Journal of Genetic Medicine

Korean Society of Medical Genetics and Genomics (대한의학유전학회)
권호 표지
DOI QR코드

DOI QR Code

Female Carriers of Duchenne Muscular Dystrophy

  • Cho, Yu Na (Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine) ;
  • Choi, Young-Chul (Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine)
  • Received : 2013.10.11
  • Accepted : 2013.12.20
  • Published : 2013.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

Dystrophinopathy, caused by mutations in the DMD gene, presents with variable clinical phenotypes ranging from the severe Duchenne muscular dystrophy (DMD) to the milder Becker muscular dystrophy(BMD) forms. DMD is a recessive X-linked form of muscular dystrophy. Two-thirds of mothers of affected males are thought to be DMD carriers. Approximately 2.5-7.8% of female DMD carriers have muscle weakness and are categorized as manifesting DMD carriers. The symptoms of female carriers of DMD range from mild muscle weakness to severe gait problems. The most commonly presented symptom is mild proximal muscle weakness, which is often asymmetric and progressive, but shows variable clinical spectrum with BMD of more severe DMD-like phenotype. Atypical presentations in manifesting carriers are myalgia or cramps without limb weakness, isolated cardiomyopathy and camptocormia. Multiplex PCR and MLPA analysis are common techniques to identify mutations in the DMD gene. Relationship between X-chromosome inactivation and clinical severity is not clear. Female carriers of DMD are not less common, and they have an important role of birth of a male DMD.

