Publications by authors named "John Vissing"

287 Publications

Plasma lactate responses during and after submaximal handgrip exercise are not diagnostically helpful in mitochondrial myopathy.

Mitochondrion 2021 Jul 15;60:21-26. Epub 2021 Jul 15.

Copenhagen Neuromuscular Center, Dept. of Neurology, Neuroscience Center, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Denmark & Dept of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

Introduction/background: Mitochondrial myopathy (MM) encompasses a clinical heterogenous group of patients that can be difficult to diagnose. The aim of this study was to investigate if changes in plasma lactate concentration during a 6-minute submaximal handgrip test (6MHGT) and a 20-minute post-exercise recovery period can be used as a diagnostic test for MM.

Methods: Twenty-nine patients with MM and nineteen healthy controls (HC) performed an intermittent handgrip exercise test at ½ Hz for 6 min at 50% of maximal voluntary contraction force. We calculated the area under the curve (AUC) of change in plasma lactate during exercise and recovery and compared AUC between groups (MM vs. HC, and between MM subgroups based on disease severity).

Results: The change in plasma lactate during exercise and recovery was similar in MM and HC (p = 0.65 and p = 0.57) and similar between MM subgroups (p ≥ 0.24).

Conclusion: Plasma lactate measured during and after a submaximal 6MHGT cannot be used as a diagnostic variable for MM.
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http://dx.doi.org/10.1016/j.mito.2021.07.002DOI Listing
July 2021

Myopathy can be a key phenotype of membrin (GOSR2) deficiency.

Hum Mutat 2021 Jun 24. Epub 2021 Jun 24.

Department of Neurology, Copenhagen Neuromuscular Center, University of Copenhagen, Copenhagen, Denmark.

T1-weighted, cross-sectional MR images showing shoulder girdle, abdominal, paraspinal, gluteal and thigh muscles almost completely replaced by fat, whereas lower leg muscles are almost unaffected i a patient who is compound heterozygous for pathogenic variants in GOSR2.
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http://dx.doi.org/10.1002/humu.24247DOI Listing
June 2021

Muscle involvement assessed by quantitative magnetic resonance imaging in patients with anoctamin 5 deficiency.

Eur J Neurol 2021 Jun 18. Epub 2021 Jun 18.

Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Objective: Using magnetic resonance imaging (MRI) and stationary dynamometry, the aim was to investigate the muscle affection in paraspinal muscles and lower extremities and compare the muscle affection in men and women with anoctamin 5 (ANO5) deficiency.

Methods: Seventeen patients (seven women) with pathogenic ANO5-mutations were included. Quantitative muscle fat fraction of back and leg muscles were assessed by Dixon MRI. Muscle strength was assessed by stationary dynamometer. Results were compared with 11 matched, healthy controls.

Results: Muscle involvement pattern in men with ANO5-deficiency is characterized by a severe fat replacement of hamstrings, adductor and gastrocnemius muscles, while paraspinal muscles are only mildly affected, while preserved gracilis and sartorius muscles were hypertrophied. Women with ANO5-myopathy, of the same age as male patients, were very mildly affected, showing muscle affection and strength resembling that found in healthy persons, with the exception of the gluteus minimus and medius and gastrocnemii muscles that were significantly replaced by fat. Although individual muscles showed clear asymmetric involvement in a few muscle groups, the overall muscle involvement was symmetric.

Conclusions: Patients with ANO5-deficiency have relatively preserved paraspinal muscles on imaging and only mild reduction of trunk extension strength in men only. Our study quantifies the large difference in muscle affection in lower extremity between women and men with ANO5-deficiency. The clinical notion is that affection may be very asymmetric in ANO5-deficiency, but the present study shows that while this may be true for a few muscles, the general impression is that muscle affection is very symmetric.
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http://dx.doi.org/10.1111/ene.14979DOI Listing
June 2021

Autophagy is affected in patients with hypokalemic periodic paralysis: an involvement in vacuolar myopathy?

Acta Neuropathol Commun 2021 06 13;9(1):109. Epub 2021 Jun 13.

Copenhagen Neuromuscular Center, section 8077, Copenhagen University Hospital: Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark.

Hypokalemic periodic paralysis is an autosomal dominant, rare disorder caused by variants in the genes for voltage-gated calcium channel Ca1.1 (CACNA1S) and Na1.4 (SCN4A). Patients with hypokalemic periodic paralysis may suffer from periodic paralysis alone, periodic paralysis co-existing with permanent weakness or permanent weakness alone. Hypokalemic periodic paralysis has been known to be associated with vacuolar myopathy for decades, and that vacuoles are a universal feature regardless of phenotype. Hence, we wanted to investigate the nature and cause of the vacuoles. Fourteen patients with the p.R528H variation in the CACNA1S gene was included in the study. Histology, immunohistochemistry and transmission electron microscopy was used to assess general histopathology, ultrastructure and pattern of expression of proteins related to muscle fibres and autophagy. Western blotting and real-time PCR was used to determine the expression levels of proteins and mRNA of the proteins investigated in immunohistochemistry. Histology and transmission electron microscopy revealed heterogenous vacuoles containing glycogen, fibrils and autophagosomes. Immunohistochemistry demonstrated autophagosomes and endosomes arrested at the pre-lysosome fusion stage. Expression analysis showed a significant decrease in levels of proteins an mRNA involved in autophagy in patients, suggesting a systemic effect. However, activation level of the master regulator of autophagy gene transcription, TFEB, did not differ between patients and controls, suggesting competing control over autophagy gene transcription by nutritional status and calcium concentration, both controlling TFEB activity. The findings suggest that patients with hypokalemic periodic paralysis have disrupted autophagic processing that contribute to the vacuoles seen in these patients.
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http://dx.doi.org/10.1186/s40478-021-01212-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201813PMC
June 2021

Nampt controls skeletal muscle development by maintaining Ca homeostasis and mitochondrial integrity.

Mol Metab 2021 Jun 11;53:101271. Epub 2021 Jun 11.

