Newcastle Mitochondrial Disease Adult Scale Research Articles

Early cardiac mechanics abnormalities in patients with mitochondrial diseases

BackgroundEvidence about early cardiac mechanics abnormalities in patients with mitochondrial diseases (MDs) before overt cardiomyopathy is limited. MethodsIn this prospective study, we performed a comparative analysis of conventional and speckle tracking echocardiographic parameters between patients with genetically identified MDs and no overt cardiomyopathy vs controls matched for age, sex and cardiovascular risk factors. The Newcastle mitochondrial disease adult scale (NMDAS) was calculated, using a threshold of > 21 as indicator of high disease severity. ResultsWe enrolled 24 MDs patients (50 % males, mean age 47.2 ± 14.3 years), the most prevalent mutation was the MT-TL1 m.3243A>G (37.5 %). In MDs patients all dimensional echocardiographic parameters were similar to controls. Conversely, albeit normal, Tissue Doppler septal systolic (p = 0.002) and early diastolic velocities (p = 0.016) were significantly lower and E/e’ ratio was higher (p = 0.032) in MDs. Moreover, LV-GLS was significantly reduced in MDs as compared to their counterparties (20.2 ± 1.6 vs 22.6 ± 1.5, p < 0.001). Similarly, LA reservoir and conduit strain were significantly lower in MDs (31.7 ± 7.0 vs 35.9 ± 6.6, p = 0.038; 19.7 ± 5.6 vs 23.1 ± 6.0, p = 0.049 respectively), while LA contractile strain was similar between the two groups. Lower values of LV-GLS were observed in patients with NMDAS > 21 vs patients with NMDAS ≤ 21 (19.0 ± 1.2 vs 21.0 ± 1.3, p = 0.001). ConclusionsIn patients with MDs and no overt cardiomyopathy Tissue Doppler and speckle tracking analysis unveil worse LV systolic and diastolic function indices as compared to controls. Reduced LV-GLS values were found especially in those with worse disease burden.

A conceptual disease model for quality of life in mitochondrial disease

BackgroundPrevious studies in patients with a mitochondrial disease (MD) highlight the high prevalence of cognitive impairments, fatigue, depression, and a lower quality of life (QoL). The relationship with biological and physiological factors remains complex. The aim of this study is to investigate the status of and interrelationships between biological and physiological functioning, cognitive functioning as well as fatigue, depression, societal participation, health perceptions, and QoL, by using the Wilson and Cleary conceptual disease model, adapted to MD.MethodsPatients with a genetically confirmed MD were included. The following health concepts in MD were investigated according to the conceptual model: (1) Biological and physiological: disease manifestation (Newcastle Mitochondrial Disease Adult Scale), (2) Symptom status: cognitive functioning, patient reported fatigue and depressive symptoms, (3) Functional health: societal participation, (4) Patient reported health perceptions, and (5) Overall QoL. Data were compared to healthy normative data and/or data from other patient groups. Correlations as well as a hierarchical regression analysis were performed to assess the relations between the different levels of health concepts in the conceptual model.ResultsOf the 95 included patients, 42% had a severe disease manifestation. Comparable or worse than normative data and other patient groups, 35% reported cognitive impairments, 80% severe fatigue, and 27% depressive symptoms. Patients experienced impairments in societal participation and QoL. Disease manifestation was significantly correlated with cognitive functioning, societal participation, physical functioning and overall QoL, but not with fatigue or depressive symptoms. Almost all outcome measures regarding functional health, health perceptions and QoL were correlated with symptom status variables. Overall QoL was significantly predicted by fatigue and physical functioning.ConclusionsSymptom status is related to the functional health, health perceptions and QoL in patients with MD. Moreover, fatigue and physical functioning are important contributors to the overall QoL of MD patients. In order to provide adequate patient care it is important to have a broad view on patients’ functioning, not only by providing a proper clinical assessment, but also to screen for symptom status; cognitive functioning, fatigue and depression.

COVID-19-Related Outcomes in Primary Mitochondrial Diseases: An International Study.