Keywords

References

  1. Moser H, Emery AE. The manifesting carrier in Duchenne muscular dystrophy. Clin Genet 1974;5:271-84.
  2. Norman A, Harper P. A survey of manifesting carriers of Duchenne and Becker muscular dystrophy in Wales. Clin Genet 1989;36:31-7.
  3. Hoffman EP, Arahata K, Minetti C, Bonilla E, Rowland LP. Dystrophinopathy in isolated cases of myopathy in females. Neurology 1992;42: 967-75. https://doi.org/10.1212/WNL.42.5.967
  4. Taylor PJ, Maroulis S, Mullan GL, Pedersen RL, Baumli A, Elakis G, et al. Measurement of the clinical utility of a combined mutation detection protocol in carriers of Duchenne and Becker muscular dystrophy. J Med Genet 2007;44:368-72. https://doi.org/10.1136/jmg.2006.047464
  5. Duchenne GB. De l'electrisation localisee et de son application a la physiologie, a la pathologie et a la therapeutique. 2nd Ed, Paris: Bailliere, 1861.
  6. Duchenne GB. De la paralysie musculaire pseudo-hypertrophique ou paralysie myo-sclerosique. Paris: P. Asselin, 1868.
  7. Gowers WR. A manual of diseases of the nervous system. London: Churchill, 1886.
  8. Greenstein RM, Reardon MP, Chan TS, Middleton AB, Mulivor RA, Greene AE, et al. An (X;11) translocation in a girl with Duchenne muscular dystrophy. Repository identification No. GM1695. Cytogenet Cell Genet 1980;27:268. https://doi.org/10.1159/000131496
  9. Davies KE, Pearson PL, Harper PS, Murray JM, O'Brien T, Sarfarazi M, et al. Linkage analysis of two cloned DNA sequences flanking the Duchenne muscular dystrophy locus on the short arm of the human X chromosome. Nucleic Acids Res 1983;11:2303-12. https://doi.org/10.1093/nar/11.8.2303
  10. Francke U, Ochs HD, de Martinville B, Giacalone J, Lindgren V, Disteche C, et al. Minor Xp21 chromosome deletion in a male associated with expression of Duchenne muscular dystrophy, chronic granulomatous disease, retinitis pigmentosa, and McLeod syndrome. Am J Hum Genet 1985;37:250-67.
  11. Boyd Y, Buckle V, Holt S, Munro E, Hunter D, Craig I. Muscular dystrophy in girls with X;autosome translocations. J Med Genet 1986;23:484-90. https://doi.org/10.1136/jmg.23.6.484
  12. Hoffman EP, Brown RH, Jr., Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 1987;51:919-28. https://doi.org/10.1016/0092-8674(87)90579-4
  13. Culligan KG, Mackey AJ, Finn DM, Maguire PB, Ohlendieck K. Role of dystrophin isoforms and associated proteins in muscular dystrophy (review). Int J Mol Med 1998;2:639-48.
  14. Matthews PM, Karpati G. Pattern of X-chromosome inactivation as a key determinant of the clinicopathologic phenotype of Duchenne muscular dystrophy carriers. Neurology 1996;46:1189-91.
  15. Pena SD, Karpati G, Carpenter S, Fraser FC. The clinical consequences of X-chromosome inactivation: Duchenne muscular dystrophy in one of monozygotic twins. J Neurol Sci 1987;79:337-44. https://doi.org/10.1016/0022-510X(87)90240-1
  16. Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol 2010;9:77-93. https://doi.org/10.1016/S1474-4422(09)70271-6
  17. Emery AE. Population frequencies of inherited neuromuscular diseases- -a world survey. Neuromuscul Disord 1991;1:19-29. https://doi.org/10.1016/0960-8966(91)90039-U
  18. Bushby KM, Goodship JA, Nicholson LV, Johnson MA, Haggerty ID, Gardner-Medwin D. Variability in clinical, genetic and protein abnormalities in manifesting carriers of Duchenne and Becker muscular dystrophy. Neuromuscul Disord 1993;3:57-64. https://doi.org/10.1016/0960-8966(93)90042-I
  19. Richards CS, Watkins SC, Hoffman EP, Schneider NR, Milsark IW, Katz KS, et al. Skewed X inactivation in a female MZ twin results in Duchenne muscular dystrophy. Am J Hum Genet 1990;46:672-81.
  20. Soltanzadeh P, Friez MJ, Dunn D, von Niederhausern A, Gurvich OL, Swoboda KJ, et al. Clinical and genetic characterization of manifesting carriers of DMD mutations. Neuromuscul Disord 2010;20:499-504. https://doi.org/10.1016/j.nmd.2010.05.010
  21. Hoogerwaard EM, Bakker E, Ippel PF, Oosterwijk JC, Majoor-Krakauer DF, Leschot NJ, et al. Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in The Netherlands: a cohort study. Lancet 1999;353:2116-9. https://doi.org/10.1016/S0140-6736(98)10028-4
  22. Grain L, Cortina-Borja M, Forfar C, Hilton-Jones D, Hopkin J, Burch M. Cardiac abnormalities and skeletal muscle weakness in carriers of Duchenne and Becker muscular dystrophies and controls. Neuromuscul Disord 2001;11:186-91. https://doi.org/10.1016/S0960-8966(00)00185-1