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Objective: NAD is a co-factor and substrate for enzymes maintaining energy homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT) controls NAD synthesis, and in skeletal muscle, NAD is essential for muscle integrity. However, the underlying molecular mechanisms by which NAD synthesis affects muscle health remain poorly understood. Thus, the objective of the current study was to delineate the role of NAMPT-mediated NAD biosynthesis in skeletal muscle development and function.

Methods: To determine the role of Nampt in muscle development and function, we generated skeletal muscle-specific Nampt KO (SMNKO) mice. We performed a comprehensive phenotypic characterization of the SMNKO mice, including metabolic measurements, histological examinations, and RNA sequencing analyses of skeletal muscle from SMNKO mice and WT littermates.

Results: SMNKO mice were smaller, with phenotypic changes in skeletal muscle, including reduced fiber area and increased number of centralized nuclei. The majority of SMNKO mice died prematurely. Transcriptomic analysis identified that the gene encoding the mitochondrial permeability transition pore (mPTP) regulator Cyclophilin D (Ppif) was upregulated in skeletal muscle of SMNKO mice from 2 weeks of age, with associated increased sensitivity of mitochondria to the Ca-stimulated mPTP opening. Treatment of SMNKO mice with the Cyclophilin D inhibitor, Cyclosporine A, increased membrane integrity, decreased the number of centralized nuclei, and increased survival.

Conclusions: Our study demonstrates that NAMPT is crucial for maintaining cellular Ca homeostasis and skeletal muscle development, which is vital for juvenile survival.
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http://dx.doi.org/10.1016/j.molmet.2021.101271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259345PMC
June 2021

Patients With Becker Muscular Dystrophy Have Severe Paraspinal Muscle Involvement.

Front Neurol 2021 21;12:613483. Epub 2021 May 21.

Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Paraspinal muscles are important for gross motor functions. Impairment of these muscles can lead to poor postural control and ambulation difficulty. Little knowledge exists about the involvement of paraspinal muscles in Becker muscular dystrophy. In this cross-sectional study, we investigated the involvement of paraspinal muscles with quantitative trunk strength measure and quantitative muscle MRI. Eighteen patients with Becker muscular dystrophy underwent trunk, hip, and thigh strength assessment using a Biodex dynamometer and an MRI Dixon scan. Fourteen age- and body mass index-matched healthy men were included for comparison. Muscle fat fraction (FF) of the paraspinal muscles (multifidus and erector spinae) was higher in participants with Becker muscular dystrophy vs. healthy controls at all three examined spinal levels (C6, Th12, and L4/L5) ( < 0.05). There was a strong and inverse correlation between paraspinal muscle FF and trunk extension strength (ρ = -0.829, < 0.001), gluteus maximus FF and hip extension strength (ρ = -0.701, = 0.005), FF of the knee extensor muscles (quadriceps and sartorius) and knee extension strength (ρ = -0.842, < 0.001), and FF of the knee flexor muscles (hamstring muscles) and knee flexion strength (ρ = -0.864, < 0.001). Fat fraction of the paraspinal muscles also correlated with muscle FF of the thigh muscles and lower leg muscles. In conclusion, patients with Becker muscular dystrophy demonstrate severe paraspinal muscular involvement indicated by low back extension strength and high levels of fat replacement, which parallel involvement of lower limb muscles. Assessment of paraspinal muscle strength and fat replacement may serve as a possible biomarker for both the clinical management and further study of the disease.
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http://dx.doi.org/10.3389/fneur.2021.613483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177107PMC
May 2021

Function, structure and quality of striated muscles in the lower extremities in patients with late onset Pompe Disease-an MRI study.

PeerJ 2021 6;9:e10928. Epub 2021 May 6.

Department of Neurology, Aarhus University Hospital, Aarhus N, Denmark.

Background: Pompe Disease (PD) is a rare inherited metabolic myopathy, caused by lysosomal--glucosidase (GAA) deficiency, which leads to glycogen accumulation within the lysosomes, resulting in cellular and tissue damage. Due to the emergence of a disease modifying treatment with recombinant GAA there has been a large increase in studies of late onset Pompe Disease (LOPD) during the last decade.

Methods: The present study evaluates muscle quality in 10 patients with LOPD receiving treatment with enzyme replacement therapy and in 10 age and gender matched healthy controls applying T-weighted Dixon MR imaging and isokinetic dynamometry. Muscle quality was determined by muscle strength in relation to muscle size (contractile cross-sectional area, CSA) and to muscle quality (fat fraction). A follow-up evaluation of the patients was performed after 8-12 months. Patient evaluations also included: six-minute walking test (6MWT), forced vital capacity, manual muscle testing and SF-36 questionnaire.

Results: Fat fraction of knee flexors (0.15 vs 0.07,  < 0.05) and hip muscles (0.11 vs 0.07,  < 0.05) were higher in patients than controls. In patients, contractile CSA correlated with muscle strength (knee flexors:  = 0.86, knee extensors:  = 0.88, hip extensors:  = 0.83,  < 0.05). No correlation was found between fat fraction and muscle strength. The fat fraction of thigh muscles did not correlate with scores from the clinical tests nor did it correlate with the 6MWT. During follow-up, the contractile CSA of the knee extensors increased by 2%. No other statistically significant change was observed. Quantitative MRI reflects muscle function in patients with LOPD, but larger long-term studies are needed to evaluate its utility in detecting changes over time.
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http://dx.doi.org/10.7717/peerj.10928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106912PMC
May 2021

No effect of resveratrol in patients with mitochondrial myopathy: A cross-over randomized controlled trial.

J Inherit Metab Dis 2021 May 2. Epub 2021 May 2.

Copenhagen Neuromuscular Center, Rigshospitalet, University hospital, Copenhagen, Denmark.

