J. Vissing

Open-label trial of anti-TNF-alpha in dermato- and polymyositis treated concomitantly with methotrexate

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.

Effect of aerobic training in patients with spinal and bulbar muscular atrophy (Kennedy disease)

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 (Vo2max), maximal work capacity (Wmax), 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: Wmax increased by 18%, and CS activity increased by 35%. There was no significant change in Vo2max 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.

Is muscle glycogenolysis impaired in X-linked phosphorylase b kinase deficiency?

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.

High prevalence of cardiac involvement in patients with myotonic dystrophy type 1: A cross-sectional study

BACKGROUNDnPatients with myotonic dystrophy type 1 (DM1) have a three-fold higher risk of sudden cardiac death (SCD) than age-matched healthy controls. Despite numerous attempts to define the cardiac phenotype and natural history, existing literature suffers from low power, selection-bias and lack of controls. Thus, the optimal strategy for assessing cardiac involvement in DM1 is unclear.nnnMETHODnIn this large single-centre study, we evaluated 129 unselected DM1 patients (49.6% men), mean (SD) age 44 (14.7) years with family history, physical examination, electrocardiogram (ECG), echocardiography, Holter-monitoring and muscle strength testing.nnnRESULTSnCardiac involvement was found in 71 patients (55%) and included: 1) Conduction abnormalities: atrio-ventricular block grade I (AVB grade I) (23.6%), AVB grade II (5.6%), right/left bundle branch block (5.5/3.2%) and prolonged QTc (7.2%); 2) arrhythmias: atrial fibrillation/flutter (4.1%), other supraventricular tachyarrhythmia (7.3%) and non-sustained ventricular tachycardia (4.1%); and 3) structural abnormalities: left ventricular systolic dysfunction (20.6%) and reduced global longitudinal strain (21.7%). A normal ECG was not significantly associated with normal findings on Holter-monitoring or echocardiography. Patients with abnormal cardiac findings had weaker muscle strength than those with normal cardiac findings: ankle dorsal flexion (median (range) 4.5 (0-5) vs. 5.0 (2.5-5), p=0.004) and handgrip (median 4.0 (0-5) vs. 4.50 (2-5), p=0.02).nnnCONCLUSIONnThe cardiac phenotype of DM1 includes a high prevalence of conduction disorders, arrhythmias and risk factors of SCD. Systematic cardiac screening with ECG, Holter-monitoring and echocardiography is needed in order to make a proper characterization of cardiac involvement in DM1.

Progression of cardiac involvement in patients with limb-girdle type 2 and Becker muscular dystrophies: A 9-year follow-up study

AIMnTo assess the degree and progression of cardiac involvement in patients with limb-girdle type 2 (LGMD2) and Becker muscular dystrophies (BMD).nnnMETHODSnA follow-up study of 100 LGMD2 (types A-L) and 30 BMD patients assessed by electrocardiogram (ECG) and echocardiography, supplemented by Holter-monitoring at follow-up.nnnRESULTSnAfter a median of 8.9years (range 0.4-13.7), twelve patients had died: LGMD2 (n=10, mean age 61±11years), BMD (n=2, age 43 and 45years). Of the remaining 118 patients, 89 completed follow-up: LGMD2 (n=64, age 48±13years) and BMD (n=25, age 40±13years). In BMD, LVEF decreased from 60% (10-62) to 50% (10-64), p=0.02 corresponding to a one percentage drop annually. Among patients with LGMD2, LVEF decreased significantly in patients with LGMD type 2I (n=28) from 59% (15-72) to 55% (20-61), p=0.03, i.e. a 0.4 percentage drop annually, and LVEF≤50% was associated with increased mortality in this subgroup. In LGMD2E, 3/5 patients (60%) at baseline and 4/5 (80%) at follow-up had LVEF≤50%. ECG abnormalities were non-progressive in BMD and in all subgroups of LGMD2. SVT and NSVT were present in both groups: BMD (3/14 (21%) and (2/14 (14%)), LGMD2 (16/51 (31%) and 8/51 (16%)), respectively, all asymptomatic.nnnCONCLUSIONnLVEF decreased significantly in patients with BMD and LGMD2I, and the majority of patients with LGMD2E had left ventricular systolic dysfunction. This study emphasizes the need for tailored regular cardiac assessments according to molecular diagnosis with special focus on BMD and LGMD types 2I and 2E.

