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Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients.

Authors
  • Molenaar, Joery P1
  • Verhoeven, Jamie I1
  • Rodenburg, Richard J2
  • Kamsteeg, Erik J3
  • Erasmus, Corrie E1
  • Vicart, Savine4
  • Behin, Anthony4
  • Bassez, Guillaume4
  • Magot, Armelle5
  • Péréon, Yann5
  • Brandom, Barbara W6
  • Guglielmi, Valeria7
  • Vattemi, Gaetano7
  • Chevessier, Frédéric8
  • Mathieu, Jean9
  • Franques, Jérôme10
  • Suetterlin, Karen11
  • Hanna, Michael G11
  • Guyant-Marechal, Lucie12
  • Snoeck, Marc M13
  • And 11 more
  • 1 Department of Neurology, Donders Centre for Medical Neuroscience, Radboud University Medical Centre, Nijmegen, The Netherlands. , (Netherlands)
  • 2 Department of Pediatrics, Translational Metabolic Laboratory, Radboud Center for Mitochondrial Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands. , (Netherlands)
  • 3 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. , (Netherlands)
  • 4 Assistance Publique-Hôpitaux de Paris, Centre de Référence des Canalopathies Musculaires, Centre de Référence des Maladies Neuromusculaires-Paris Est et Service de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. , (France)
  • 5 CHU Nantes, Centre de Référence Maladies Neuromusculaires AOC, Nantes, France. , (France)
  • 6 Department of Anesthesiology, Children's Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • 7 Department of Neurosciences, Biomedicine and Movement Sciences, Section of Clinical Neurology, University of Verona, Verona, Italy. , (Italy)
  • 8 CureVac AG, Tübingen, Germany. , (Germany)
  • 9 Neuromuscular Clinic, Centre de Réadaptation en Déficience Physique de Jonquière, Jonquière, Québec, Canada. , (Canada)
  • 10 Centre de référence des maladies neuromusculaires et de la SLA, hôpital La Timone, AP-HM, Aix-Marseille université, avenue Jean-Moulin, Marseille, France. , (France)
  • 11 MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
  • 12 Department of Neurology, Rouen University Hospital, France. , (France)
  • 13 Department of Anaesthesiology, Canisius-Wilhelmina Ziekenhuis, Nijmegen, The Netherlands. , (Netherlands)
  • 14 Department of Neurology, Salford Royal NHS Foundation Trust, Greater Manchester, UK.
  • 15 Nerve-Muscle Unit, Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV), Lausanne, Switzerland. , (Switzerland)
  • 16 Neuromuscular Area, Biodonostia Health Research Institute, Department of Neurology, University Hospital Donostia, CIBERNED, San Sebastián, Spain. , (Spain)
  • 17 Hospital Galdakao-Usansolo in Biscay, Basque Country, Spain. , (Spain)
  • 18 Sozialpädiatrisches Zentrum Frankfurt Mitte, Neuromuskulares Zentrum, Frankfurt, Germany. , (Germany)
  • 19 Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands. , (Netherlands)
  • 20 Departments of Anesthesia and Biomedicine, Basel University and Basel University Hospital, Basel, Switzerland. , (Switzerland)
  • 21 Department of Life Sciences, University of Ferrara, Ferrara, Italy. , (Italy)
Type
Published Article
Journal
Brain
Publisher
Oxford University Press
Publication Date
Feb 01, 2020
Volume
143
Issue
2
Pages
452–466
Identifiers
DOI: 10.1093/brain/awz410
PMID: 32040565
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies. © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.

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