Mitochondrial myopathies (MM) are caused by mutations that typically affect genes involved in oxidative phosphorylation. Main symptoms are exercise intolerance and fatigue. Currently, there is no specific treatment for MM. Resveratrol (RSV) is a nutritional supplement that in preclinical studies has been shown to stimulate mitochondrial function. We hypothesized that RSV could improve exercise capacity in patients with MM. The study design was randomized, double-blind, cross-over and placebo-controlled. Eleven patients with genetically verified MM were randomized to receive either 1000 mg/day RSV or placebo (P) for 8 weeks followed by a 4-week washout and then the opposite treatment. Primary outcomes were changes in heart rate (HR) during submaximal cycling exercise and peak oxygen utilization (VO max) during maximal exercise. Secondary outcomes included reduction in perceived exertion, changes in lactate concentrations, self-rated function (SF-36) and fatigue scores (FSS), activities of electron transport chain complexes I and IV in mononuclear cells and mitochondrial biomarkers in muscle tissue among others. There were no significant differences in primary and secondary outcomes between treatments. Mean HR changes were -0.3 ± 4.3 (RSV) vs 1.8 ± 5.0 bpm (P), P = .241. Mean VO max changes were 0.7 ± 1.4 (RSV) vs -0.2 ± 2.3 mL/min/kg (P), P = .203. The study provides evidence that 1000 mg RSV daily is ineffective in improving exercise capacity in adults with MM. These findings indicate that previous in vitro studies suggesting a therapeutic potential for RSV in MM, do not translate into clinically meaningful effects in vivo.
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http://dx.doi.org/10.1002/jimd.12393DOI Listing
May 2021

Exercise Testing, Physical Training and Fatigue in Patients with Mitochondrial Myopathy Related to mtDNA Mutations.

J Clin Med 2021 Apr 20;10(8). Epub 2021 Apr 20.

Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet University Hospital of Copenhagen, 2100 Copenhagen, Denmark.

Mutations in mitochondrial DNA (mtDNA) cause disruption of the oxidative phosphorylation chain and impair energy production in cells throughout the human body. Primary mitochondrial disorders due to mtDNA mutations can present with symptoms from adult-onset mono-organ affection to death in infancy due to multi-organ involvement. The heterogeneous phenotypes that patients with a mutation of mtDNA can present with are thought, at least to some extent, to be a result of differences in mtDNA mutation load among patients and even among tissues in the individual. The most common symptom in patients with mitochondrial myopathy (MM) is exercise intolerance. Since mitochondrial function can be assessed directly in skeletal muscle, exercise studies can be used to elucidate the physiological consequences of defective mitochondria due to mtDNA mutations. Moreover, exercise tests have been developed for diagnostic purposes for mitochondrial myopathy. In this review, we present the rationale for exercise testing of patients with MM due to mutations in mtDNA, evaluate the diagnostic yield of exercise tests for MM and touch upon how exercise tests can be used as tools for follow-up to assess disease course or effects of treatment interventions.
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http://dx.doi.org/10.3390/jcm10081796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074604PMC
April 2021

E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases. Report from the 1st eNMD Congress: Nice, France, March 22-23, 2019.

J Neuromuscul Dis 2021 Apr 2. Epub 2021 Apr 2.

Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice, Peripheral Nervous System and Muscle Department, Rare Neuromuscular Disease Reference Center, ERN-Euro-NMD, Nice, France.

By definition, neuromuscular diseases are rare and fluctuating in terms of symptoms; patients are often lately diagnosed, do not have enough information to understand their condition and be proactive in their management. Usually, insufficient resources or services are available, leading to patients' social burden. From a medical perspective, the rarity of such diseases leads to the unfamiliarity of the medical staff and caregiver and an absence of consensus in disease assessment, treatment, and management. Innovations have to be developed in response to patients' and physicians' unmet needs.It is vital to improve several aspects of patients' quality of life with a better comprehension of their disease, simplify their management and follow-up, help their caregiver, and reduce the social and economic burden for living with a rare debilitating disease. Database construction regrouping patients' data and symptoms according to specific country registration on data privacy will be critical in establishing a clear consensus on neuromuscular disease treatment.Clinicians also need technological innovations to help them recognize neuromuscular diseases, find the best therapeutic approach based on medical consensus, and tools to follow patients' states regularly. Diagnosis also has to be improved by implementing automated systems to analyze a considerable amount of data, representing a significant step forward to accelerate the diagnosis and the patients' follow up. Further, the development of new tools able to precisely measure specific outcomes reliably is of the matter of importance in clinical trials to assess the efficacy of a newly developed compound.In this context, the creation of an expert community is essential to communicate and share ideas. To this end, 97 clinicians, healthcare professionals, researchers, and representatives of private companies from 9 different countries met to discuss the new perspective and challenges to develop and implement innovative tools in the field of neuromuscular diseases.Keywords.
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http://dx.doi.org/10.3233/JND-210655DOI Listing
April 2021

Antimyostatin Treatment in Health and Disease: The Story of Great Expectations and Limited Success.

Cells 2021 Mar 3;10(3). Epub 2021 Mar 3.

Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark.

In the past 20 years, myostatin, a negative regulator of muscle mass, has attracted attention as a potential therapeutic target in muscular dystrophies and other conditions. Preclinical studies have shown potential for increasing muscular mass and ameliorating the pathological features of dystrophic muscle by the inhibition of myostatin in various ways. However, hardly any clinical trials have proven to translate the promising results from the animal models into patient populations. We present the background for myostatin regulation, clinical and preclinical results and discuss why translation from animal models to patients is difficult. Based on this, we put the clinical relevance of future antimyostatin treatment into perspective.
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http://dx.doi.org/10.3390/cells10030533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001237PMC
March 2021

Zilucoplan: An Investigational Complement C5 Inhibitor for the Treatment of Acetylcholine Receptor Autoantibody-Positive Generalized Myasthenia Gravis.

Expert Opin Investig Drugs 2021 May 1;30(5):483-493. Epub 2021 Apr 1.

Department of Neurology, Institute of Translational Neurology, University of Münster, Münster, Germany.

Introduction: Generalized myasthenia gravis (gMG) is an autoimmune disorder in which pathogenic autoantibodies damage the neuromuscular junction, causing disabling or life-threatening muscle weakness. Most treatments nonspecifically inhibit aspects of the immune system, do not directly address the causal mechanisms of tissue damage, and often have side-effect profiles that negatively impact patients. Understanding of the central pathogenic role of the complement cascade in gMG is advancing, and a new complement-targeting treatment is under investigation.

Areas Covered: We provide an overview of gMG etiology, the complement cascade, current treatments, and the investigational gMG therapy zilucoplan. Zilucoplan is a small, subcutaneously administered, macrocyclic peptide that inhibits cleavage of complement component C5 and the subsequent formation of the membrane attack complex.

