Journal of Neurology

, Volume 251, Issue 10, pp 1173–1182 | Cite as

Myotonic dystrophy type 2 and related myotonic disorders



The myotonic dystrophies are a group of dominantly inherited disorders characterized by muscle wasting, myotonia, cataracts, hypogonadism and other system manifestations. Myotonic dystrophy type 1 (DM1) results from an unstable expansion of a CTG repeat in 3’ UTR of the DM protein kinase (DMPK) gene on chromosome 19q 13.3. Myotonic dystrophy type 2 (DM2) is caused by an unstable expansion of a CCTG tetraplet repeat in intron 1 of the zinc finger 9 (ZFN9 gene) on chromosome 3q 21.3. However, the clinical diagnosis of DM2 is more complex than that of DM1, and conventional molecular genetic methods used for diagnosis of DM1 are not helpful for DM2. We here describe the detailed clinical, laboratory and biomolecular tests to identify DM2 and related myotonic disorders. At present, foci of accumulated noncoding CCTG repeat RNA (ribonuclear inclusions) in the cell nuclei are thought to interfere with the regulation and expression of several genes at the basis of multisystemic aspects of myotonic dystrophy type 2.

Key words

myotonic dystrophy type 2 myotonic dystrophy type 1 DM1 DM2 DMPK ZFN9 


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  1. 1.
    Bachinski LL, Udd B, Meola G, Sansone V, Bassez G, Eymard B, Thornton CA, Moxley RT, Harper PS, Rogers MT, Jurkat-Rott K, Lehmann-Horn F, Wieser T, Gamez J, Navarro C, Bottani A, Kohler A, Shriver MD, Sallinen R, Wessman M, Zhang S, Wright FA, Krahe R (2003) Confirmation of the type 2 myotonic dystrophy (CCTG)n expansion mutation in patients with proximal myotonic myopathy/proximal myotonic dystrophy of different European origins: a single shared haplotype indicates an ancestral founder effect. Am J Hum Gen 73:835–848CrossRefGoogle Scholar
  2. 2.
    Bassez G, Attarian S, Laforet P, Azulay JP, Rouche A, Ferrer X, Urtizberea JA, Pellissier JF, Duboc D, Fardeau M, Pouget J, Eymard B (2001) Myopathie proximale avec myotonie (PROMM): étude clinique et histologique. Rev Neurol (Paris)2:209–218Google Scholar
  3. 3.
    Buj-Bello A, Furling D, Tronchère H, Laporte J, Lerouge T, Butler-Browne GS, Mandel JL (2002) Muscle-specific alternative splicing of myotubularin-related 1 gene is impaired in DM1 muscle cells. Hum Mol Genet 11:2297–2307CrossRefPubMedGoogle Scholar
  4. 4.
    Chu K, Cho J-W, Song E-C, Jeon BS (2002) A patient with proximal myotonic myopathy and parkinsonism. Can J Neurol Sci 29:188–190PubMedGoogle Scholar
  5. 5.
    Davis BM, McCurrach ME, Taneja KL, Singer RH, Housman DE (1997) Expansion of a CUG trinucleotide repeat in the 3’ untranslated region of myotonic dystrophy protein kinase transcripts results in nuclear retention of transcripts. Proc Natl Acad Sci USA 94:7388–7393CrossRefPubMedGoogle Scholar
  6. 6.
    Day JW, Roelofs R, Leroy B, Pech I, Penzow K, Ranum LP (1999) Clinical and genetic characteristics of a five-generation family with a novel form of myotonic dystrophy (DM2). Neuromuscul Disord 9:19–27CrossRefPubMedGoogle Scholar
  7. 7.
    Day JW, Ricker K, Jacobsen JF, l Rasmussen LJ, Dick KA, Kress W, Schneider C, Koch MC, Beilman GJ, Harrison AR, Dalton JC, Ranum LP (2003) Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology 60:657–664PubMedGoogle Scholar
  8. 8.
