Abstract
Centronuclear myopathies (CNMs) are a group of clinically and genetically heterogeneous muscle disorders. Here, we report a cohort of seven CNM patients with their clinical, histological, and morphological features. In addition, using the next-generation sequencing (NGS) technique (5/7 patients), we identified small indels: intronic, exonic, and missense mutations in MTM1, DNM2, and RYR1 genes. Further genetic studies revealed skewed X-chromosome inactivation in two female patients carrying MTM1 mutations. Based on the results of genetic analysis, these seven patients were classified as (1) X-linked recessive myotubular myopathy (patients 1–3) with MTM1 mutations and mild phenotype, (2) the autosomal dominant CNM (patients 4–6) with DNM2 mutations, and (3) the autosomal recessive CNM (patient 7) with RYR1 mutations. In all patients, histological findings featured a high proportion of fibers with central nuclei. Radial arrangement of the sarcoplasmic strands was observed in DNM2-CNM and RYR1-CNM patients. Muscle magnetic resonance imaging (MRI) revealed a proximal pattern of involvement presented in both MTM1-CNM and RYR1-CNM patients. A distal pattern of involvement was present in DNM2-CNM patients. Our findings thereby identified a number of novel features that expand the reported clinicopathological phenotype of CNMs in China.
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References
Jungbluth H, Gautel M (2014) Pathogenic mechanisms in centronuclear myopathies. Front Aging Neurosci 6:339
Pierson CR, Tomczak K, Agrawal P, Moghadaszadeh B, Beggs AH (2005) X-linked myotubular and centronuclear myopathies. J Neuropathol Exp Neurol 64:555–564
McEntagart M, Parsons G, Buj-Bello A, Biancalana V, Fenton I, Little M, Krawczak M, Thomas N, Herman G, Clarke A, Wallgren-Pettersson C (2002) Genotype-phenotype correlations in X-linked myotubular myopathy. Neuromuscul Disord 12:939–946
Biancalana V, Scheidecker S, Miguet M, Laquerrière A, Romero NB, Stojkovic T, Abath Neto O, Mercier S, Voermans N, Tanner L, Rogers C, Ollagnon-Roman E, Roper H, Boutte C, Ben-Shachar S, Lornage X, Vasli N, Schaefer E, Laforet P, Pouget J, Moerman A, Pasquier L, Marcorelle P, Magot A, Küsters B, Streichenberger N, Tranchant C, Dondaine N, Schneider R, Gasnier C, Calmels N, Kremer V, Nguyen K, Perrier J, Kamsteeg EJ, Carlier P, Carlier RY, Thompson J, Boland A, Deleuze JF, Fardeau M, Zanoteli E, Eymard B, Laporte J (2017) Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues. Acta Neuropathol 134:889–904
Majczenko K, Davidson AE, Camelo-Piragua S, Agrawal PB, Manfready RA, Li X, Joshi S, Xu J, Peng W, Beggs AH, Li JZ, Burmeister M, Dowling JJ (2012) Dominant mutation of CCDC78 in a unique congenital myopathy with prominent internal nuclei and atypical cores. Am J Hum Genet 91:365–371
Bohm J, Biancalana V, Malfatti E et al (2014) Adult-onset autosomal dominant centronuclear myopathy due to BIN1 mutations. Brain 137:3160–3170
Tosch V, Rohde HM, Tronchere H et al (2006) A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy. Hum Mol Genet 15:3098–3106
Romero NB (2010) Centronuclear myopathies: a widening concept. Neuromuscul Disord 20:223–228
Wilmshurst JM, Lillis S, Zhou H, Pillay K, Henderson H, Kress W, Müller CR, Ndondo A, Cloke V, Cullup T, Bertini E, Boennemann C, Straub V, Quinlivan R, Dowling JJ, al- Sarraj S, Treves S, Abbs S, Manzur AY, Sewry CA, Muntoni F, Jungbluth H (2010) RYR1 mutations are a common cause of congenital myopathies with central nuclei. Ann Neurol 68:717–726
Romero NB, Bitoun M (2011) Centronuclear myopathies. Semin Pediatr Neurol 18:250–256
Ceyhan-Birsoy O, Agrawal PB, Hidalgo C, Schmitz-Abe K, DeChene ET, Swanson LC, Soemedi R, Vasli N, Iannaccone ST, Shieh PB, Shur N, Dennison JM, Lawlor MW, Laporte J, Markianos K, Fairbrother WG, Granzier H, Beggs AH (2013) Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. Neurology 81:1205–1214
Agrawal PB, Pierson CR, Joshi M, Liu X, Ravenscroft G, Moghadaszadeh B, Talabere T, Viola M, Swanson LC, Haliloğlu G, Talim B, Yau KS, Allcock RJN, Laing NG, Perrella MA, Beggs AH (2014) SPEG interacts with myotubularin, and its deficiency causes centronuclear myopathy with dilated cardiomyopathy. Am J Hum Genet 95:218–226
Zhao Y, Hu J, Zhao Z, Shen H, Bing Q, Li N (2016) Next generation sequencing reveals ryanodine receptor 1 mutations in a Chinese central core disease cohort. Muscle Nerve 54:432–438
Radic CP, Rossetti LC, Abelleyro MM, Tetzlaff T, Candela M, Neme D, Sciuccati G, Bonduel M, Medina-Acosta E, Larripa IB, de Tezanos Pinto M, de Brasi CD (2015) Phenotype-genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation. J Thromb Haemost 13:530–539
