQL, PHQ-9, and CBI to evaluate disease burden, QoL, disability, and caregiver burden. Data were analysed using descriptive statistics and correlation coefficients to assess the relationships between these factors. Results A total of 27 patients with ME were identified, with a mean age of 10.14 years, 88.9% of whom were children. The cohort comprised 18 (66.7%) males and 9 (33.3%) females, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and Leigh syndrome were the most common subtypes. Significant correlations were found between QoL scores and caregiver burden, with CHU-9D showing negative correlations with PHQ-9 and CBI and positive correlations with PedsQL and health utility scores. Additionally, 44.4% of patients reported severe financial burdens, and 57.7% of caregivers experienced moderate to severe levels of burden. Conclusion Our findings highlight the complex relationships between financial strain, QoL, and caregiver burden in ME. This underscores the need for comprehensive, patient-centered care and targeted policy interventions to alleviate patient and caregiver burdens. Further research is essential to develop effective support systems and improve overall outcomes. Mitochondrial encephalomyopathy rare diseases caregiver burden financial burden quality of life assessment scales Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Mitochondrial encephalomyopathy (ME) represent a group of inherited disorders arising from mitochondrial or nuclear DNA mutations, resulting in dysfunctions within the mitochondrial respiratory chain. These mutations hinder energy production, particularly in high-energy organs such as the brain, muscles, and heart. Consequently, individuals with ME may experience a range of clinical symptoms, including muscle weakness, seizures, stroke-like episodes, and progressive neurological decline ( 1 , 2 ). The most common subtypes of ME include MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes), MERRF (Myoclonic Epilepsy with Ragged Red Fibers), and Leigh Syndrome. Each subtype is associated with distinct genetic causes and clinical manifestations ( 3 – 5 ). The most commonly identified mutation linked to MELAS is the m.3243A > G mutation in mtDNA. In contrast, Leigh Syndrome is often associated with mutations in both mtDNA (such as ATP6) and nuclear genes (like SURF1) ( 6 – 8 ). These mutations lead to defective oxidative phosphorylation, resulting in energy depletion in tissues with high metabolic demands, particularly affecting the central nervous system and muscles ( 2 ). Despite significant advancements in genetic testing, the clinical presentation of ME remains highly variable, even among individuals with the same genetic mutation. This variability poses challenges for early diagnosis and timely intervention, which are critical for mitigating disease severity and enhancing patient outcomes ( 3 , 9 ). Currently, management strategies emphasise symptom relief through medications and physical therapy ( 7 , 10 , 11 ). ME has profound effects on patients' quality of life (QoL), hindering daily activities due to fatigue, pain, and mobility issues, while cognitive impairments and neurological decline heighten these difficulties ( 12 ). Social isolation and psychological distress, including anxiety and depression, are common due to the illness’s progressive nature ( 13 ). Caregivers, too, endure substantial emotional and financial strain, often leading to burnout that affects family dynamics and diminishes overall QoL ( 14 , 15 ). Despite progress in genetic diagnostics and awareness, ME remains underdiagnosed, partly due to its variable presentation. Insufficient epidemiological data and an unclear disease trajectory make it challenging for clinicians to provide optimal care. Additionally, the specific interplay between financial burdens, perceived disability, and caregiver experiences among families dealing with ME is poorly understood. Financial toxicity and limited access to healthcare resources often exacerbate these financial strains, emphasising the need to understand how socioeconomic factors influence the financial burdens of families facing ME ( 16 , 17 ). The complexity of these interrelationships underscores the necessity of gaining deeper insights into the factors that affect both patients and caregivers in the context of ME. This study aims to examine the genetic and clinical aspects of ME, focusing on the relationship between disease burden, QoL, perceived financial burden, and caregiver burden among patients diagnosed with ME. By examining these factors, we aim to underscore the need for improved diagnostics and support systems, with results that inform policy and clinical practices to better serve patients and their families. Methods Study Design and Population This cross-sectional study focused on pediatric and adult patients diagnosed with mitochondrial encephalomyopathy (ME) as well as their caregivers. Participants were recruited from the Haikou Affiliated Hospital of Xiangya Medical College, Central South University, between January and December 2023. Eligibility was determined based on a confirmed genetic diagnosis of ME, which required specific clinical symptoms affecting the nervous and muscular systems, substantiated by genetic testing. This testing was complemented by clinical evaluations and MRI scans by experienced neurologists and MRI diagnostic specialists utilising the Morava scale to assess the severity of the disease ( 18 ). The study population was further categorised by genetic subtype to investigate correlations between specific mutations, disease severity, quality of life, and caregiver burden. Patients diagnosed with ME forms outside the targeted subtypes or those who opted out of participation were excluded from the research. Only those participants who met the inclusion criteria and completed the survey were included in the final analysis. Ethics This cross-sectional study was conducted in accordance with the Declaration of Helsinki. The Institutional Review Board (IRB) of the Haikou Affiliated Hospital of Xiangya Medical College, Central South University approved the study to ensure compliance with ethical standards. Written informed consent was obtained from all patients or their caregivers. Quality of Life (QoL) Outcome Measures EQ-5D-3L The EQ-5D-3L is a widely used tool for assessing health-related quality of life (HRQoL). It evaluates five key dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression, each with three levels of severity (no problems, some problems, and extreme problems) ( 19 ). These dimensions generate a single index score derived from country-specific value sets, with scores ranging from less than 0 (indicating a health state worse than death) to 1 (representing perfect health). PedsQL The Paediatric Quality of Life Inventory (PedsQL) assesses the health-related quality of life (HRQoL) in children and adolescents. It consists of 23 items that can be self-reported by children or reported by caregivers, grouped into four domains: Physical Functioning (8 items), Emotional Functioning (5 items), Social Functioning (5 items), and School Functioning (5 items) ( 20 ). Responses are rated on a 5-point Likert scale, ranging from 0 (never a problem) to 4 (almost always a problem), and scores are reversed and converted to a 0-100 scale. Higher scores indicate better HRQoL, with summary scores for overall HRQoL, physical health, and psychosocial health. PHQ-9 The Patient Health Questionnaire-9 (PHQ-9) is a self-reported tool for evaluating the severity of depressive symptoms ( 21 , 22 ). It consists of nine questions assessing symptoms experienced over the past two weeks, rated on a 4-point Likert scale (0 = not at all, 1 = several days, 2 = more than half the days, 3 = nearly every day). The total score ranges from 0 to 27, with higher scores indicating more severe depression. Severity is categorised as 0–4 (minimal or none), 5–9 (mild), 10–14 (moderate), 15–19 (moderately severe), and 20–27 (severe depression). CHU-9D The Child Health Utility 9-Dimensional (CHU-9D) tool is designed to assess HRQoL in children and adolescents. It measures nine dimensions: Worried, Sad, Pain, Tired, Annoyed, Schoolwork/homework, Sleep, Daily routine, and Ability to join in activities ( 23 , 24 ). Each item is rated on a 5-point scale, with responses indicating levels of severity, from no problems ( 1 ) to severe problems ( 5 ). These responses are translated into a utility score between 0 and 1, where 0 represents the worst imaginable health state (death), and 1 represents perfect health. CBI The Caregiver Burden Inventory (CBI) evaluates the burden experienced by caregivers of individuals with chronic conditions. It assesses five dimensions of caregiver burden: time-dependence, developmental, physical, social, and emotional ( 25 ). The CBI consists of 24 items, rated on a 5-point Likert scale (0 = not at all descriptive, 4 = very descriptive). Total scores for each dimension range from 0 to 96, with caregiver burden categorised as little or no burden (0–20), mild to moderate burden ( 21 – 40 ), moderate to severe burden (41–60), and severe burden (61–96). OSSS-3 The Oslo Social Support Scale (OSSS-3) is a brief, three-item self-report measure of perceived social support. It assesses the number of close confidants, interest and concern from others, and practical help from neighbours ( 26 ). The total score ranges from 3 to 14, with scores indicating poor social support ( 3 – 8 ), moderate social support ( 9 – 11 ), or strong social support ( 12 – 14 ). Statistical Analysis All participants who satisfied the inclusion criteria were incorporated into the analysis. Categorical variables were reported as counts and percentages, whereas continuous variables were presented as means and standard deviations. Spearman’s correlation coefficient was utilised to evaluate the relationships between continuous variables. The ANOVA test was employed to compare QoL measurements across varying levels of perceived financial burden and disability. All statistical analyses were conducted using IBM SPSS Statistics for Windows, Version 22 (IBM Corp., Armonk, NY, USA), with a significance level set at P < 0.05. Results General Characteristics of Socio-Demographics Table 1 displays key characteristics of 27 patients diagnosed with distinct mitochondrial encephalomyopathy (ME). The average age was 10.14 years (SD 9.24), with the youngest patient being just one month old and the oldest being 36 years old. There were 18 male patients (66.7%) and nine female patients (33.3%), with the majority being children (88.9%). The most identified ME subtypes were MELAS and Leigh syndrome (6 patients each, 22.2%), followed by COXPD1 (5 patients, 18.5%). Additionally, there were two patients each for MERRF, EMPF1, and COQ10D (7.4% each). In terms of age range, 63.0% of the patients (17/27) were 0–9 years old, 25.9% (7/27) were 10–19 years old, 7.4% (2/27) were 20–29 years old, and 3.7% (1/27) were 30–39 years old. Approximately 25.9% of the patients had a family history of ME. Additional details on the number of referrals, outpatient visits, and inpatient visits are available in Table 1. Among the 27 patients, 12 (44.4%) opted for rehabilitation intervention. Of those seeking rehabilitation due to their medical condition, 25.9% required it always and frequently, 11.1% required it sometimes, and 14.8% required it occasionally. For individuals who did not pursue rehabilitation programmes, 33.3% cited high costs, 29.6% found it ineffective, and 14.8% lacked local rehabilitation services or advanced technology (Fig. 1 A, 1 B). A significant 59.3% of patients required full-time care from their families, while 33.3% had to miss work or be absent to care for their patients (Fig. 1 C). Among those who needed care from a family member or friend, 62.9% needed it always, 14.8% needed it frequently, 11.1% needed it sometimes, 3.7% required it occasionally, and 