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Impaired skeletal muscle oxidative phosphorylation in patients with severe mitochondrial respiratory chain defects results in disabling exercise intolerance that is associated with a markedly blunted capacity of muscle to increase oxygen utilization in relation to circulatory and ventilatory responses that increase oxygen delivery to muscle during exercise. The range of oxidative limitation and the relationship between the severity of oxidative defects and physiological responses to exercise among a broader spectrum of mitochondrial respiratory chain defects has not been defined. We evaluated oxidative capacity and circulatory and ventilatory responses to maximal cycle exercise in 40 patients with biochemically and/or molecularly defined mitochondrial myopathy (MM) associated with varying levels of exercise tolerance, and compared responses with those in healthy sedentary individuals. In the MM patients, mean peak work capacity (0.88 +/- 0.6 W/kg) and oxygen uptake (VO(2), 16 +/- 8 ml/kg/min) were significantly lower (P < 0.01) than in controls (mean work capacity = 2.2 +/- 0.7 W/kg; VO(2) = 32 +/- 7 ml/kg/min), but the patient range was broad (0.17-3.2 W/kg; 6-47 ml/kg/min). Oxidative capacity in patients was limited by the ability of muscle to extract available oxygen from blood [mean peak systemic arteriovenous O(2) difference (a-vO(2)); patients = 7.7 +/- 3.5, range 2.7-17.6 ml/dl, controls = 15.2 +/- 2.1 ml/dl], as indicated by a linear correlation between peak VO(2) and peak systemic a-vO(2) difference (r(2) = 0.69). In the patients, the increase in cardiac output relative to VO(2) (mean DeltaQ/DeltaVO(2) = 15.0 +/- 13.6; range 3.3-73) and ventilation (mean peak VE/VO(2) = 65 +/- 24; range 21-104) were exaggerated compared with controls (mean DeltaQ/DeltaVO(2) = 5.1 +/- 0.7; VE/VO(2) = 41.2 +/- 7.4, P < 0.01). There was a negative exponential relationship between DeltaQ/DeltaVO(2) and peak systemic a-vO(2) difference (r(2) = 0.92) and between peak VE/VO(2) and systemic a-vO(2) difference (r(2) = 0.53). In patients with heteroplasmic mtDNA mutations, we found an inverse relationship between the proportion of skeletal muscle mutant mtDNA and peak extraction of available oxygen during exercise (r(2) = 0.70). We conclude that the degree of exercise intolerance in MM correlates directly with the severity of impaired muscle oxidative phosphorylation as indicated by the peak capacity for muscle oxygen extraction. Exaggerated circulatory and ventilatory responses to exercise are direct consequences of the level of impaired muscle oxidative phosphorylation and increase exponentially in relation to an increasing severity of oxidative impairment. In patients with mtDNA mutations, muscle mutation load governs mitochondrial capacity for oxidative phosphorylation and determines exercise capacity.

Introduction : Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody‐positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open‐label extension of REGAIN, evaluating eculizumab's long‐term safety and efficacy. Methods : Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients. Results : The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN ( P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open‐label eculizumab ( P < 0.0001). Discussion : These findings provide evidence for the long‐term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 2019

BackgroundOutcome measures for clinical trials in neuromuscular diseases are typically based on physical assessments which are dependent on patient effort, combine the effort of different muscle groups, and may not be sensitive to progression over short trial periods in slow-progressing diseases. We hypothesised that quantitative fat imaging by MRI (Dixon technique) could provide more discriminating quantitative, patient-independent measurements of the progress of muscle fat replacement within individual muscle groups.ObjectiveTo determine whether quantitative fat imaging could measure disease progression in a cohort of limb-girdle muscular dystrophy 2I (LGMD2I) patients over a 12 month period.Methods32 adult patients (17 male;15 female) from 4 European tertiary referral centres with the homozygous c.826C>A mutation in the fukutin-related protein gene (FKRP) completed baseline and follow up measurements 12 months later. Quantitative fat imaging was performed and muscle fat fraction change was compared with (i) muscle strength and function assessed using standardized physical tests and (ii) standard T1-weighted MRI graded on a 6 point scale.ResultsThere was a significant increase in muscle fat fraction in 9 of the 14 muscles analyzed using the quantitative MRI technique from baseline to 12 months follow up. Changes were not seen in the conventional longitudinal physical assessments or in qualitative scoring of the T1w images.ConclusionsQuantitative muscle MRI, using the Dixon technique, could be used as an important longitudinal outcome measure to assess muscle pathology and monitor therapeutic efficacy in patients with LGMD2I.

Udd b , c , d , on behalf of the LGMD workshop study group

The clinical phenotype of 45 genetically confirmed McArdle patients is described.In the majority of patients (84%), the onset of symptoms was from early childhood, but diagnosis was frequently delayed until after 30 years of age. Not all patients could recognise a second wind, although it was always seen with exercise assessment. A history of myoglobinuria was not universal, and episodes of acute renal failure had occurred in a minority (11%). The condition does not appear to adversely affect pregnancy and childbirth. Clinical examination was normal in most patients, muscle hypertrophy was present in 24% and mild muscle wasting and weakness was seen only in patients over 40 years of age and was limited to shoulder girdle and axial muscles. The serum creatine kinase (CK) was elevated in all but one pregnant patient. Screening for the mutations p.Arg50X (R50X) and p.Gly205Ser (G205S) showed at least one mutated allele in 96% of Caucasian British patients, with an allele frequency of 77% for p.Arg50X in this population. A 12-minute walking test to evaluate patients is described, results demonstrated a wide spectrum of severity with the range of distance walked being 195-1980 metres, the mean distance walked was 512m suggesting significant functional impairment in most patients.

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype–phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot–Marie–Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.