Caveolinopathy: Clinical, histological, and muscle imaging features and follow-up in a multicenter retrospective cohort.
CAV3
caveolin-3
muscle imaging
myopathy
rippling muscle disease
Journal
European journal of neurology
ISSN: 1468-1331
Titre abrégé: Eur J Neurol
Pays: England
ID NLM: 9506311
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
revised:
10
02
2023
received:
05
12
2022
accepted:
13
04
2023
medline:
6
7
2023
pubmed:
11
5
2023
entrez:
11
5
2023
Statut:
ppublish
Résumé
CAV3 gene mutations, mostly inherited as an autosomal dominant trait, cause various skeletal muscle diseases. Clinical presentations encompass proximal myopathy, distal myopathy, or isolated persistent high creatine kinase (CK) with a major overlapping phenotype. Twenty-three patients with CAV3 symptomatic mutations, from 16 different families, were included in a retrospective cohort. Mean follow-up duration was 24.2 ± 15.0 years. Clinical and functional data were collected during the follow-up. The results of muscle imaging, electroneuromyography, muscle histopathology, immunohistochemistry, and caveolin-3 Western blot analysis were also compiled. Exercise intolerance was the most common phenotype (52%). Eighty percent of patients had calf hypertrophy, and only 65% of patients presented rippling. One patient presented initially with camptocormia. A walking aid was required in only two patients. Electroneuromyography was mostly normal. CK level was elevated in all patients. No patient had cardiac or respiratory impairment. Muscle imaging showed fatty involvement of semimembranosus, semitendinosus, rectus femoris, biceps brachialis, and spinal muscles. Almost all (87%) of the biopsies were abnormal but without any specific pattern. Whereas a quarter of patients had normal caveolin-3 immunohistochemistry results, Western blots disclosed a reduced amount of the protein. We report nine mutations, including four not previously described. No phenotype-genotype correlation was evidenced. Caveolinopathy has diverse clinical, muscle imaging, and histological presentations but often has limited functional impact. Mild forms of the disease, an atypical phenotype, and normal caveolin-3 immunostaining are pitfalls leading to misdiagnosis.
Sections du résumé
BACKGROUND AND PURPOSE
CAV3 gene mutations, mostly inherited as an autosomal dominant trait, cause various skeletal muscle diseases. Clinical presentations encompass proximal myopathy, distal myopathy, or isolated persistent high creatine kinase (CK) with a major overlapping phenotype.
METHODS
Twenty-three patients with CAV3 symptomatic mutations, from 16 different families, were included in a retrospective cohort. Mean follow-up duration was 24.2 ± 15.0 years. Clinical and functional data were collected during the follow-up. The results of muscle imaging, electroneuromyography, muscle histopathology, immunohistochemistry, and caveolin-3 Western blot analysis were also compiled.
RESULTS
Exercise intolerance was the most common phenotype (52%). Eighty percent of patients had calf hypertrophy, and only 65% of patients presented rippling. One patient presented initially with camptocormia. A walking aid was required in only two patients. Electroneuromyography was mostly normal. CK level was elevated in all patients. No patient had cardiac or respiratory impairment. Muscle imaging showed fatty involvement of semimembranosus, semitendinosus, rectus femoris, biceps brachialis, and spinal muscles. Almost all (87%) of the biopsies were abnormal but without any specific pattern. Whereas a quarter of patients had normal caveolin-3 immunohistochemistry results, Western blots disclosed a reduced amount of the protein. We report nine mutations, including four not previously described. No phenotype-genotype correlation was evidenced.
CONCLUSIONS
Caveolinopathy has diverse clinical, muscle imaging, and histological presentations but often has limited functional impact. Mild forms of the disease, an atypical phenotype, and normal caveolin-3 immunostaining are pitfalls leading to misdiagnosis.
Substances chimiques
Caveolin 3
0
Types de publication
Multicenter Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2506-2517Informations de copyright
© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.