7.4% did not need it (Fig. 1 D). In addition, 16 (59.3%) patients reported experiencing discrimination due to their condition. In comparison, 5 (18.5%) could not tell, and 6 (22.2%) did not report any discrimination (Fig. 1 E). As indicated in Table 1, 24 (88.9%) patients incurred debt due to the high cost of treatment, with 33.3% having 30,000–60,000 CNY debt, 25.9% having 0–30,000 CNY, 25.9% having 100,000-200,000 CNY, and 14.8% having 60,000-100,000 CNY debt. The average diagnostic delay was 1.9 (SD 2.6) years, ranging from 0 to 10.8 years. The diagnostic odyssey took an average of 1.67 (SD 0.83) years to reach a definitive diagnosis. More than half (55.6%) of the patients were diagnosed within a year, 22.2% were diagnosed within 1 to 3 years, and the remaining 22.2% took longer than three years to be diagnosed (Table 1). On average, patients reported 3.48 (SD 2.06) distinct symptoms at the onset of the disease. The most common first reported symptom was motor retardation (25.9%), followed by delayed motor development (22.2%). Other frequently reported symptoms included seizures (14.8%), gastrointestinal dysfunction (11.1%) and headache (11.1%). Symptoms like lung infection (7.4%) and muscle weakness (7.4%) were less commonly the first reported (Fig. 2 A). Thus, muscle-related issues (delayed motor development) dominate as the first signs of disease, suggesting they may serve as early indicators of this condition. Subsequently, seizures (11.4%) and muscle weakness (12.0%) were the most commonly reported symptoms overall. Other prevalent symptoms included mental retardation (10.8%); dysarthria (speech difficulties, 9.0%); malnutrition (7.2%), and delayed motor development (7.2%). Symptoms such as motor retardation (5.9%), gastrointestinal (GI) dysfunction (5.9%), and lung infection (5.4%) were moderately common. Less common symptoms included headache, respiratory symptoms, hearing impairment, and cardiac insufficiency (3.0% or less) (Fig. 2 B). Thus, neuromuscular symptoms (e.g., motor retardation, seizures, muscle weakness) were the most frequently reported overall, emphasising the need to monitor these signs for early diagnosis and management. Phenotype and Genotype Analysis Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) was identified as the most prevalent mitochondrial DNA (mtDNA) disease, accounting for 46.2% of cases within the cohort, Leigh syndrome accounted for 30.8% of individuals, Myoclonic epilepsy with ragged red fibres (MERRF) represented 15.4% of patients, and Leber's hereditary optic neuropathy (LHON) was 7.7% of cases (Fig. 3 A). Among nuclear DNA (nDNA)-related diseases, combined oxidative phosphorylation deficiency (COXPD1), encephalopathy due to defective mitochondrial and peroxisomal fission 1 (EMPF1), and primary coenzyme Q10 deficiency (COQ10D7) were the most frequently encountered, each constituting 14.3% of cases, and were linked to metabolic or mitochondrial dysfunctions. Leigh syndrome’s prominence in nDNA-related diseases highlighted its unique dual classification across both DNA types (Fig. 3 B). In the analysis of mtDNA variants, the m.3243A > G mutation was the most prevalent, evident in 38.5% of cases associated with MELAS and the m.10191T > C variant was 15.4%. Several additional variants accounted for 7.7% each (Fig. 3 C). Concerning nDNA variants, three mutations—c.334A > G, c.370G > A, and c.688G > A—were the most common, each representing 14.3% of cases. Additionally, other variants contributed 7.1% each (Fig. 3 D). mtDNA mutations primarily included point mutations or deletions within mitochondrial genes, whereas nDNA variants presented as point mutations, deletions, or compound variants in nuclear genes (Table 2). Correlation of QoL and caregiver burden The study examined the correlation between quality of life, caregiver burden, and social support among patients and caregivers. The findings revealed that most patients completed various questionnaires such as CHU-9D (n = 13, 48.1%), EQ-5D-3L (n = 12, 44.4%), OSSS-3 (n = 23, 85.2%), PHQ-9 (n = 14, 51.9%), and PedsQL (n = 13, 48.1%), while caregivers completed the CBI (n = 26, 96.3%). The mean scores (SD) for the different scales were as follows: CHU-9D: 8.92 (6.30), EQ-5D-3L: 9.08 (2.43), OSSS-3: 6.43 (1.88), PHQ-9: 5.57 (6.01), CBI: 40.15 (16.73), and PedsQL: 55.03 (26.84) (Table 1). The assessment of health status using the EQ-5D-3L revealed that 41.7% of respondents reported their health as being in the worst state, and 50.0% described their health as moderate. Only a small segment (8.3%) indicated they were in the best health state (Fig. 4 A). This finding suggests that most individuals are facing poor to moderate health, highlighting significant challenges within the population. In terms of depression, assessed through the PHQ-9 scale, a substantial majority (64.3%) reported minimal to no depressive symptoms. However, 14.3% experienced mild or moderate depression. In comparison, 7.1% reported severe depression (Fig. 4 B). These results indicate that, although most respondents exhibit low levels of depression, a significant minority grapples with mild to severe depression due to their health condition. Regarding caregiver burden, evaluated using the Caregiver Burden Inventory (CBI), 57.7% reported experiencing a moderate to severe burden, while 23.1% described their burden as mild to moderate. Only 15.4% felt little to no burden, and 3.8% reported experiencing a severe burden (Fig. 4 C). Furthermore, a significant majority (78.3%) of respondents reported experiencing poor social support, as measured by the OSSS-3 scale. In contrast, 21.7% reported having moderate social support (Fig. 4 D). This suggests that social isolation or inadequate social support is a pressing concern that could exacerbate both health and caregiving challenges. The Spearman’s correlation analysis revealed several significant relationships. The diagnostic delay showed a negative correlation with PHQ-9 total score (rho = -0.492, p < 0.037), CBI total score (rho = -0.370, p < 0.031), developmental burden (rho = -0.420, p < 0.016), physical burden (rho = -0.388, p < 0.032) and level of caregiver burden (rho = -0.410, p < 0.019). Similarly, the number of symptoms correlated negatively with PHQ-9 total score (rho = -0.643, p < 0.007), CBI total score (rho = -0.482, p < 0.006), developmental burden (rho = -0.416, p < 0.017) and physical burden (rho = -0.501, p < 0.005). The CHU-9D demonstrated moderate negative correlations with the PHQ-9 total score (rho = -0.554, p < 0.031), strong negative correlation with the CBI total score (rho = -0.895, p < 0.001), and levels of caregiver burden (rho = -0.935, p < 0.000), time-dependence burden (rho = -0.682, p < 0.005), developmental burden (rho = -0.698, p < 0.004), physical burden (rho = -0.794, p < 0.001), and emotional burden (rho = -0.755, p < 0.001). Additionally, the CHU-9D strongly positively correlated with the PedsQL total score (rho = 0.702, p < 0.004) and its subdomains: physical functioning (rho = 0.524, p < 0.033), emotional functioning (rho = 0.565, p = 0.022), social functioning (rho = 0.666, p < 0.006), school functioning (rho = 0.746, p < 0.011), and psychosocial functioning (rho = 0.736, p < 0.002). It also showed a strong positive correlation with health utility score (rho = 0.857, p < 0.000) and levels of health state (rho = 0.742, p < 0.004). Furthermore, the OSSS-3 total score showed moderate positive correlations with the health utility score (rho = 0.512, p < 0.044) and PedsQL emotional functioning (rho = 0.564, p < 0.022). It also strongly negatively correlated with the level of health state (rho = -0.716, p < 0.004). The PHQ-9 total score exhibited positive correlations with the CBI total score (rho = 0.690, p < 0.005), developmental burden (rho = 0.553, p < 0.025), physical burden (rho = 0.672, p < 0.006), social burden (rho = 0.510, p < 0.038), and level of caregiver burden (rho = 0.700, p < 0.004). It also showed moderate negative correlations with the PedsQL total score (rho = -0.522, p < 0.041), as well as with the subscales of emotional functioning (rho = -0.60, p < 0.007), social functioning (rho = -0.530, p < 0.038), and psychosocial functioning (rho = -0.575, p < 0.025). The CBI total score was negatively correlated with the PedsQL total score (rho = -0.702, p < 0.004) and its subdomains, which include physical function (rho = -0.542, p < 0.028), emotional functioning (rho = -0.599, p < 0.015), social functioning (rho = -0.665, p < 0.007), school functioning (rho = -0.726, p < 0.013), and psychosocial functioning (rho = -0.735, p < 0.002). It was positively correlated with the level of health state (rho = 0.695, p < 0.009) and the level of depression (rho = 0.517, p < 0.035). The PedsQL total score exhibited a positive correlation with health utility score (rho = 0.714, p < 0.007) and a negative correlation with developmental burden (rho = -0.806, p < 0.000), physical burden (rho = -0.699, p < 0.004), emotional burden (rho = -0.663, p < 0.007), and the level of caregiver burden (rho = -0.672, p < 0.006). Correlation of patients’ perceived financial burden and their caregivers Patients were surveyed to assess the impact of their condition on their family's financial well-being. Results indicated that 44.4% (12/27) reported severe perceived financial burden, 29.6% (9/27) reported moderate financial burden, 18.5% (5/27) reported mild financial burden, and 7.4% (2/27) reported relatively low financial burden (Fig. 1 F). The perceived financial burden was found to have a moderate negative correlation with the CHU-9D total score (rho = -0.658, p < 0.007), a moderate negative correlation with the utility health score (rho = -0.566, p < 0.027), and negatively correlated with diagnostic delay (rho = -0.399, p < 0.020). Moreover, the perceived financial burden showed a moderate negative correlation with the PedsQL total scores (rho = -0.555, p < 0.024), as well as with its subdomains: social functioning (rho = -0.504, p < 0.039), school functioning (rho = -0.619, p < 0.038), and psychosocial functioning (rho = -0.555, p < 0.024). On the other hand, perceived financial burden was found to have a positive correlation with disability (rho = 0.339, p < 0.042). The PHQ-9 total score and the level of depression were moderately positively correlated (rho = 0.624, p < 0.009; rho = 0.461, p < 0.048, respectively), as was the CBI total score and the level of caregiver burden (rho = 0.526, p < 0.003, rho = 0.503, p < 0.004, respectively). Further analysis of the CBI revealed that perceived financial burden showed moderate positive correlations with the time-dependence burden (rho = 0.561, p < 0.001), developmental burden (rho = 0.529, p < 0.003), and physical burden (rho = 0.581, p < 0.001). However, no significant correlation was found between social (rho = 0.290, p = 0.075) and emotional (rho = 0.027, p = 0.448) burden (Table 3). The ANOVA analysis revealed significant differences in the perceived financial burden for CHU-9D (F = 8.035, p = 0.006), PedsQL total score (F = 4.588, p = 0.033), and its subdomains such as social functioning (F = 4.423, p = 0.036) and psychosocial functioning (F = 4.701, p = 0.031). Moreover, the CBI total score (F = 7.430, p = 0.001), level of caregiver burden (F = 5.970, p = 0.004), time-dependence burden (F = 11.319, p = 0.000), developmental burden (F = 6.761, p = 0.002), and physical burden (F = 4.980, p = 0.009) all displayed significant differences in perceived financial burden. Correlation of disability and QoL In the study, out of 27 participants, 14 (51.9%) had multiple disabilities, 7 (25.9%) reported having one disability, and 6 (22.2%) had no disabilities (Fig. 4 E). The findings revealed that the presence of a disability had a moderate negative correlation with the CHU-9D scale (rho = -0.643, p < 0.009). Similarly, there was a strong negative correlation between the PedsQL total score (rho = -0.806, p < 0.000) and