Abstract
The onset and symptoms of the myotonic dystrophies are diverse, complicating their diagnoses and limiting a comprehensive approach to their clinical care. This report analyzes the diagnostic delay (time from onset of first symptom to diagnosis) in a large sample of myotonic dystrophy (DM) patients enrolled in the US National Registry [679 DM type 1 (DM1) and 135 DM type 2 (DM2) patients]. Age of onset averaged 34.0 ± 14.1 years in DM2 patients compared to 26.1 ± 13.2 years in DM1 (p < 0.0001). The most common initial symptom in DM2 patients was leg weakness (32.6 %) compared to grip myotonia in DM1 (38.3 %). Pain was reported as the first symptom in 11.1 % of DM2 and 3.0 % of DM1 patients (p < 0.0001). Reaching the correct diagnosis in DM2 took 14 years on average (double the time compared to DM1) and a significantly higher percentage of patients underwent extended workup including electromyography, muscle biopsies, and finally genetic testing. DM patients who were index cases experienced similar diagnostic delays to non-index cases of DM. Further evaluation of how to shorten these diagnostic delays and limit their impact on burdens of disease, family planning, and symptom management is needed.
Similar content being viewed by others
References
Harper PS (2001) Myotonic dystrophy. W.B Saunders Company, London
Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, Hunter K, Stanton VP, Thirion JP, Hudson T, Sohn R, Zemelman B, Snell RG, Rundle SA, Crow S, Davies J, Shelbourne P, Buxton J, Jones C, Juvonen V, Johnson K, Harper PS, Shaw DJ, Housman DE (1992) 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 68:799–808
Fu YH, Pizzuti A, Fenwick RG Jr, King J, Rajnarayan S, Dunne PW, Dubel J, Nasser GA, Ashizawa T, de Jong P, Wieringa B, Korneluk R, Perryman MB, Epstein HF, Caskey CT (1992) An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255:1256–1258
Mahadevan M, Tsilfidis C, Sabourin L, Shutler G, Amemiya C, Jansen G, Neville C, Narang M, Barcelo J, O’Hoy K, Leblond S, Earle-MacDonald J, De Jong P, Wieringa B, Korneluk R (1992) Myotonic dystrophy mutation: an unstable CTG repeat in the 3’ untranslated region of the gene. Science 255:1253–1255
Liquori CL, Ricker K, Moseley ML, 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 293:864–867
Ranum LP, Rasmussen PF, Benzow KA, Koob MD, Day JW (1998) Genetic mapping of a second myotonic dystrophy locus. Nat Genet 19:196–198
Cho DH, Tapscott SJ (2007) Myotonic dystrophy: emerging mechanisms for DM1 and DM2. Biochim Biophys Acta 1772:195–204
Day JW, Ricker K, Jacobsen JF, 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 60:657–664
Osborne RJ, Thornton CA (2006) RNA-dominant diseases. Hum Mol Genet 15 Spec No 2:R162-R169
Udd B, Krahe R (2012) The myotonic dystrophies: molecular, clinical, and therapeutic challenges. Lancet Neurol 11:891–905
Douniol M, Jacquette A, Cohen D, Bodeau N, Rachidi L, Angeard N, Cuisset JM, Vallee L, Eymard B, Plaza M, Heron D, Guile JM (2012) Psychiatric and cognitive phenotype of childhood myotonic dystrophy type 1. Dev Med Child Neurol 54:905–911
Schara U, Schoser BG (2006) Myotonic dystrophies type 1 and 2: a summary on current aspects. Semin Pediatr Neurol 13:71–79
Ricker K, Koch MC, Lehmann-Horn F, Pongratz D, Otto M, Heine R, Moxley RT (1994) Proximal myotonic myopathy: a new dominant disorder with myotonia, muscle weakness and cataracts. Neurology 44:1448–1452
Thornton CA, Griggs RC, Moxley RT (1994) Myotonic dystrophy with no trinucleotide repeat expansion. Ann Neurol 35:269–272
Meola G, Moxley RT III (2004) Myotonic dystrophy type 2 and related myotonic disorders. J Neurol 251:1173–1182
Udd B, Meola G, Krahe R, Wansink DG, Bassez G, Kress W, Schoser B, Moxley R (2011) Myotonic dystrophy type 2 (DM2) and related disorders Report of the 180th ENMC Workshop including guidelines on diagnostics and management 3–5 December 2010, Naarden, The Netherlands. Neuromuscul Disord 21:443–450
Gaul C, Schmidt T, Windisch G, Wieser T, Muller T, Vielhaber S, Zierz S, Leplow B (2006) Subtle cognitive dysfunction in adult onset myotonic dystrophy type 1 (DM1) and type 2 (DM2). Neurology 67:350–352
Minnerop M, Weber B, Schoene-Bake JC, Roeske S, Mirbach S, Anspach C, Schneider-Gold C, Betz RC, Helmstaedter C, Tittgemeyer M, Klockgether T, Kornblum C (2011) The brain in myotonic dystrophy 1 and 2: evidence for a predominant white matter disease. Brain 134:3530–3546