    Ebralidze A, Wang Y, Petkova V, Ebralidse K, Junghans RP (2004) RNA leaching of transcription factors disrupts transcription in myotonic dystrophy. Science 303:383–387CrossRefPubMedGoogle Scholar
  9. 9.
    Eger K, Schulte-Mattler WJ, Zierz S (1997) Proximal myotonic myopathy (PROMM). Nervenarzt 68:839–844CrossRefPubMedGoogle Scholar
  10. 10.
    Fardaei M, Larkin K, Brook D, Hamshere MG (2001) In vivo co-localisation of MBNL protein with DMPK expanded-repeat transcripts. Nuclei Acid Res 29:2766–2771CrossRefGoogle Scholar
  11. 11.
    Flachenecker P, Schneider C, Cursiefen S, Ricker K, Toyka KV, Reiners K, (2003) Assessment of cardiovascular autonomic function in myotonic dystrophy type 2 (DM2/PROMM). Neuromuscul Disord 3:289–293CrossRefGoogle Scholar
  12. 12.
    Harper PS (2001) Myotonic dystrophy. Major problems in neurology. WB Saunders Co (3rd ed), London, vol. 37Google Scholar
  13. 13.
    Hund E, Jansen O, Koch MC, Ricker K, Fogel W, Niedermaier N, Otto M, Kuhn E Meinck HM (1997) Proximal myotonic myopathy with MRI white matter abnormalities of the brain. Neurology 48:33–37PubMedGoogle Scholar
  14. 14.
    Jakubiczka S, Vielhaber S, Kress W, Kupferling P, Reuner U, Kunath B, Wieacker P (2004) Improvement of the diagnostic procedure in proximal myotonic myopathy/myotonic dystrophy type 2. Neurogenetics 5:55–59CrossRefPubMedGoogle Scholar
  15. 15.
    Kanadia RN, Johnstone KA, Mankodi A, Lungu C, Thornton CA, Esson D, Timmers AM, Hauswirth WW, Swanson MS (2003) A muscleblind knockout model for myotonic dystrophy. Science 302:1978–1980CrossRefPubMedGoogle Scholar
  16. 16.
    Kassubek J, Juengling FD, Hoffmann S, Rosenbohm A, Kurt A, Jurkat-Rott K, Steinbach P, Wolf M, Ludolph AC, Lehmann-Horn F, Lerche H, Weber YG (2003) Quantification of brain atrophy in patients with myotonic dystrophy and proximal myotonic myopathy: a controlled 3-dimensional magnetic resonance imaging study. Neurosci Lett 348:73–76CrossRefPubMedGoogle Scholar
  17. 17.
    Kohler A, Burkhard P, Hefft S, Bottani A, Pizzolato GP, Magistris MR (2000) Proximal myotonic myopathy: clinical, electrophysiological and pathological findings in a family. Eur Neurol 43:50–53CrossRefPubMedGoogle Scholar
  18. 18.
    Kress W, Mueller-Myhsok B, Ricker K, Schneider C, Koch MC, Toyka KV, Mueller CR,Grimm T (2000) Proof of genetic heterogeneity in the proximal myotonic myopathy syndrome (PROMM) and its relationship to myotonic dystrophy type 2 (DM2). Neuromuscul Disord 10:478–480CrossRefPubMedGoogle Scholar
  19. 19.
    Lamont PJ, Jacob RL, Mastaglia FL, Laing NG (2004) An expansion in the ZNF9 gene causes PROMM in a previously described family with an incidental CLCN1 mutation. J Neurol Neurosurg Psychiatry 75:343CrossRefGoogle Scholar
  20. 20.
    Liquori C, Ricker K, Moseley M, Jacobsen JF, Kress W, Naylor SL, Day JW, Ranum LP (2001) Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293:864–867CrossRefPubMedGoogle Scholar
  21. 21.
    Liquori CL, Ikeda Y, Weatherspoon M, Ricker K, Schoser BG, Dalton JC, Day JW, Ranum LP (2003) Myotonic dystrophy type 2: human founder haplotype and evolutionary conservation of the repeat tract. Am J Hum Gen 73:849–862CrossRefGoogle Scholar
  22. 22.
    Mankodi A, Logigian E, Callahan L, McClain C, White R, Henderson D, Krym M, Thornton CA (2000) Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science 289:1769–1773CrossRefPubMedGoogle Scholar
  23. 23.
