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

Détails

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Etat: Public
Version: Final published version
Licence: CC BY-NC 4.0
ID Serval
serval:BIB_7161A2C99F6F
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients.
Périodique
Brain
Auteur⸱e⸱s
Molenaar J.P., Verhoeven J.I., Rodenburg R.J., Kamsteeg E.J., Erasmus C.E., Vicart S., Behin A., Bassez G., Magot A., Péréon Y., Brandom B.W., Guglielmi V., Vattemi G., Chevessier F., Mathieu J., Franques J., Suetterlin K., Hanna M.G., Guyant-Marechal L., Snoeck M.M., Roberts M.E., Kuntzer T., Fernandez-Torron R., Martínez-Arroyo A., Seeger J., Kusters B., Treves S., van Engelen B.G., Eymard B., Voermans N.C., Sternberg D.
ISSN
1460-2156 (Electronic)
ISSN-L
0006-8950
Statut éditorial
Publié
Date de publication
01/02/2020
Peer-reviewed
Oui
Volume
143
Numéro
2
Pages
452-466
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
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.
Mots-clé
Adolescent, Adult, Calcium-Transporting ATPases/genetics, Child, Female, Humans, Male, Muscle, Skeletal/metabolism, Muscle, Skeletal/physiopathology, Muscular Diseases/genetics, Mutation/genetics, Myotonia Congenita/genetics, Phenotype, Sarcoplasmic Reticulum/metabolism, Young Adult, ATP2A1, Brody disease, calcium, genotype, phenotype
Pubmed
Web of science
Création de la notice
17/02/2020 15:19
Dernière modification de la notice
15/01/2021 7:10
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