Clinical aspects, molecular pathomechanisms and management of myotonic dystrophies

Giovanni Meola, Giovanni Meola

Abstract

Myotonic dystrophy (DM) is the most common adult muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia and multiorgan involvement. To date two distinct forms caused by similar mutations have been identified. Myotonic dystrophy type 1 (DM1, Steinert's disease) was described more than 100 years ago and is caused by a (CTG)n expansion in DMPK, while myotonic dystrophy type 2 (DM2) was identified only 18 years ago and is caused by a (CCTG)n expansion in ZNF9/CNBP. When transcribed into CUG/CCUG-containing RNA, mutant transcripts aggregate as nuclear foci that sequester RNA-binding proteins, resulting in spliceopathy of downstream effector genes. Despite clinical and genetic similarities, DM1 and DM2 are distinct disorders requiring different diagnostic and management strategies. DM1 may present in four different forms: congenital, early childhood, adult onset and late-onset oligosymptomatic DM1. Congenital DM1 is the most severe form of DM characterized by extreme muscle weakness and mental retardation. In DM2 the clinical phenotype is extremely variable and there are no distinct clinical subgroups. Congenital and childhood-onset forms are not present in DM2 and, in contrast to DM1, myotonia may be absent even on EMG. Due to the lack of awareness of the disease among clinicians, DM2 remains largely underdiagnosed. The delay in receiving the correct diagnosis after onset of first symptoms is very long in DM: on average more than 5 years for DM1 and more than 14 years for DM2 patients. The long delay in the diagnosis of DM causes unnecessary problems for the patients to manage their lives and anguish with uncertainty of prognosis and treatment.

Keywords: Myotonic dystrophy type 1 (Dm1); management; myotonic dystrophy type 2 (Dm2).

Figures

Figure 1.
Figure 1.
Fluorescence in situ hybridization (FISH) in combination with MBNL1-immunofluorescence on DM2 muscle section. A. Visualization of (CCTG)n expansion on muscle section by FISH using (CAGG)5 specific probe. Red spots within myonuclei (blue, DAPI) represent ribonuclear inclusions containing accumulated mutant RNAs. B. Visualization of nuclear foci of MBNL1 (green spots) colocalizing with ribonuclear inclusions in A.
Figure 2.
Figure 2.
Panel showing muscle histology in DM1 and DM2. A-C. Transversal sections from DM1 muscle biopsies. A. Haematoxylin & Eosin: fiber size variation and central nuclei (arrows) are present. B, C. The population of atrophic fibers (white arrow) are preferentially type 1 fibers as demonstrated in sections stained for ATPase pH 4.3 (B, dark brown) or immunostained for myosin MHCslow (C, brown). Black arrow indicate centrally located nuclei. D-E Transversal sections from DM2 muscle biopsies. D. Haematoxylin & Eosin: as in DM1 muscle, fiber size variation and central nuclei (arrows) are present. Abundant nuclear clumps are also present (arrow heads) despite the muscle shows an early stage pathology. E, F. Type 2 fibers are predominantly affected in DM2 muscle: in routine laboratory muscle staining such as ATPase pH 10.0 (E) or immunostaining for myosin MHCfast (F), type 2 fiber atrophy (white arrows) and type 2 central nucleation (black arrow) are commonly observed.

References

    1. Harper PS. Myotonic Dystrophy. In: Karpati G., Hilton-Jones D., Griggs R.C., editors. Disorders of Voluntary Muscle. Cambridge, UK: Cambridge University Press; 2001. pp. 541–559.
    1. Brook JD, 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 member. Cell. 1992;68:799–808.
    1. Fu YH, Pizzuti A, Fenwick RG, Jr, et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science. 1992;255:1256–1258.
    1. 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;255:1253–1255.
    1. Thornton CA, Griggs RC, Moxley RT., 3rd Myotonic dystrophy with no trinucleotide repeat expansion. Ann Neurol. 1994;35:269–272.
    1. Ricker K, Koch MC, Lehmann-Horn F, et al. Proximal myotonic myopathy: a new dominant disorder with myotonia, muscle weakness, and cataracts. Neurology. 1994;44:1448–1452.
    1. Udd B, Krahe R, Wallgren-Pettersson C, et al. Proximal myotonic dystrophy: a family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: heterogeneity of proximal myotonic syndromes? Neuromuscular Disord. 1997;4:217–228.