Background and ObjectivesTo identify factors associated with severe coronavirus disease 2019 (COVID-19), defined by hospitalization status, in patients with primary mitochondrial diseases (PMDs), thereby enabling future risk stratification and informed management decisions.MethodsWe undertook a cross-sectional, international, registry-based study. Data were extracted from the International Neuromuscular COVID-19 Database and collected between May 1, 2020, and May 31, 2021. The database included subjects with (1) PMD diagnosis (any age), clinically/histopathologically suspected and/or genetically confirmed; and (2) COVID-19 diagnosis classified as “confirmed”, “probable”, or “suspected” based on World Health Organization definitions. The primary outcome was hospitalization because of COVID-19. We collected demographic information, smoking status, coexisting comorbidities, outcomes after COVID-19 infection, and PMD genotype-phenotype. Baseline status was assessed using the modified Rankin scale (mRS) and the Newcastle Mitochondrial Disease Adult Scale (NMDAS).ResultsSeventy-nine subjects with PMDs from 10 countries were included (mean age 41.5 ± 18 years): 25 (32%) were hospitalized, 48 (61%) recovered fully, 28 (35%) improved with sequelae, and 3 (4%) died. Statistically significant differences in hospitalization status were observed in baseline status, including the NMDAS score (p = 0.003) and mRS (p = 0.001), presence of respiratory dysfunction (p < 0.001), neurologic involvement (p = 0.003), and more than 4 comorbidities (p = 0.002). In multivariable analysis, respiratory dysfunction was independently associated with COVID-19 hospitalization (odds ratio, 7.66; 95% CI, 2–28; p = 0.002).DiscussionRespiratory dysfunction is an independent risk factor for severe COVID-19 in PMDs while high disease burden and coexisting comorbidities contribute toward COVID-19–related hospitalization. These findings will enable risk stratification and informed management decisions for this vulnerable population.

Lower urinary tract dysfunction in adult patients with mitochondrial disease.

Mitochondrial diseases present with a spectrum of clinical features, usually with multiorgan involvement and are often characterized by a loss of smooth muscle function. Hence, we hypothesized that mitochondrial dysfunction may contribute to lower urinary tract (LUT) dysfunction. We performed a prospective cohort study at a single, quaternary, mitochondrial disease referral center, enrolling consecutive adult patients with genetically confirmed mitochondrial disease. Data regarding baseline characteristics and disease burden were gathered. LUT dysfunction was assessed using the International Consultation on Incontinence Modular Questionnaire-Lower Urinary Tract Symptoms (ICIQ-LUTS) questionnaire, bladder voiding efficiency (BVE), and bladder diaries. Patients with one or more features of LUT dysfunction were offered urodynamic testing. A total of 109 patients were included. Twenty-six percent of patients manifested at least one feature of LUT dysfunction, which was objectively confirmed in all 14 patients who consented to urodynamic investigation. Disease burden, defined by the Newcastle Mitochondrial Disease Adult Scale (NMDAS), demonstrated a linear relationship with ICIQ-LUTS severity (P = .01), with a statistically significant relationship between NMDAS-gastrointestinal scores and LUTS scores (P < .001). Limitations include mutational heterogeneity across the patient cohort. This is the largest study exploring LUT in patients with mitochondrial disease and supports previous smaller studies suggesting LUT dysfunction is underrecognized in patients with mitochondrial disease and impacts considerably on their quality of life. We propose a clinical guideline for identifying mitochondrial disease patients at risk of LUT dysfunction.

Macular impairment in mitochondrial diseases: a potential biomarker of disease severity

The high-energy demands of the retina are thought to contribute to its particular vulnerability to mitochondrial dysfunction. Photoreceptors are the cells with the higher oxygen consumption within the retina, and among these, the cones contain more mitochondria and have a higher energy demand than rods. A cohort of twenty-two patients with genetically-defined mitochondrial diseases (MDs) were enrolled to determine if the macula is functionally and anatomically impaired in these metabolic disorders. Visual acuity and fERG amplitude of patients with primary mitochondrial dysfunction were reduced compared to controls. Furthermore, SD-OCT layer segmentation showed a reduction of retinal and outer nuclear layer (ONL) volume in the macula of the patients. fERG amplitude showed a positive correlation with both ONL volume and thickness. A negative relationship was noted between fERG amplitude and disease severity assessed with Newcastle Mitochondrial Disease Adult Scale. In conclusion, MDs are associated with functional and anatomical alteration of macular cone system, characterized by its strong correlation with clinical disease severity suggesting a role as a potential biomarker of primary mitochondrial disorders.