Bevilacqua JA, Bitoun M, Biancalana V, Oldfors A, Stoltenburg G, Claeys KG, Lacène E, Brochier G, Manéré L, Laforêt P, Eymard B, Guicheney P, Fardeau M, Romero NB (2009) “Necklace” fibers, a new histological marker of late-onset MTM1-related centronuclear myopathy. Acta Neuropathol 117:283–291
Casar-Borota O, Jacobsson J, Libelius R, Oldfors CH, Malfatti E, Romero NB, Oldfors A (2015) A novel dynamin-2 gene mutation associated with a late-onset centronuclear myopathy with necklace fibres. Neuromuscul Disord 25:345–348
Tanner SM, Schneider V, Thomas NS, Clarke A, Lazarou L, Liechti-Gallati S (1999) Characterization of 34 novel and six known MTM1 gene mutations in 47 unrelated X-linked myotubular myopathy patients. Neuromuscul Disord 9:41–49
Hammans SR, Robinson DO, Moutou C, Kennedy CR, Dennis NR, Hughes PJ, Ellison DW (2000) A clinical and genetic study of a manifesting heterozygote with X-linked myotubular myopathy. Neuromuscul Disord 10:133–137
Bitoun M, Maugenre S, Jeannet PY, Lacène E, Ferrer X, Laforêt P, Martin JJ, Laporte J, Lochmüller H, Beggs AH, Fardeau M, Eymard B, Romero NB, Guicheney P (2005) Mutations in dynamin 2 cause dominant centronuclear myopathy. Nat Genet 37:1207–1209
Bevilacqua JA, Monnier N, Bitoun M, Eymard B, Ferreiro A, Monges S, Lubieniecki F, Taratuto AL, Laquerrière A, Claeys KG, Marty I, Fardeau M, Guicheney P, Lunardi J, Romero NB (2011) Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization. Neuropathol Appl Neurobiol 37:271–284
Hwang JH, Zorzato F, Clarke NF, Treves S (2012) Mapping domains and mutations on the skeletal muscle ryanodine receptor channel. Trends Mol Med 18:644–657
Biancalana V, Caron O, Gallati S et al (2003) Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype. Hum Genet 112:135–142
Quijano-Roy S, Carlier RY, Fischer D (2011) Muscle imaging in congenital myopathies. Semin Pediatr Neurol 18:221–229
Yu S, Manson J, White S, Bourne A, Waddy H, Davis M, Haan E (2003) X-linked myotubular myopathy in a family with three adult survivors. Clin Genet 64:148–152
Hoffjan S, Thiels C, Vorgerd M, Neuen-Jacob E, Epplen JT, Kress W (2006) Extreme phenotypic variability in a German family with X-linked myotubular myopathy associated with E404K mutation in MTM1. Neuromuscul Disord 16:749–753
Sustersic B, Neubauer D (2005) Long-term survivor with X-linked myotubular myopathy. Dev Med Child Neurol 47:358–359
Spath MA, Nillesen WN, Smits AP et al (2010) X chromosome inactivation does not define the development of premature ovarian failure in fragile X premutation carriers. Am J Med Genet A 152A:387–393
Kristiansen M, Knudsen GP, Tanner SM, McEntagart M, Jungbluth H, Muntoni F, Sewry C, Gallati S, Ørstavik KH, Wallgren-Pettersson C (2003) X-inactivation patterns in carriers of X-linked myotubular myopathy. Neuromuscul Disord 13:468–471
Susman RD, Quijano-Roy S, Yang N, Webster R, Clarke NF, Dowling J, Kennerson M, Nicholson G, Biancalana V, Ilkovski B, Flanigan KM, Arbuckle S, Malladi C, Robinson P, Vucic S, Mayer M, Romero NB, Urtizberea JA, García-Bragado F, Guicheney P, Bitoun M, Carlier RY, North KN (2010) Expanding the clinical, pathological and MRI phenotype of DNM2-related centronuclear myopathy. Neuromuscul Disord 20:229–237
Lin P, Liu X, Zhao D, Dai T, Wu H, Gong Y, Yan C (2016) DNM2 mutations in Chinese Han patients with centronuclear myopathy. Neurol Sci 37:995–998
Jeub M, Bitoun M, Guicheney P, Kappes-Horn K, Strach K, Druschky KF, Weis J, Fischer D (2008) Dynamin 2-related centronuclear myopathy: clinical, histological and genetic aspects of further patients and review of the literature. Clin Neuropathol 27:430–438
Bohm J, Biancalana V, Dechene ET et al (2012) Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy. Hum Mutat 33:949–959
Abath Neto O, Moreno CAM, Malfatti E et al (2017) Common and variable clinical, histological, and imaging findings of recessive RYR1-related centronuclear myopathy patients. Neuromuscul Disord 27:975–985
Bohm J, Vasli N, Malfatti E et al (2013) An integrated diagnosis strategy for congenital myopathies. PLoS One 8:e67527
Klein A, Jungbluth H, Clement E, Lillis S, Abbs S, Munot P, Pane M, Wraige E, Schara U, Straub V, Mercuri E, Muntoni F (2011) Muscle magnetic resonance imaging in congenital myopathies due to ryanodine receptor type 1 gene mutations. Arch Neurol 68:1171–1179
Acknowledgements
We thank the patients and their family members described for their cooperation in this study, and Dr. Jian Wu from MyGenostics Inc. for his excellent technical assistance.
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Zhao, Y., Zhao, Z., Shen, H. et al. Characterization and genetic diagnosis of centronuclear myopathies in seven Chinese patients. Neurol Sci 39, 2043–2051 (2018). https://doi.org/10.1007/s10072-018-3534-8
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DOI: https://doi.org/10.1007/s10072-018-3534-8