Skip to main content
SpringerLink
Log in

Neuromuscular Diseases

  • Chapter
Molecular Pathology in Clinical Practice

  • 3573 Accesses

Abstract

This chapter describes clinical manifestations, pathology, and the molecular diagnosis of selected neuromuscular disorders which are commonly tested for in the molecular pathology laboratory. Neuromuscular function can be impaired as a result of defects in the nervous system, muscle, or both. The disorders described are all heritable. However the disorders have different patterns of inheritance and are caused by different types of mutations. The molecular assay utilized is determined by the type of mutation to be identified. The molecular testing allows for more accurate diagnostic, carrier, predictive, and prenatal testing. The clinical utility, interpretation, and laboratory issues will be described for each disorder.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Emery AEH. Muscle histology and creatine kinase levels in the fetus in Duchenne muscular dystrophy. Nature. 1977;266:472–3.

    Article  CAS  PubMed  Google Scholar 

  2. Moser H. Duchenne muscular dystrophy: pathogenetic aspects and genetic prevention. Hum Genet. 1984;66:17–34.

    Article  CAS  PubMed  Google Scholar 

  3. Hoffman EP, Brown RH, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987;51:919–28.

    Article  CAS  PubMed  Google Scholar 

  4. Koenig M, Hoffman EP, Bertelson CJ, et al. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell. 1987;50:509–17.

    Article  CAS  PubMed  Google Scholar 

  5. Ahn AH, Kunkel LM. The structural and functional diversity of dystrophin. Nat Genet. 1993;3:283–7.

    Article  CAS  PubMed  Google Scholar 

  6. Hoffman EP, Fischbeck K, Brown RH, et al. Dystrophin characterization in muscle biopsies from Duchenne and Becker muscular dystrophy patients. N Engl J Med. 1988;318:1363–8.

    Article  CAS  PubMed  Google Scholar 

  7. Darras BT, Blattner P, Harper JF, et al. Intragenic deletions in 21 Duchenne muscular dystrophy (DMD)/Becker muscular dystrophy (BMD) families studied with the dystrophin cDNA: location of breakpoints on HindIII and BglII exon-containing fragment maps, meiotic and mitotic origin of mutations. Am J Hum Genet. 1988;43:620–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Forrest SM, Cross GS, Flint T, et al. Further studies of gene deletions that cause Duchenne and Becker muscular dystrophies. Genomics. 1988;2:109–17.

    Article  CAS  PubMed  Google Scholar 

  9. Monaco AP, Bertelson CJ, Liechti-Gallati S, et al. An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics. 1988;2:90–5.

    Article  CAS  PubMed  Google Scholar 

  10. Roberts RG, Gardner RJ, Bobrow M. Searching for the 1 in 2,400,000: a review of dystrophin gene point mutations. Hum Mutat. 1994;4:1–11.

    Article  CAS  PubMed  Google Scholar 

  11. Prior TW, Papp AC, Snyder PJ, et al. A missense mutation in the dystrophin gene in a Duchenne muscular dystrophy patient. Nat Genet. 1993;4:357–61.

    Article  CAS  PubMed  Google Scholar 

  12. Prior TW, Bartolo C, Pearl DK, et al. Spectrum of small mutations in the dystrophin coding region. Am J Hum Genet. 1995;57:22–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Prior TW, Friedman KJ, Highsmith WE, et al. Molecular probe protocol for determining carrier status in Duchenne and Becker muscular dystrophies. Clin Chem. 1990;36:441–6.

    CAS  PubMed  Google Scholar 

  14. Chamberlain JS, Gibbs RA, Ranier JE, et al. Deletion screening of the Duchenne muscular dystrophy locus via multiplex DNA amplification. Nucleic Acids Res. 1988;16:11141–56.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Lalic T, Vossen RH, Coffa J, et al. Deletion and duplication screening in the DMD gene using MLPA. Eur J Hum Genet. 2005;13:1231–4.

    Article  CAS  PubMed  Google Scholar 

  16. Bakker E, Van Broeckhoven C, Bonten EJ, et al. Germline mosaicism and Duchenne muscular dystrophy mutations. Nature. 1987;329:554–7.

    Article  CAS  PubMed  Google Scholar 

  17. Harper PS. Congenital myotonic dystrophy in Britain, II: genetic basis. Arch Dis Child. 1975;50:514–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Brook HG, McCurrach ME, Harley HG, et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family. Cell. 1992;68:799–808.

    Article  CAS  PubMed  Google Scholar 

  19. Fu YH, Pizzuti A, Fenwick R, et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science. 1992;255:1256–8.

    Article  CAS  PubMed  Google Scholar 

  20. Mahadevan M, Tsilfidis C, Sabourin L, et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science. 1992;255:1253–5.

    Article  CAS  PubMed  Google Scholar 

  21. Ranum LP, Day JW. Myotonic dystrophy: RNA pathogenesis comes into focus. Am J Hum Genet. 2004;74:793–804.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Sabouri LA, Mahadevan MS, Narang M, et al. Effect of the myotonic dystrophy mutation on mRNA levels of the DM gene. Nat Genet. 1993;4:233–8.

    Article  CAS  PubMed  Google Scholar 

  23. Barcelo JM, Mahadevan MS, Tsilfidis C, et al. Intergenerational stability of the myotonic dystrophy protomutation. Hum Mol Genet. 1993;2:705–9.