Six-year prospective follow-up study in 151 carriers of the mitochondrial DNA 3243 A>G variant

BackgroundThe mitochondrial DNA (mDNA) 3243A>G variant is the most common pathogenic variant of the mDNA. To interpret results of clinical trials in mitochondrial disease, it is important to have a...

Cognitive Profile of Patients With Mitochondrial Chronic Progressive External Ophthalmoplegia.

Mitochondrial chronic progressive external ophthalmoplegia (CPEO) is a major manifestation of human mitochondrial encephalomyopathies. Previous studies have shown cognitive deficits in patients with mitochondrial diseases. However, these studies often included patients with heterogeneous subtypes of mitochondrial diseases. Here, we aimed to provide a better cognitive profile of patients with CPEO by applying a comprehensive battery of neuropsychological assessments in a pure sample of patients with CPEO. We recruited 28 patients with CPEO (19 women, age 16–62 years) and 38 age- and education-matched healthy control subjects (25 women, age 16–60 years). The neuropsychological assessments covered global cognition and five cognitive domains (executive functions, language, working memory, memory, and visuospatial functions). We found that the patients were impaired in global cognition [Montreal Cognitive Assessment (MoCA)], executive functions [Trail Making Test Part B (TMT-B)], and language [Boston Naming Test (BNT)], but not in working memory, memory or visuospatial functions. Moreover, individual patients' performances in the TMT-B (completion time) were predicted by the severity of non-ophthalmoplegia mitochondrial symptoms/signs [Newcastle Mitochondrial Disease Adult Scale (NMDAS)] and duration of the mitochondrial disease (years). Namely, patients with more severe non-ophthalmoplegia mitochondrial symptoms/signs and a longer disease duration took a longer time to complete the TMT-B. No clinical measures predicted individual patients' performances in the BNT.

Therapeutic potential of pyruvate therapy for patients with mitochondrial diseases: a systematic review.

Background:Mitochondrial disease is a term used to describe a set of heterogeneous genetic diseases caused by impaired structure or function of mitochondria. Pyruvate therapy for mitochondrial disease is promising from a clinical point of view.Methods:According to PRISMA guidelines, the following databases were searched to identify studies regarding pyruvate therapy for mitochondrial disease: PubMed, EMBASE, Cochrane Library, and Clinicaltrials. The search was up to April 2019. The endpoints were specific biomarkers (plasma level of lactate, plasma level of pyruvate, L/P ratio) and clinical rating scales [Japanese mitochondrial disease-rating scale (JMDRS), Newcastle Mitochondrial Disease Adult Scale (NMDAS), and others]. Two researchers independently screened articles, extracted data, and assessed the quality of the studies.Results:A total of six studies were included. Considerable differences were noted between studies in terms of study design, patient information, and outcome measures. The collected evidence may indicate an effective potential of pyruvate therapy on the improvement of mitochondrial disease. The majority of the common adverse events of pyruvate therapy were diarrhea and short irritation of the stomach.Conclusion:Pyruvate therapy with no serious adverse events may be a potential therapeutic candidate for patients with incurable mitochondrial diseases, such as Leigh syndrome. However, recent evidence taken from case series and case reports, and theoretical supports of basic research are not sufficient. The use of global registries to collect patient data and more adaptive trial designs with larger numbers of participants are necessary to clarify the efficacy of pyruvate therapy.

Appendicular skeletal muscle mass: A more sensitive biomarker of disease severity than BMI in adults with mitochondrial diseases

The study aimed to evaluate the body composition of patients with mitochondrial diseases (MD) and correlate it with disease severity. Overall, 89 patients (age ≥ 18 years) with MD were recruited, including 49 with chronic progressive external ophthalmoplegia (CPEO) and 40 with mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS). Body composition, including fat mass index (FMI), fat-free mass index (FFMI), skeletal muscle mass index (SMI), and appendicular skeletal muscle mass index (ASMI), were examined using multifrequency bioelectric impedance analysis. Clinical assessments, including muscle strength, usual gait speed, and disease severity determined by the Newcastle Mitochondrial Disease Adult Scale score (NMDAS), were performed. The comparisons between patients group and age- and gender-matched healthy controls, as well as the correlations between anthropometric measurements, body composition, and disease severity were analyzed. Height, weight, body mass index (BMI), FFMI, SMI, and ASMI were significantly lower in patients with MD than in healthy controls. Notably, low muscle mass was noted in 69.7% (62/89) of MD patients, with 22 patients also presenting with compromised physical performance as indicated by decreased gait speed, resulting in 24.7% satisfied the sarcopenia diagnostic criteria. Disease severity was more negatively correlated with ASMI than it was with height, weight, and BMI. Subgroup analysis showed that in the MELAS subgroup, disease severity was negatively correlated with height, weight, and ASMI; whereas in the CPEO subgroup, it was only negatively correlated with ASMI and SMI. Additionally, ASMI was positively associated with muscle strength. Altogether, compared with BMI, ASMI is a more sensitive biomarker predicting disease severity of MD, both in MELAS and CPEO patients.