    1. Ranum LP, Rasmussen PF, Benzow KA, et al. Genetic mapping of a second myotonic dystrophy locus. Nature Genetics. 1998;19:196–198.
    1. Liquori CL, Ricker K, Moseley ML, et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science. 2001;293:864–867.
    1. Ashizawa T, Baiget M. New nomenclature and DNA testing guidelines for myotonic dystrophy type 1 (DM1). The International Myotonic Dystrophy Consortium (IDMC) Neurology. 2000;54:1218–1221.
    1. Day JW, Roelofs R, Leroy B, et al. Clinical and genetic characteristics of a five-generation family with a novel form of myotonic dystrophy (DM2) Neuromuscular Disord. 1999;9:19–27.
    1. Day JW, Ricker K, Jacobsen JF, et al. Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology. 2003;60:657–664.
    1. Ashizawa T. Myotonic dystrophy as a brain disorder. Arch Neurol. 1998;55:291–293.
    1. Spranger M, Spranger S, Tischendorf M, et al. Myotonic dystrophy. The role of large triplet repeat length in the development of mental retardation. Arch Neurol. 1997;54:251–254.
    1. Joseph JT, Richards CS, Anthony DC, et al. Congenital myotonic dystrophy pathology and somatic mosaicism. Neurology. 1997;49:1457–1460.
    1. Harper PS, Engelen B, Eymard B, et al. Myotonic dystrophy: present management, future therapy. Neuromuscul Disord. 2002;12:596–599.
    1. O'Brien TA, Harper PS. Course, prognosis and complications of childhood-onset myotonic dystrophy. Dev Med Child Neurol. 1984;26:62–67.
    1. Steyaert J, Die-Smulders C, Fryns JP, et al. Behavioral phenotype in childhood type of dystrophia myotonica. Am J Med Genet. 2000;96:888–889.
    1. Bassez G, Lazarus A, Desguerre I, et al. Severe cardiac arrhythmias in young patients with myotonic dystrophy type 1. Neurology. 2004;63:1939–1941.
    1. Chebel S, Ben Hamda K, Boughammoura A, et al. Cardiac involvement in Steinert's myotonic dystrophy. Rev Neurol. 2005;161:932–939.
    1. Montella L, Caraglia M, Addeo R, et al. Atrial fibrillation following chemotherapy for stage IIIE diffuse large B-cell gastric lymphoma in a patient with myotonic dystrophy (Steinert's disease) Ann Hematol. 2005;84:192–193.
    1. Dello Russo A, Pelargonio G, Parisi Q, et al. Widespread electroanatomic alterations of right cardiac chambers in patients with myotonic dystrophy type 1. J Cardiovasc Electrophysiol. 2006;17:34–40.
    1. Garrott HM, Walland MJ, O'Day J. Recurrent posterior capsular opacification and capsulorhexis contracture after cataract surgery in myotonic dystrophy. Clin Experiment Ophthalmol. 2004;32:653–655.
    1. Delaporte C. Personality patterns in patients with myotonic dystrophy. Arch Neurol. 1998;55:635–640.
    1. Winblad S, Lindberg C, Hansen S. Temperament and character in patients with classical myotonic dystrophy type 1 (DM-1) Neuromuscul Disord. 2005;15:287–292.
    1. Barnes PR, Hilton-Jones D, Norbury G, et al. Incorrect diagnosis of myotonic dystrophy and its potential consequences revealed by subsequent direct genetic analysis. J Neurol Neurosurg Psychiatry. 1994;57:662–662.
    1. Udd B, Meola G, Krahe R, et al. 140th ENMC International Workshop: myotonic dystrophy DM2/PROMM and other myotonic dystrophies with guidelines on management. Neuromuscul Disord. 2006;16:403–413.
    1. Udd B, Meola G, Krahe R, et al. Report of the 115th ENMC workshop: myotonic dystrophies. 3rd workshop, 14-16 February 2003, Naarden, the Netherlands. Neuromuscul Disord. 2003;13:589–596.
    1. Auvinen S, Suominen T, Hannonen P, et al. Myotonic dystrophy type 2 found in two of sixty-three persons diagnosed as having fibromyalgia. Arthritis Rheum. 2008;58:3627–3631.