    Article  CAS  PubMed  Google Scholar 

  24. Anvret M, Ahlberg G, Grandell U, et al. Larger expansions of the CTG repeat in muscle compared to lymphocytes from patients with myotonic dystrophy. Hum Mol Genet. 1993;2:1397–400.

    Article  CAS  PubMed  Google Scholar 

  25. Liquori C, Ricker K, Mosley M, et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science. 2001;293:864–7.

    Article  CAS  PubMed  Google Scholar 

  26. Pearn J. Incidence, prevalence, and gene frequency studies of chronic childhood spinal muscular atrophy. J Med Genet. 1978;15:409–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Lefebvre S, Burglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80:155–65.

    Article  CAS  PubMed  Google Scholar 

  28. McAndrew PE, Parsons DW, Simard LR, et al. Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number. Am J Hum Genet. 1997;60:1411–22.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Mailman MD, Heinz JW, Papp AC, et al. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med. 2002;4:20–6.

    Article  CAS  PubMed  Google Scholar 

  30. Velasco E, Valero C, Valero A, Moreno F, Hernandez-Chico C. Molecular analysis of the SMN and NAIP genes in Spanish spinal muscular atrophy (SMA) families and correlation between number of copies of cBCD 541 and SMA phenotype. Hum Mol Genet. 1996;5:257–63.

    Article  CAS  PubMed  Google Scholar 

  31. Talbot K, Ponting CP, Theodosiou AM, et al. Missense mutation clustering in the survival motor neuron gene: a role for a conserved tyrosine and glycine rich region of the protein RNA metabolism? Hum Mol Genet. 1997;6:497–501.

    Article  CAS  PubMed  Google Scholar 

  32. Liu Q, Dreyruss G. A novel nuclear structure containing the survival of motor neurons protein. EMBO J. 1996;15:3355–65.

    Google Scholar 

  33. Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy. Hum Mutat. 2000;15:228–37.

    Article  CAS  PubMed  Google Scholar 

  34. Parsons DW, McAndrew PE, Iannaccone ST, et al. Intragenic telSMN mutations: frequency, distribution, evidence of a founder effect and modification of spinal muscular atrophy phenotype by cenSMN copy number. Am J Hum Genet. 1998;63:1712–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Hendrickson BC, Donohoe C, Akmaev VR, et al. Differences in SMN1 allele frequencies among ethnic groups within North America. J Med Genet. 2009;46:641–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Huang C-H, Chang Y-Y, Chen C-H. Copy number analysis of survival motor neuron genes by multiplex ligation-dependent probe amplification. Genet Med. 2007;9:241–8.

    Article  PubMed  Google Scholar 

  37. Wirth B, Rudnik-Schoneborn S, Hahnen E, et al. Prenatal prediction in families with autosomal recessive proximal spinal muscular atrophy (5q11.2-q13.3): molecular genetics and clinical experience in 109 cases. Prenat Diagn. 1995;15:407–17.

    Article  CAS  PubMed  Google Scholar 

  38. Mailman MD, Hemingway T, Darsey RL, et al. Hybrids monosomal for human chromosome 5 reveal the presence of a spinal muscular atrophy (SMA) carrier with two SMN1 copies on one chromosome. Hum Genet. 2001;108:109–15.

    Article  CAS  PubMed  Google Scholar 

  39. Berenberg R, Pellock J, DiMauro S, et al. Lumping or splitting? “Ophthalmopelgia-plus” or Kearns-Sayre syndrome? Ann Neurol. 1977;1:37–42.

    Article  CAS  PubMed  Google Scholar 

  40. Moraes CT, DiMauro S, Zeviani M, et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med. 1989;320:1293–9.

    Article  CAS  PubMed  Google Scholar 

  41. Hirano M, Ricci E, Koenigsberger MR, et al. MELAS: an original case and clinical criteria for diagnosis. Neuromuscul Disord. 1992;2:125–35.

    Article  CAS  PubMed  Google Scholar 

  42. Goto Y, Nonaka I, Horai S. A mutation in the tRNALeu (UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990;348:651–3.

    Article  CAS  PubMed  Google Scholar 

  43. Silvestri G, Ciafaloni E, Santorelli FM, et al. Clinical features associated with the A > G transition at nucleotide 8344 of mtDNA (“MERRF mutation”). Neurology. 1993;43:1200–6.

    Article  CAS  PubMed  Google Scholar 

  44. Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset: a sex-linked recessive trait. Neurology. 1968;18:671–80.

    Article  CAS  PubMed  Google Scholar 

  45. La Spada AR, Wilson AR, Lubahn DB. Androgen receptor mutations in X-linked spinal muscular atrophy. Nature. 1991;353:77–9.

    Article  Google Scholar 

  46. Amato AA, Prior TW, Barohn R, Snyder P, Papp A, Mendell JR. Kennedy’s disease: a clinicopathologic correlation with mutations in the androgen receptor gene. Neurology. 1993;43:791–4.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Ohio State University Medical Center, 125 Hamilton Hall, 1645 Neil Ave., Columbus, OH, 43210, USA

    Thomas W. Prior Ph.D.

Authors
  1. Thomas W. Prior Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas W. Prior Ph.D. .

Editor information

Editors and Affiliations

  1. Pathology and Laboratory Medicine, University of Vermont College of Medicine and University of Vermont Medical Center, Burlington, Vermont, USA

    Debra G.B. Leonard

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Prior, T.W. (2016). Neuromuscular Diseases. In: Leonard, D. (eds) Molecular Pathology in Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-19674-9_9

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-19674-9_9

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-19673-2

  • Online ISBN: 978-3-319-19674-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation