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Congenital Myopathies and Related Diseases

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Abstract

Congenital myopathies (CM) are a gamut of clinicopathologically and genetically distinct disorders characterized by early-onset hypotonia and muscle weakness and inherited in autosomal dominant, recessive, or X-linked manner. Sometimes sporadic forms are seen. Respiratory muscle weakness is often severe and out of proportion to that of limb muscle weakness. Serum CK levels are usually within normal limits. The pathological abnormality common to most of the CM is the presence of hypotrophic type 1 fibers expressing slow myosin, which may sometimes be the only abnormality. Additional pathological features may include cytoplasmic bodies, nemaline rods, cores, tubular aggregates, central nuclei, caps, etc. Muscle biopsies can also show more than one of the aforementioned findings. There is a very high rate of phenotypic variability and genetic heterogeneity with respect to congenital myopathies [1]. Myocyte necrosis and endomysial fibrosis are rare features and when present prompt alternative diagnosis. The categories of CM are broad and encompass several entities, and discussing each detailed is beyond the scope of this chapter. Only the common CM are discussed, and the readers are requested to refer dedicated papers on individual CM.

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References

  1. Sewry CA, Wallgren-Pettersson C. Myopathology in congenital myopathies. Neuropathol Appl Neurobiol. 2017;43:5–23.

    Article  CAS  Google Scholar 

  2. Shy GM, Engel WK, Somers JE, et al. Nemaline myopathy. A new congenital myopathy. Brain. 1963;86:793–810.

    Article  CAS  Google Scholar 

  3. Maggi L, Scoto M, Cirak S, et al. Congenital myopathies—clinical features and frequency of individual subtypes diagnosed over a 5-year period in the United Kingdom. Neuromuscul Disord. 2013;23:195–205.

    Article  CAS  Google Scholar 

  4. Wallgren-Pettersson C, Sewry CA, Nowak KJ, et al. Nemaline myopathies. Semin Pediatr Neurol. 2011;18:230–8.

    Article  Google Scholar 

  5. Wallgren-Pettersson C, Lehtokari VL, Kalimo H, et al. Distal myopathy caused by homozygous missense mutations in the nebulin gene. Brain. 2007;130:1465–76.

    Article  Google Scholar 

  6. Wallgren-Pettersson C, Pelin K, Hilpela P, et al. Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy. Neuromuscul Disord. 1999;9:564–72.

    Article  CAS  Google Scholar 

  7. Malfatti E, Romero NB. Nemaline myopathies: state of the art. Rev Neurol (Paris). 2016;172:614–9.

    Article  CAS  Google Scholar 

  8. Malfatti E, Lehtokari VL, Bohm J, et al. Muscle histopathology in nebulin-related nemaline myopathy: ultrastrastructural findings correlated to disease severity and genotype. Acta Neuropathol Commun. 2014;2:44.

    Article  Google Scholar 

  9. Romero NB, Lehtokari VL, Quijano-Roy S, et al. Core-rod myopathy caused by mutations in the nebulin gene. Neurology. 2009;73:1159–61.

    Article  CAS  Google Scholar 

  10. Jain RK, Jayawant S, Squier W, et al. Nemaline myopathy with stiffness and hypertonia associated with an ACTA1 mutation. Neurology. 2012;78:1100–3.

    Article  CAS  Google Scholar 

  11. Finsterer J, Stollberger C. Review of cardiac disease in nemaline myopathy. Pediatr Neurol. 2015;53:473–7.

    Article  Google Scholar 

  12. Sewry CA, Holton JL, Dick DJ, et al. Zebra body myopathy is caused by a mutation in the skeletal muscle actin gene (ACTA1). Neuromuscul Disord. 2015;25:388–91.

    Article  CAS  Google Scholar 

  13. Gupta VA, Ravenscroft G, Shaheen R, et al. Identification of KLHL41 mutations implicates BTB-Kelch-mediated ubiquitination as an alternate pathway to myofibrillar disruption in nemaline myopathy. Am J Hum Genet. 2013;93:1108–17.

    Article  CAS  Google Scholar 

  14. Yuen M, Sandaradura SA, Dowling JJ, et al. Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy. J Clin Investig. 2014;124:4693–708.

    Article  CAS  Google Scholar 

  15. Malfatti E, Bohm J, Lacene E, et al. A premature stop codon in MYO18B is associated with severe nemaline myopathy with cardiomyopathy. J Neuromuscul Dis. 2015;2:219–27.

    Article  Google Scholar 

  16. Alazami AM, Kentab AY, Faqeih E, et al. A novel syndrome of Klippel-Feil anomaly, myopathy, and characteristic facies is linked to a null mutation in MYO18B. J Med Genet. 2015;52:400–4.