    1. Suominen T, Schoser B, Raheem O, et al. High frequency of cosegregating CLCN1 mutations among myotonic dystrophy type 2 patients from Finland and Germany. J Neurol. 2008;255:1731–1736.
    1. Ricker K, Koch MC, Lehmann-Horn F, et al. Proximal myotonic myopathy. Clinical features of a multisystem disorder similar to myotonic dystrophy. Arch Neurol. 1995;52:25–31.
    1. Meola G. Clinical and genetic heterogeneity in myotonic dystrophies. Muscle Nerve. 2000;12:1789–1799.
    1. Moxley RT, III, Meola G, Udd B, et al. Report of the 84th ENMC Workshop: PROMM (Proximal Myotonic Myopathy) and Other Myotonic Dystrophy-Like Syndromes: 2nd Workshop. 13-15th October, 2000. Loosdrecht, The Netherlands. Neuromuscular Disord. 2002;12:306–317.
    1. Schoser BG, Kress W, Walter MC, et al. Homozygosity for CCTG mutation in myotonic dystrophy type 2. Brain. 2004;127:1868–1877.
    1. George A, Schneider-Gold C, Zier S, et al. Musculoskeletal pain in patients with myotonic dystrophy type 2. Arch Neurol. 2004;61:1938–1942.
    1. Meola G, Sansone V, Marinou K, et al. Proximal myotonic myopathy: a syndrome with a favourable prognosis? J Neurol Sci. 2002;193:89–96.
    1. Flachenecker P, Schneider C, Cursiefen S, et al. Assessment of cardiovascular autonomic function in myotonic dystrophy type 2 (DM2/PROMM) Neuromuscul Disord. 2003;13:289–293.
    1. Schoser BG, Ricker K, Schneider-Gold C, et al. Sudden cardiac death in myotonic dystrophy type 2. Neurology. 2004;63:2402–2404.
    1. Meola G, Sansone V, Perani D, et al. Reduced cerebral blood flow and impaired visual-spatial function in proximal myotonic myopathy. Neurology. 1999;5:1042–1050.
    1. Newman B, Meola G, O'Donovan DG, et al. Proximal myotonic myopathy (PROMM) presenting as myotonia during pregnancy. Neuromuscul Disord. 1999;9:144–149.
    1. Savkur RS, Philips AV, Cooper TA. Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nature Genet. 2001;29:40–47.
    1. Meola G, Sansone V, Perani D, et al. Executive dysfunction and avoidant personality trait in myotonic dystrophy type 1 (DM1) and in proximal myotonic myopathy (DM2/PROMM) Neuromuscular Disord. 2003;13:813–821.
    1. Savkur RS, Philips AV, Cooper TA, et al. Insulin receptor splicing alteration in myotonic dystrophy type 2. Am J Hum Genet. 2004;74:1309–1313.
    1. Rudnik-Schoneborn S, Schneider-Gold C, Raabe U, et al. Outcome and effect of pregnancy in myotonic dystrophy type 2. Neurology. 2006;66:579–580.
    1. Schoser B, Timchenko L. Myotonic dystrophies 1 and 2: complex diseases with complex mechanisms. Curr Genomics. 2010;11:77–90.
    1. Bachinsky LL, Czernuszewicz T, Ramagli LS, et al. Premutation allele pool in myotonic dystrophy type 2. Neurology. 2009;72:490–497.
    1. Lavedan C, Hofmann-Radvanyi H, Shelbourne P, et al. Myotonic dystrophy: size and sex-dependent dynamics of CTG meiotic instability, and somatic mosaicism. Am J Hujm Genet. 1993;52:875–883.
    1. Monckton DG, Wong LI, Ashizawa T, et al. Somatic mosaicism, germline expansions, germline reversions and intergenerational reductions in myotonic dystrophy males: small pool PCR analyses. Hum Mol Genet. 1995;4:1–8.
    1. Brunner HG, Bruggenwirth HT, Nillesen W, et al. Influence of sex of the transmitting parent as well as of parental allele size on the CTG expansion in myotonic dystrophy (DM) Am J Hum Genet. 1993;53:1016–1023.
    1. Die-Smulders CE, Smeets HJ, Loots W, et al. Paternal transmission of congenital myotonic dystrophy. J Med Genet. 1997;34:930–933.