Franc DT, Muetzel RL, Robinson PR, Rodriguez CP, Dalton JC, Naughton CE, Mueller BA, Wozniak JR, Lim KO, Day JW (2012) Cerebral and muscle MRI abnormalities in myotonic dystrophy. Neuromuscul Disord 22:483–491
Kornblum C, Reul J, Kress W, Grothe C, Amanatidis N, Klockgether T, Schroder R (2004) Cranial magnetic resonance imaging in genetically proven myotonic dystrophy type 1 and 2. J Neurol 251:710–714
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 (DM-1) and in proximal myotonic myopathy (PROMM/DM-2). Neuromuscul Disord 13:813–821
Sansone V, Gandossini S, Cotelli M, Calabria M, Zanetti O, Meola G (2007) Cognitive impairment in adult myotonic dystrophies: a longitudinal study. Neurol Sci 28:9–15
Hilbert JE, Luebbe EA, Martens WB, Moxley RT III, Registry Scientific Advisory Committee (2009) Diagnostic odyssey of myotonic dystrophy type 2 (DM2) patients, Poster P4–08; 9th international myotonic dystrophy consortium meeting; Wurzburg Germany. Med Gen 21:444
Milone M, Batish SD, Daube JR (2009) Myotonic dystrophy type 2 with focal asymmetric muscle weakness and no electrical myotonia. Muscle Nerve 39:383–385
Young NP, Daube JR, Sorenson EJ, Milone M (2010) Absent, unrecognized, and minimal myotonic discharges in myotonic dystrophy type 2. Muscle Nerve 41:758–762
Auvinen S, Suominen T, Hannonen P, Bachinski LL, Krahe R, Udd B (2008) Myotonic dystrophy type 2 found in two of sixty-three persons diagnosed as having fibromyalgia. Arthritis Rheum 58:3627–3631
Suominen T, Bachinski LL, Auvinen S, Hackman P, Baggerly KA, Angelini C, Peltonen L, Krahe R, Udd B (2011) Population frequency of myotonic dystrophy: higher than expected frequency of myotonic dystrophy type 2 (DM2) mutation in Finland. Eur J Hum Genet 19:776–782
Foff EP, Mahadevan MS (2011) Therapeutics development in myotonic dystrophy type 1. Muscle Nerve 44:160–169
Lee JE, Bennett CF, Cooper TA (2012) RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1. Proc Natl Acad Sci USA 109:4221–4226
Wheeler TM, Leger AJ, Pandey SK, MacLeod AR, Nakamori M, Cheng SH, Wentworth BM, Bennett CF, Thornton CA (2012) Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature 488:111–115
Hilbert JE, Kissel JT, Luebbe EA, Martens WB, McDermott MP, Sanders DB, Tawil R, Thornton CA, Moxley RT III (2012) If you build a rare disease registry, will they enroll and will they use it? Methods and data from the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD). Contemp Clin Trials 33:302–311
Heatwole C, Bode R, Johnson N, Quinn C, Martens W, McDermott MP, Rothrock N, Thornton C, Vickrey B, Victorson D, Moxley R III (2012) Patient-reported impact of symptoms in myotonic dystrophy type 1 (PRISM-1). Neurology 79:348–357
Rubinstein YR, Groft SC, Bartek R, Brown K, Christensen RA, Collier E, Farber A, Farmer J, Ferguson JH, Forrest CB, Lockhart NC, McCurdy KR, Moore H, Pollen GB, Richesson R, Miller VR, Hull S, Vaught J (2010) Creating a global rare disease patient registry linked to a rare diseases biorepository database: rare disease-HUB (RD-HUB). Contemp Clin Trials 31:394–404
Thompson R, Schoser B, Monckton DG, Blonsky K, Lochmuller H (2009) Patient Registries and Trial Readiness in Myotonic Dystrophy–TREAT-NMD/Marigold International Workshop Report. Neuromuscul Disord 19:860–866
Ciafaloni E, Fox DJ, Pandya S, Westfield CP, Puzhankara S, Romitti PA, Mathews KD, Miller TM, Matthews DJ, Miller LA, Cunniff C, Druschel CM, Moxley RT (2009) Delayed diagnosis in duchenne muscular dystrophy: data from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). J Pediatr 155:380–385
Schneider C, Ziegler A, Ricker K, Grimm T, Kress W, Reimers CD, Meinck H, Reiners K, Toyka KV (2000) Proximal myotonic myopathy: evidence for anticipation in families with linkage to chromosome 3q. Neurology 55:383–388
George A, Schneider-Gold C, Zier S, Reiners K, Sommer C (2004) Musculoskeletal pain in patients with myotonic dystrophy type 2. Arch Neurol 61:1938–1942
Suokas KI, Haanpaa M, Kautiainen H, Udd B, Hietaharju AJ (2012) Pain in patients with myotonic dystrophy type 2: a postal survey in Finland. Muscle Nerve 45:70–74
Gagnon C, Chouinard MC, Laberge L, Veillette S, Begin P, Breton R, Jean S, Brisson D, Gaudet D, Mathieu J (2010) Health supervision and anticipatory guidance in adult myotonic dystrophy type 1. Neuromuscul Disord 20:847–851
