#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Muscular biopsy in myotonic dystrophy in the era of molecular genetics


Authors: Z. Lukáš 1;  I. Kroupová 1;  J. Bednařík 2;  M. Falk 3;  L. Fajkusová 4;  J. Sedláčková 4;  I. Valášková 5;  S. Voháňka 2
Authors‘ workplace: Ústav patologie LF MU a FN Brno 1;  Neurologická klinika LF MU a FN Brno 2;  Biofyzikální ústav AV ČR, Brno 3;  Centrum molekulární biologie a genové terapie hematoonkologické kliniky LF MU a FN Brno 4;  Oddělení klinické genetiky FN Brno 5
Published in: Cesk Slov Neurol N 2007; 70/103(4): 395-401
Category: Short Communication

Podpořeno grantem IGA MZ ČR NR 8052-3

Overview

The histopatological features of both so far defined types of myotonic dystrophy (DM1 and DM2) are very similar, the affected muscles show a typical pattern of changes. The examination of muscle biopsies in situ may also bring about revealing of expansions of CUG or CCUG repetitons in transcripts of the mutated DNA, the genetic basis of the diseases, which may be demonstreated by FISH (fluorescence in situ hybridization) as intranuclear focal accumulation of the transcript. In order to evaluate the importance of muscle biopsy including FISH at the time, when the diagnosis of DM is based on DNA analysis from blood lymphocytes, we analysed the results of histopathological examination of 34 patients, where the biopsy was indicated by clinical suspicion of myotonic dystrophy. The diagnosis was verified by mutation analysis of DNA for both DM1 and DM2. The examination was supplemented by FISH in 27 patients. The diagnosis of DM1 was confirmed in 13 patients, DM2 in 10 patients, the diagnosis of DM1 or DM2 was not confirmed in 11 patients. The biopsy brought about confirmation or precision-specification of the clinical diagnosis or suggested the diagnosis of DM in the majority of the patients. The bioptic findings in some patients with DM were atypical: in two cases there was inflammatory infiltration, in one case a picture resembling congenital myopathy. On the other hand, histopathological features of myotonic dystrophy were present in several biopsies where the diagnosis of DM was not confirmed. Focal accumulation of CUG/CCUG repeats in myonuclei was demonstrated by fluorescence in situ hybridization – in accordance with the DNA examination – in 23 patients, 13 with DM1 and 10 with DM2. Mutation analysis of the DNA isolated from blood leukocytes represent the method of choice if the diagnosis of DM is suspected. On the other hand, muscle biopsy may reveal histopathological features that may indicate subsequent molecular genetic examination of the patient if the results of the clinical examination are equivocal or atypical. FISH in the biopsy may reveal the intranuclear focal accumulation of the RNA transcripts in cells and tissues of the affected patiens and, in this way, to suggest a possible participation of them in the pathogenesis of the disease.

Key words:
myotonic dystrophy – biopsy – molecular genetics – diagnosis


Sources

1. Harper PS. Myotonic dystrophy. London: WB Saunders 2001.

2. Brook JD, McCurah ME, Harley HG, Buckler AJ, Church D, Aburatani H et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3´ end of a transcript encoding a protein kinasae family member. Cell 1992; 68: 799-808.

3. Fu YH, Pizzuti A, Fenwick Jr RG, King J, Rajnarayan S, Dunne PW et al. An unstable triplet repeat in a gene related to myotonic dystrophy. Science 1992; 255: 1256-1258.

4. Davis BM, McCurach ME, Taneja K, Singer RH, Housman DE. 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 1997; 94: 7388-7393.

5. Mankodi A, Logigian E, Callahan L, McClain C, White R, Henderson D et al. Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science 2000; 289: 1769-1772.

6. Buxton J, Shelbourne P, Davies J, Jones C, Van Tongeren T, Aslanidis C et al. Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy. Nature 1992; 355: 547-548.

7. Cheng S, Barcelo JM, Korneluk RG. Characterization of large CTG repeat expansions in myotonic dystrophy alleles using PCR. Hum Mut 1996; 7: 304-310.

8. Schalling M, Hudson TJ, Buetow KH, Housman DE. Direct detection of novel trinucleotide repeats in the human genome. Nature genetics 1993; 4: 135-139.