    1. Hamshere MG, Harley H, Harper P, et al. Myotonic dystrophy: the correlation of (CTG) repeat length in leukocytes with age at onset is significant only for patients with small expansions. J Med Genet. 1999;36:59–61.
    1. Thornton C, Johnson K, Moxley RT., 3rd Myotonic dystrophy patients have larger CTG expansions in skeletal muscle than in leukocytes. Ann Neurol. 1994;35:104–107.
    1. Jiang H, Mankodi A, Swanson MS, et al. Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Hum Mol Genet. 2004;13:3079–3088.
    1. Lin X, Miller JW, Mankodi A, et al. Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. Hum Mol Genet. 2006;15:2087–2097.
    1. Mankodi A, Lin X, Blaxall BC, et al. Nuclear RNA foci in the heart in myotonic dystrophy. Circ Res. 2005;97:1152–1155.
    1. Kuyumcu-Martinez NM, Wang GS, Cooper TA. Increased steadystate levels of CUGBP1 in myotonic dystrophy 1 are due to PKCmediated hyperphosphorylation. Mol Cell. 2007;28:68–78.
    1. Cardani R, Bugiardini E, Renna LV, et al. Overexpression of CUGBP1 in skeletal muscle from adult classic myotonic dystrophy type 1 but not from myotonic dystrophy type 2. PLOS one. 2013;8(12):e83777–e83777.
    1. Ranum LP, Cooper TA. RNA-mediated neuromuscular disorders. Annu Rev Neurosci. 2006;29:259–277.
    1. Salisbury E, Schoser B, Schneider-Gold C, et al. Expression of RNA CCUG repeats dysregulates translation and degradation of proteins in myotonic dystrophy 2 patients. Am J Pathol. 2009;175:748–762.
    1. Osborne RJ, Thornton CA. RNA-dominant diseases. Hum Mol Genet. 2006;15:R162–R169.
    1. Fardaei M, Rogers MT, Thorpe HM, et al. Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded- repeat transcripts in DM1 and DM2 cells. Hum Mol Genet. 2002;11:805–814.
    1. Pelletier R, Hamel F, Beaulieu D, et al. Absence of a differentiation defect in muscle satellite cells from DM2 patients. Neurobiol Dis. 2009;36:181–190.
    1. Fakan S. Perichromatin fibrils are in situ forms of nascent transcriptions. Trend Cell Biol. 1994;4:86–90.
    1. Perdoni F, Malatesta M, Cardani R, et al. RNA/MBNL1-containing foci in myoblast nuclei from patients affected by myotonic dystrophy type 2: an immunocytochemical study. Eur J Histochem. 2009;53:151–158.
    1. Philips AV, Timchenko LT, Cooper TA. Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science. 1998;280:737–741.
    1. Charlet-B N, Savkur RS, Singh G, et al. Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol Cell. 2002;10:45–53.
    1. Mankodi A, Takahashi MP, Jiang H, et al. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell. 2002;10:35–44.
    1. Pascual M, Vicente M, Monferrer L, et al. The muscle blind family of proteins: an emerging class of regulators of developmentally programmed alternative splicing. Differentiation. 2006;74:65–80.
    1. Barreau C, Paillard L, Mereau A, et al. Mammalian CELF/Brunolike RNA-binding proteins: molecular characteristics and biological functions. Biochimie. 2006;88:515–525.
    1. Greco S, Perfetti A, Fasanaro P, et al. Deregulated microRNAs in myotonic dystrophy type 2. PLOS one. 2012;7(6):e39732–e39732.
    1. Gambardella S, Rinaldi F, Lepore SM, et al. Overexpression of microRNA- 206 in the skeletal muscle from myotonic dystrophy type 1 patients. J Transl Med. 2010;8:48–54.
    1. Perbellini R, Greco S, Sarra-Ferraris G, et al. Dysregulation and cellular mislocalization of specific miRNAs in myotonic dystrophy type 1. Neuromuscul Disord. 2011;21:81–88.
    1. Rau F, Freyermuth F, Fugier C, et al. Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy. Nat Struct Mol Biol. 2011;18:840–845.
    1. Maeda M, Taft CS, Bush EW, et al. Identification, tissue-specific expression, and subcellular localization of the 80- and 71- kDa forms of myotonic dystrophy kinase protein. J Biol Chem. 1995;270:20246–20249.