    Mankodi A, Urbinati CR, Yuan QP, Moxley RT, Sansone V, Krym M, Henderson D, Schalling M, Swanson MS, Thornton CA (2001) Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. Hum Mol Genet 10:2165–2170CrossRefPubMedGoogle Scholar
  24. 24.
    Mankodi A, Takahashi MP, Jiang H, Beck CL, Bowers WJ, Moxley RT, Cannon SC, Thornton CA (2002) Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel premRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell 10:35–44CrossRefPubMedGoogle Scholar
  25. 25.
    Mankodi A, Thornton CA (2002) Myotonic syndromes. Curr Opin Neurol 15:545–552CrossRefPubMedGoogle Scholar
  26. 26.
    Mankodi A, Teng-Umnuay P, Krym M, Henderson D, Swanson M, Thornton CA (2003) Ribonuclear inclusions in skeletal muscle in myotonic dystrophy types 1 and 2. Ann Neurol 54:760–768CrossRefPubMedGoogle Scholar
  27. 27.
    Mastaglia FL, Harker N, Philips BA, Day TJ, Hankey GJ, Laing NG, Fabian V, Kakulas BA (1998) Dominantly inherited proximal myotonic myopathy and leukoencephalopathy in a family with an incidental CLCN1 mutation. J Neurol Neurosurg Psychiatry 64:543–547PubMedGoogle Scholar
  28. 28.
    Meola G, Sansone V, Radice S, Skradski S, Ptacek L (1996) A family with an unusual myotonic and myopathic phenotype and no CTG expansion (proximal myotonic myopathy syndrome): a challenge for future molecular studies. Neuromuscul Disord 6:143–150CrossRefPubMedGoogle Scholar
  29. 29.
    Meola G, Sansone V, Perani D, Colleluori A, Cappa S, Cotelli M, Fazio F, Thornton CA, Moxley RT (1999) Reduced cerebral blood flow and impaired visual-spatial function in proximal myotonic myopathy. Neurology 53:1042–1050PubMedGoogle Scholar
  30. 30.
    Meola G (2000) Clinical and genetic heterogeneity in myotonic dystrophies. Muscle Nerve 23:1789–1799CrossRefPubMedGoogle Scholar
  31. 31.
    Meola G, Sansone V, Marinou K, Cotelli M, Moxley RT 3rd, Thornton CA, De Ambroggi L (2002) Proximal myotonic myopathy: a syndrome with a favourable prognosis? J Neurol Sci 193:89–96CrossRefPubMedGoogle Scholar
  32. 32.
    Meola G, Sansone V, Perani D, Scarone S, Cappa S, Dragoni C, Cattaneo E, Cotelli M, Gobbo C, Fazio F, Siciliano G, Mancuso M, Vitelli E, Zhang S, Krahe R, Moxley RT (2003) Executive dysfunction and avoidant personality trait in myotonic dystrophy type 1 (DM1) and in proximal myotonic myopathy (DM2/PROMM). Neuromuscul Disord 13:813–821CrossRefPubMedGoogle Scholar
  33. 33.
    Moxley RT, Meola G, Udd B, Ricker K (2002) 84th ENMC International Workshop: PROMM (Proximal Myotonic Myopathy) and other Proximal Myotonic Syndromes—Workshop Report: Neuromuscul Disord 12:306–317CrossRefPubMedGoogle Scholar
  34. 34.
    Moxley RT, Meola G (2003) The myotonic dystrophies. In Rosenberg RN, Prusiner SB, Di Mauro S, Barchi RL, Nestler EJ (ed) The molecular and genetic basis of neurologic and psychiatric disease. Butterworth-Heinemann, Philadelphia, chapter 47, pp 511–518Google Scholar
  35. 35.
    Newman B, Meola G, O’Donovan DG, Schapira AHV, Kingston H (1999) Proximal myotonic myopathy (PROMM) presenting as myotonia during pregnancy. Neuromuscul Disord 9:144–149CrossRefPubMedGoogle Scholar
  36. 36.
    Philips AV, Timchenko LT, Cooper TA (1998) Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science 280:737–741CrossRefPubMedGoogle Scholar
  37. 37.
    Phillips MF, Rogers MT, Barnetson R, Braun C, Harley HG, Myring J, Stevens D, Wiles CM, Harper PS (1998) PROMM: the expanding phenotype. A family with a proximal myopathy, myotonia and deafness. Neuromuscul Disord 8:439–446CrossRefPubMedGoogle Scholar
  38. 38.
    Ranum LPW, Rasmussen PF, Benzow KA, Koob MD, Day JW (1998) Genetic mapping of a second myotonic dystrophy locus. Nat Genet 19:196–198CrossRefPubMedGoogle Scholar
  39. 39.
    Ranum LPW, Day JW (2002) Myotonic dystrophy: clinical and molecular parallels between myotonic dystrophy type 1 and type 2. Curr Neurol Neurosci Rep 2:465–470PubMedGoogle Scholar
  40. 40.
    Ranum LPW, Day JW (2002) Dominantly inherited non-coding microsatellite expansion disorders. Curr Opin Gen & Dev 12:266–271Google Scholar
  41. 41.
    Ricker K, Koch MC, Lehmann-Horn F, Pongratz D, Otto M Heine R, Moxley RT 3rd. (1994) Proximal myotonic myopathy: a new dominant disorder with myotonia,muscle weakness, and cataracts. Neurology 44:1448–1452PubMedGoogle Scholar
  42. 42.
    Ricker K, Koch MC, Lehmann-Horn F, Pongratz D, Speich N, Reiners K, Schneider C, Moxley RT 3rd (1995) Proximal myotonic myopathy. Clinical features of a multisystem disorder similar to myotonic dystrophy. Arch. Neurol 52:25–31PubMedGoogle Scholar
  43. 43.
    Ricker K, Grimm T, Koch MC, Schneider C, Kress W, Reimers CD, Schulte-Mattler W, Mueller-Myhsok B, Toyka KV, Mueller CR (1999) Linkage of proximal myotonic myopathy to chromosome 3q. Neurology 52:170–171PubMedGoogle Scholar
  44. 44.
    Rimbaux S, Pellieux S, Bergemer AM, Saïkali I, Gherardi R, Fouquet B (2003) Camptocormie rèvèlatrice d’une myopathie myotonique proximale. Rev Neurol (Paris) 159:678–680PubMedGoogle Scholar
  45. 45.
    Sallinen R, Vihola A, Bachinski LL, Huoponen K, Haapasalo H, Hackman P, Zhang S, Sirito M, Kalimo H, Meola G, Horelli-Kuitunen N, Wessmann M, Krahe R, Udd B (2004) New methods for molecular diagnosis and demonstration of the (CCTG)n mutation in myotonic dystrophy type 2 (DM2). Neuromuscul Disord 14:274–283CrossRefPubMedGoogle Scholar
  46. 46.
    Sander HW, Tavoulareas GP, Chokroverty S (1996) Heat-sensitive myotonia in proximal myotonic myopathy. Neurology 47:956–962PubMedGoogle Scholar
  47. 47.
    Sansone V, Griggs RC, Moxley RT (2000) Hypothyroidism unmasking proximal myotonic myopathy. Neuromuscul Disord 10:165–172CrossRefPubMedGoogle Scholar
  48. 48.
    Savkur RS, Philips AV, Cooper TA (2001) Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nature Genet 29:40–47CrossRefPubMedGoogle Scholar
  49. 49.
    Savkur RS, Philips AV, Cooper TA, Dalton JC, Moseley ML, Ranum LP, Day JW (2004) Insulin receptor splicing alteration in myotonic dystrophy type 2. Am J Hum Genet 74:1309–1313CrossRefPubMedGoogle Scholar
  50. 50.
    Schneider C, Grimm T, Kress W, Sommer C, Müller CR (2000) Hyperparathyroidism in a patient with proximal myotonic myopathy (PROMM). Neuromuscul Disord 10:481–483CrossRefPubMedGoogle Scholar
  51. 51.
    Schneider C, Wessig C, Müller CR, Brechtelsbauer D, Grimm T (2001) Proximal myotonic myopathy and proximal myotonic dystrophy: Two different entities? The phenotypic variability of proximal myotonic syndromes. Neuromuscul Disord 11:485–488CrossRefPubMedGoogle Scholar
  52. 52.
    Schneider C, Pedrosa Gil F, Schneider M, Anetseder M, Kress W, Müller CR (2002) Intolerance to neuroleptics and susceptibility for malignant hypertermia in a patient with proximal myotonic myopathy (PROMM) and schizophrenia. Neuromuscul Disord 12:31–35CrossRefPubMedGoogle Scholar
  53. 53.