9. Taneja KL. Localization of trinucleotide repeat sequences in myotonic dystrophy cells using a single fluorochrome –labeled PNA probe. Biotechniques 1998; 24: 472-476.

10. Jiang H, Mankodi A, Swanson MS, Moxley RT, Thornton CA. Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Human molecular genetics 2004; 13: 3079-3088.

11. Thornton CA, Griggs RC, Moxley RT. Myotonic dystrophy with no trinucleotide repeat expansion. Ann Neurol 1994; 35: 269-272.

12. Ricker K, Koch MC, Lehmann-Horn F, Pongraz D, Otto M, Heine R et al. Proximal myotonic myopathy: a new dominant disorder with myotonia, muscle weakness and cataracts. Neurology 1994; 44: 1448-1452.

13. Liquori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor SL et al. Myotoni dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 2001; 293: 864-867.

14. Sallinen R, Vihola A, Bachinski LL, Huoponen K, Haapasalo H, Hackman P et al. New methods of molecular diagnosis and demonstration of the (CCTG)n mutation in myotonic dystrophy type 2 (MD2). Neuromusc Disord 2004; 14: 274-283.

15. Cardani R, Mancinelli E, Sansone V, Rotondo G, Meola G. Biomolecular identification of (CCTG)n mutation in myotonic dystrophy type 2 (DM2) by FISH on muscle biopsy. Eur H Histochem 2004; 48: 437-442.

16. Day JW, Ranum LPW. RNA pathogenesis of the myotonic dystrophies. Neuromusc Disord 2005; 15: 5-16.

17. Ranum LPW, Day JW. Myotonic dystrophy: RNA pathogenesis comes into focus. Am J Hum Genet 2004; 74: 793-804.

18. Pongratz D, Schultz D, Koppenwallner C, Hubner G. Wertigkeit der Muskelbiopsie in der diagnostik der dystrophia myotonica (Curschmann-Steinert). Klin Wschr 1979; 57: 215-224.

19. Falk M, Vojtěšková M, Lukáš Z, Kroupová I, Froster U. Simple procedure for automatic detection of unstable alleles in myotonic dystrophy and Huntington´s disease loci. Genetic testing 2006; 10: 83-94.

20. Voháňka S, Bednařík J, Fajkusová L, Sedláčková J. Myotonická dystrofie typ 2: vzácné nebo časté onemocnění v České rerpublice? Česk Slov Neurol N 2005; 68/101: 390-393.

21. Dubowitz V. Muscle biopsy. A practical approach. Bailliére Tindall 1985.

22. Carpenter S, Karpati G. Pathology of skeletal muscle. Oxford University Press 2001.

23. Schoser BG, Schneider-Gold C, Kress W, Goebel HH, Reilich P, Koch MC et al. Muscle pathology in 57 patients with myotonic dystrophy type 2. Muscle Nerve 2004; 29: 275-281.

24. Vihola A, Bassez G, Meola G, Zhang S, Haapasalo H, Paetau A et al. Histopathological differences of myotonic dystrophy type 1 (DM1) and PROMM/DM2. Neurology 2003; 60: 1854-1857.

25. Day JW, Ricker K, Jacobsen JF, Rasmussen LJ, Dick KA, Kress W et al. Myotonic dystrophy type 2: molecular diagnosis and clinical spectrum. Neurology 2003; 60:657-664.

26. Bundschu HD, Hauger W, Lang HD. Myotonische dystrophie Curschmann-Steinert. Dtsch Med Wschr 1975; 100: 1337-1341.

27. Hübner G. Ringbinden der quergestreiften Muskulatur. Acta neuropath 1977; 38: 27-32.

28. Kinoshita M, Takahashi R, Hasegawa T, Komori T, Nagasawa R, Hirose K et al. (CTG)n expansions in various tissues from a myotonic dystrophy patient. Muscle Nerve 1996; 19: 240-242.

Labels
Paediatric neurology Neurosurgery Neurology

Article was published in

Czech and Slovak Neurology and Neurosurgery

Issue 4

2007 Issue 4

Most read in this issue
Topics Journals
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#