Biomarkers and clinical rating scales for sodium pyruvate therapy in patients with mitochondrial disease

Biomarkers and two clinical rating scales—the Japanese mitochondrial disease-rating scale (JMDRS) and Newcastle mitochondrial disease adult scale (NMDAS)—are clinically used when treating patients with mitochondrial disease. We explored the biomarker(s) and clinical rating scale(s) that are appropriate in preparing the protocol for a future clinical trial of sodium pyruvate (SP) therapy. A 48-week, prospective, single-centre, exploratory, clinical study enrolled 11 Japanese adult patients with genetically, biochemically, and clinically confirmed mitochondrial disease; they had intractable lactic acidosis and received SP (0.5 g/kg t.i.d. PO). Plasma concentrations of lactate and pyruvate, lateral ventricular levels of lactate, and serum concentrations of growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 were measured at baseline and at weeks 12 and 48 of SP therapy. At week 48, plasma lactate (P = .004), the lactate/pyruvate ratio (P = .012), serum GDF15 (P = .020), and lateral ventricular lactate (P = .038) decreased significantly from the baseline values; the JMDRS and NMDAS scores did not decrease significantly, although the NMDAS overall score showed a strong tendency (P = .059). Two patients with end-stage MELAS at baseline died during SP therapy. The present study showed significant decreases in plasma and lateral ventricular lactate, the L/P ratio, and serum GDF15. Therefore, the protocol for a future clinical study of SP therapy in this patient population needs to include plasma and lateral ventricular lactate, the L/P ratio, and serum GDF15 as diagnostic indicators, and exclude patients with end-stage mitochondrial disease.

Intra-patient variability of heteroplasmy levels in urinary epithelial cells in carriers of the m.3243A>G mutation.

BackgroundThe mitochondrial DNA m.3243A>G mutation is one the most prevalent mutation causing mitochondrial disease in adult patients. Several cohort studies have used heteroplasmy levels in urinary epithelial cells (UEC) to correlate the genotype of the patients to the clinical severity. However, the interpretation of these data is hampered by a lack of knowledge on the intra‐patient variability of the heteroplasmy levels. The goal of this study was to determine the day‐to‐day variation of the heteroplasmy levels in UEC.MethodsFifteen carriers of the m.3243A>G mutation collected five urine samples in a 14‐day window. Heteroplasmy levels of the m.3243A>G mutation were determined in these samples. Data from the national cohort study, including Newcastle Mitochondrial Disease Adult Scale scores and clinical diagnosis, were used.ResultsIn the samples of six patients, heteroplasmy levels were within a 5% margin. In the samples collected from five patients, the margin was >20%.ConclusionHeteroplasmy levels of UEC in carriers of the m.3243A>G mutation have a significant day‐to‐day variation. The interpretation of a correlation between heteroplasmy levels in urine and disease severity is therefore not reliable. Therefore, heteroplasmy levels in UEC should not be used as a prognostic biomarker in these patients.

Height as a Clinical Biomarker of Disease Burden in Adult Mitochondrial Disease.