Références
Woodman SE, Sotgia F, Galbiati F, Minetti C, Lisanti MP. Caveolinopathies: mutations in caveolin-3 cause four distinct autosomal dominant muscle diseases. Neurology. 2004;62(4):538-543. doi:10.1212/WNL.62.4.538
Gazzerro E, Bonetto A, Minetti C. Caveolinopathies. Handbook of Clinical Neurology. Vol 101. Elsevier; 2011:135-142. doi:10.1016/B978-0-08-045031-5.00010-4
Papadopoulos C, Papadimas GK, Kekou K, et al. Caveolinopathies in Greece. Neurologist. 2015;20(1):8-12. doi:10.1097/NRL.0000000000000036
Straub V, Murphy A, Udd B, et al. 229th ENMC international workshop: limb girdle muscular dystrophies - nomenclature and reformed classification Naarden, The Netherlands, 17-19 March 2017. Neuromuscul Disord. 2018;28(8):702-710. doi:10.1016/j.nmd.2018.05.007
Aboumousa A, Hoogendijk J, Charlton R, et al. Caveolinopathy - new mutations and additional symptoms. Neuromuscul Disord. 2008;18(7):572-578. doi:10.1016/j.nmd.2008.05.003
Scalco RS, Gardiner AR, Pitceathly RDS, et al. CAV3 mutations causing exercise intolerance, myalgia and rhabdomyolysis: expanding the phenotypic spectrum of caveolinopathies. Neuromuscul Disord. 2016;26(8):504-510. doi:10.1016/j.nmd.2016.05.006
Pradhan BS, Prószyński TJ. A role for Caveolin-3 in the pathogenesis of muscular dystrophies. Int J Mol Sci. 2020;21(22):8736. doi:10.3390/ijms21228736
Fanin M, Angelini C. Muscle pathology in dysferlin deficiency. Neuropathol Appl Neurobiol. 2002;28(6):461-470. doi:10.1046/j.1365-2990.2002.00417.x
Udd B, Stenzel W, Oldfors A, et al. 1st ENMC European meeting: the EURO-NMD pathology working group recommended standards for muscle pathology Amsterdam, The Netherlands, 7 December 2018. Neuromuscul Disord. 2019;29(6):483-485. doi:10.1016/j.nmd.2019.03.002
Traverso M, Gazzerro E, Assereto S, et al. Caveolin-3 T78M and T78K missense mutations lead to different phenotypes in vivo and in vitro. Lab Invest. 2008;88(3):275-283. doi:10.1038/labinvest.3700713
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med off J Am Coll Med Genet. 2015;17(5):405-424. doi:10.1038/gim.2015.30
Mercuri E, Cini C, Counsell S, et al. Muscle MRI findings in a three-generation family affected by Bethlem myopathy. Eur J Paediatr Neurol. 2002;6(6):309-314. doi:10.1053/ejpn.2002.0618
Hogrel JY, Laforet P, Ben Yaou R, Chevrot M, Eymard B, Lombes A. A non-ischemic forearm exercise test for the screening of patients with exercise intolerance. Neurology. 2001;56(12):1733-1738. doi:10.1212/WNL.56.12.1733
Carbone I, Bruno C, Sotgia F, et al. Mutation in the CAV3 gene causes partial caveolin-3 deficiency and persistent elevated levels of serum creatine kinase. Neurology. 2000;54(6):1373-1376. doi:10.1212/WNL.54.6.1373
Kubisch C, Ketelsen UP, Goebel I, Omran H. Autosomal recessive rippling muscle disease with homozygousCAV3 mutations. Ann Neurol. 2005;57(2):303-304. doi:10.1002/ana.20350
Betz RC, Schoser BG, Kasper D, et al. Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease. Nat Genet. 2001;28(3):218-219. doi:10.1038/90050
Töpf A, Johnson K, Bates A, et al. Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness. Genet Med off J Am Coll Med Genet. 2020;22(9):1478-1488. doi:10.1038/s41436-020-0840-3