its subdomains, including physical functioning (rho = -0.769, p < 0.001), emotional functioning (rho = -0.477, p < 0.050), social functioning (rho = -0.813, p < 0.000), school functioning (rho = -0.694, p < 0.019), and psychosocial functioning (rho = -0.827, p < 0.000). The health utility score also demonstrated a moderate negative correlation (rho = -0.629, p < 0.014. Furthermore, the study identified a moderately positive correlation between the CBI total score (rho = 0.476, p < 0.014) and the level of caregiver burden (rho = 0.420, p < 0.016). Additionally, various aspects of caregiver burden, such as time-dependence burden (rho = 0.633, p < 0.000), developmental burden (rho = 0.343, p < 0.043), physical burden (rho = 0.409, p < 0.019), and emotional burden (rho = 0.337, p < 0.046), showed significantly positive correlations with the presence of disability (Table 3). The ANOVA analysis revealed significant differences in the absence or presence of disability for several measures. Precisely, the CBI total score (F = 4.909, p = 0.017), level of caregiver burden (F = 3.452, p = 0.049), and time-dependence burden (F = 7.433, p = 0.003) all showed substantial differences. Similarly, the PedsQL total score (F = 14.931, p = 0.001) and its subdomains - physical functioning (F = 18.481, p = 0.000), social functioning (F = 11.344, p = 0.003), and psychosocial functioning (F = 9.380, p = 0.005) - also demonstrated meaningful distinctions. However, the CHU-9D score did not reach statistical significance (F = 3.862, p = 0.057). Discussion This study presents a thorough analysis of the clinical, disease burden, and quality of life (QoL) dimensions related to mitochondrial encephalomyopathy (ME), emphasising its substantial effect on patients and their caregivers. The findings not only corroborate existing literature but also expand upon it, offering fresh insights into the intricate challenges posed by this rare disorder on patients’ quality of life and caregiver burden. The study cohort was predominantly composed of children, who accounted for 88.9% of participants, with a mean age of 10.14 years. This suggests an early onset of ME ( 27 , 28 ). Notably, common subtypes such as MELAS and Leigh syndrome were identified in 22.2% of the cases, underscoring the necessity for specialised paediatric care ( 7 , 27 , 29 ). While ME typically presents in childhood, participant ages varied from 1 month to 36 years, encompassing adult-onset conditions like Leber's Hereditary Optic Neuropathy (LHON) ( 30 ). The diagnostic delay of approximately 1.9 years underscores a notable gap in the early recognition and intervention of mitochondrial diseases, despite significant advancements in genetic and clinical diagnostics ( 31 ). Participants exhibited a range of symptoms, with the most prevalent being motor retardation (25.9%) and delayed motor development (22.2%). The management of these symptoms had a negative impact on the QoL in both physical and psychosocial domains, consistent with previous research ( 32 , 33 ). The most common mutations in this cohort included the m.3243A > G mutation in MELAS and mutations in both mitochondrial and nuclear genes in patients with Leigh syndrome. The m.3243A > G mutation was associated with an increased incidence of stroke-like episodes, corroborating past reports ( 4 , 34 ). Additionally, patients with MELAS mutations displayed a variable range of symptoms at onset, including fatigue, muscle weakness, and cognitive impairment—frequently noted among MELAS patients ( 2 ). In contrast, patients diagnosed with Leigh syndrome, often resulting from mutations in both mitochondrial and nuclear genes, demonstrated a more pronounced early-onset neurological decline, characterised by severe cognitive impairment and significant motor disabilities. These genetic differences manifested in the patients' functional impairments, as they reported markedly lower scores on QoL assessments, particularly in the physical and psychosocial domains. This aligns with clinical expectations that nuclear mutations typically lead to more severe and early-onset manifestations ( 7 , 35 ). Additionally, approximately 25.9% of patients reported a family history of ME, suggesting a hereditary component, although this figure may not fully account for sporadic mitochondrial mutations. Quality of life (QoL), as assessed through the CHU-9D, EQ-5D-3L and PedsQL instruments, was significantly impaired in all patients with ME, particularly in physical and emotional functioning domains. The mean scores of QoL assessment scales in our cohort were lower than the established standard norm, reflecting a considerable burden of disease ( 36 , 37 ). Strong negative correlations were observed between QoL scores and perceived disability (rho = -0.643, p < 0.009), underscoring how functional limitations adversely affect quality of life. The presence of disability correlated with significantly lower scores on both the CHU-9D and PedsQL assessments, suggesting that genetic factors associated with disability contribute to diminished QoL outcomes. More than half of the patients (51.9%) reported experiencing multiple disabilities, which were linked to lower QoL and increased caregiver burden, consistent with findings from similar studies ( 38 , 39 ). Disability among ME patients was frequently related to reduced mobility, cognitive decline, and fatigue, all of which severely hindered their ability to perform daily activities. Additionally, 59.3% of participants reported experiences of discrimination, while 78.3% indicated a lack of social support, highlighting the social isolation that individuals with rare diseases often endure. The financial burden associated with ME was a significant finding in this study, with 44.4% of patients and their families reporting severe financial stress. This burden is intensified by the high costs of treatment, including rehabilitation and long-term care, which are major contributors to their financial strain. A substantial majority of patients (88.9%) reported incurring debt related to medical expenses, with 33.3% owing between 30,000 and 60,000 CNY and 25.9% facing debt between 100,000 and 200,000 CNY. These financial challenges are consistent with other studies that show how rare diseases place considerable economic pressure on families ( 40 ). Moreover, 59.3% of patients required full-time care, limiting caregivers' ability to maintain employment and attend to their health needs. This finding aligns with existing research that indicates rare diseases often result in significant economic burdens, especially in healthcare systems with insufficient insurance coverage ( 40 , 41 ). Additionally, the financial strain was found to have a negative correlation with QoL scores, particularly in the CHU-9D, PedsQL, and CBI domains, further affecting the well-being of patients and caregivers. The economic burden was strongly correlated with perceived disability (rho = 0.339, p < 0.042) and QoL scores (rho = -0.555, p < 0.024). This suggests that more severe disease leads to more significant financial and emotional strain. Nearly 58% of caregivers reported experiencing moderate to severe burdens. Caregivers reported higher scores in the time-dependence (rho = 0.633, p < 0.000), developmental burden (rho = 0.343, p < 0.043), and emotional burden (rho = 0.337, p < 0.046) domains. These results are consistent with previous studies indicating that caregivers of individuals with rare and severe neurological conditions experience significant emotional and physical strain ( 32 , 33 ). Thus, the inverse correlations between patient-reported outcomes and caregiver burden suggest that addressing caregiver needs is vital for providing holistic care. The need for rehabilitation services was evident, with 44.4% of patients requiring them. Nevertheless, high costs (33.3%) and a lack of local options (14.8%) posed significant barriers to accessing rehabilitation services. The demands of full-time caregiving further strained caregivers, leading to absenteeism and financial hardships. In our study, 57.7% of caregivers reported experiencing moderate to severe burdens, highlighting the physical, emotional, and time-related challenges that come with caregiving for individuals with ME ( 42 , 43 ). These findings emphasise the urgent need for improved access to rehabilitation services and enhanced financial support for affected families. Our findings underscore several actionable recommendations for clinical practice and policy development. First, the early identification of neuromuscular symptoms, especially motor retardation and seizures, should prompt clinicians to suspect mitochondrial dysfunction and refer patients for genetic testing in a timely manner. Second, the financial burden associated with ME calls for the establishment of enhanced insurance frameworks and financial assistance programmes specifically designed for rare diseases. Third, developing comprehensive care models that incorporate genetic counselling, rehabilitation, mental health services, and social support is essential. These models should be informed by interdisciplinary collaborations and a patient-centred approach to adequately meet the diverse needs of ME patients and their families. This study provides valuable insights; however, it is limited by its relatively small sample size and single-centre design, which may restrict the generalizability of the findings. Secondly, using self-reported measures to assess QoL and caregiver burden could introduce subjectivity and bias, as patient and caregiver perceptions may vary based on personal experiences, psychological states, and cultural factors. This could lead to overestimation or underestimation of certain aspects, such as the financial burden or the severity of the disability. Future research should focus on larger, multicentre cohorts to validate these results and examine regional and cultural variations in the management of ME. Additionally, longitudinal studies are necessary to assess disease progression and their impact on quality of life. Nevertheless, our study highlights the significant disease burden and poor quality of life faced by ME patients and their caregivers. Conclusion This study emphasises the intricate clinical, genetic, and psychosocial challenges encountered by patients with mitochondrial encephalomyopathy and their caregivers. Effectively addressing these challenges necessitates a multidisciplinary approach that integrates medical, psychological, and social interventions. By encouraging early diagnosis, enhancing access to care, and implementing targeted policy measures, we can significantly improve the quality of life and outcomes for those affected by this debilitating condition. Abbreviations adPEO: autosomal dominant progressive external ophthalmoplegia; CBI: Caregiver burden inventory; CHU-9D: Child health utility-9 dimension; COQ10D: Primary coenzyme Q10 deficiency; COXPD: Combined oxidative phosphorylation deficiency; ECHSID: Mitochondrial short-chain enoyl-coA hydratase 1 deficiency; EQ-5D-3L: European quality of life 5-dimension 3-level; EMPF1: Encephalopathy due to defective mitochondrial and peroxisomal fission 1; HRQoL: Health-related quality of life; LHON: Leber’s hereditary optic neuropathy; MCIDN2O; Mitochondrial complex 1 deficiency, nuclear type 20; MELAS: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; ME: Mitochondrial encephalomyopathy; MERRF: Myoclonic epilepsy with ragged red fibres; OSSS-3: Oslo social support scale-3; PedsQL: Paediatric quality of life inventory; PHQ-9: Patient health questionnaire-9; QoL: Quality of life Declarations Ethics approval and consent to participate Not applicable Consent for publication Not applicable Availability of data and materials All data are included in the main manuscript. Competing interests Not applicable Funding National Natural Science Foundation of China (82260665) Authors' contributions Conceptualisation: Lu J, Dumbuya JS and Tian C; Methodology: Dumbuya JS, Tian C and Deng L; Validation: Chen L, Ahmad B and Dumbuya JS; Formal Analysis: Dumbuya JS, Tian C and Deng L; Investigation: Deng L, Dumbuya JS and Chen L; Data Curation: Deng L, Ahmad B and Tian C; Writing – Original Draft Preparation: Dumbuya JS, Tian C and Deng L; Writing – Review & Editing: Tian C, Ahmad B, Dumbuya JS and Lu J; Visualisation: Dumbuya JS and Tian C; Supervision: Chen L and Lu J; Funding Acquisition: Lu J. All authors read and approved the final manuscript. Acknowledgements The authors are grateful to the High-Level Scientific Research Startup Funding, Affiliated Hospital of Guangdong Medical University (1057z20230003, 1057z20230042). References DiMauro S, Schon EA. Mitochondrial Respiratory-Chain Diseases. N Engl J Med. 2003 Jun 26;348(26):2656–68. 