ContextAbnormal growth and short stature are observed in patients with mitochondrial disease, but it is unclear whether there is a relationship between final adult height and disease severity.ObjectiveTo determine whether patients with genetically confirmed mitochondrial disease are shorter than their peers and whether stature is related to disease severity.DesignAnalysis of final adult height in relation to disease severity as determined by the Newcastle Mitochondrial Disease Adult Scale (NMDAS).SettingUK Mitochondrial Disease Patient Cohort (Mito Cohort).Patients575 patients were identified with recorded height, weight, and molecular genetic diagnosis of mitochondrial disease within the Mito Cohort.Main Outcome MeasuresAdult height, body mass index (BMI), and their association with genetic subgroup and disease severity.ResultsAdults with mitochondrial disease were short, with a mean height of −0.49 SD (95% CI, −0.58 to −0.39; n = 575) compared with UK reference data. Patients were overweight, with a BMI SD of 0.52 (95% CI, 0.37 to 0.67; n = 472). The most common genetic subgroup (m.3243A>G mutation) had a height SD of −0.70 (95% CI, −0.85 to −0.54; n = 234) and a BMI SD of 0.12 (95% CI, −0.10 to 0.34; n = 212). NMDAS scores were negatively correlated with height SD (r = −0.25; 95% CI, −0.33 to −0.17; P < 0.001, n = 533). Rate of disease progression also correlated negatively with adult height (P < 0.001).ConclusionFinal height in mitochondrial disease reflects disease severity and rate of disease progression. Mitochondrial dysfunction and associated subclinical comorbidities affect growth plate physiology.

Phenotypic heterogeneity in m.3243A>G mitochondrial disease: The role of nuclear factors.

ObjectiveThe pathogenic mitochondrial DNA m.3243A>G mutation is associated with a wide range of clinical features, making disease prognosis extremely difficult to predict. We aimed to understand the cause of this heterogeneity.MethodsWe examined the phenotypic profile of 238 adult m.3243A>G carriers (patients and asymptomatic carriers) from the UK MRC Mitochondrial Disease Patient Cohort using the Newcastle Mitochondrial Disease Adult Scale. We modeled the role of risk factors for the development of specific phenotypes using proportional odds logistic regression. As mitochondria are under the dual control of their own and the nuclear genome, we examined the role of additive nuclear genetic factors in the development of these phenotypes within 46 pedigrees from the cohort.ResultsSeizures and stroke‐like episodes affect 25% and 17% of patients, respectively; more common features include hearing impairment, gastrointestinal disturbance, psychiatric involvement, and ataxia. Age, age‐adjusted blood heteroplasmy levels, and sex are poor predictors of phenotypic severity. Hearing impairment, diabetes, and encephalopathy show the strongest associations, but pseudo‐R 2 values are low (0.14–0.17). We found a high heritability estimate for psychiatric involvement (h 2=0.76, P = 0.0003) and moderate estimates for cognition (h 2=0.46, P = 0.0021), ataxia (h 2 = 0.45, P = 0.0011), migraine (h 2 = 0.41, P = 0.0138), and hearing impairment (h2 = 0.40, P = 0.0050).InterpretationOur results provide good evidence for the presence of nuclear genetic factors influencing clinical outcomes in m.3234A>G‐related disease, paving the way for future work identifying these through large‐scale genetic linkage and association studies, increasing our understanding of the pathogenicity of m.3243A>G and providing improved estimates of prognosis.

Growth Differentiation Factor 15 Is a Novel Diagnostic Biomarker of Mitochondrial Diseases.

The present study aimed to investigate whether serum growth differentiation factor 15 concentration is a valuable and reliable diagnostic biomarker of mitochondrial diseases. We examined consecutive patients with mitochondrial diseases, in comparison with patients with non-mitochondrial disease neuromuscular disorders and healthy controls. The serum concentrations of growth differentiation factor 15 were measured by ELISA, and compared with those of FGF21, lactate, and creatine kinase. We also evaluated the correlations between growth differentiation factor 15 concentrations and the Newcastle Mitochondrial Disease Adult Scale, numbers of ragged-red fibers, and COX-negative fibers in the biopsied muscles. The median serum growth differentiation factor 15 concentration was significantly elevated in 42 patients with mitochondrial diseases, compared with 20 patients with non-mitochondrial disease neuromuscular disorders and 50 healthy controls. The area under the curve of growth differentiation factor 15 for the diagnosis of muscle-manifesting mitochondrial diseases was 0.999, in comparison with those area under the curves of the other biomarkers including fibroblast growth factor 21 (0.935, p<0.01), lactate (0.845 for p<0.001), and creatine kinase (0.575, p<0.001). Growth differentiation factor 15 was significantly correlated with mitochondrial disease severity and the proportion of ragged-red fibers identified in the biopsied muscles. Circulating growth differentiation factor 15 measurement is a superior biomarker with high sensitivity and specificity, which can be used as a non-invasive test to screen for primary mitochondrial diseases and dysmetabolic myopathy with associated mitochondrial dysfunction in susceptible individuals.