Mathieu J, Allard P, Gobeil G, Girard M, De Braekeleer M, Begin P (1997) Anesthetic and surgical complications in 219 cases of myotonic dystrophy. Neurology 49:1646–1650
Veyckemans F, Scholtes JL (2013) Myotonic Dystrophies type 1 and 2: anesthetic care. Paediatr Anaesth [Epub ahead of print]
Groh WJ, Groh MR, Saha C, Kincaid JC, Simmons Z, Ciafaloni E, Pourmand R, Otten RF, Bhakta D, Nair GV, Marashdeh MM, Zipes DP, Pascuzzi RM (2008) Electrocardiographic abnormalities and sudden death in myotonic dystrophy type 1. N Engl J Med 358:2688–2697
Groh WJ, Bhakta D (2012) Arrhythmia management in myotonic dystrophy type 1. JAMA 308:337–338
Sansone VA, Brigonzi E, Schoser B, Villani S, Gaeta M, De Ambroggi G, Bandera F, De Ambroggi L, Meola G (2012) The frequency and severity of cardiac involvement in myotonic dystrophy type 2 (DM2): Long-term outcomes. Int J Cardiol [Epub ahead of print]
Wahbi K, Meune C, Porcher R, Becane HM, Lazarus A, Laforet P, Stojkovic T, Behin A, Radvanyi-Hoffmann H, Eymard B, Duboc D (2012) Electrophysiological study with prophylactic pacing and survival in adults with myotonic dystrophy and conduction system disease. JAMA 307:1292–1301
Das M, Moxley RT III, Hilbert JE, Martens WB, Letren L, Greene MH, Gadalla SM (2012) Correlates of tumor development in patients with myotonic dystrophy. J Neurol 259:2161–2166
Gadalla SM, Lund M, Pfeiffer RM, Gortz S, Mueller CM, Moxley RT III, Kristinsson SY, Bjorkholm M, Shebl FM, Hilbert JE, Landgren O, Wohlfahrt J, Melbye M, Greene MH (2011) Cancer risk among patients with myotonic muscular dystrophy. JAMA 306:2480–2486
Mueller CM, Hilbert JE, Martens W, Thornton CA, Moxley RT III, Greene MH (2009) Hypothesis: neoplasms in myotonic dystrophy. Cancer Causes Control 20:2009–2020
Win AK, Perattur PG, Pulido JS, Pulido CM, Lindor NM (2012) Increased cancer risks in myotonic dystrophy. Mayo Clin Proc 87:130–135
Meola G (2010) Myotonic dystrophies as a brain disorder. Neurol Sci 31:863–864
Acknowledgments
In memory of Shannon Lord, whose insight and passion contributed to the content of this paper and who as a patient advocate, was an influential advisor of the NIH sponsored National Registry of Myotonic Dystrophy and FSHD Patients and Family Members. Shannon made important contributions to patients with myotonic dystrophy, their family members, and the entire research community for over 20 years. She created the Hunter Fund for myotonic dystrophy; catalyzed the creation of the Myotonic Dystrophy Foundation, serving as its founding chair; and was a pivotal member of the Registry’s Scientific Advisory Committee. Her “odyssey” and passion to improve the care of patients with myotonic dystrophy will continue to inspire our hearts, minds, and research. The Registry is supported through the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Neurological Disorders and Stroke (NIH Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center grant #U54-NS048843 and NIH contracts #N01-AR-5-2274 and #NO1-AR-0-2250).
Conflicts of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
The Registry Scientific Advisory Committee members are given in “Appendix”.
Appendix
Appendix
Internal Steering Committee Members: Principal Investigator: Richard T. Moxley, III, MD; Co-investigators: Michael P. McDermott, PhD; Rabi Tawil, MD; and Charles A. Thornton, MD; University of Rochester Medical Center, Rochester, NY.
Scientific Advisory Committee Members: Tetsuo Ashizawa, University of Florida; Richard J. Barohn, University of Kansas; Paula R. Clemens, University of Pittsburgh; P. Michael Conneally, Indiana University; John W. Day, Stanford University; Denise A. Figlewicz, University of Western Ontario; Jacqueline M. Jackson, Indiana University; John T. Kissel, Ohio State University; Shannon Lord, Patient Advocate; Katherine D. Mathews, University of Iowa; Donald B. Sanders, Duke University; Stephen J. Tapscott, University of Washington.
Rights and permissions
About this article
Cite this article
Hilbert, J.E., Ashizawa, T., Day, J.W. et al. Diagnostic odyssey of patients with myotonic dystrophy. J Neurol 260, 2497–2504 (2013). https://doi.org/10.1007/s00415-013-6993-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-013-6993-0