Search

Item does not contain fulltext

International audience; The role of brain dystrophin in muscular dystrophy: Implications for clinical care and translational research, Hoofddorp, the Netherlands, November 29 th-December 1 st 2019

ObjectiveTo investigate intrarater reliability and concurrent and construct validity of muscle strength, balance, and functional mobility measures in individuals with noncongenital myotonic dystrophy type 1 (DM1).MethodsSeventy-eight adults with noncongenital DM1 participated in visit 1, and 73 of the them participated in visit 2 separated by 1 to 2 weeks. The assessments consisted of muscle strength tests with handheld dynamometry (HHD) and stationary dynamometry in the lower limb. The balance tests consisted of the step test, Timed Up and Go test, feet-together stance, tandem stance, 1-leg stance, and modified Clinical Test of Sensory Integration and Balance on a balance platform. The functional mobility tests consisted of the 10-m walk test (10mWT) and 10-times Sit-to-Stand test.ResultsThe HHD and stationary dynamometry had sufficient intrarater reliability for most muscle groups on a group (SEM% ≤15%) and individual (minimal detectable difference [MDD95%] ≤30%) level, but the HHD was most reliable. Stationary dynamometry measured a higher torque than HHD for all extensor muscles, but for single individuals, none of the devices were favored. Overall, intrarater reliability and validity were sufficient only for the dynamic balance tests, not the static balance tests. Both functional mobility tests were sufficiently reliable and valid, but the 10mWT was most reliable.ConclusionOverall, HHD is recommended as a reliable and valid tool for single individuals and for flexor muscles on a group level. For balance assessments, the dynamic balance tests are recommended as the most valid and reliable balance tests. Both functional mobility tests are recommended for valid and reliable outcomes, but the 10mWT was superior for reliability.

Twenty participants, including one patient representative, from 9 countries (UK, Spain, France, Sweden, Finland, Denmark, Italy, Germany and USA) attended the workshop, the aims of which were to agree on the best practice strategies for diagnosis and management of McArdle disease (GSDV) and related rare glycolytic disorders of skeletal muscle.

Metabolic myopathies encompass muscle glycogenoses (GSD) and disorders of muscle fat oxidation (FAOD). FAODs and GSDs can be divided into two main clinical phenotypes; those with static symptoms related to fixed muscle weakness and atrophy, and those with dynamic, exercise-related symptoms that are brought about by a deficient supply of ATP. Together with mitochondrial myopathies, metabolic myopathies are unique among muscle diseases, as the limitation in exercise performance is not solely caused by structural damage of muscle, but also or exclusively related to energy deficiency. ATP consumption can increase 50-100-fold in contracting, healthy muscle from rest to exercise, and testing patients with exercise is therefore an appropriate approach to disclose limitations in work capacity and endurance in metabolic myopathies. Muscles rely almost exclusively on muscle glycogen in the initial stages of exercise and at high work intensities. Thus, patients with GSDs typically have symptoms early in exercise, have low peak work capacities and develop painful contractures in exercised muscles. Muscle relies on fat oxidation at rest and to a great extent during prolonged exercise, and therefore, patients with FAODs typically develop symptoms later in exercise than patients with GSDs. Due to the exercise-related symptoms in metabolic myopathies, patients generally have been advised to shun physical training. However, immobility is associated with multiple health issues, and may even cause unwanted metabolic adaptations, such as increased dependence on glycogen use and a reduced capacity for fatty acid oxidation, which is detrimental in GSDs. Training has not been studied systematically in any FAODs and in just a few GSDs. However, studies on single bouts of exercise in most metabolic myopathies show that particularly moderate intensity aerobic exercise is well tolerated in these conditions. Even low-intensity resistance training of short duration is tolerated in McArdle disease. Training in patients with FAOD potentially can also expand the metabolic bottleneck by increasing expression of the defective, but partially functional enzyme. Exercise performance in metabolic myopathies can be improved by different fuel supplementations and dietary interventions and should be considered as adjunct therapy to exercise training.