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Front Public Health. 2022;10:1054931. Zanganeh M, Adab P, Li B, Frew E. An assessment of the construct validity of the Child Health Utility 9D-CHN instrument in school-aged children: evidence from a Chinese trial. Health Qual Life Outcomes. 2021 Aug 26;19(1):205. Greco A, Pancani L, Sala M, Annoni AM, Steca P, Paturzo M, et al. Psychometric characteristics of the caregiver burden inventory in caregivers of adults with heart failure. Eur J Cardiovasc Nurs. 2017 Aug 1;16(6):502–10. Kocalevent RD, Berg L, Beutel ME, Hinz A, Zenger M, Härter M, et al. Social support in the general population: standardization of the Oslo social support scale (OSSS-3). BMC Psychol. 2018 Jul 17;6(1):31. Alves CAPF, Teixeira SR, Martin-Saavedra JS, Guimarães Gonçalves F, Lo Russo F, Muraresku C, et al. Pediatric Leigh Syndrome: Neuroimaging Features and Genetic Correlations. Ann Neurol. 2020 Aug;88(2):218–32. Watson-Fargie T, Marshall V, Fullerton NE, Leach V, Pilz D, Hemingbrough CVY, et al. Leigh syndrome: an adult presentation of a paediatric disease. Pract Neurol. 2024 Jan 23;24(1):45–50. Lee S, Na JH, Lee YM. Epilepsy in Leigh Syndrome With Mitochondrial DNA Mutations. Front Neurol. 2019;10:496. Moura-Coelho N, Pinto Proença R, Tavares Ferreira J, Cunha JP. Late-onset Leber’s hereditary optic neuropathy: the role of environmental factors in hereditary diseases. BMJ Case Rep. 2019 Mar 20;12(3):e227977. Phillips C, Parkinson A, Namsrai T, Chalmers A, Dews C, Gregory D, et al. Time to diagnosis for a rare disease: managing medical uncertainty. A qualitative study. Orphanet J Rare Dis. 2024 Aug 14;19(1):297. Zhao X, Yu M, Zhang W, Hou Y, Yuan Y, Wang Z. Demographic characteristics, diagnostic challenges, treatment patterns, and caregiver burden of mitochondrial diseases: a retrospective cross-sectional study. Orphanet J Rare Dis. 2024 Aug 2;19(1):287. Senger BA, Ward LD, Barbosa-Leiker C, Bindler RC. The Parent Experience of Caring for a Child with Mitochondrial Disease. J Pediatr Nurs. 2016;31(1):32–41. Karicheva OZ, Kolesnikova OA, Schirtz T, Vysokikh MY, Mager-Heckel AM, Lombès A, et al. Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria. Nucleic Acids Res. 2011 Oct;39(18):8173–86. Zhao X, Chen B, Wu L, Zhao G. Role of mitochondria in nuclear DNA damage response. Genome Instab Dis. 2022 Oct 20;3(6):285–94. Long JC, Best S, Hatem S, Theodorou T, Catton T, Murray S, et al. The long and winding road: perspectives of people and parents of children with mitochondrial conditions negotiating management after diagnosis. Orphanet J Rare Dis. 2021 Jul 13;16(1):310. Moretti A, Cianci P, De Paoli A, Meroni F, Tajè S, Mariani M, et al. Burden of care in families of patients with rare genetic diseases: analysis of a large Italian cohort. Eur J Med Genet. 2021 Jul;64(7):104230. Vonneilich N, Lüdecke D, Kofahl C. The impact of care on family and health-related quality of life of parents with chronically ill and disabled children. Disabil Rehabil. 2016 Apr;38(8):761–7. Balbo N, Bolano D. Child disability as a family issue: a study on mothers’ and fathers’ health in Italy. Eur J Public Health. 2024 Feb 5;34(1):79–84. Angelis A, Tordrup D, Kanavos P. Socio-economic burden of rare diseases: A systematic review of cost of illness evidence. Health Policy. 2015 Jul;119(7):964–79. Li J, Jiao C, Nicholas S, Wang J, Chen G, Chang J. Impact of Medical Debt on the Financial Welfare of Middle- and Low-Income Families across China. Int J Environ Res Public Health. 2020 Jun 26;17(12):4597. Hauptman AJ, Augustine EF, Brown HB. The Psychiatric Care of Children and Young Adults With Neurodegenerative Diseases. J Am Acad Child Adolesc Psychiatry. 2024 Feb 8;S0890-8567(24)00060-1. Yang X, Yoo HK, Amin S, Cheng WY, Sundaresan S, Zhang L, et al. Clinical and humanistic burden among pediatric patients with neurofibromatosis type 1 and plexiform neurofibroma in the USA. Childs Nerv Syst ChNS Off J Int Soc Pediatr Neurosurg. 2022 Aug;38(8):1513–22. Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Tables13.docx Table2Geneticvariantsandclinicalfeatures.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5916685","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":408656454,"identity":"5c744c5b-1ce7-4b0a-8dec-791530d20443","order_by":0,"name":"John Sieh Dumbuya","email":"","orcid":"","institution":"Affiliated Hospital of Guangdong Medical University","correspondingAuthor":false,"prefix":"","firstName":"John","middleName":"Sieh","lastName":"Dumbuya","suffix":""},{"id":408656455,"identity":"c9fe0514-c2d0-4c39-898a-487cdddc73ae","order_by":1,"name":"Chuan Tian","email":"","orcid":"","institution":"Affiliated Hospital of Guangdong Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chuan","middleName":"","lastName":"Tian","suffix":""},{"id":408656456,"identity":"18ffbff9-8142-4b65-a499-63f43b6ab045","order_by":2,"name":"Lin Deng","email":"","orcid":"","institution":"The 958 Hospital of the People’s Liberation Army","correspondingAuthor":false,"prefix":"","firstName":"Lin","middleName":"","lastName":"Deng","suffix":""},{"id":408656457,"identity":"b713b1cf-7b94-4615-b9e6-7dff67117af1","order_by":3,"name":"Bashir Ahmad","email":"","orcid":"","institution":"Affiliated Hospital of Guangdong Medical University","correspondingAuthor":false,"prefix":"","firstName":"Bashir","middleName":"","lastName":"Ahmad","suffix":""},{"id":408656458,"identity":"4ec1b43d-bafe-4488-bbd4-d5f2a04fd0da","order_by":4,"name":"Xiuling Chen","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Xiuling","middleName":"","lastName":"Chen","suffix":""},{"id":408656459,"identity":"f185316e-e49a-4d0c-abb4-137a6cf66b82","order_by":5,"name":"Jun Lu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAv0lEQVRIiWNgGAWjYBACPgbG5gcf/9nI8TMzH35AlBY2BuY2wxlsacaS7WxpBkRqYW+Q5mE7lLjhPI+CBHFaJBIbjHl4DjBuPszDYMBQYxNNlJaHcyTuMJsd5j3wgOFYWm4DMVoM3hg8YzM7zJdgwNhwmDgtEjwJh3mMm3kMJIjWIslz4LCEATPRWngethnObEgzkDgMDOQEYvzCz57++MHHBpv6/v7Dhx98qLEhrAUVJJCmfBSMglEwCkYBLgAAmtI9erIc1XcAAAAASUVORK5CYII=","orcid":"","institution":"Affiliated Hospital of Guangdong Medical University","correspondingAuthor":true,"prefix":"","firstName":"Jun","middleName":"","lastName":"Lu","suffix":""}],"badges":[],"createdAt":"2025-01-28 07:08:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5916685/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5916685/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":75189612,"identity":"12670d61-9a51-401c-8cf0-f80d72848c08","added_by":"auto","created_at":"2025-01-31 18:04:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":237247,"visible":true,"origin":"","legend":"\u003cp\u003eRehabilitation status, those who need rehabilitation (A) and reasons for not doing rehabilitation (B); Missed work (C), Needing care from family or friend (D), Discrimination (E) and Perceived financial burden on families (F)\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5916685/v1/f84cb17339858db21fcff64d.png"},{"id":75189616,"identity":"62e992f2-4585-40bf-8a69-dabb8d0ff481","added_by":"auto","created_at":"2025-01-31 18:04:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":196647,"visible":true,"origin":"","legend":"\u003cp\u003eReported symptoms (A) First reported symptoms (B) Most common reported symptoms by patients\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-5916685/v1/6d74e0871d9af5e29e247f4b.png"},{"id":75189614,"identity":"bb1e207c-e12a-4d88-bdeb-568af6c4bc67","added_by":"auto","created_at":"2025-01-31 18:04:06","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":438030,"visible":true,"origin":"","legend":"\u003cp\u003eME disease type and variant (A) Mitochondrial DNA disease (B) Nuclear DNA disease (C) Mitochondrial DNA variant (D) Nuclear DNA variant\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNotes:\u003c/strong\u003e adPEO: autosomal dominant progressive external ophthalmoplegia; COQ10D: Primary coenzyme Q10 deficiency; COXPD: Combined oxidative phosphorylation deficiency; ECHSID: Mitochondrial short-chain enoyl-coA hydratase 1 deficiency; EMPF1: Encephalopathy due to defective mitochondrial and peroxisomal fission 1; LHON: Leber’s hereditary optic neuropathy; MCIDN2O; Mitochondrial complex 1 deficiency, nuclear type 20; MELAS: Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes; ME: Mitochondrial encephalomyopathy; MERRF: Myoclonic epilepsy with ragged red fibres\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-5916685/v1/fb20b104273c193f281e998b.png"},{"id":75189618,"identity":"5f7230a4-7d5a-4108-be2f-d684d6f917a3","added_by":"auto","created_at":"2025-01-31 18:04:07","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":355536,"visible":true,"origin":"","legend":"\u003cp\u003eLevel of health state (A) Level of depression (B) Level of caregiver burden (C) Social support status (D) Disability (E)\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-5916685/v1/5b31ffc3df292908e1592584.png"},{"id":75300951,"identity":"4c856484-835b-495d-b16a-dfa85e58f6b6","added_by":"auto","created_at":"2025-02-03 07:38:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2084857,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5916685/v1/576c6ee2-0ec5-4c8b-b94b-88f8121d21f5.pdf"},{"id":75189609,"identity":"004496e4-0992-42c3-bb11-7b0b4af2c659","added_by":"auto","created_at":"2025-01-31 18:04:06","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17202,"visible":true,"origin":"","legend":"","description":"","filename":"Tables13.docx","url":"https://assets-eu.researchsquare.com/files/rs-5916685/v1/97627c026c88e8edda0a75cf.docx"},{"id":75189617,"identity":"36e2ca37-6deb-4663-919e-fcd03d381a99","added_by":"auto","created_at":"2025-01-31 18:04:06","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":13127,"visible":true,"origin":"","legend":"","description":"","filename":"Table2Geneticvariantsandclinicalfeatures.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5916685/v1/000b417022f7485c4a2cfe97.