Expert Opinion: In a randomized, double-blind, placebo-controlled, phase 2 clinical trial, zilucoplan demonstrated clinically meaningful complement inhibition in patients with acetylcholine receptor-positive gMG. Zilucoplan, a first-of-its-kind cyclic peptide targeting C5, appears to be a therapeutic option for the treatment of gMG based on available pharmacokinetic/pharmacodynamic data and phase 1 and 2 efficacy, safety, and tolerability data with limited long-term follow-up. Zilucoplan use earlier in the treatment paradigm would be suitable in this population should phase 3 efficacy and safety data be equally favorable.
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http://dx.doi.org/10.1080/13543784.2021.1897567DOI Listing
May 2021

Combined Muscle Biopsy and Comprehensive Electrophysiology in General Anesthesia is Valuable in Diagnosis of Neuromuscular Disease in Children.

Neuropediatrics 2021 Mar 11. Epub 2021 Mar 11.

Department of Paediatrics, Copenhagen University Hospital, Rigshospitalet, Denmark.

Aim:  The diagnostic workup in patients with delayed motor milestones suspected of having either myopathy or a congenital myasthenic syndrome is complex. Our hypothesis was that performance of a muscle biopsy and neurophysiology including stimulated single-fiber electromyography during an anesthetic procedure, combined with genetic testing has a high diagnostic quality.

Materials And Methods:  Clinical and paraclinical data were retrospectively collected from 24 patients aged from 1 month to 10 years (median: 5.2 years).

Results:  Neurophysiology examination was performed in all patients and was abnormal in 11 of 24. No patients had findings suggestive of a myasthenic syndrome. Muscle biopsy was performed in 21 of 24 and was normal in 16. Diagnostic findings included nemaline rods, inclusion bodies, fiber size variability, and type-II fiber atrophy. Genetic testing with either a gene panel or exome sequencing was performed in 18 of 24 patients, with pathogenic variants detected in , , , , , and genes.

Conclusion:  Results supporting a neuromuscular abnormality were found in 15 of 24. In six patients (25%), we confirmed a genetic diagnosis and 12 had a clinical neuromuscular diagnosis. The study suggests that combined use of neurophysiology and muscle biopsy in cases where genetic testing does not provide a diagnosis can be useful in children with delayed motor milestones and clinical evidence of a neuromuscular disease.
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http://dx.doi.org/10.1055/s-0041-1726120DOI Listing
March 2021

Improving Care and Empowering Adults Living with SMA: A Call to Action in the New Treatment Era.

J Neuromuscul Dis 2021 Feb 24. Epub 2021 Feb 24.

MDUK Neuromuscular Center, Department of Paediatrics, University of Oxford, Oxford, UK.

While Spinal Muscular Atrophy (SMA) has historically been managed with supportive measures, the emergence of innovative medicines has given those living with SMA hope for improved quality of life and has revolutionized care. Despite these advances, the use of therapies and changes in disease management strategies have focused on pediatric populations, leaving adults living with SMA, and those transitioning into adulthood, relatively neglected. Through a multi-faceted approach that gathered unbiased perspectives from clinical experts, validated insights from individuals with lived experiences, and substantiated findings with evidence from the literature, we have exposed unmet needs that are hindering the field and, ultimately, impacting care and quality of life for adults living with SMA. Here, we set new aspirations and calls to action to inspire continued research in this field, stimulate dialogue across the SMA community and inform policies that deliver effective management and care throughout an adult's journey living with SMA.
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http://dx.doi.org/10.3233/JND-200611DOI Listing
February 2021

Progression or Not - A Small Natural History Study of Genetical Confirmed Congenital Myopathies.

J Neuromuscul Dis 2021 Feb 19. Epub 2021 Feb 19.

Copenhagen Neuromuscular Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.

Background: Clinical characteristics of patients with congenital myopathies (CM) are well known but there is a lack of knowledge about the natural history and course of disease of the different genetic subtypes. in 2010 we assessed the national cohort of Danish patients with CM to decide genetic diagnosing and describe genotype- phenotype relationships.AIM of this follow-up study was to evaluate the course of disease since the initial study and to evaluate the applicability of standard assessment methods to reflect change over time and patients own opinion on the course of disease.

Methods: All available genetically diagnosed patients studied by us in 2010 (n = 41) were invited to the follow-up study; assessment of motor function (MFM-32), muscle strength (MRC %)and respiratory function (FVC %) and prime assessor were the same as in the initial study. Patients were asked whether the course of disease had progresses, was stable or had improved.

Results: 23 patients (15-61 y) accepted the invitation. Mean follow-up time was 7.7 years. Loss of muscle strength was more prominent in patients with mutations in DNM2, RYR1 and TPM2/3 genes and deterioration in FVC % was more evident in patients carrying NEB and ACTA1 gene mutations. MFM-sum score was less sensitive to change compared to MRC-sum score. In general, agreement between the patient's own opinion of the course of disease and results of assessments was good.

Conclusion: The number of patients in the study is too small to be conclusive, but the results indicate that CM can be stable or slowly progressive depending on the genetic subtype.
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http://dx.doi.org/10.3233/JND-200574DOI Listing
February 2021

251st ENMC international workshop: Polyglucosan storage myopathies 13-15 December 2019, Hoofddorp, the Netherlands.

Neuromuscul Disord 2021 05 23;31(5):466-477. Epub 2021 Jan 23.

Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.

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http://dx.doi.org/10.1016/j.nmd.2021.01.010DOI Listing
May 2021

Efficacy and Safety of Bimagrumab in Sporadic Inclusion Body Myositis: Long-term Extension of RESILIENT.

Neurology 2021 03 17;96(12):e1595-e1607. Epub 2021 Feb 17.

From the Department of Neurology (A.A.A.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Medical Research Council Centre for Neuromuscular Diseases (M.G.H., P.M.M.) and Institute of Neurology, Department of Neuromuscular Diseases & Centre for Rheumatology (P.M.M.), University College London; Department of Rheumatology & Queen Square Centre for Neuromuscular Diseases (P.M.M.), University College London Hospitals NHS Foundation Trust; Department of Rheumatology (P.M.M.), Northwick Park Hospital, London North West University Healthcare NHS Trust, UK; Department of Neurology (U.A.B.), Leiden University Medical Center, Netherlands; National Institute for Health Research Manchester Biomedical Research Centre (H.C.), Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, The University of Manchester, UK; Department of Internal Medicine and Clinical Immunology (O.B.), Pitié-Salpêtrière Hospital, Sorbonne Université, Paris, France; Novartis Healthcare Pvt. Ltd. (K.A.K), Hyderabad, India; Novartis Pharmaceuticals (M.W., D.A.P.), East Hanover, NJ; Novartis Pharma AG (L.B.T., A.A.S-T.), Basel, Switzerland; Department of Neurology (T.E.L.), The Johns Hopkins University School of Medicine, Baltimore, MD; Institute for Immunology & Infectious Diseases (M.N.), Fiona Stanley Hospital, Murdoch University and Notre Dame University, Perth; Department of Neurology (C.L.), Royal North Shore Hospital, New South Wales; Calvary Health Care Bethlehem (K.A.R.), Caulfield South, Australia; Department of Neurology (M.d.V), Amsterdam University Medical Centre, the Netherlands; Department of Medicine (D.P.A.), University of Miami, FL; Department of Neurology (R.J.B., M.M.D.), University of Kansas Medical Center, Kansas City; Department of Neurology (J.A.L.M.), Newcastle upon Tyne Hospitals NHS Foundation Trust, UK; Department of Neurology (J.T.K.), The Ohio State University Wexner Medical Center, Columbus; Neuromuscular Research Center (B.O., N.C.J.), UC Davis School of Medicine, Sacramento, CA; Department of Neurology (P.V.d.B.), University Hospital Saint-Luc, University of Louvain, Brussels; Neuromuscular Reference Centre, Department of Neurology (J.B.), Antwerp University Hospital; Institute Born-Bunge (J.B.), University of Antwerp; Department of Neurology (J.L.d.B.), Ghent University Hospital, Belgium; Department of Neurology (C.K.), Oregon Health & Science University, Portland; Department of Neurology (W.S.D.), Massachusetts General Hospital, Neuromuscular Diagnostic Center and Electromyography Laboratory, Boston; Department of Neurology (M.M.), Fondazione Policlinico Universitario Agostino Gemelli IRCCS; Università Cattolica del Sacro Cuore (M.M.), Rome, Italy; Department of Neurology (S.P.N.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (H.H.J.), University Hospital and University of Zurich, Switzerland; Department of Neurosciences (E.P.), University of Padova School of Medicine; Fondazione IRCCS Istituto Neurologico Carlo Besta (L.M.), Milan; Unit of Neurology and Neuromuscular Disorders (C.R.), Azienda Ospedaliera Universitaria Policlinico G Martino, University of Messina; Center for Neuromuscular Diseases (M.F.), Unit of Neurology, ASST Spedali Civili and University of Brescia, Italy; Nerve and Muscle Center of Texas (A.I.S.), Houston; Neuromuscular Research Center (K.S.), Phoenix, AZ; Department of Neurology (N.A.G.), ALS & Neuromuscular Center, University of California Irvine, Orange; Department of Neurology (M.M.-Y.), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo; Department of Neurology (S.Y.), Kumamoto University Hospital; Department of Neurology (N.S.), Tohoku University Hospital, Miyagi; Department of Neurology (M.A.), Tohoku University School of Medicine, Sendai; Department of Neurology (M.K.), Nagoya University Hospital, Aichi; Department of Neurology (H.M.), Osaka City General Hospital; Wakayama Medical University Hospital (K.M.); Tokushima University Hospital (H.N.); Department of Neuromuscular Research (I.N.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; RTI Health Solutions (C.D.R., V.S.L.W.), Research Triangle Park, NC; Copenhagen Neuromuscular Center (J.V.), Rigshospitalet, University of Copenhagen, Denmark; and UCB (L.Z.A.), Bulle, Switzerland. H.N. is currently affiliated with the Department of Neurology, Kanazawa Medical University, Ishikawa, Japan. B.O. is currently affiliated with the Department of Neurology, Mayo Clinic, Jacksonville, FL.

Objective: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM).

Methods: Participants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety.

Results: Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively).

Conclusion: Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint.

Clinical Trial Registration: Clinicaltrials.gov identifier NCT02573467.

Classification Of Evidence: This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.
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http://dx.doi.org/10.1212/WNL.0000000000011626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032371PMC
March 2021

Quantitative Muscle MRI as Outcome Measure in Patients With Becker Muscular Dystrophy-A 1-Year Follow-Up Study.

Front Neurol 2020 5;11:613489. Epub 2021 Jan 5.

Department of Neurology, Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

With the advent of emerging molecular therapies for muscular dystrophies, the need for knowledge about natural history course of such diseases is of utmost importance in the preparation for future trials. However, for Becker muscular dystrophy such knowledge is scarce. In this 1-year follow-up study, we examined disease progression in Becker muscular dystrophy by monitoring changes in MRI-assessed muscle fat fraction (FF) in axial and lower limb muscles and quantitative muscle strength of axial muscles. Sixteen patients with Becker muscular dystrophy were investigated by (1) muscle strength of the trunk using a Biodex dynamometer and (2) Dixon muscle MRI of paraspinal and lower limb muscles. Quantitative MRI data was analyzed in two parts: The first part consisted of all participants ( = 16). The second analysis assessed two separate groups comprising lesser affected participants ( = 5) and more severely affected patients ( = 11). Trunk extension and flexion strength remained stable from baseline to follow-up. MRI did not show any significant increase in muscle FF % from baseline to follow-up in all patients, except for multifidus at the spinal level T12 ( = 0.01). However, when we analyzed the two subgroups, according to disease severity, FF% increased in the lesser severely affected group at L4/L5 erector spinae ( = 0.047), sartorius ( = 0.028), gracilis ( = 0.009), tibialis anterior ( = 0.047), peroneals ( = 0.028), and gastrocnemius medialis ( = 0.009), while the severely affected group only increased significantly at T12 multifidus ( = 0.028) and T12 erector spinae ( = 0.011). No difference in muscle strength was observed in the two subgroups. Our results add to the existing knowledge about the natural rate of disease progression in BMD. As quantitative MRI was able to identify changes where strength assessment was not, MRI could be a strong biomarker for change in BMD. However, our findings show that it is important to stratify patients with BMD according to phenotype for future clinical trials.
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http://dx.doi.org/10.3389/fneur.2020.613489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813752PMC
January 2021

Preclinical Research in Glycogen Storage Diseases: A Comprehensive Review of Current Animal Models.

Int J Mol Sci 2020 Dec 17;21(24). Epub 2020 Dec 17.

Mitochondrial and Neuromuscular Disorders Unit, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.

GSD are a group of disorders characterized by a defect in gene expression of specific enzymes involved in glycogen breakdown or synthesis, commonly resulting in the accumulation of glycogen in various tissues (primarily the liver and skeletal muscle). Several different GSD animal models have been found to naturally present spontaneous mutations and others have been developed and characterized in order to further understand the physiopathology of these diseases and as a useful tool to evaluate potential therapeutic strategies. In the present work we have reviewed a total of 42 different animal models of GSD, including 26 genetically modified mouse models, 15 naturally occurring models (encompassing quails, cats, dogs, sheep, cattle and horses), and one genetically modified zebrafish model. To our knowledge, this is the most complete list of GSD animal models ever reviewed. Importantly, when all these animal models are analyzed together, we can observe some common traits, as well as model specific differences, that would be overlooked if each model was only studied in the context of a given GSD.
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http://dx.doi.org/10.3390/ijms21249621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766110PMC
December 2020

Data from the European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC).

Orphanet J Rare Dis 2020 11 24;15(1):330. Epub 2020 Nov 24.

Copenhagen Neuromuscular Center, Section 6921, Rigshospitalet, University of Copenhagen, 2100, Copenhagen, Denmark.

Background: The European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) was launched to register rare muscle glycogenoses in Europe, to facilitate recruitment for research trials and to learn about the phenotypes and disseminate knowledge about the diseases through workshops and websites. A network of twenty full and collaborating partners from eight European countries and the US contributed data on rare muscle glycogenosis in the EUROMAC registry. After approximately 3 years of data collection, the data in the registry was analysed.

Results: Of 282 patients with confirmed diagnoses of muscle glycogenosis, 269 had McArdle disease. New phenotypic features of McArdle disease were suggested, including a higher frequency (51.4%) of fixed weakness than reported before, normal CK values in a minority of patients (6.8%), ptosis in 8 patients, body mass index above background population and number of comorbidities with a higher frequency than in the background population (hypothyroidism, coronary heart disease).

Conclusions: The EUROMAC project and registry have provided insight into new phenotypic features of McArdle disease and the variety of co-comorbidities affecting people with McArdle disease. This should lead to better management of these disorders in the future, including controlling weight, and preventive screening for thyroid and coronary artery diseases, as well as physical examination with attention on occurrence of ptosis and fixed muscle weakness. Normal serum creatine kinase in a minority of patients stresses the need to not discard a diagnosis of McArdle disease even though creatine kinase is normal and episodes of myoglobinuria are absent.
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http://dx.doi.org/10.1186/s13023-020-01562-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687836PMC
November 2020

Efficacy and Safety of Rozanolixizumab in Moderate to Severe Generalized Myasthenia Gravis: A Phase 2 Randomized Control Trial.

Neurology 2021 02 20;96(6):e853-e865. Epub 2020 Nov 20.

From Toronto General Hospital (V.B.), University Health Network, University of Toronto, Canada; Department of Neurology (M. Benatar), Miller School of Medicine, University of Miami, FL; Department of Neurology (H.A.), Aarhus University Hospital; Department of Neurology, Rigshospitalet (J.V.), University of Copenhagen, Denmark; UCB Pharma (M. Brock), Raleigh, NC; UCB Pharma (B.G., P.K., F.W.), Monheim-am-Rhein, Germany; iMed Communications (L.G.), Macclesfield, UK; and Neuromuscular Reference Centre, Department of Neurology (P.V.d.B.), University Hospital Saint-Luc, University of Louvain, Brussels, Belgium.

Objective: To explore the clinical efficacy and safety of subcutaneous (SC) rozanolixizumab, an anti-neonatal Fc receptor humanized monoclonal antibody, in patients with generalized myasthenia gravis (gMG).

Methods: In this phase 2a, randomized, double-blind, placebo-controlled, 2-period, multicenter trial (NCT03052751), patients were randomized (1:1) in period 1 (days 1-29) to 3 once-weekly (Q1W) SC infusions of rozanolixizumab 7 mg/kg or placebo. In period 2 (days 29-43), patients were re-randomized to either rozanolixizumab 7 mg/kg or 4 mg/kg (3 Q1W SC infusions), followed by an observation period (days 44-99). Primary endpoint was change from baseline to day 29 in Quantitative Myasthenia Gravis (QMG) score. Secondary endpoints were change from baseline to day 29 in MG-Activities of Daily Living (MG-ADL) and MG-Composite (MGC) scores and safety.

Results: Forty-three patients were randomized (rozanolixizumab 21, placebo 22 [period 1]). Least squares (LS) mean change from baseline to day 29 for rozanolixizumab vs placebo was as follows: QMG (LS mean -1.8 vs -1.2, difference -0.7, 95% upper confidence limit [UCL] 0.8; = 0.221; not statistically significant), MG-ADL (LS mean -1.8 vs -0.4, difference -1.4, 95% UCL -0.4), and MGC (LS mean -3.1 vs -1.2, difference -1.8, 95% UCL 0.4) scores. Efficacy measures continued to improve with rozanolixizumab 7 mg/kg in period 2. The most common adverse event in period 1 was headache (rozanolixizumab 57%, placebo 14%).

Conclusion: Whereas change from baseline in QMG was not statistically significant, the data overall suggest rozanolixizumab may provide clinical benefit in patients with gMG and was generally well tolerated. Phase 3 evaluation is ongoing (NCT03971422).