It is not clear to what extent skeletal muscle is affected in patients with medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD). l-Carnitine is commonly used as a supplement in patients with MCADD, although its beneficial effect has not been verified.We investigated (1) fuel utilization during prolonged low-intensity exercise in patients with MCADD and (2) the influence of 4 weeks of oral l-carnitine supplementation on fuel utilization during exercise.Four asymptomatic patients with MCADD and 11 untrained, healthy, age- and sex-matched control subjects were included. The subjects performed a 1-hour cycling test at a constant workload corresponding to 55% of Vo2max, while fat and carbohydrate metabolism was assessed, using the stable isotope technique and indirect calorimetry. The patients ingested 100 mg/kg/d of l-carnitine for 4 weeks, after which the cycling tests were repeated.At rest, palmitate oxidation and total fatty acid oxidation (FAO) rates were similar in patients and healthy control subjects. During constant workload cycling, palmitate oxidation and FAO rates increased in both groups, but increased 2 times as much in healthy control subjects as in patients (P = .007). Palmitate oxidation and FAO rates were unchanged by the l-carnitine supplementation.Our results indicate that patients with MCADD have an impaired ability to increase FAO during exercise but less so than that observed in patients with a number of other disorders of fat oxidation, which explains the milder skeletal muscle phenotype in MCADD. The use of carnitine supplementation in MCADD cannot be supported by the present findings.

Objective: We examined the effect of aerobic exercise in patients with spinal and bulbar muscular atrophy (SBMA). SBMA is caused by a defect androgen receptor. This defect causes motor neuron death, but considering the important function of androgens in muscle, it is possible that muscle damage in SBMA also occurs independently of motor neuron damage. Methods: Eight patients with SBMA engaged in regular cycling exercise for 12 weeks. Maximum oxygen uptake (Vo 2max ), maximal work capacity (W max ), muscle morphology, citrate synthase (CS) activity, body composition, EMG, static strength measurements, lung function, plasma proteins, and hormones were evaluated before and after training. Evaluation of improvements in activities of daily living (ADL) was conducted after training. Results: W max increased by 18%, and CS activity increased by 35%. There was no significant change in Vo 2max or any of the other variables examined before and after training, and the patients with SBMA did not feel improvements in ADL. Conclusions: Frequent, moderate-intensity aerobic conditioning is of little beneficial effect in patients with spinal and bulbar muscular atrophy (SBMA). High levels of plasma creatine kinase and muscle regeneration indicate a primary myopathic affection, which, in parallel with the motor neuron deficiency, may attenuate the response to exercise training in patients with SBMA.

The most common clinical phenotype caused by a mtDNA mutation in complex I of the mitochondrial respiratory chain is Leber hereditary optic neuropathy. We report a family with a novel maternally inherited homoplasmic mtDNA m.4087A>G mutation in the ND1 gene (MT-ND1) associated with isolated myopathy, recurrent episodes of myoglobinuria, and rhabdomyolysis. DNA from blood in seven family members and muscle from four family members were PCR amplified and sequenced directly and assessed for the m.4087A>G variation in MT-ND1. Mitochondrial enzyme activity in all muscle biopsies was measured. PCR and direct sequencing of the MT-ND1 genes from blood showed that all seven family members were homoplasmic for the m.4087A>G mutation (NC_012920.1:c.781A>G). The mutation predicts a threonine to alanine substitution at position 261 (p.T261A). The same mutation was found in muscle of all four family members available for muscle biopsy, and biochemical analyses revealed an isolated complex I defect in muscle of all family members (range 22–52% of normal). Muscle morphology showed severe myopathic changes with internal nuclei in multiple fibers of all family members. Monosymptomatic myopathy with recurrent myoglobinuria is a rare phenotype of mitochondrial myopathies. We report this phenotype in a family affected by a novel homoplasmic mutation in MT-ND1. It is the first time such a phenotype has been associated with complex I gene mutations and a homoplasmic mutation of mtDNA.

The authors report a 27-year-old man with B12-responsive mut- methylmalonic aciduria associated with pure muscle symptoms. Two mutations were found in the methylmalonyl-CoA mutase gene. An exercise test showed a reduced maximal workload and reduced oxygen uptake, and a muscle biopsy showed subsarcolemmal accumulation of mitochondria and normal respiratory chain enzyme activities. These findings may be caused by inhibition of mitochondrial energy metabolism by methylmalonate or its metabolites.

The effect of 42-48 h of immobilization by casting on maximal velocity of 3-O-methylglucose (3-MG) transport in skeletal muscle was studied in the perfused rat hindquarter. Immobilization resulted in a decrease of approximately 42% for maximum insulin-stimulated 3-MG transport in fast-twitch red fibers and a decrease of approximately 42% for contraction-stimulated transport in slow-twitch red fibers compared with nonimmobilized control muscle. No effect of immobilization on 3-MG transport was found in fast-twitch white muscle. Combination of insulin and muscle contractions always resulted in glucose transport that was identical in immobilized and control muscle. Western blot did not detect a decrease in GLUT-1 or GLUT-4 protein with immobilization. Furthermore, in fast-twitch red fibers, insulin receptor number and receptor kinase activity did not differ between immobilized and control muscle. It is concluded that during short-term immobilization a resistance of muscle glucose transport to stimulation develops that is fiber type specific and selective for insulin or contractions. The resistance can be overcome by the combined action of insulin and contractions and reflect factors other than glucose transporter number and insulin receptor binding and receptor kinase activity.