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical Features, Disease Burden and Impact on Quality of Life in Patients with Mitochondrial Encephalomyopathy","fulltext":[{"header":"Background","content":"\u003cp\u003eMitochondrial encephalomyopathy (ME) represent a group of inherited disorders arising from mitochondrial or nuclear DNA mutations, resulting in dysfunctions within the mitochondrial respiratory chain. These mutations hinder energy production, particularly in high-energy organs such as the brain, muscles, and heart. Consequently, individuals with ME may experience a range of clinical symptoms, including muscle weakness, seizures, stroke-like episodes, and progressive neurological decline (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The most common subtypes of ME include MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes), MERRF (Myoclonic Epilepsy with Ragged Red Fibers), and Leigh Syndrome. Each subtype is associated with distinct genetic causes and clinical manifestations (\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The most commonly identified mutation linked to MELAS is the m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G mutation in mtDNA. In contrast, Leigh Syndrome is often associated with mutations in both mtDNA (such as ATP6) and nuclear genes (like SURF1) (\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). These mutations lead to defective oxidative phosphorylation, resulting in energy depletion in tissues with high metabolic demands, particularly affecting the central nervous system and muscles (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Despite significant advancements in genetic testing, the clinical presentation of ME remains highly variable, even among individuals with the same genetic mutation. This variability poses challenges for early diagnosis and timely intervention, which are critical for mitigating disease severity and enhancing patient outcomes (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Currently, management strategies emphasise symptom relief through medications and physical therapy (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eME has profound effects on patients' quality of life (QoL), hindering daily activities due to fatigue, pain, and mobility issues, while cognitive impairments and neurological decline heighten these difficulties (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Social isolation and psychological distress, including anxiety and depression, are common due to the illness\u0026rsquo;s progressive nature (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Caregivers, too, endure substantial emotional and financial strain, often leading to burnout that affects family dynamics and diminishes overall QoL (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Despite progress in genetic diagnostics and awareness, ME remains underdiagnosed, partly due to its variable presentation. Insufficient epidemiological data and an unclear disease trajectory make it challenging for clinicians to provide optimal care. Additionally, the specific interplay between financial burdens, perceived disability, and caregiver experiences among families dealing with ME is poorly understood. Financial toxicity and limited access to healthcare resources often exacerbate these financial strains, emphasising the need to understand how socioeconomic factors influence the financial burdens of families facing ME (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). The complexity of these interrelationships underscores the necessity of gaining deeper insights into the factors that affect both patients and caregivers in the context of ME.\u003c/p\u003e \u003cp\u003eThis study aims to examine the genetic and clinical aspects of ME, focusing on the relationship between disease burden, QoL, perceived financial burden, and caregiver burden among patients diagnosed with ME. By examining these factors, we aim to underscore the need for improved diagnostics and support systems, with results that inform policy and clinical practices to better serve patients and their families.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Population\u003c/h2\u003e \u003cp\u003e This cross-sectional study focused on pediatric and adult patients diagnosed with mitochondrial encephalomyopathy (ME) as well as their caregivers. Participants were recruited from the Haikou Affiliated Hospital of Xiangya Medical College, Central South University, between January and December 2023. Eligibility was determined based on a confirmed genetic diagnosis of ME, which required specific clinical symptoms affecting the nervous and muscular systems, substantiated by genetic testing. This testing was complemented by clinical evaluations and MRI scans by experienced neurologists and MRI diagnostic specialists utilising the Morava scale to assess the severity of the disease (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). The study population was further categorised by genetic subtype to investigate correlations between specific mutations, disease severity, quality of life, and caregiver burden. Patients diagnosed with ME forms outside the targeted subtypes or those who opted out of participation were excluded from the research. Only those participants who met the inclusion criteria and completed the survey were included in the final analysis.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthics\u003c/h3\u003e\n\u003cp\u003e This cross-sectional study was conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e \u003cp\u003e The Institutional Review Board (IRB) of the Haikou Affiliated Hospital of Xiangya Medical College, Central South University approved the study to ensure compliance with ethical standards. Written informed consent was obtained from all patients or their caregivers.\u003c/p\u003e\n\u003ch3\u003eQuality of Life (QoL) Outcome Measures\u003c/h3\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eEQ-5D-3L\u003c/h2\u003e \u003cp\u003eThe EQ-5D-3L is a widely used tool for assessing health-related quality of life (HRQoL). It evaluates five key dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression, each with three levels of severity (no problems, some problems, and extreme problems) (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). These dimensions generate a single index score derived from country-specific value sets, with scores ranging from less than 0 (indicating a health state worse than death) to 1 (representing perfect health).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePedsQL\u003c/h3\u003e\n\u003cp\u003eThe Paediatric Quality of Life Inventory (PedsQL) assesses the health-related quality of life (HRQoL) in children and adolescents. It consists of 23 items that can be self-reported by children or reported by caregivers, grouped into four domains: Physical Functioning (8 items), Emotional Functioning (5 items), Social Functioning (5 items), and School Functioning (5 items) (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Responses are rated on a 5-point Likert scale, ranging from 0 (never a problem) to 4 (almost always a problem), and scores are reversed and converted to a 0-100 scale. Higher scores indicate better HRQoL, with summary scores for overall HRQoL, physical health, and psychosocial health.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePHQ-9\u003c/h2\u003e \u003cp\u003eThe Patient Health Questionnaire-9 (PHQ-9) is a self-reported tool for evaluating the severity of depressive symptoms (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). It consists of nine questions assessing symptoms experienced over the past two weeks, rated on a 4-point Likert scale (0\u0026thinsp;=\u0026thinsp;not at all, 1\u0026thinsp;=\u0026thinsp;several days, 2\u0026thinsp;=\u0026thinsp;more than half the days, 3\u0026thinsp;=\u0026thinsp;nearly every day). The total score ranges from 0 to 27, with higher scores indicating more severe depression. Severity is categorised as 0\u0026ndash;4 (minimal or none), 5\u0026ndash;9 (mild), 10\u0026ndash;14 (moderate), 15\u0026ndash;19 (moderately severe), and 20\u0026ndash;27 (severe depression).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCHU-9D\u003c/h3\u003e\n\u003cp\u003eThe Child Health Utility 9-Dimensional (CHU-9D) tool is designed to assess HRQoL in children and adolescents. It measures nine dimensions: Worried, Sad, Pain, Tired, Annoyed, Schoolwork/homework, Sleep, Daily routine, and Ability to join in activities (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Each item is rated on a 5-point scale, with responses indicating levels of severity, from no problems (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) to severe problems (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). These responses are translated into a utility score between 0 and 1, where 0 represents the worst imaginable health state (death), and 1 represents perfect health.\u003c/p\u003e\n\u003ch3\u003eCBI\u003c/h3\u003e\n\u003cp\u003eThe Caregiver Burden Inventory (CBI) evaluates the burden experienced by caregivers of individuals with chronic conditions. It assesses five dimensions of caregiver burden: time-dependence, developmental, physical, social, and emotional (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). The CBI consists of 24 items, rated on a 5-point Likert scale (0\u0026thinsp;=\u0026thinsp;not at all descriptive, 4\u0026thinsp;=\u0026thinsp;very descriptive). Total scores for each dimension range from 0 to 96, with caregiver burden categorised as little or no burden (0\u0026ndash;20), mild to moderate burden (\u003cspan additionalcitationids=\"CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e), moderate to severe burden (41\u0026ndash;60), and severe burden (61\u0026ndash;96).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eOSSS-3\u003c/h2\u003e \u003cp\u003eThe Oslo Social Support Scale (OSSS-3) is a brief, three-item self-report measure of perceived social support. It assesses the number of close confidants, interest and concern from others, and practical help from neighbours (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). The total score ranges from 3 to 14, with scores indicating poor social support (\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), moderate social support (\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), or strong social support (\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eAll participants who satisfied the inclusion criteria were incorporated into the analysis. Categorical variables were reported as counts and percentages, whereas continuous variables were presented as means and standard deviations. Spearman\u0026rsquo;s correlation coefficient was utilised to evaluate the relationships between continuous variables. The ANOVA test was employed to compare QoL measurements across varying levels of perceived financial burden and disability. All statistical analyses were conducted using IBM SPSS Statistics for Windows, Version 22 (IBM Corp., Armonk, NY, USA), with a significance level set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eGeneral Characteristics of Socio-Demographics\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;1 displays key characteristics of 27 patients diagnosed with distinct mitochondrial encephalomyopathy (ME). The average age was 10.14 years (SD 9.24), with the youngest patient being just one month old and the oldest being 36 years old. There were 18 male patients (66.7%) and nine female patients (33.3%), with the majority being children (88.9%). The most identified ME subtypes were MELAS and Leigh syndrome (6 patients each, 22.2%), followed by COXPD1 (5 patients, 18.5%). Additionally, there were two patients each for MERRF, EMPF1, and COQ10D (7.4% each). In terms of age range, 63.0% of the patients (17/27) were 0\u0026ndash;9 years old, 25.9% (7/27) were 10\u0026ndash;19 years old, 7.4% (2/27) were 20\u0026ndash;29 years old, and 3.7% (1/27) were 30\u0026ndash;39 years old. Approximately 25.9% of the patients had a family history of ME. Additional details on the number of referrals, outpatient visits, and inpatient visits are available in Table\u0026nbsp;1.\u003c/p\u003e \u003cp\u003eAmong the 27 patients, 12 (44.4%) opted for rehabilitation intervention. Of those seeking rehabilitation due to their medical condition, 25.9% required it always and frequently, 11.1% required it sometimes, and 14.8% required it occasionally. For individuals who did not pursue rehabilitation programmes, 33.3% cited high costs, 29.6% found it ineffective, and 14.8% lacked local rehabilitation services or advanced technology (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA, \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). A significant 59.3% of patients required full-time care from their families, while 33.3% had to miss work or be absent to care for their patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). Among those who needed care from a family member or friend, 62.9% needed it always, 14.8% needed it frequently, 11.1% needed it sometimes, 3.7% required it occasionally, and 7.4% did not need it (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD). In addition, 16 (59.3%) patients reported experiencing discrimination due to their condition. In comparison, 5 (18.5%) could not tell, and 6 (22.2%) did not report any discrimination (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE). As indicated in Table\u0026nbsp;1, 24 (88.9%) patients incurred debt due to the high cost of treatment, with 33.3% having 30,000\u0026ndash;60,000 CNY debt, 25.9% having 0\u0026ndash;30,000 CNY, 25.9% having 100,000-200,000 CNY, and 14.8% having 60,000-100,000 CNY debt.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe average diagnostic delay was 1.9 (SD 2.6) years, ranging from 0 to 10.8 years. The diagnostic odyssey took an average of 1.67 (SD 0.83) years to reach a definitive diagnosis. More than half (55.6%) of the patients were diagnosed within a year, 22.2% were diagnosed within 1 to 3 years, and the remaining 22.2% took longer than three years to be diagnosed (Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eOn average, patients reported 3.48 (SD 2.06) distinct symptoms at the onset of the disease. The most common first reported symptom was motor retardation (25.9%), followed by delayed motor development (22.2%). Other frequently reported symptoms included seizures (14.8%), gastrointestinal dysfunction (11.1%) and headache (11.1%). Symptoms like lung infection (7.4%) and muscle weakness (7.4%) were less commonly the first reported (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Thus, muscle-related issues (delayed motor development) dominate as the first signs of disease, suggesting they may serve as early indicators of this condition. Subsequently, seizures (11.4%) and muscle weakness (12.0%) were the most commonly reported symptoms overall. Other prevalent symptoms included mental retardation (10.8%); dysarthria (speech difficulties, 9.0%); malnutrition (7.2%), and delayed motor development (7.2%). Symptoms such as motor retardation (5.9%), gastrointestinal (GI) dysfunction (5.9%), and lung infection (5.4%) were moderately common. Less common symptoms included headache, respiratory symptoms, hearing impairment, and cardiac insufficiency (3.0% or less) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Thus, neuromuscular symptoms (e.g., motor retardation, seizures, muscle weakness) were the most frequently reported overall, emphasising the need to monitor these signs for early diagnosis and management.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003ePhenotype and Genotype Analysis\u003c/h2\u003e \u003cp\u003eMitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) was identified as the most prevalent mitochondrial DNA (mtDNA) disease, accounting for 46.2% of cases within the cohort, Leigh syndrome accounted for 30.8% of individuals, Myoclonic epilepsy with ragged red fibres (MERRF) represented 15.4% of patients, and Leber's hereditary optic neuropathy (LHON) was 7.7% of cases (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Among nuclear DNA (nDNA)-related diseases, combined oxidative phosphorylation deficiency (COXPD1), encephalopathy due to defective mitochondrial and peroxisomal fission 1 (EMPF1), and primary coenzyme Q10 deficiency (COQ10D7) were the most frequently encountered, each constituting 14.3% of cases, and were linked to metabolic or mitochondrial dysfunctions. Leigh syndrome\u0026rsquo;s prominence in nDNA-related diseases highlighted its unique dual classification across both DNA types (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). In the analysis of mtDNA variants, the m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G mutation was the most prevalent, evident in 38.5% of cases associated with MELAS and the m.10191T\u0026thinsp;\u0026gt;\u0026thinsp;C variant was 15.4%. Several additional variants accounted for 7.7% each (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). Concerning nDNA variants, three mutations\u0026mdash;c.334A\u0026thinsp;\u0026gt;\u0026thinsp;G, c.370G\u0026thinsp;\u0026gt;\u0026thinsp;A, and c.688G\u0026thinsp;\u0026gt;\u0026thinsp;A\u0026mdash;were the most common, each representing 14.3% of cases. Additionally, other variants contributed 7.1% each (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD). mtDNA mutations primarily included point mutations or deletions within mitochondrial genes, whereas nDNA variants presented as point mutations, deletions, or compound variants in nuclear genes (Table\u0026nbsp;2).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation of QoL and caregiver burden\u003c/h2\u003e \u003cp\u003eThe study examined the correlation between quality of life, caregiver burden, and social support among patients and caregivers. The findings revealed that most patients completed various questionnaires such as CHU-9D (n\u0026thinsp;=\u0026thinsp;13, 48.1%), EQ-5D-3L (n\u0026thinsp;=\u0026thinsp;12, 44.4%), OSSS-3 (n\u0026thinsp;=\u0026thinsp;23, 85.2%), PHQ-9 (n\u0026thinsp;=\u0026thinsp;14, 51.9%), and PedsQL (n\u0026thinsp;=\u0026thinsp;13, 48.1%), while caregivers completed the CBI (n\u0026thinsp;=\u0026thinsp;26, 96.3%). The mean scores (SD) for the different scales were as follows: CHU-9D: 8.92 (6.30), EQ-5D-3L: 9.08 (2.43), OSSS-3: 6.43 (1.88), PHQ-9: 5.57 (6.01), CBI: 40.15 (16.73), and PedsQL: 55.03 (26.84) (Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eThe assessment of health status using the EQ-5D-3L revealed that 41.7% of respondents reported their health as being in the worst state, and 50.0% described their health as moderate. Only a small segment (8.3%) indicated they were in the best health state (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA). This finding suggests that most individuals are facing poor to moderate health, highlighting significant challenges within the population. In terms of depression, assessed through the PHQ-9 scale, a substantial majority (64.3%) reported minimal to no depressive symptoms. However, 14.3% experienced mild or moderate depression. In comparison, 7.1% reported severe depression (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB). These results indicate that, although most respondents exhibit low levels of depression, a significant minority grapples with mild to severe depression due to their health condition. Regarding caregiver burden, evaluated using the Caregiver Burden Inventory (CBI), 57.7% reported experiencing a moderate to severe burden, while 23.1% described their burden as mild to moderate. Only 15.4% felt little to no burden, and 3.8% reported experiencing a severe burden (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC). Furthermore, a significant majority (78.3%) of respondents reported experiencing poor social support, as measured by the OSSS-3 scale. In contrast, 21.7% reported having moderate social support (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eD). This suggests that social isolation or inadequate social support is a pressing concern that could exacerbate both health and caregiving challenges.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe Spearman\u0026rsquo;s correlation analysis revealed several significant relationships. The diagnostic delay showed a negative correlation with PHQ-9 total score (rho = -0.492, p\u0026thinsp;\u0026lt;\u0026thinsp;0.037), CBI total score (rho = -0.370, p\u0026thinsp;\u0026lt;\u0026thinsp;0.031), developmental burden (rho = -0.420, p\u0026thinsp;\u0026lt;\u0026thinsp;0.016), physical burden (rho = -0.388, p\u0026thinsp;\u0026lt;\u0026thinsp;0.032) and level of caregiver burden (rho = -0.410, p\u0026thinsp;\u0026lt;\u0026thinsp;0.019). Similarly, the number of symptoms correlated negatively with PHQ-9 total score (rho = -0.643, p\u0026thinsp;\u0026lt;\u0026thinsp;0.007), CBI total score (rho = -0.482, p\u0026thinsp;\u0026lt;\u0026thinsp;0.006), developmental burden (rho = -0.416, p\u0026thinsp;\u0026lt;\u0026thinsp;0.017) and physical burden (rho = -0.501, p\u0026thinsp;\u0026lt;\u0026thinsp;0.005). The CHU-9D demonstrated moderate negative correlations with the PHQ-9 total score (rho = -0.554, p\u0026thinsp;\u0026lt;\u0026thinsp;0.031), strong negative correlation with the CBI total score (rho = -0.895, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and levels of caregiver burden (rho = -0.935, p\u0026thinsp;\u0026lt;\u0026thinsp;0.000), time-dependence burden (rho = -0.682, p\u0026thinsp;\u0026lt;\u0026thinsp;0.005), developmental burden (rho = -0.698, p\u0026thinsp;\u0026lt;\u0026thinsp;0.004), physical burden (rho = -0.794, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and emotional burden (rho = -0.755, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Additionally, the CHU-9D strongly positively correlated with the PedsQL total score (rho\u0026thinsp;=\u0026thinsp;0.702, p\u0026thinsp;\u0026lt;\u0026thinsp;0.004) and its subdomains: physical functioning (rho\u0026thinsp;=\u0026thinsp;0.524, p\u0026thinsp;\u0026lt;\u0026thinsp;0.033), emotional functioning (rho\u0026thinsp;=\u0026thinsp;0.565, p\u0026thinsp;=\u0026thinsp;0.022), social functioning (rho\u0026thinsp;=\u0026thinsp;0.666, p\u0026thinsp;\u0026lt;\u0026thinsp;0.006), school functioning (rho\u0026thinsp;=\u0026thinsp;0.746, p\u0026thinsp;\u0026lt;\u0026thinsp;0.011), and psychosocial functioning (rho\u0026thinsp;=\u0026thinsp;0.736, p\u0026thinsp;\u0026lt;\u0026thinsp;0.002). It also showed a strong positive correlation with health utility score (rho\u0026thinsp;=\u0026thinsp;0.857, p\u0026thinsp;\u0026lt;\u0026thinsp;0.000) and levels of health state (rho\u0026thinsp;=\u0026thinsp;0.742, p\u0026thinsp;\u0026lt;\u0026thinsp;0.004). Furthermore, the OSSS-3 total score showed moderate positive correlations with the health utility score (rho\u0026thinsp;=\u0026thinsp;0.512, p\u0026thinsp;\u0026lt;\u0026thinsp;0.044) and PedsQL emotional functioning (rho\u0026thinsp;=\u0026thinsp;0.564, p\u0026thinsp;\u0026lt;\u0026thinsp;0.022). It also strongly negatively correlated with the level of health state (rho = -0.716, p\u0026thinsp;\u0026lt;\u0026thinsp;0.004).\u003c/p\u003e \u003cp\u003eThe PHQ-9 total score exhibited positive correlations with the CBI total score (rho\u0026thinsp;=\u0026thinsp;0.690, p\u0026thinsp;\u0026lt;\u0026thinsp;0.005), developmental burden (rho\u0026thinsp;=\u0026thinsp;0.553, p\u0026thinsp;\u0026lt;\u0026thinsp;0.025), physical burden (rho\u0026thinsp;=\u0026thinsp;0.672, p\u0026thinsp;\u0026lt;\u0026thinsp;0.006), social burden (rho\u0026thinsp;=\u0026thinsp;0.510, p\u0026thinsp;\u0026lt;\u0026thinsp;0.038), and level of caregiver burden (rho\u0026thinsp;=\u0026thinsp;0.700, p\u0026thinsp;\u0026lt;\u0026thinsp;0.004). It also showed moderate negative correlations with the PedsQL total score (rho = -0.522, p\u0026thinsp;\u0026lt;\u0026thinsp;0.041), as well as with the subscales of emotional functioning (rho = -0.60, p\u0026thinsp;\u0026lt;\u0026thinsp;0.007), social functioning (rho = -0.530, p\u0026thinsp;\u0026lt;\u0026thinsp;0.038), and psychosocial functioning (rho = -0.575, p\u0026thinsp;\u0026lt;\u0026thinsp;0.025). The CBI total score was negatively correlated with the PedsQL total score (rho = -0.702, p\u0026thinsp;\u0026lt;\u0026thinsp;0.004) and its subdomains, which include physical function (rho = -0.542, p\u0026thinsp;\u0026lt;\u0026thinsp;0.028), emotional functioning (rho = -0.599, p\u0026thinsp;\u0026lt;\u0026thinsp;0.015), social functioning (rho = -0.665, p\u0026thinsp;\u0026lt;\u0026thinsp;0.007), school functioning (rho = -0.726, p\u0026thinsp;\u0026lt;\u0026thinsp;0.013), and psychosocial functioning (rho = -0.735, p\u0026thinsp;\u0026lt;\u0026thinsp;0.002). It was positively correlated with the level of health state (rho\u0026thinsp;=\u0026thinsp;0.695, p\u0026thinsp;\u0026lt;\u0026thinsp;0.009) and the level of depression (rho\u0026thinsp;=\u0026thinsp;0.517, p\u0026thinsp;\u0026lt;\u0026thinsp;0.035). The PedsQL total score exhibited a positive correlation with health utility score (rho\u0026thinsp;=\u0026thinsp;0.714, p\u0026thinsp;\u0026lt;\u0026thinsp;0.007) and a negative correlation with developmental burden (rho = -0.806, p\u0026thinsp;\u0026lt;\u0026thinsp;0.000), physical burden (rho = -0.699, p\u0026thinsp;\u0026lt;\u0026thinsp;0.004), emotional burden (rho = -0.663, p\u0026thinsp;\u0026lt;\u0026thinsp;0.007), and the level of caregiver burden (rho = -0.672, p\u0026thinsp;\u0026lt;\u0026thinsp;0.006).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation of patients\u0026rsquo; perceived financial burden and their caregivers\u003c/h2\u003e \u003cp\u003ePatients were surveyed to assess the impact of their condition on their family's financial well-being. Results indicated that 44.4% (12/27) reported severe perceived financial burden, 29.6% (9/27) reported moderate financial burden, 18.5% (5/27) reported mild financial burden, and 7.4% (2/27) reported relatively low financial burden (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF).\u003c/p\u003e \u003cp\u003eThe perceived financial burden was found to have a moderate negative correlation with the CHU-9D total score (rho = -0.658, p\u0026thinsp;\u0026lt;\u0026thinsp;0.007), a moderate negative correlation with the utility health score (rho = -0.566, p\u0026thinsp;\u0026lt;\u0026thinsp;0.027), and negatively correlated with diagnostic delay (rho = -0.399, p\u0026thinsp;\u0026lt;\u0026thinsp;0.020). Moreover, the perceived financial burden showed a moderate negative correlation with the PedsQL total scores (rho = -0.555, p\u0026thinsp;\u0026lt;\u0026thinsp;0.024), as well as with its subdomains: social functioning (rho = -0.504, p\u0026thinsp;\u0026lt;\u0026thinsp;0.039), school functioning (rho = -0.619, p\u0026thinsp;\u0026lt;\u0026thinsp;0.038), and psychosocial functioning (rho = -0.555, p\u0026thinsp;\u0026lt;\u0026thinsp;0.024). On the other hand, perceived financial burden was found to have a positive correlation with disability (rho\u0026thinsp;=\u0026thinsp;0.339, p\u0026thinsp;\u0026lt;\u0026thinsp;0.042). The PHQ-9 total score and the level of depression were moderately positively correlated (rho\u0026thinsp;=\u0026thinsp;0.624, p\u0026thinsp;\u0026lt;\u0026thinsp;0.009; rho\u0026thinsp;=\u0026thinsp;0.461, p\u0026thinsp;\u0026lt;\u0026thinsp;0.048, respectively), as was the CBI total score and the level of caregiver burden (rho\u0026thinsp;=\u0026thinsp;0.526, p\u0026thinsp;\u0026lt;\u0026thinsp;0.003, rho\u0026thinsp;=\u0026thinsp;0.503, p\u0026thinsp;\u0026lt;\u0026thinsp;0.004, respectively). Further analysis of the CBI revealed that perceived financial burden showed moderate positive correlations with the time-dependence burden (rho\u0026thinsp;=\u0026thinsp;0.561, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), developmental burden (rho\u0026thinsp;=\u0026thinsp;0.529, p\u0026thinsp;\u0026lt;\u0026thinsp;0.003), and physical burden (rho\u0026thinsp;=\u0026thinsp;0.581, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, no significant correlation was found between social (rho\u0026thinsp;=\u0026thinsp;0.290, p\u0026thinsp;=\u0026thinsp;0.075) and emotional (rho\u0026thinsp;=\u0026thinsp;0.027, p\u0026thinsp;=\u0026thinsp;0.448) burden (Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003eThe ANOVA analysis revealed significant differences in the perceived financial burden for CHU-9D (F\u0026thinsp;=\u0026thinsp;8.035, p\u0026thinsp;=\u0026thinsp;0.006), PedsQL total score (F\u0026thinsp;=\u0026thinsp;4.588, p\u0026thinsp;=\u0026thinsp;0.033), and its subdomains such as social functioning (F\u0026thinsp;=\u0026thinsp;4.423, p\u0026thinsp;=\u0026thinsp;0.036) and psychosocial functioning (F\u0026thinsp;=\u0026thinsp;4.701, p\u0026thinsp;=\u0026thinsp;0.031). Moreover, the CBI total score (F\u0026thinsp;=\u0026thinsp;7.430, p\u0026thinsp;=\u0026thinsp;0.001), level of caregiver burden (F\u0026thinsp;=\u0026thinsp;5.970, p\u0026thinsp;=\u0026thinsp;0.004), time-dependence burden (F\u0026thinsp;=\u0026thinsp;11.319, p\u0026thinsp;=\u0026thinsp;0.000), developmental burden (F\u0026thinsp;=\u0026thinsp;6.761, p\u0026thinsp;=\u0026thinsp;0.002), and physical burden (F\u0026thinsp;=\u0026thinsp;4.980, p\u0026thinsp;=\u0026thinsp;0.009) all displayed significant differences in perceived financial burden.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation of disability and QoL\u003c/h2\u003e \u003cp\u003eIn the study, out of 27 participants, 14 (51.9%) had multiple disabilities, 7 (25.9%) reported having one disability, and 6 (22.2%) had no disabilities (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eE). The findings revealed that the presence of a disability had a moderate negative correlation with the CHU-9D scale (rho = -0.643, p\u0026thinsp;\u0026lt;\u0026thinsp;0.009). Similarly, there was a strong negative correlation between the PedsQL total score (rho = -0.806, p\u0026thinsp;\u0026lt;\u0026thinsp;0.000) and its subdomains, including physical functioning (rho = -0.769, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), emotional functioning (rho = -0.477, p\u0026thinsp;\u0026lt;\u0026thinsp;0.050), social functioning (rho = -0.813, p\u0026thinsp;\u0026lt;\u0026thinsp;0.000), school functioning (rho = -0.694, p\u0026thinsp;\u0026lt;\u0026thinsp;0.019), and psychosocial functioning (rho = -0.827, p\u0026thinsp;\u0026lt;\u0026thinsp;0.000). The health utility score also demonstrated a moderate negative correlation (rho = -0.629, p\u0026thinsp;\u0026lt;\u0026thinsp;0.014. Furthermore, the study identified a moderately positive correlation between the CBI total score (rho\u0026thinsp;=\u0026thinsp;0.476, p\u0026thinsp;\u0026lt;\u0026thinsp;0.014) and the level of caregiver burden (rho\u0026thinsp;=\u0026thinsp;0.420, p\u0026thinsp;\u0026lt;\u0026thinsp;0.016). Additionally, various aspects of caregiver burden, such as time-dependence burden (rho\u0026thinsp;=\u0026thinsp;0.633, p\u0026thinsp;\u0026lt;\u0026thinsp;0.000), developmental burden (rho\u0026thinsp;=\u0026thinsp;0.343, p\u0026thinsp;\u0026lt;\u0026thinsp;0.043), physical burden (rho\u0026thinsp;=\u0026thinsp;0.409, p\u0026thinsp;\u0026lt;\u0026thinsp;0.019), and emotional burden (rho\u0026thinsp;=\u0026thinsp;0.337, p\u0026thinsp;\u0026lt;\u0026thinsp;0.046), showed significantly positive correlations with the presence of disability (Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003eThe ANOVA analysis revealed significant differences in the absence or presence of disability for several measures. Precisely, the CBI total score (F\u0026thinsp;=\u0026thinsp;4.909, p\u0026thinsp;=\u0026thinsp;0.017), level of caregiver burden (F\u0026thinsp;=\u0026thinsp;3.452, p\u0026thinsp;=\u0026thinsp;0.049), and time-dependence burden (F\u0026thinsp;=\u0026thinsp;7.433, p\u0026thinsp;=\u0026thinsp;0.003) all showed substantial differences. Similarly, the PedsQL total score (F\u0026thinsp;=\u0026thinsp;14.931, p\u0026thinsp;=\u0026thinsp;0.001) and its subdomains - physical functioning (F\u0026thinsp;=\u0026thinsp;18.481, p\u0026thinsp;=\u0026thinsp;0.000), social functioning (F\u0026thinsp;=\u0026thinsp;11.344, p\u0026thinsp;=\u0026thinsp;0.003), and psychosocial functioning (F\u0026thinsp;=\u0026thinsp;9.380, p\u0026thinsp;=\u0026thinsp;0.005) - also demonstrated meaningful distinctions. However, the CHU-9D score did not reach statistical significance (F\u0026thinsp;=\u0026thinsp;3.862, p\u0026thinsp;=\u0026thinsp;0.057).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study presents a thorough analysis of the clinical, disease burden, and quality of life (QoL) dimensions related to mitochondrial encephalomyopathy (ME), emphasising its substantial effect on patients and their caregivers. The findings not only corroborate existing literature but also expand upon it, offering fresh insights into the intricate challenges posed by this rare disorder on patients\u0026rsquo; quality of life and caregiver burden.\u003c/p\u003e \u003cp\u003eThe study cohort was predominantly composed of children, who accounted for 88.9% of participants, with a mean age of 10.14 years. This suggests an early onset of ME (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Notably, common subtypes such as MELAS and Leigh syndrome were identified in 22.2% of the cases, underscoring the necessity for specialised paediatric care (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). While ME typically presents in childhood, participant ages varied from 1 month to 36 years, encompassing adult-onset conditions like Leber's Hereditary Optic Neuropathy (LHON) (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). The diagnostic delay of approximately 1.9 years underscores a notable gap in the early recognition and intervention of mitochondrial diseases, despite significant advancements in genetic and clinical diagnostics (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eParticipants exhibited a range of symptoms, with the most prevalent being motor retardation (25.9%) and delayed motor development (22.2%). The management of these symptoms had a negative impact on the QoL in both physical and psychosocial domains, consistent with previous research (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). The most common mutations in this cohort included the m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G mutation in MELAS and mutations in both mitochondrial and nuclear genes in patients with Leigh syndrome. The m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G mutation was associated with an increased incidence of stroke-like episodes, corroborating past reports (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Additionally, patients with MELAS mutations displayed a variable range of symptoms at onset, including fatigue, muscle weakness, and cognitive impairment\u0026mdash;frequently noted among MELAS patients (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). In contrast, patients diagnosed with Leigh syndrome, often resulting from mutations in both mitochondrial and nuclear genes, demonstrated a more pronounced early-onset neurological decline, characterised by severe cognitive impairment and significant motor disabilities. These genetic differences manifested in the patients' functional impairments, as they reported markedly lower scores on QoL assessments, particularly in the physical and psychosocial domains. This aligns with clinical expectations that nuclear mutations typically lead to more severe and early-onset manifestations (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Additionally, approximately 25.9% of patients reported a family history of ME, suggesting a hereditary component, although this figure may not fully account for sporadic mitochondrial mutations.\u003c/p\u003e \u003cp\u003eQuality of life (QoL), as assessed through the CHU-9D, EQ-5D-3L and PedsQL instruments, was significantly impaired in all patients with ME, particularly in physical and emotional functioning domains. The mean scores of QoL assessment scales in our cohort were lower than the established standard norm, reflecting a considerable burden of disease (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Strong negative correlations were observed between QoL scores and perceived disability (rho = -0.643, p\u0026thinsp;\u0026lt;\u0026thinsp;0.009), underscoring how functional limitations adversely affect quality of life. The presence of disability correlated with significantly lower scores on both the CHU-9D and PedsQL assessments, suggesting that genetic factors associated with disability contribute to diminished QoL outcomes. More than half of the patients (51.9%) reported experiencing multiple disabilities, which were linked to lower QoL and increased caregiver burden, consistent with findings from similar studies (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Disability among ME patients was frequently related to reduced mobility, cognitive decline, and fatigue, all of which severely hindered their ability to perform daily activities. Additionally, 59.3% of participants reported experiences of discrimination, while 78.3% indicated a lack of social support, highlighting the social isolation that individuals with rare diseases often endure.