Quality of life, fatigue and mental health in patients with the m.3243A > G mutation and its correlates with genetic characteristics and disease manifestation.

BackgroundMitochondrial 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.MethodsSeventy-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.ResultsPatients 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.ConclusionsPatient 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.

Preliminary Evaluation of Clinician Rated Outcome Measures in Mitochondrial Disease.

Background: Currently there are no known cures and few effective treatments for mitochondrial disorders. It is also true there is a lack of knowledge about suitable clinician rated outcomes and how these change over time in this patient cohort.Objective: We sought to evaluate the validity and responsiveness to change of clinician rated outcome measures in patients with m.3243A>G-related mitochondrial disease.Methods: We assessed the six minute timed walk (6MTW), 10 meter walk / test (10MWT), Timed up and Go (TUG) and the 5 times sit to stand (5XSTS), in 18 patients (12 sedentary controls), at baseline and a subgroup of 10 control-matched patients following a 16-week structured aerobic exercise intervention program.Results: All outcome measures assessed were valid and able to differentiate between patients and controls. Disease severity, as measured by the Newcastle Mitochondrial Disease Adult Scale, correlated with TUG (r = 0.54, p = 0.020) and 10MWT (r = 0.47, p = 0.050). Receiver Operating Curve analysis revealed 5XSTS to be the most responsive measure (AUC 0.931; 95% CI 0.84– 1.00) with responsiveness to change, post intervention, emulating disease burden variance.Conclusions: The 5XSTS can be used to discriminate between mitochondrial patients and sedentary controls with high accuracy. The 10MWT and TUG may serve as suitable and clinically relevant clinician rated measures to track disease progression and assess intervention.

Serum FGF21 levels in adult m.3243A>G carriers: clinical implications.

To determine the value of fibroblast growth factor 21 (FGF21), a recently discovered biomarker for mitochondrial disease, in predicting clinical disease severity and disease progression in adult carriers of the m.3243A>G mutation. In the context of a national inventory, the heteroplasmy levels of the m.3243A>G mutation were measured in leukocytes and urinary epithelial cells. The Newcastle Mitochondrial Disease Adult Scale score was determined and blood was drawn for measuring FGF21 concentration. Twenty-five of the included initial patients studied were then selected randomly for a follow-up study. This prognostic study included 99 adult carriers of the m.3243A>G mutation. Our analysis revealed a moderate, significant correlation between FGF21 concentration and disease severity (r = 0.49; p = <0.001). No significant correlations were found between disease severity and the heteroplasmy percentage determined in urinary epithelial cells or the heteroplasmy percentage determined in leukocytes. Weak but significant correlations were also found between FGF21 concentration and the severity of the myopathy (r = 0.38; p = <0.001) and between the concentration of FGF21 and the severity of the encephalopathy (r = 0.30; p = <0.001). Repeated measurements following 25 subjects for 2 years revealed no significant correlation between FGF21 concentration and disease progression. Measuring FGF21 concentration had little added value in monitoring and predicting the disease course in this specific patient group.

Disease progression in patients with single, large-scale mitochondrial DNA deletions

Single, large-scale deletions of mitochondrial DNA are a common cause of mitochondrial disease and cause a broad phenotypic spectrum ranging from mild myopathy to devastating multi-system syndromes such as Kearns-Sayre syndrome. Studies to date have been inconsistent on the value of putative predictors of clinical phenotype and disease progression such as mutation load and the size or location of the deletion. Using a cohort of 87 patients with single, large-scale mitochondrial DNA deletions we demonstrate that a variety of outcome measures such as COX-deficient fibre density, age-at-onset of symptoms and progression of disease burden, as measured by the Newcastle Mitochondrial Disease Adult Scale, are significantly (P < 0.05) correlated with the size of the deletion, the deletion heteroplasmy level in skeletal muscle, and the location of the deletion within the genome. We validate these findings with re-analysis of 256 cases from published data and clarify the previously conflicting information of the value of these predictors, identifying that multiple regression analysis is necessary to understand the effect of these interrelated predictors. Furthermore, we have used mixed modelling techniques to model the progression of disease according to these predictors, allowing a better understanding of the progression over time of this strikingly variable disease. In this way we have developed a new paradigm in clinical mitochondrial disease assessment and management that sidesteps the perennial difficulty of ascribing a discrete clinical phenotype to a broad multi-dimensional and progressive spectrum of disease, establishing a framework to allow better understanding of disease progression.