    Article  CAS  Google Scholar 

  17. Riazi S, Kraeva N, Hopkins PM. Malignant hyperthermia in the post-genomics era: new perspectives on an old concept. Anesthesiology. 2017;128(1):168–80.

    Article  Google Scholar 

  18. Dowling JJ, Lillis S, Amburgey K, et al. King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromuscul Disord. 2011;21:420–7.

    Article  Google Scholar 

  19. Quinlivan R, Jungbluth H. Myopathic causes of exercise intolerance with rhabdomyolysis. Dev Med Child Neurol. 2012;54:886–91.

    Article  Google Scholar 

  20. Voermans NC, Snoeck M, Jungbluth H. RYR1-related rhabdomyolysis: A common but probably underdiagnosed manifestation of skeletal muscle ryanodine receptor dysfunction. Rev Neurol (Paris). 2016;172:546–58.

    Article  CAS  Google Scholar 

  21. Loseth S, Voermans NC, Torbergsen T, et al. A novel late-onset axial myopathy associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene. J Neurol. 2013;260:1504–10.

    Article  CAS  Google Scholar 

  22. Sewry CA, Muller C, Davis M, et al. The spectrum of pathology in central core disease. Neuromuscul Disord. 2002;12:930–8.

    Article  CAS  Google Scholar 

  23. Wilmshurst JM, Lillis S, Zhou H, et al. RYR1 mutations are a common cause of congenital myopathies with central nuclei. Ann Neurol. 2010;68:717–26.

    Article  CAS  Google Scholar 

  24. Jungbluth H, Zhou H, Sewry CA, et al. Centronuclear myopathy due to a de novo dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromuscul Disord. 2007;17:338–45.

    Article  Google Scholar 

  25. Monnier N, Romero NB, Lerale J, et al. An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor. Hum Mol Genet. 2000;9:2599–608.

    Article  CAS  Google Scholar 

  26. Jungbluth H, Sewry CA, Buj-Bello A, et al. Early and severe presentation of X-linked myotubular myopathy in a girl with skewed X-inactivation. Neuromuscul Disord. 2003;13:55–9.

    Article  CAS  Google Scholar 

  27. Dahl N, Hu LJ, Chery M, et al. Myotubular myopathy in a girl with a deletion at Xq27-q28 and unbalanced X inactivation assigns the MTM1 gene to a 600-kb region. Am J Hum Genet. 1995;56:1108–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Tanner SM, Orstavik KH, Kristiansen M, et al. Skewed X-inactivation in a manifesting carrier of X-linked myotubular myopathy and in her non-manifesting carrier mother. Hum Genet. 1999;104:249–53.

    Article  CAS  Google Scholar 

  29. Savarese M, Di Fruscio G, Torella A, et al. The genetic basis of undiagnosed muscular dystrophies and myopathies: results from 504 patients. Neurology. 2016;87:71–6.

    Article  Google Scholar 

  30. Longo G, Russo S, Novelli G, et al. Mutation spectrum of the MTM1 gene in XLMTM patients: 10 years of experience in prenatal and postnatal diagnosis. Clin Genet. 2016;89:93–8.

    Article  CAS  Google Scholar 

  31. Hedberg C, Lindberg C, Mathe G, et al. Myopathy in a woman and her daughter associated with a novel splice site MTM1 mutation. Neuromuscul Disord. 2012;22:244–51.

    Article  Google Scholar 

  32. Hnia K, Vaccari I, Bolino A, et al. Myotubularin phosphoinositide phosphatases: cellular functions and disease pathophysiology. Trends Mol Med. 2012;18:317–27.

    Article  CAS  Google Scholar 

  33. Al-Qusairi L, Laporte J. T-tubule biogenesis and triad formation in skeletal muscle and implication in human diseases. Skelet Muscle. 2011;1:26.

    Article  CAS  Google Scholar 

  34. Laporte J, Kress W, Mandel JL. Diagnosis of X-linked myotubular myopathy by detection of myotubularin. Ann Neurol. 2001;50:42–6.

    Article  CAS  Google Scholar 

  35. Lawlor MW, Beggs AH, Buj-Bello A, et al. Skeletal muscle pathology in X-linked myotubular myopathy: review with cross-species comparisons. J Neuropathol Exp Neurol. 2016;75:102–10.

    Article  CAS  Google Scholar 

  36. Romero NB. Centronuclear myopathies: a widening concept. Neuromuscul Disord. 2010;20:223–8.

    Article  Google Scholar 

  37. Liewluck T, Lovell TL, Bite AV, et al. Sporadic centronuclear myopathy with muscle pseudohypertrophy, neutropenia, and necklace fibers due to a DNM2 mutation. Neuromuscul Disord. 2010;20:801–4.

    Article  Google Scholar 

  38. Agrawal PB, Pierson CR, Joshi M, et al. SPEG interacts with myotubularin, and its deficiency causes centronuclear myopathy with dilated cardiomyopathy. Am J Hum Genet. 2014;95:218–26.