  23. Ceulemans BP, Storm K, Reyniers E, Jr., Callewaert L, Martin JJ. Muscle pain as the only presenting symptom in a girl with dystrophinopathy. Pediatr Neurol 2008;38:64-6. https://doi.org/10.1016/j.pediatrneurol.2007.09.006
  24. Kinoshita H, Goto Y, Ishikawa M, Uemura T, Matsumoto K, Hayashi YK, et al. A carrier of Duchenne muscular dystrophy with dilated cardiomyopathy but no skeletal muscle symptom. Brain Dev 1995;17: 202-5. https://doi.org/10.1016/0387-7604(95)00018-7
  25. Mirabella M, Servidei S, Manfredi G, Ricci E, Frustaci A, Bertini E, et al. Cardiomyopathy may be the only clinical manifestation in female carriers of Duchenne muscular dystrophy. Neurology 1993;43:2342-5. https://doi.org/10.1212/WNL.43.11.2342
  26. Walcher T, Kunze M, Steinbach P, Sperfeld AD, Burgstahler C, Hombach V, et al. Cardiac involvement in a female carrier of Duchenne muscular dystrophy. Int J Cardiol 2010;138:302-5. https://doi.org/10.1016/j.ijcard.2008.06.084
  27. Findlay AR, Lewis S, Sahenk Z, Flanigan KM. Camptocormia as a late presentation in a manifesting carrier of duchenne muscular dystrophy. Muscle Nerve 2013;47:124-7. https://doi.org/10.1002/mus.23497
  28. Griggs RC, Mendell JR, Brooke MH, Fenichel GM, Miller JP, Province M, et al. Clinical investigation in Duchenne dystrophy: V. Use of creatine kinase and pyruvate kinase in carrier detection. Muscle Nerve 1985;8:60-7. https://doi.org/10.1002/mus.880080111
  29. Matsumura K, Nakano I, Fukuda N, Ikehira H, Tateno Y, Aoki Y. Duchenne muscular dystrophy carriers. Proton spin-lattice relaxation times of skeletal muscles on magnetic resonance imaging. Neuroradiology 1989;31:373-6. https://doi.org/10.1007/BF00343858
  30. Foley JM, Jayaraman RC, Prior BM, Pivarnik JM, Meyer RA. MR measurements of muscle damage and adaptation after eccentric exercise. J Appl Physiol (1985) 1999;87:2311-8. https://doi.org/10.1152/jappl.1999.87.6.2311
  31. Mathur S, Vohra RS, Germain SA, Forbes S, Bryant ND, Vandenborne K, et al. Changes in muscle T2 and tissue damage after downhill running in mdx mice. Muscle Nerve 2011;43:878-86. https://doi.org/10.1002/mus.21986
  32. Forbes SC, Lott DJ, Finkel RS, Senesac C, Byrne BJ, Sweeney HL, et al. MRI/ MRS evaluation of a female carrier of Duchenne muscular dystrophy. Neuromuscul Disord 2012;22 Suppl 2:S111-21. https://doi.org/10.1016/j.nmd.2012.05.013
  33. Arahata K, Ishihara T, Kamakura K, Tsukahara T, Ishiura S, Baba C, et al. Mosaic expression of dystrophin in symptomatic carriers of Duchenne's muscular dystrophy. N Engl J Med 1989;320:138-42. https://doi.org/10.1056/NEJM198901193200302
  34. Na SJ, Kim WJ, Kim SM, Lee KO, Yoon B, Choi YC. Clinical, immunohistochemical, Western blot, and genetic analysis in dystrophinopathy. J Clin Neurosci 2013;20:1099-105. https://doi.org/10.1016/j.jocn.2012.09.021
  35. Hoogerwaard EM, Ginjaar IB, Bakker E, de Visser M. Dystrophin analysis in carriers of Duchenne and Becker muscular dystrophy. Neurology 2005;65:1984-6. https://doi.org/10.1212/01.wnl.0000188909.89849.59
  36. Azofeifa J, Voit T, Hubner C, Cremer M. X-chromosome methylation in manifesting and healthy carriers of dystrophinopathies: concordance of activation ratios among first degree female relatives and skewed inactivation as cause of the affected phenotypes. Hum Genet 1995;96: 167-76. https://doi.org/10.1007/BF00207374
  37. Singh V, Sinha S, Mishra S, Chaturvedi LS, Pradhan S, Mittal RD, et al. Proportion and pattern of dystrophin gene deletions in north Indian Duchenne and Becker muscular dystrophy patients. Hum Genet 1997;99:206-8. https://doi.org/10.1007/s004390050340
  38. Lai PS, Takeshima Y, Adachi K, Van Tran K, Nguyen HT, Low PS, et al. Comparative study on deletions of the dystrophin gene in three Asian populations. J Hum Genet 2002;47:552-5. https://doi.org/10.1007/s100380200084
  39. Khalap N, Joshi V, Ladiwalla U, Khadilkar S, Mahajan S. A report on higher frequency of DMD gene deletion in the Indian subcontinent. Indian J Hum Genet 1997;3:117-20.
  40. Baumbach LL, Chamberlain JS, Ward PA, Farwell NJ, Caskey CT. Molecular and clinical correlations of deletions leading to Duchenne and Becker muscular dystrophies. Neurology 1989;39:465-74. https://doi.org/10.1212/WNL.39.4.465