Objective: To examine metabolism during exercise in 2 patients with muscle phosphorylase kinase (PHK) deficiency and to further define the phenotype of this rare glycogen storage disease (GSD). Methods: Patient 1 (39 years old) had mild exercise-induced forearm pain, and EMG showed a myopathic pattern. Patient 2 (69 years old) had raised levels of creatine kinase (CK) for more than 6 months after statin treatment. Both patients had increased glycogen levels in muscle and PHK activity PHKA1 gene. The metabolic response to anaerobic forearm exercise and aerobic cycle exercise was studied in the patients and 5 healthy subjects. Results: Ischemic exercise showed a normal 5-fold increase in plasma lactate (peak 5.7 and 6.9 mmol/L) but an exaggerated 5-fold increase in ammonia (peak 197 and 171 μmol/L; control peak range 60–113 μmol/L). An incremental exercise test to exhaustion revealed a blunted lactate response (5.4 and 4.8 mmol/L) vs that for control subjects (9.6 mmol/L; range 7.1–14.3 mmol/L). Fat and carbohydrate oxidation rates at 70% of peak oxygen consumption were normal. None of the patients developed a second wind phenomenon or improved their work capacity with an IV glucose infusion. Conclusion: Our findings demonstrate that muscle PHK deficiency may present as an almost asymptomatic condition, despite a mild impairment of muscle glycogenolysis, raised CK levels, and glycogen accumulation in muscle. The relative preservation of glycogenolysis is probably explained by an alternative activation of myophosphorylase by AMP and P i at high exercise intensities. Neurology ® 2012;78:265–268

Contains fulltext : 69600.pdf (Publisher’s version ) (Closed access) OBJECTIVE: It is unclear to what extent muscle phosphorylase b kinase (PHK) deficiency is associated with exercise-related symptoms and impaired muscle metabolism, because 1) only four patients have been characterized at the molecular level, 2) reported symptoms have been nonspecific, and 3) lactate responses to ischemic handgrip exercise have been normal. METHODS: We studied a 50-year-old man with X-linked PHK deficiency using ischemic forearm and cycle ergometry exercise tests to define the derangement of muscle metabolism. We compared our findings with those in patients with McArdle disease and in healthy subjects. RESULTS: Sequencing of PHKA1 showed a novel pathogenic mutation (c.831G>A) in exon 7. There was a normal increase of plasma lactate during forearm ischemic exercise, but lactate did not change during dynamic, submaximal exercise in contrast to the fourfold increase in healthy subjects. Constant workload elicited a second wind in all patients with McArdle disease, but not in the patient with PHK deficiency. IV glucose administration appeared to improve exercise tolerance in the patient with PHK deficiency, but not to the same extent as in the patients with McArdle disease. Lipolysis was higher in the patient with PHK deficiency than in controls. CONCLUSION: These findings demonstrate that X-linked PHK deficiency causes a mild metabolic myopathy with blunted muscle glycogen breakdown and impaired lactate production during dynamic exercise, which impairs oxidative capacity only marginally. The different response of lactate to submaximal and maximal exercise is likely related to differential activation mechanisms for myophosphorylase.

Patients with the adult-onset myopathic form of very-long-chain acyl–coenzyme A dehydrogenase (VLCAD) deficiency are characterized by muscle pain, rhabdomyolysis, and myoglobinuria after prolonged exercise or fasting.1,2 The residual VLCAD activity in these patients is sufficient to maintain normal oxidation of fat at rest, but fat oxidation does not increase during exercise.3 This probably causes an energy deficit and IM accumulation of fat intermediates that may induce the exercise-induced symptoms.3 Free fatty acids (FFAs) are an important energy source during fasting and prolonged exercise. Patients with VLCAD deficiency have therefore been encouraged to avoid fasting, and have been treated with carbohydrate-rich/low-fat diets or dietary supplements of medium-chain triglyceride (MCT).1,2 Theoretically, MCT could be beneficial in VLCAD deficiency, because MCT bypasses the metabolic block, and the breakdown products of MCT enter the hepatic portal vein just minutes after ingestion.4 These recommendations, however, are based on uncontrolled case reports. In placebo-controlled trials, we studied the effect of IV glucose and MCT on exercise performance in VLCAD deficiency. ### Methods. We studied two unrelated Dutch men, aged 33 and 38 …