    Schoser BGH, Schneider-Gold C, Kress W, Goebel HH, Reilich P, Koch MC, Pongratz DE, Toyka KV, Lochmüller H, Ricker K (2004) Muscle pathology in 57 patients with myotonic dystrophy type 2. Muscle Nerve 29:275–281CrossRefPubMedGoogle Scholar
  54. 54.
    Sergeant N, Sablonniere B, Schraen-Maschke S, Ghestem A, Maurage CA, Wattez A, Vermersch P, Delacourte A (2001) Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1. Hum Mol Genet 10:2143–2155CrossRefPubMedGoogle Scholar
  55. 55.
    Serratrice J, Weiller PJ, Pouget J, Serratrice G (2000) An unrecognized cause of camptocormia: proximal myotonic myopathy. Press Med 29:1121–1123Google Scholar
  56. 56.
    Sun C, Henriksen OA, Tranebjaerg L (1999) Proximal myotonic myopathy: clinical and molecular investigation of a Norvegian family with PROMM. Clin Genet 56:457–461CrossRefPubMedGoogle Scholar
  57. 57.
    Taneja KL, McCurrach ME, Schalling M, Housman D, Singer RH (1995) Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J Cell Biol 128:995–1002CrossRefPubMedGoogle Scholar
  58. 58.
    The International Myotonic Dystrophy Consortium (IDMC) (2000) New nomenclature and DNA testing guidelines for myotonic dystrophy type 1. Neurology 54:1218–1221PubMedGoogle Scholar
  59. 59.
    Thornton CA, Griggs RC, Moxley RT (1994) Myotonic dystrophy with no trinucleotide repeat expansion. Ann Neurol 35:269–272PubMedGoogle Scholar
  60. 60.
    Timchenko NA, Cai ZJ, Welm AL, Reddy S, Ashizawa T, Timchenko LT (2001) RNA CUG repeats sequester CUGBP1 and alter protein levels and activity of CUGPB1. J Biol Chem 276:7820–7826CrossRefPubMedGoogle Scholar
  61. 61.
    Udd B, Krahe R, Wallgren-Petterson C, Falck B, Kalimo H (1997) Proximal myotonic dystrophy—a family with autosomal dominant muscular dystrophy, cataracts, hearing loss, and hypogonadism: heterogeneity of proximal myotonic disorders. Neuromuscul Disord 7:217–228CrossRefPubMedGoogle Scholar
  62. 62.
    Udd B, Meola G, Krahe R, Thornton C, Ranum L, Day J, Bassez G, Ricker K (2003) Report of the 115th ENMC workshop: DM2/PROMM and other myotonic dystrophies. 3rd Workshop, 14–16 February 2003, Naarden, The Netherlands. Neuromuscul Disord 13:589–596CrossRefPubMedGoogle Scholar
  63. 63.
    Vihola A, Bassez G, Meola G, Zhang S, Haapasalo H, Paetau A, Mancinelli E, Rouche A, Hogrel JY, Laforet P, Maisonobe T, Pellissier JF, Krahe R, Eymard B, Udd B (2003) Histopathological differences of myotonic dystrophy type 1 (DM1) and PROMM/DM2. Neurology 60:1854–1857PubMedGoogle Scholar
  64. 64.
    von zur Muhlen F, Klass C, Kreuzer H, Mall G, Giese A, Reimer CD (1998) Cardiac involvement in proximal myotonic myopathy. Heart 79:619–621PubMedGoogle Scholar
  65. 65.
    Wang J, Pegoraro E, Menegazzo E, Giannarelli M, Hoop RC, Angelini C, Hoffman EP (1995) Myotonic Dystrophy: evidence for a possibile dominant-negative RNA mutation. Hum Mol Genet 4:599–606PubMedGoogle Scholar
  66. 66.
    Wieser T, Bönsch D, Eger K, Schulte-Mattler W, Zierz S (2000) A family with PROMM not linked to the recently mapped PROMM locus DM2. Neuromuscul Disord 10:141–143CrossRefPubMedGoogle Scholar

Copyright information

© Steinkopff Verlag 2004

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of Milan, Istituto Policlinico San DonatoSan Donato Milanese, MilanItaly
  2. 2.Department of NeurologyUniversity of Rochester, Strong Memorial HospitalRochesterUSA

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