Classification Of Evidence: This study provides Class I evidence that for patients with gMG, rozanolixizumab is well-tolerated, but did not significantly improve QMG score.
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http://dx.doi.org/10.1212/WNL.0000000000011108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105899PMC
February 2021

Mutation Load of Single, Large-Scale Deletions of mtDNA in Mitotic and Postmitotic Tissues.

Front Genet 2020 2;11:547638. Epub 2020 Oct 2.

Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

It is generally accepted that patients with chronic progressive ophthalmoplegia caused by single large-scale deletion (SLD) of mitochondrial DNA (mtDNA) only harbor mutation in skeletal and eye muscles. The aim of this study was to investigate the presence and the level of heteroplasmy of mtDNA deletions in mitotic tissues of patients displaying mtDNA deletion of mitotic tissues in patients with SLDs and pure muscle phenotype. MtDNA mutation load was studied in three mitotic (urine epithelial cells, buccal mucosa, and blood) and one postmitotic (skeletal muscle) tissues in 17 patients with SLDs of mtDNA and pure muscle involvement. All patients had mtDNA deletion in skeletal muscle, and 78% of the patients also displayed the mtDNA deletion in mitotic tissues. The mtDNA mutation load was higher in skeletal muscle versus mitotic tissues. The mtDNA mutation load did not correlate with age of sampling of tissues, but there was a correlation between the mtDNA mutations load in skeletal muscle and (1) the site of 5' end breaking point of the SLD, (2) the size of SLD, (3) the number of affected tRNAs, and (4) age at onset ( > 0.58, < 0.05). The findings indicate that mtDNA mutation in mitotic tissue is common in patients with SLDs of mtDNA. The lack of correlation between age of tissue sampling, age at onset, and mtDNA mutation load in mitotic tissues indicates that there is no extensive post-natal modification of mtDNA mutation load in mitotic tissues of patients with pure muscle phenotype.
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http://dx.doi.org/10.3389/fgene.2020.547638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566915PMC
October 2020

Bimagrumab vs Optimized Standard of Care for Treatment of Sarcopenia in Community-Dwelling Older Adults: A Randomized Clinical Trial.

JAMA Netw Open 2020 10 1;3(10):e2020836. Epub 2020 Oct 1.

Translational Medicine and Musculoskeletal Diseases Research, Novartis Institutes for BioMedical Research, Basel, Switzerland.

Importance: The potential benefit of novel skeletal muscle anabolic agents to improve physical function in people with sarcopenia and other muscle wasting diseases is unknown.

Objective: To confirm the safety and efficacy of bimagrumab plus the new standard of care on skeletal muscle mass, strength, and physical function compared with standard of care alone in community-dwelling older adults with sarcopenia.

Design, Setting, And Participants: This double-blind, placebo-controlled, randomized clinical trial was conducted at 38 sites in 13 countries among community-dwelling men and women aged 70 years and older meeting gait speed and skeletal muscle criteria for sarcopenia. The study was conducted from December 2014 to June 2018, and analyses were conducted from August to November 2018.

Interventions: Bimagrumab 700 mg or placebo monthly for 6 months with adequate diet and home-based exercise.

Main Outcomes And Measures: The primary outcome was the change in Short Physical Performance Battery (SPPB) score after 24 weeks of treatment. Secondary outcomes included 6-minute walk distance, usual gait speed, handgrip strength, lean body mass, fat body mass, and standard safety parameters.

Results: A total of 180 participants were recruited, with 113 randomized to bimagrumab and 67 randomized to placebo. Among these, 159 participants (88.3%; mean [SD] age, 79.1 [5.3] years; 109 [60.6%] women) completed the study. The mean SPPB score increased by a mean of 1.34 (95% CI, 0.90 to 1.77) with bimagrumab vs 1.03 (95% CI, 0.53 to 1.52) with placebo (P = .13); 6-minute walk distance increased by a mean of 24.60 (95% CI, 7.65 to 41.56) m with bimagrumab vs 14.30 (95% CI, -4.64 to 33.23) m with placebo (P = .16); and gait speed increased by a mean of 0.14 (95% CI, 0.09 to 0.18) m/s with bimagrumab vs 0.11 (95% CI, 0.05 to 0.16) m/s with placebo (P = .16). Bimagrumab was safe and well-tolerated and increased lean body mass by 7% (95% CI, 6% to 8%) vs 1% (95% CI, 0% to 2%) with placebo, resulting in difference of 6% (95% CI, 4% to 7%) (P < .001).

Conclusions And Relevance: This randomized clinical trial found no significant difference between participants treated with bimagrumab vs placebo among older adults with sarcopenia who had 6 months of adequate nutrition and light exercise, with physical function improving in both groups. Bimagrumab treatment was safe, well-tolerated, increased lean body mass, and decreased fat body mass. The effects of sarcopenia, an increasing cause of disability in older adults, can be reduced with proper diet and exercise.

Trial Registration: ClinicalTrials.gov Identifier: NCT02333331; EudraCT number: 2014-003482-25.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.20836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573681PMC
October 2020

Creation and implementation of a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC registry).

Orphanet J Rare Dis 2020 10 15;15(1):187. Epub 2020 Oct 15.

Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, and Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Pg. Vall d'Hebron 119, 08035, Barcelona, Catalonia, Spain.

Background: International patient registries are of particular importance for rare disorders, as they may contribute to overcome the lack of knowledge derived from low number of patients and limited awareness of these diseases, and help to learn more about their geographical or population-based specificities, which is relevant for research purposes and for promoting better standards of care and diagnosis. Our objective was to create and implement a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) and to disseminate the knowledge of these disorders.

Results: Teams from nine different countries (United Kingdom, Spain, Italy, France, Germany, Denmark, Greece, Turkey and USA) created a consortium that developed the first European registry dedicated to rare muscle glycogenoses. A work plan was implemented to design the database and platform that constitute the registry, by choosing clinical, genetics and molecular variables of interest, based on experience gained from previous national registries for similar metabolic disorders. Among dissemination activities, several teaching events were organized in different countries, especially those where the consortium considered the awareness of these diseases needs to be promoted among health professionals and patients.