Sugie H, Fukuda T, Ito M, Sugie Y, Kojoh T, Nonaka I. Novel exon 11 skipping mutation in a patient with glycogen storage disease type IIId. J Inherit Metab Dis. 2001;24(5):535-545. doi:10.1023/a:1012459625902
Baux D, Van Goethem C, Ardouin O, et al. MobiDetails: online DNA variants interpretation. Eur J Hum Genet. 2021;29(2):356-360. doi:10.1038/s41431-020-00755-z
Penttilä S, Palmio J, Suominen T, et al. Eight new mutations and the expanding phenotype variability in muscular dystrophy caused by ANO5. Neurology. 2012;78(12):897-903. doi:10.1212/WNL.0b013e31824c4682
Fulizio L, Chiara Nascimbeni A, Fanin M, et al. Molecular and muscle pathology in a series of caveolinopathy patients. Hum Mutat. 2005;25(1):82-89. doi:10.1002/humu.20119
Fischer D, Schroers A, Blümcke I, et al. Consequences of a novel caveolin-3 mutation in a large German family: novel cav-3 mutation. Ann Neurol. 2003;53(2):233-241. doi:10.1002/ana.10442
Ishiguro K, Nakayama T, Yoshioka M, et al. Characteristic findings of skeletal muscle MRI in caveolinopathies. Neuromuscul Disord. 2018;28(10):857-862. doi:10.1016/j.nmd.2018.07.010
Witting N, Andersen LK, Vissing J. Axial myopathy: an overlooked feature of muscle diseases. Brain. 2016;139(1):13-22. doi:10.1093/brain/awv332
Barroso F, Nogués M, Leiguarda R, Taratuto A. G.P.8.09 exercise intolerance and rippling syndrome in caveolinopathy. Neuromuscul Disord. 2007;17(9-10):812-813. doi:10.1016/j.nmd.2007.06.174
Chen J, Zeng W, Han C, Wu J, Zhang H, Tong X. Mutation in the caveolin-3 gene causes asymmetrical distal myopathy: Caveolinopathy. Neuropathology. 2016;36(5):485-489. doi:10.1111/neup.12297
Dubey D, Beecher G, Hammami MB, et al. Identification of caveolae-associated protein 4 autoantibodies as a biomarker of immune-mediated rippling muscle disease in adults. JAMA Neurol. 2022;79(8):808-816. doi:10.1001/jamaneurol.2022.1357
Schulte-Mattler WJ, Kley RA, Rothenfußer-Korber E, et al. Immune-mediated rippling muscle disease. Neurology. 2005;64(2):364-367. doi:10.1212/01.WNL.0000149532.52938.5B
Bettini M, Gonorazky H, Chaves M, et al. Immune-mediated rippling muscle disease and myasthenia gravis. J Neuroimmunol. 2016;299:59-61. doi:10.1016/j.jneuroim.2016.08.011
Ullrich ND, Fischer D, Kornblum C, et al. Alterations of excitation-contraction coupling and excitation coupled Ca2+ entry in human myotubes carrying CAV3 mutations linked to rippling muscle. Hum Mutat. 2011;32(3):309-317. doi:10.1002/humu.21431
Sinha B, Köster D, Ruez R, et al. Cells respond to mechanical stress by rapid disassembly of caveolae. Cell. 2011;144(3):402-413. doi:10.1016/j.cell.2010.12.031
Lo HP, Nixon SJ, Hall TE, et al. The caveolin-cavin system plays a conserved and critical role in mechanoprotection of skeletal muscle. J Cell Biol. 2015;210(5):833-849. doi:10.1083/jcb.201501046
Dewulf M, Köster DV, Sinha B, et al. Dystrophy-associated caveolin-3 mutations reveal that caveolae couple IL6/STAT3 signaling with mechanosensing in human muscle cells. Nat Commun. 2019;10(1):1974. doi:10.1038/s41467-019-09405-5