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

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 ancilla...

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Autores principales: Molenaar, Joery P, Verhoeven, Jamie I, Rodenburg, Richard J, Kamsteeg, Erik J, Erasmus, Corrie E, Vicart, Savine, Behin, Anthony, Bassez, Guillaume, Magot, Armelle, Péréon, Yann, Brandom, Barbara W, Guglielmi, Valeria, Vattemi, Gaetano, Chevessier, Frédéric, Mathieu, Jean, Franques, Jérôme, Suetterlin, Karen, Hanna, Michael G, Guyant-Marechal, Lucie, Snoeck, Marc M, Roberts, Mark E, Kuntzer, Thierry, Fernandez-Torron, Roberto, Martínez-Arroyo, Amaia, Seeger, Juergen, Kusters, Benno, Treves, Susan, van Engelen, Baziel G, Eymard, Bruno, Voermans, Nicol C, Sternberg, Damien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7009512/
https://www.ncbi.nlm.nih.gov/pubmed/32040565
http://dx.doi.org/10.1093/brain/awz410
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author Molenaar, Joery P
Verhoeven, Jamie I
Rodenburg, Richard J
Kamsteeg, Erik J
Erasmus, Corrie E
Vicart, Savine
Behin, Anthony
Bassez, Guillaume
Magot, Armelle
Péréon, Yann
Brandom, Barbara W
Guglielmi, Valeria
Vattemi, Gaetano
Chevessier, Frédéric
Mathieu, Jean
Franques, Jérôme
Suetterlin, Karen
Hanna, Michael G
Guyant-Marechal, Lucie
Snoeck, Marc M
Roberts, Mark E
Kuntzer, Thierry
Fernandez-Torron, Roberto
Martínez-Arroyo, Amaia
Seeger, Juergen
Kusters, Benno
Treves, Susan
van Engelen, Baziel G
Eymard, Bruno
Voermans, Nicol C
Sternberg, Damien
author_facet Molenaar, Joery P
Verhoeven, Jamie I
Rodenburg, Richard J
Kamsteeg, Erik J
Erasmus, Corrie E
Vicart, Savine
Behin, Anthony
Bassez, Guillaume
Magot, Armelle
Péréon, Yann
Brandom, Barbara W
Guglielmi, Valeria
Vattemi, Gaetano
Chevessier, Frédéric
Mathieu, Jean
Franques, Jérôme
Suetterlin, Karen
Hanna, Michael G
Guyant-Marechal, Lucie
Snoeck, Marc M
Roberts, Mark E
Kuntzer, Thierry
Fernandez-Torron, Roberto
Martínez-Arroyo, Amaia
Seeger, Juergen
Kusters, Benno
Treves, Susan
van Engelen, Baziel G
Eymard, Bruno
Voermans, Nicol C
Sternberg, Damien
author_sort Molenaar, Joery P
collection PubMed
description 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 Ca(2+) 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.
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spelling pubmed-70095122020-02-13 Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients Molenaar, Joery P Verhoeven, Jamie I Rodenburg, Richard J Kamsteeg, Erik J Erasmus, Corrie E Vicart, Savine Behin, Anthony Bassez, Guillaume Magot, Armelle Péréon, Yann Brandom, Barbara W Guglielmi, Valeria Vattemi, Gaetano Chevessier, Frédéric Mathieu, Jean Franques, Jérôme Suetterlin, Karen Hanna, Michael G Guyant-Marechal, Lucie Snoeck, Marc M Roberts, Mark E Kuntzer, Thierry Fernandez-Torron, Roberto Martínez-Arroyo, Amaia Seeger, Juergen Kusters, Benno Treves, Susan van Engelen, Baziel G Eymard, Bruno Voermans, Nicol C Sternberg, Damien Brain Original Articles 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 Ca(2+) 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. Oxford University Press 2020-02 2020-02-08 /pmc/articles/PMC7009512/ /pubmed/32040565 http://dx.doi.org/10.1093/brain/awz410 Text en © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Articles
Molenaar, Joery P
Verhoeven, Jamie I
Rodenburg, Richard J
Kamsteeg, Erik J
Erasmus, Corrie E
Vicart, Savine
Behin, Anthony
Bassez, Guillaume
Magot, Armelle
Péréon, Yann
Brandom, Barbara W
Guglielmi, Valeria
Vattemi, Gaetano
Chevessier, Frédéric
Mathieu, Jean
Franques, Jérôme
Suetterlin, Karen
Hanna, Michael G
Guyant-Marechal, Lucie
Snoeck, Marc M
Roberts, Mark E
Kuntzer, Thierry
Fernandez-Torron, Roberto
Martínez-Arroyo, Amaia
Seeger, Juergen
Kusters, Benno
Treves, Susan
van Engelen, Baziel G
Eymard, Bruno
Voermans, Nicol C
Sternberg, Damien
Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients
title Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients
title_full Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients
title_fullStr Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients
title_full_unstemmed Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients
title_short Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients
title_sort clinical, morphological and genetic characterization of brody disease: an international study of 40 patients
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7009512/
https://www.ncbi.nlm.nih.gov/pubmed/32040565
http://dx.doi.org/10.1093/brain/awz410
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