Conclusion: EUROMAC represents a step forward in the knowledge of those disorders to which it is dedicated, and will have relevant clinical outcomes at the diagnostic, epidemiological, clinical and research level.
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http://dx.doi.org/10.1186/s13023-020-01455-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558742PMC
October 2020

Phenotypic Spectrum of α-Dystroglycanopathies Associated With the c.919T>a Variant in the FKRP Gene in Humans and Mice.

J Neuropathol Exp Neurol 2020 12;79(12):1257-1264

Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Mutations in the fukutin-related protein gene, FKRP, are the most frequent single cause of α-dystroglycanopathy. Rare FKRP mutations are clinically not well characterized. Here, we review the phenotype associated with the rare c.919T>A mutation in FKRP in humans and mice. We describe clinical and paraclinical findings in 6 patients, 2 homozygous, and 4-compound heterozygous for c.919T>A, and compare findings with a mouse model we generated, which is homozygous for the same mutation. In patients, the mutation at the homozygous state is associated with a severe congenital muscular dystrophy phenotype invariably characterized by severe multisystem disease and early death. Compound heterozygous patients have a severe limb-girdle muscular dystrophy phenotype, loss of ambulation before age 20 and respiratory insufficiency. In contrast, mice homozygous for the same mutation show no symptoms or signs of muscle disease. Evidence therefore defines the FKRP c.919T>A as a very severe mutation in humans. The huge discrepancy between phenotypes in humans and mice suggests that differences in protein folding/processing exist between human and mouse Fkrp. This emphasizes the need for more detailed structural analyses of FKRP and shows the challenges of developing appropriate animal models of dystroglycanopathies that mimic the disease course in humans.
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http://dx.doi.org/10.1093/jnen/nlaa120DOI Listing
December 2020

Effect of Aerobic Exercise Training and Deconditioning on Oxidative Capacity and Muscle Mitochondrial Enzyme Machinery in Young and Elderly Individuals.

J Clin Med 2020 Sep 26;9(10). Epub 2020 Sep 26.

Department of Neurology, Copenhagen Neuromuscular Center, Rigshospitalet, DK-2100 Copenhagen, Denmark.

Mitochondrial dysfunction is thought to be involved in age-related loss of muscle mass and function (sarcopenia). Since the degree of physical activity is vital for skeletal muscle mitochondrial function and content, the aim of this study was to investigate the effect of 6 weeks of aerobic exercise training and 8 weeks of deconditioning on functional parameters of aerobic capacity and markers of muscle mitochondrial function in elderly compared to young individuals. In 11 healthy, elderly (80 ± 4 years old) and 10 healthy, young (24 ± 3 years old) volunteers, aerobic training improved maximal oxygen consumption rate by 13%, maximal workload by 34%, endurance capacity by 2.4-fold and exercise economy by 12% in the elderly to the same extent as in young individuals. This evidence was accompanied by a similar training-induced increase in muscle citrate synthase (CS) (31%) and mitochondrial complex I-IV activities (51-163%) in elderly and young individuals. After 8 weeks of deconditioning, endurance capacity (-20%), and enzyme activity of CS (-18%) and complex I (-40%), III (-25%), and IV (-26%) decreased in the elderly to a larger extent than in young individuals. In conclusion, we found that elderly have a physiological normal ability to improve aerobic capacity and mitochondrial function with aerobic training compared to young individuals, but had a faster decline in endurance performance and muscle mitochondrial enzyme activity after deconditioning, suggesting an age-related issue in maintaining oxidative metabolism.
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http://dx.doi.org/10.3390/jcm9103113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601902PMC
September 2020

Vacuoles, Often Containing Glycogen, Are a Consistent Finding in Hypokalemic Periodic Paralysis.

J Neuropathol Exp Neurol 2020 10;79(10):1127-1129

Copenhagen Neuromuscular Center, Department of Neurology.

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http://dx.doi.org/10.1093/jnen/nlaa063DOI Listing
October 2020

New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy.

Brain 2020 09;143(9):2696-2708

Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genova, Italy.

Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3-6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.
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http://dx.doi.org/10.1093/brain/awaa228DOI Listing
September 2020

Age-Associated Salivary MicroRNA Biomarkers for Oculopharyngeal Muscular Dystrophy.

Int J Mol Sci 2020 Aug 22;21(17). Epub 2020 Aug 22.

Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, 6525AJ Nijmegen, The Netherlands.

Small non-coding microRNAs (miRNAs) are involved in the regulation of mRNA stability. Their features, including high stability and secretion to biofluids, make them attractive as potential biomarkers for diverse pathologies. This is the first study reporting miRNA as potential biomarkers for oculopharyngeal muscular dystrophy (OPMD), an adult-onset myopathy. We hypothesized that miRNA that is differentially expressed in affected muscles from OPMD patients is secreted to biofluids and those miRNAs could be used as biomarkers for OPMD. We first identified candidate miRNAs from OPMD-affected muscles and from muscles from an OPMD mouse model using RNA sequencing. We then compared the OPMD-deregulated miRNAs to the literature and, subsequently, we selected a few candidates for expression studies in serum and saliva biofluids using qRT-PCR. We identified 126 miRNAs OPMD-deregulated in human muscles, but 36 deregulated miRNAs in mice only (pFDR < 0.05). Only 15 OPMD-deregulated miRNAs overlapped between the in humans and mouse studies. The majority of the OPMD-deregulated miRNAs showed opposite deregulation direction compared with known muscular dystrophies miRNAs (myoMirs), which are associated. In contrast, similar dysregulation direction was found for 13 miRNAs that are common between OPMD and aging muscles. A significant age-association ( < 0.05) was found for 17 OPMD-deregulated miRNAs (13.4%), whereas in controls, only six miRNAs (1.4%) showed a significant age-association, suggesting that miRNA expression in OPMD is highly age-associated. miRNA expression in biofluids revealed that OPMD-associated deregulation in saliva was similar to that in muscles, but not in serum. The same as in muscle, miRNA expression levels in saliva were also found to be associated with age ( < 0.05). Moreover, the majority of OPMD-miRNAs were found to be associated with dysphagia as an initial symptom. We suggest that levels of specific miRNAs in saliva can mark muscle degeneration in general and dysphagia in OPMD.
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http://dx.doi.org/10.3390/ijms21176059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503697PMC
August 2020
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