Background/Aims: To determine the efficacy of infliximab combined with weekly methotrexate in drug-naive recent-onset dermatomyositis and polymyositis. Methods: A multicentre open-label controlled trial was conducted. Disease activity was assessed using patient’s and physician’s disease activity assessment, manual muscle testing (MMT), handheld dynamometry, and serum CK. The primary objective was to assess the efficacy using MMT after a period of 26 weeks. Results: The study was terminated prematurely because of a low inclusion rate and a high drop-out rate due to disease progression and the occurrence of an infusion reaction. The few patients who did reach the primary endpoint showed improvement in all aspects studied. Conclusion: Infliximab combined with weekly methotrexate might be safe and well tolerated in a small subgroup of patients with drug-naive recent-onset myositis. At present, we do not advocate the use of this treatment because treatment response cannot be predicted beforehand.

Debrancher deficiency is an inborn error of glycogen metabolism. Glycogen is an essential energy source for skeletal muscle during exercise and it is interesting that Debrancher deficiency is not associated with dynamic exercise induced symptoms. We hypothesized that in patients with Debrancher deficiency type IIIa, without significant weakness or muscle wasting, we would observe an exercise intolerance. The aim was to examine excercise tolerance in patients with Debrancher deficiency. Six patients (aged 15–37-years) were included. We determined peak work capacity, and the response to forearm exercise. We measured substrate metabolism during cycling exercise at 70% of VO2peak. Finally, in an attempt to circumvent the metabolic block and improve exercise tolerance, the patients were given a glucose infusion during constant load cycling. VO2peak was reduced below normal in all subjects (25.4 ml/kg/min, range; 16.1–29.6). In addition the rise in plasma lactate after peak exercise was only 1.7-fold and only 1.6-fold after forearm exercise. Cycling at 70% of VO2peak was not well tolerated and was associated with muscle pain and excessive fatigue, and a rapid development of hypoglycemia IV glucose infusion improved work capacity (heart rate during exercise was lowered to 131 bpm vs. 135 bpm with saline infusion, p = 0.036), and the Wpeak was increased by 30% (108 Watts with glucose vs. 83 Watts with saline infusion, p = 0.018). This is the first study to quantify exercise intolerance in Debrancher deficiency. We demonstrate that Debrancher deficiency is associated with exercise intolerance and dynamic exercise related symptoms not only as a consequence of a reduced glycogenolytic capacity in skeletal muscle, but also due to the liver involvement in this glycogen storage disease. Intravenous glucose infusion improves exercise tolerance and it seems likely that an oral glucose load, may have the same effect.

Bezafibrate up-regulate enzyme activities of carnitine palmitoyltransferase (CPT) II and very long-chain acyl-CoA-dehydrogenase (VLCAD) in patients with defects in these enzyme, when assessed in vitro and increased quality of life scores in an uncontrolled study in six CPT II patients. In CPT II and VLCAD deficiencies, fatty acid oxidation (FAO) is normal at rest, but residual enzyme activity is insufficient to increase FAO during exercise. We hypothesized that Bezafibrate would increase FAO and lower perceived exertion during exercise in patients with CPT II and VLCAD deficiencies. We studied the effect of Bezafibrate/placebo on total FAO by indirect calorimetry and palmitate turnover using stable isotope methodology during cycling exercise in 10 patients with recurrent episodes of rhabdomyolysis caused by CPT II (n = 5) and VLCAD (n = 5) deficiencies. The study design was 3-month, randomized, double-blind, cross-over (EudraCT: 2008-006704-27). Primary endpoints were FAO and heart rate during exercise. Bezafibrate lowered LDL, triglyceride and free fatty acid concentrations, but palmitate oxidation and total FAO at rest and during exercise, as well as activity levels scored by Bouchard questionnaires, were not changed by Bezafibrate. Bezafibrate does not improve clinical symptoms or FAO during exercise in patients with CPT II and VLCAD deficiencies. These findings indicate that previous in vitro studies suggesting a therapeutic potential for fibrates, do not translate into clinically meaningful effects in vivo.

Item does not contain fulltext Two sisters developed gastrointestinal malabsorption with pain and unsteady gait due to polyneuropathy at age 15. Both had ophthalmoplegia, neurogenic EMG, and COX-negative muscle fibers. One patient had low muscle complex I-IV activity, multiple mtDNA deletions, and depletion, but no thymidine phosphorylase (TP) or dNT-2 gene mutations. TP activity and brain MRI were normal. The condition resembles mitochondrial neurogastrointestinal encephalomyopathy, except for the absence of leukoencephalopathy, and is likely caused by a nuclear DNA mutation that disrupts intergenomic signaling.