    1. Huichalaf C, Schoser B, Schneider-Gold C, et al. Reduction of the rate of protein translation in patients with myotonic dystrophy 2. J Neurosci. 2009;29:9042–9049.
    1. Raheem O, Olufemi SE, Bachinski LL, et al. Mutant (CCTG)n expansion causes abnormal expression of Zinc finger protein 9 (ZNF9) in myotonic dystrophy type 2. Am J Pathol. 2010;177:3025–3036.
    1. Reddy S, Smith DB, Rich MM, et al. Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy. Nat Genet. 1996;13:325–335.
    1. Chen W, Wang Y, Abe Y, et al. Haploinsuffciency for Znf9 in Znf9+/- mice is associated with multiorgan abnormalities resembling myotonic dystrophy. J Mol Biol. 2007;368:8–17.
    1. Day JW, Ranum LP. Genetics and molecular pathogenesis of the myotonic dystrophies. Curr Neurol Neurosci Rep. 2005;5:55–59.
    1. Bonifazi E, Vallo L, Giardina E, et al. A long PCR-based molecular protocol for detecting normal and expanded ZNF9 alleles in myotonic dystrophy type 2. Diagn Mol Pathol. 2004;13:164–166.
    1. Catalli C, Morgante A, Iraci R, et al. Validation of sensitivity and specificity of tetraplet primed PCR (TP-PCR) in the molecular diagnosis of myotonic dystrophy type 2. J Mol Diagn. 2010;12:601–606.
    1. Bachinski LL, Udd B, Meola G, et al. 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 Genet. 2003;73:835–848.
    1. Mankodi A, Urbinati CR, Yuan QP, et al. Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. Hum Mol Genet. 2001;10:2165–2170.
    1. Cardani R, Mancinelli E, Sansone V, et al. Biomolecular identification of (CCTG)n mutation in myotonic dystrophy type 2 (DM2) by FISH on muscle biopsy. Eur J Histochem. 2004;48:437–442.
    1. Sallinen R, Vihola A, Bachinski LL, et al. New methods for molecular diagnosis and demonstration of the (CCTG)n mutation in myotonic dystrophy type 2 (DM2) Neuromuscul Disord. 2004;14:274–283.
    1. Cardani R, Mancinelli E, Rotondo G, et al. Muscleblind-like protein 1 nuclear sequestration is a molecular pathology marker of DM1 and DM2. Eur J Histochem. 2006;50:177–182.
    1. Schoser BG, Schneider-Gold C, Kress W, et al. Muscle pathology in 57 patients with myotonic dystrophy type 2. Muscle Nerve. 2004;29:275–281.
    1. Vihola A, Bachinski LL, Sirito M, et al. Differences in aberrant expression and splicing of sarcomeric proteins in the myotonic dystrophies DM1 and DM2. Acta Neuropathol. 2010;119:465–479.
    1. Vihola A, Bassez G, Meola G, et al. Histopathological differences of myotonic dystrophy type 1 (DM1) and PROMM/DM2. Neurology. 2003;60:1854–1857.
    1. Bassez G, Chapoy E, Bastuji-Garin S, et al. Type 2 myotonic dystrophy can be predicted by the combination of type 2 muscle fiber central nucleation and scattered atrophy. J Neuropathol Exp Neurol. 2008;67:319–325.
    1. Pisani V, Panico MB, Terracciano C, et al. Preferential central nucleation of type 2 myofibers is an invariable feature of myotonic dystrophy type 2. Muscle Nerve. 2008;38:1405–1411.
    1. Kwiecinski H, Ryniewicz B, Ostrzycki A. Treatment of myotonia with antiarrhythmic drugs. Acta Neurologica Scandinavica. 1992;86:371–375.
    1. Meola G, Sansone V. Cerebral involvement in myotonic dystrophies. Muscle Nerve. 2007;36:294–306.
    1. Chang L, Ernst T, Osborn D, et al. Proton spectroscopy in myotonic dystrophy: correlations with CTG repeats. Arch Neurol. 1998;55:305–311.
    1. Akiguchi I, Nakano S, Shiino A, et al. Brain proton magnetic resonance spectroscopy and brain atrophy in myotonic dystrophy. Arch Neurol. 1999;56:325–330.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel