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Background: More than half of the patients harbouring the m.3243A > G mutation were found to have trouble maintaining balance when walking in a recent study by our group. Others demonstrated that these patients had an abnormal gait pattern, as quantified by gait analysis. Gait analysis is an emerging method to quantify subtle changes in walking pattern, also during therapeutic interventions. Therefore, we aimed to test the reliability and reproducibility of gait analysis and select the most suitable protocol for this group of patients using a GAITRite electronic walkway. Four different protocols were tested: normal walking, dual task, post exercise and after a ten minutes of rest.Results: In total 36 patients with the m.3243A > G mutation and 50 healthy controls were enrolled in this study. Overall high intra class correlation coefficients were found in all experimental conditions for both patients and healthy controls indicating good reproducibility. Marked differences in gait between patients and controls were observed and were in line with the only available exploratory study performed. There was a good correlation between both the overall NMDAS score, NMDAS subscale scores, both markers for disease severity, and specific gait parameters.Conclusions: The observed reliability of the test makes GAITRite a suitable instrument for intervention studies in patients with mitochondrial disease. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial disorders belong to the most prevalent inherited metabolic diseases with the m.3243A > G mutation reflecting being one of the most common mutations in mitochondrial DNA. Previous studies showed little relationship between mitochondrial genetics and disease manifestation. Relationship between genotype and disease manifestation with patient reported quality of life and other patient reported outcomes is still unexplored.Methods: Seventy-two out of the 122 invited adult patients with m.3243A > G mutation completed online standardized questionnaires on quality of life, functional impairment, fatigue and mental health as assessed by the RAND-SF36, the Sickness Impact Profile (SIP), the Checklist Individual Strength (CIS) and the Hospital Anxiety and Depression scale (HADS). Data were related to clinical manifestation reflected by the Newcastle Mitochondrial Disease Adult Scale (NMDAS) score and heteroplasmy levels of the mutation in urine epithelial cells.Results: Patients reported impaired quality of life. Sixty percent showed severe levels of fatigue, and 37% showed clinical relevant mental health problems, which was significantly more than healthy norms. These patient reported health outcomes showed negligible relationship with levels of heteroplasmy (r = <.30) and weak (.30 < r < .50) to moderate (.50 < r < .70) relationship with clinical manifestation.Conclusions: Patient reported outcomes on quality of life, fatigue and mental health problems, are only partly reflected by clinical assessments. In order to support patients more effectively, integration of patient reported outcomes, alongside symptoms of their disease, in clinical practice is warranted. [ABSTRACT FROM AUTHOR]

Background: Being diagnosed with mitochondrial disease due to the m.3243A > G mutation is frequently preceded by a long diagnostic process. The disease itself is characterized by heterogeneous course and expression, so leaving patients with considerable uncertainty regarding their prognosis and treatment possibilities. This could easily result in fear of disease progression. This study investigated the presence of this fear and its correlates with genetic characteristics and clinical disease severity in m.3243A > G carriers.Methods: In total 125 eligible m.3243A > G mutation carriers were invited to participate in this cross-sectional study. After informed consent, participants completed questionnaires including items on socio-demographics, fear of progression, depression, anxiety, and quality of life. Clinical disease severity was assessed by the NMDAS questionnaire. Heteroplasmy levels were assessed in leucocytes, urine epithelial cells and buccal mucosa.Results: Seventy-six carriers participated in this study. Results showed that 18% reported high fear of progression. Fear of progression was significantly related to all domains of quality of life. Furthermore, fear of progression was moderately correlated with feelings of depression (r = .37), and anxiety (r = .44). Patients with moderate or severe clinical symptoms on the NMDAS experienced more fear of progression than patients with mild clinical symptoms. Fear of progression was weakly correlated with heteroplasmy in leucocytes (r = .27) and buccal mucosa (r = .31).Conclusions: A substantial part of m.3243A > G mutation carriers experience high levels of fear of progression which coincide with significantly lower quality of life. Only a small relation with disease characteristics was found. The impact of receiving a diagnosis without therapeutic possibilities on fear is important to consider. [ABSTRACT FROM AUTHOR]

Abstract We used a comprehensive metabolomics approach to study the altered urinary metabolome of two mitochondrial myopathy, encephalopathy lactic acidosis and stroke like episodes (MELAS) cohorts carrying the m.3243A>G mutation. The first cohort were used in an exploratory phase, identifying 36 metabolites that were significantly perturbed by the disease. During the second phase, the 36 selected metabolites were able to separate a validation cohort of MELAS patients completely from their respective control group, suggesting usefulness of these 36 markers as a diagnostic set. Many of the 36 perturbed metabolites could be linked to an altered redox state, fatty acid catabolism and one-carbon metabolism. However, our evidence indicates that, of all the metabolic perturbations caused by MELAS, stalled fatty acid oxidation prevailed as being particularly disturbed. The strength of our study was the utilization of five different analytical platforms to generate the robust metabolomics data reported here. We show that urine may be a useful source for disease-specific metabolomics data, linking, amongst others, altered one-carbon metabolism to MELAS. The results reported here are important in our understanding of MELAS and might lead to better treatment options for the disease. Highlights • We used a comprehensive metabolomics approach to study the altered urinary metabolome of two MELAS cohorts • From the first cohort, 36 metabolites were identified that were significantly perturbed by the disease • These 36 metabolites were able to separate a validation cohort of MELAS patients from their respective control group • Many of the perturbed metabolites was linked to an altered redox state, fatty acid catabolism and one-carbon metabolism • We show that urine may be a useful source for disease-specific metabolomics data [ABSTRACT FROM AUTHOR]