\u003c/p\u003e \u003cp\u003eThe financial burden associated with ME was a significant finding in this study, with 44.4% of patients and their families reporting severe financial stress. This burden is intensified by the high costs of treatment, including rehabilitation and long-term care, which are major contributors to their financial strain. A substantial majority of patients (88.9%) reported incurring debt related to medical expenses, with 33.3% owing between 30,000 and 60,000 CNY and 25.9% facing debt between 100,000 and 200,000 CNY. These financial challenges are consistent with other studies that show how rare diseases place considerable economic pressure on families (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMoreover, 59.3% of patients required full-time care, limiting caregivers' ability to maintain employment and attend to their health needs. This finding aligns with existing research that indicates rare diseases often result in significant economic burdens, especially in healthcare systems with insufficient insurance coverage (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). Additionally, the financial strain was found to have a negative correlation with QoL scores, particularly in the CHU-9D, PedsQL, and CBI domains, further affecting the well-being of patients and caregivers. The economic burden was strongly correlated with perceived disability (rho\u0026thinsp;=\u0026thinsp;0.339, p\u0026thinsp;\u0026lt;\u0026thinsp;0.042) and QoL scores (rho = -0.555, p\u0026thinsp;\u0026lt;\u0026thinsp;0.024). This suggests that more severe disease leads to more significant financial and emotional strain. Nearly 58% of caregivers reported experiencing moderate to severe burdens. Caregivers reported higher scores in the time-dependence (rho\u0026thinsp;=\u0026thinsp;0.633, p\u0026thinsp;\u0026lt;\u0026thinsp;0.000), developmental burden (rho\u0026thinsp;=\u0026thinsp;0.343, p\u0026thinsp;\u0026lt;\u0026thinsp;0.043), and emotional burden (rho\u0026thinsp;=\u0026thinsp;0.337, p\u0026thinsp;\u0026lt;\u0026thinsp;0.046) domains. These results are consistent with previous studies indicating that caregivers of individuals with rare and severe neurological conditions experience significant emotional and physical strain (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Thus, the inverse correlations between patient-reported outcomes and caregiver burden suggest that addressing caregiver needs is vital for providing holistic care.\u003c/p\u003e \u003cp\u003eThe need for rehabilitation services was evident, with 44.4% of patients requiring them. Nevertheless, high costs (33.3%) and a lack of local options (14.8%) posed significant barriers to accessing rehabilitation services. The demands of full-time caregiving further strained caregivers, leading to absenteeism and financial hardships. In our study, 57.7% of caregivers reported experiencing moderate to severe burdens, highlighting the physical, emotional, and time-related challenges that come with caregiving for individuals with ME (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). These findings emphasise the urgent need for improved access to rehabilitation services and enhanced financial support for affected families.\u003c/p\u003e \u003cp\u003eOur findings underscore several actionable recommendations for clinical practice and policy development. First, the early identification of neuromuscular symptoms, especially motor retardation and seizures, should prompt clinicians to suspect mitochondrial dysfunction and refer patients for genetic testing in a timely manner. Second, the financial burden associated with ME calls for the establishment of enhanced insurance frameworks and financial assistance programmes specifically designed for rare diseases. Third, developing comprehensive care models that incorporate genetic counselling, rehabilitation, mental health services, and social support is essential. These models should be informed by interdisciplinary collaborations and a patient-centred approach to adequately meet the diverse needs of ME patients and their families.\u003c/p\u003e \u003cp\u003eThis study provides valuable insights; however, it is limited by its relatively small sample size and single-centre design, which may restrict the generalizability of the findings. Secondly, using self-reported measures to assess QoL and caregiver burden could introduce subjectivity and bias, as patient and caregiver perceptions may vary based on personal experiences, psychological states, and cultural factors. This could lead to overestimation or underestimation of certain aspects, such as the financial burden or the severity of the disability. Future research should focus on larger, multicentre cohorts to validate these results and examine regional and cultural variations in the management of ME. Additionally, longitudinal studies are necessary to assess disease progression and their impact on quality of life. Nevertheless, our study highlights the significant disease burden and poor quality of life faced by ME patients and their caregivers.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study emphasises the intricate clinical, genetic, and psychosocial challenges encountered by patients with mitochondrial encephalomyopathy and their caregivers. Effectively addressing these challenges necessitates a multidisciplinary approach that integrates medical, psychological, and social interventions. By encouraging early diagnosis, enhancing access to care, and implementing targeted policy measures, we can significantly improve the quality of life and outcomes for those affected by this debilitating condition.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eadPEO: autosomal dominant progressive external ophthalmoplegia; CBI: Caregiver burden inventory; CHU-9D: Child health utility-9 dimension; COQ10D: Primary coenzyme Q10 deficiency; COXPD: Combined oxidative phosphorylation deficiency; ECHSID: Mitochondrial short-chain enoyl-coA hydratase 1 deficiency; \u0026nbsp;EQ-5D-3L: European quality of life 5-dimension 3-level; EMPF1: Encephalopathy due to defective mitochondrial and peroxisomal fission 1; HRQoL: Health-related quality of life; LHON: Leber\u0026rsquo;s hereditary optic neuropathy; MCIDN2O; Mitochondrial complex 1 deficiency, nuclear type 20; MELAS: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; ME: Mitochondrial encephalomyopathy; MERRF: Myoclonic epilepsy with ragged red fibres; OSSS-3: Oslo social support scale-3; PedsQL: Paediatric quality of life inventory; PHQ-9: Patient health questionnaire-9; QoL: Quality of life\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data are included in the main manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNational Natural Science Foundation of China (82260665)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualisation: Lu J, Dumbuya JS and Tian C; Methodology: Dumbuya JS, Tian C and Deng L; Validation: Chen L, Ahmad B and Dumbuya JS; Formal Analysis: Dumbuya JS, Tian C and Deng L; Investigation: Deng L, Dumbuya JS and Chen L; Data Curation: Deng L, Ahmad B and Tian C; Writing – Original Draft Preparation: Dumbuya JS, Tian C and Deng L; Writing – Review \u0026amp; Editing: Tian C, Ahmad B, Dumbuya JS and Lu J; Visualisation: Dumbuya JS and Tian C; Supervision: Chen L and Lu J; Funding Acquisition: Lu J. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to the High-Level Scientific Research Startup Funding, Affiliated Hospital of Guangdong Medical University (1057z20230003, 1057z20230042).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDiMauro S, Schon EA. Mitochondrial Respiratory-Chain Diseases. N Engl J Med. 2003 Jun 26;348(26):2656\u0026ndash;68. \u003c/li\u003e\n\u003cli\u003eGorman GS, Schaefer AM, Ng Y, Gomez N, Blakely EL, Alston CL, et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol. 2015 May;77(5):753\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003ePfeffer G, Majamaa K, Turnbull DM, Thorburn D, Chinnery PF. Treatment for mitochondrial disorders. 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Health Policy. 2015 Jul;119(7):964\u0026ndash;79. \u003c/li\u003e\n\u003cli\u003eLi J, Jiao C, Nicholas S, Wang J, Chen G, Chang J. Impact of Medical Debt on the Financial Welfare of Middle- and Low-Income Families across China. Int J Environ Res Public Health. 2020 Jun 26;17(12):4597. \u003c/li\u003e\n\u003cli\u003eHauptman AJ, Augustine EF, Brown HB. The Psychiatric Care of Children and Young Adults With Neurodegenerative Diseases. J Am Acad Child Adolesc Psychiatry. 2024 Feb 8;S0890-8567(24)00060-1. \u003c/li\u003e\n\u003cli\u003eYang X, Yoo HK, Amin S, Cheng WY, Sundaresan S, Zhang L, et al. Clinical and humanistic burden among pediatric patients with neurofibromatosis type 1 and plexiform neurofibroma in the USA. Childs Nerv Syst ChNS Off J Int Soc Pediatr Neurosurg. 2022 Aug;38(8):1513\u0026ndash;22.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Mitochondrial encephalomyopathy, rare diseases, caregiver burden, financial burden, quality of life, assessment scales","lastPublishedDoi":"10.21203/rs.3.rs-5916685/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5916685/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMitochondrial encephalomyopathy (ME) significantly impacts patient quality of life (QoL) and imposes burdens on caregivers. This study examined disease burden, financial strain, QoL, disability levels, and caregiver burden among patients with ME to identify critical relationships.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e A cross-sectional study was conducted on ME patients and caregivers at Haikou Affiliated Hospital of Xiangya Medical College, Central South University, utilising validated scales including CHU-9D, PedsQL, PHQ-9, and CBI to evaluate disease burden, QoL, disability, and caregiver burden. Data were analysed using descriptive statistics and correlation coefficients to assess the relationships between these factors.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 27 patients with ME were identified, with a mean age of 10.14 years, 88.9% of whom were children. The cohort comprised 18 (66.7%) males and 9 (33.3%) females, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and Leigh syndrome were the most common subtypes. Significant correlations were found between QoL scores and caregiver burden, with CHU-9D showing negative correlations with PHQ-9 and CBI and positive correlations with PedsQL and health utility scores. Additionally, 44.4% of patients reported severe financial burdens, and 57.7% of caregivers experienced moderate to severe levels of burden.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur findings highlight the complex relationships between financial strain, QoL, and caregiver burden in ME. This underscores the need for comprehensive, patient-centered care and targeted policy interventions to alleviate patient and caregiver burdens. Further research is essential to develop effective support systems and improve overall outcomes.\u003c/p\u003e","manuscriptTitle":"Clinical Features, Disease Burden and Impact on Quality of Life in Patients with Mitochondrial Encephalomyopathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-31 18:04:02","doi":"10.21203/rs.3.rs-5916685/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"da96aad7-022b-4de6-97b7-d2904e6c57c8","owner":[],"postedDate":"January 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-03T07:38:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-31 18:04:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5916685","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5916685","identity":"rs-5916685","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}