  41. Hu X, Ray PN, Murphy EG, Thompson M, Worton R. Duplicational mutation at the Duchenne muscular dystrophy locus: its frequency, distribution, origin, and phenotypegenotype correlation. Am J Hum Genet 1990;46:682-95.
  42. Prior TW, Bridgeman SJ. Experience and strategy for the molecular testing of Duchenne muscular dystrophy. J Mol Diagn 2005;7:317-26. https://doi.org/10.1016/S1525-1578(10)60560-0
  43. Lalic T, Vossen RH, Coffa J, Schouten JP, Guc-Scekic M, Radivojevic D, et al. Deletion and duplication screening in the DMD gene using MLPA. Eur J Hum Genet 2005;13:1231-4. https://doi.org/10.1038/sj.ejhg.5201465
  44. Stuppia L, Antonucci I, Palka G, Gatta V. Use of the MLPA Assay in the Molecular Diagnosis of Gene Copy Number Alterations in Human Genetic Diseases. Int J Mol Sci 2012;13:3245-76. https://doi.org/10.3390/ijms13033245
  45. Song TJ, Lee KA, Kang SW, Cho H, Choi YC. Three cases of manifesting female carriers in patients with Duchenne muscular dystrophy. Yonsei Med J 2011;52:192-5. https://doi.org/10.3349/ymj.2011.52.1.192
  46. Cho H, Hong JM, Lee KA, Choi YC. Clinical usefulness of molecular diagnosis in dystrophin gene mutations using the multiplex ligationdependent probe amplification (MLPA) method. J Korean Neurol Assoc 2010;28:22-6.
  47. Sellner LN, Taylor GR. MLPA and MAPH: new techniques for detection of gene deletions. Hum Mutat 2004;23:413-9. https://doi.org/10.1002/humu.20035
  48. Flanigan KM, von Niederhausern A, Dunn DM, Alder J, Mendell JR, Weiss RB. Rapid direct sequence analysis of the dystrophin gene. Am J Hum Genet 2003;72:931-9. https://doi.org/10.1086/374176
  49. Dent KM, Dunn DM, von Niederhausern AC, Aoyagi AT, Kerr L, Bromberg MB, et al. Improved molecular diagnosis of dystrophinopathies in an unselected clinical cohort. Am J Med Genet A 2005;134:295-8.
  50. Yasuma F, Konagaya M, Sakai M, Kuru S, Kawamura T. A new lease on life for patients with Duchenne muscular dystrophy in Japan. Am J Med 2004;117:363.
  51. Jeppesen J, Green A, Steffensen BF, Rahbek J. The Duchenne muscular dystrophy population in Denmark, 1977-2001: prevalence, incidence and survival in relation to the introduction of ventilator use. Neuromuscul Disord 2003;13:804-12. https://doi.org/10.1016/S0960-8966(03)00162-7
  52. Lim LE, Rando TA. Technology insight: therapy for Duchenne muscular dystrophy-an opportunity for personalized medicine? Nat Clin Pract Neurol 2008;4:149-58. https://doi.org/10.1038/ncpneuro0737
  53. van Ommen GJ, van Deutekom J, Aartsma-Rus A. The therapeutic potential of antisense-mediated exon skipping. Curr Opin Mol Ther 2008;10:140-9.
  54. van Deutekom JC, Janson AA, Ginjaar IB, Frankhuizen WS, Aartsma-Rus A, Bremmer-Bout M, et al. Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med 2007;357:2677-86. https://doi.org/10.1056/NEJMoa073108
  55. Yoshioka M, Yorifuji T, Mituyoshi I. Skewed X inactivation in manifesting carriers of Duchenne muscular dystrophy. Clin Genet 1998;53:102-7.
  56. Pegoraro E, Schimke RN, Arahata K, Hayashi Y, Stern H, Marks H, et al. Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females. Am J Hum Genet 1994;54:989-1003.
  57. Wenger SL, Steele MW, Hoffman EP, Barmada MA, Wessel HB. X inactivation and dystrophin studies in a t(X;12) female: evidence for biochemical normalization in Duchenne muscular dystrophy carriers. Am J Med Genet 1992;43:1012-5. https://doi.org/10.1002/ajmg.1320430619
  58. Juan-Mateu J, Rodriguez MJ, Nascimento A, Jimenez-Mallebrera C, Gonzalez-Quereda L, Rivas E, et al. Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy. Orphanet J Rare Dis 2012;7:82. https://doi.org/10.1186/1750-1172-7-82
  59. Brioschi S, Gualandi F, Scotton C, Armaroli A, Bovolenta M, Falzarano MS, et al. Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype. BMC Med Genet 2012;13:73.
  60. Matthews PM, Benjamin D, Van Bakel I, Squier MV, Nicholson LV, Sewry C, et al. Muscle X-inactivation patterns and dystrophin expression in Duchenne muscular dystrophy carriers. Neuromuscul Disord 1995;5: 209-20. https://doi.org/10.1016/0960-8966(94)00057-G
  61. Sumita DR, Vainzof M, Campiotto S, Cerqueira AM, Canovas M, Otto PA, et al. Absence of correlation between skewed X inactivation in blood and serum creatine-kinase levels in Duchenne/Becker female carriers. Am J Med Genet 1998;80:356-61. https://doi.org/10.1002/(SICI)1096-8628(19981204)80:4<356::AID-AJMG10>3.0.CO;2-O