Mitochondrial Retinal Dystrophy Associated with the m.3243A>G Mutation

To describe the spectrum of retinal abnormalities associated with the m.3243A>G mutation in the mitochondrial MTTL1 gene and to analyze putative correlations among the severity of retinal abnormalities, disease severity in other organ systems, and heteroplasmy levels. Observational, cohort-based, cross-sectional study. Twenty-nine patients carrying the m.3243A>G mutation. Extensive clinical examinations, including visual acuity testing, indirect ophthalmoscopy, color fundus photography, fundus autofluorescence (FAF), high-resolution optical coherence tomography (OCT), and central visual field analysis. In selected patients, Goldmann perimetry, fluorescein angiography, full-field electroretinography (ERG) and electro-oculography (EOG), and color vision testing were performed. Heteroplasmy levels of the m.3243A>G mutation were measured in leukocytes, urinary epithelial cells (UECs), and buccal mucosa. The Newcastle Mitochondrial Disease Adult Scale (NMDAS) score was measured for all patients. Age at onset, visual acuity, fundus appearance, FAF, OCT findings, systemic disease features, heteroplasmy levels, and NMDAS scores. Twenty-five of the 29 mutation carriers (86%) had retinal abnormalities that could be classified into 4 grades. Six patients (21%) had grade 1 retinal dystrophy with fine pigment abnormalities that were clearly visible with FAF and fluorescein angiography. Eleven patients (38%) had grade 2 abnormalities that were characterized by yellowish or mildly pigmented deposits in the early stage; in advanced grade 2, these pigment changes encompassed the entire macula and often encircled the optic disc. Six patients (21%) had grade 3 disease in which profound chorioretinal atrophy was present outside the fovea. Two patients (7%) with retinal abnormalities had grade 4 disease, in which the fovea was affected by atrophy, with marked loss of visual acuity. The grade of mitochondrial retinal dystrophy correlated significantly with both age (r = -0.483, P = 0.008) and visual acuity (r = -0.614, P < 0.001), whereas no correlation was observed with heteroplasmy level or overall disease involvement. Mitochondrial retinal dystrophy associated with the m.3243A>G mutation has specific characteristics that can be classified into 4 grades based on the findings on ophthalmoscopy, FAF, and OCT. However, because the maternal inheritance pattern can be masked and the systemic disease associations can be variable or even absent, the disease may be misdiagnosed.

Concentric hypertrophic remodelling and subendocardial dysfunction in mitochondrial DNA point mutation carriers†

AimsHypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Screening strategies for cardiac disease are unclear. We investigated whether myocardial abnormalities could be identified in mitochondrial DNA mutation carriers without clinical cardiac involvement.Methods and resultsCardiac magnetic resonance imaging was performed in 22 adult patients with mitochondrial disease due to the m.3243A>G mutation, but no known cardiac involvement, and 22 age- and gender-matched control subjects: (i) Phosphorus-31- magnetic resonance spectroscopy, (ii) cine imaging (iii), cardiac tagging and (iv) late gadolinium enhancement (LGE) imaging. Disease burden was determined using the Newcastle Mitochondrial Disease Adult Scale (NMDAS) and urinary mutation load. Compared with control subjects, patients had an increased left ventricular mass index (LVMI), LV mass to end-diastolic volume (M/V) ratio, wall thicknesses (all P < 0.01), torsion and torsion to endocardial strain ratio (both P < 0.05). Longitudinal shortening was decreased in patients (P < 0.0001) and correlated with an increased LVMI (r = −0.52, P < 0.03), but there were no differences in the diastolic function. Among patients there was no correlation of LVMI or the M/V ratio with diabetic or hypertensive status, but the mutation load and NMDAS correlated with the LVMI (r = 0.71 and r = 0.79, respectively, both P < 0.001). The phosphocreatine/adenosine triphosphate ratio was decreased in patients (P < 0.001) but did not correlate with other parameters. No patients displayed focal LGE.ConclusionConcentric remodelling and subendocardial dysfunction occur in patients carrying m.3243A>G mutation without clinical cardiac disease. Patients with higher mutation loads and disease burden may be at increased risk of cardiac involvement.