Myocardial fibrosis in patients with myotonic dystrophy type 1: a cardiovascular magnetic resonance study

BackgroundMyotonic dystrophy type 1 (DM1) is associated with increased cardiac morbidity and mortality. Therefore, assessment of cardiac involvement and risk stratification for sudden cardiac death is crucial. Nevertheless, optimal screening-procedures are not clearly defined. ECG, echocardiography and Holter-monitoring are useful but insufficient. Cardiovascular magnetic resonance (CMR) can provide additional information of which myocardial fibrosis may be relevant.The purpose of this study was to describe the prevalence of myocardial fibrosis in patients with DM1 assessed by CMR, and the association between myocardial fibrosis and abnormal findings on ECG, Holter-monitoring and echocardiography.MethodsWe selected 30 unrelated patients with DM1: 18 patients (10 men, mean age 51 years) with, and 12 patients (7 men, mean age 41 years) without abnormal findings on ECG and Holter-monitoring.Patients were evaluated with medical history, physical examination, ECG, Holter-monitoring, echocardiography and CMR.ResultsMyocardial fibrosis was found in 12/30 (40%, 9 men). The presence of myocardial fibrosis was associated with the following CMR-parameters: increased left ventricular mass (median (range) 55 g/m2 (43–83) vs. 46 g/m2 (36–64), p = 0.02), increased left atrial volume (median (range) 52 ml/m2 (36–87) vs. 46 ml/m2 (35–69), p = 0.04) and a trend toward lower LVEF (median (range) 63% (38–71) vs. 66% (60–80), p = 0.06). Overall, we found no association between the presence of myocardial fibrosis and abnormal findings on: ECG (p = 0.71), Holter-monitoring (p = 0.27) or echocardiographic measurements of left ventricular volumes, ejection fraction or global longitudinal strain (p = 0.18).ConclusionPatients with DM1 had a high prevalence of myocardial fibrosis which was not predicted by ECG, Holter-monitoring or echocardiography. CMR add additional information to current standard cardiac assessment and may prove to be a clinically valuable tool for risk stratification in DM1.

EFFECTS OF IV GLUCOSE AND ORAL MEDIUM-CHAIN TRIGLYCERIDE IN PATIENTS WITH VLCAD DEFICIENCY

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.nn### Methods.nnWe studied two unrelated Dutch men, aged 33 and 38 …

Contractile properties are disrupted in Becker muscular dystrophy, but not in limb girdle type 2I

We investigated whether a linear relationship between muscle strength and cross‐sectional area (CSA) is preserved in calf muscles of patients with Becker muscular dystrophy (BMD, nu2009=u200914) and limb‐girdle type 2I muscular dystrophy (LGMD2I, nu2009=u200911), before and after correcting for muscle fat infiltration. The Dixon magnetic resonance imaging technique was used to quantify fat and calculate a fat‐free contractile CSA. Strength was assessed by dynamometry. Muscle strength/CSA relationships were significantly lower in patients versus controls. The strength/contractile‐CSA relationship was still severely lowered in BMD, but was almost normalized in LGMD2I. Our findings suggest close to intact contractile properties in LGMD2I, which are severely disrupted in BMD. Ann Neurol 2016;80:466–471

Exercise Intolerance and Myoglobinuria Associated with a Novel Maternally Inherited MT-ND1 Mutation

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.

T.P.47 Bezafibrate does not improve fat oxidation in patients with disorders of fat metabolism; a double blind, randomized clinical trial

Abstract 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 (nxa0=xa05) and VLCAD (nxa0=xa05) 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.