    Article  CAS  Google Scholar 

  39. Sewry CA, Quinlivan RC, Squier W, et al. A rapid immunohistochemical test to distinguish congenital myotonic dystrophy from X-linked myotubular myopathy. Neuromuscul Disord. 2012;22:225–30.

    Article  Google Scholar 

  40. Soussi-Yanicostas N, Chevallay M, Laurent-Winter C, et al. Distinct contractile protein profile in congenital myotonic dystrophy and X-linked myotubular myopathy. Neuromuscul Disord. 1991;1:103–11.

    Article  CAS  Google Scholar 

  41. Bitoun M, Maugenre S, Jeannet PY, et al. Mutations in dynamin 2 cause dominant centronuclear myopathy. Nat Genet. 2005;37:1207–9.

    Article  CAS  Google Scholar 

  42. Bitoun M, Bevilacqua JA, Prudhon B, et al. Dynamin 2 mutations cause sporadic centronuclear myopathy with neonatal onset. Ann Neurol. 2007;62:666–70.

    Article  CAS  Google Scholar 

  43. Toussaint A, Cowling BS, Hnia K, et al. Defects in amphiphysin 2 (BIN1) and triads in several forms of centronuclear myopathies. Acta Neuropathol. 2011;121:253–66.

    Article  Google Scholar 

  44. Carmignac V, Salih MA, Quijano-Roy S, et al. C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy. Ann Neurol. 2007;61:340–51.

    Article  CAS  Google Scholar 

  45. Ceyhan-Birsoy O, Agrawal PB, Hidalgo C, et al. Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. Neurology. 2013;81:1205–14.

    Article  CAS  Google Scholar 

  46. Seidman JG, Seidman C. The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell. 2001;104:557–67.

    Article  CAS  Google Scholar 

  47. Richard P, Charron P, Carrier L, et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003;107:2227–32.

    Article  Google Scholar 

  48. Lamont PJ, Udd B, Mastaglia FL, et al. Laing early onset distal myopathy: slow myosin defect with variable abnormalities on muscle biopsy. J Neurol Neurosurg Psychiatry. 2006;77:208–15.

    Article  CAS  Google Scholar 

  49. Cullup T, Lamont PJ, Cirak S, et al. Mutations in MYH7 cause Multi-minicore Disease (MmD) with variable cardiac involvement. Neuromuscul Disord. 2012;22:1096–104.

    Article  CAS  Google Scholar 

  50. Martinsson T, Oldfors A, Darin N, et al. Autosomal dominant myopathy: missense mutation (Glu-706 --> Lys) in the myosin heavy chain IIa gene. Proc Natl Acad Sci U S A. 2000;97:14614–9.

    Article  CAS  Google Scholar 

  51. Tajsharghi H, Hilton-Jones D, Raheem O, et al. Human disease caused by loss of fast IIa myosin heavy chain due to recessive MYH2 mutations. Brain. 2010;133:1451–9.

    Article  Google Scholar 

  52. Tajsharghi H, Oldfors A. Myosinopathies: pathology and mechanisms. Acta Neuropathol. 2013;125:3–18.

    Article  CAS  Google Scholar 

  53. Willis T, Hedberg-Oldfors C, Alhaswani Z, et al. A novel MYH2 mutation in family members presenting with congenital myopathy, ophthalmoplegia and facial weakness. J Neurol. 2016;263:1427–33.

    Article  CAS  Google Scholar 

  54. Fontaine B. Muscle channelopathies and related diseases. Handb Clin Neurol. 2013;113:1433–6.

    Article  Google Scholar 

  55. Cannon SC. Pathomechanisms in channelopathies of skeletal muscle and brain. Annu Rev Neurosci. 2006;29:387–415.

    Article  CAS  Google Scholar 

  56. Lehmann-Horn F, Jurkat-Rott K, Rudel R, et al. Diagnostics and therapy of muscle channelopathies—Guidelines of the Ulm Muscle Centre. Acta Myol. 2008;27:98–113.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Raja Rayan DL, Hanna MG. Skeletal muscle channelopathies: nondystrophic myotonias and periodic paralysis. Curr Opin Neurol. 2010;23:466–76.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    Balan Louis Gaspar & Rakesh Kumar Vasishta

  2. Division of Neuropathology, Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    Bishan Dass Radotra

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  1. Balan Louis Gaspar
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  2. Rakesh Kumar Vasishta
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Gaspar, B.L., Vasishta, R.K., Radotra, B.D. (2019). Congenital Myopathies and Related Diseases. In: Myopathology. Springer, Singapore. https://doi.org/10.1007/978-981-13-1462-9_11

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  • DOI: https://doi.org/10.1007/978-981-13-1462-9_11

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  • Online ISBN: 978-981-13-1462-9

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