Phenotype-genotype relationships in muscle diseases

Phenotype-genotype relationships in muscle diseases

Our center constantly works on understanding the relationship between phenotype and genotype in various muscle diseases, and to understand the mechanisms underlying variability. We have made advances in the understanding of genotype-phenotype relations in several muscular dystrophies, mitochondrial diseases, congenital myopathies, metabolic myopathies, and myotonic dystrophy. We have discovered new modes of inheritance in mitochondrial diseases, limb girdle muscular dystrophies, and carnitine palmitoyltransferase deficiency II, and identified new disease entities for muscle glycogenosis, mitochondrial myopathies and muscular dystrophies. Current studies in this field mainly focus on muscular dystrophies and channelopathies.


References

  • Witting N, Werlauff U, Duno M, Vissing J. Phenotypes, genotypes and prevalence of congenital myopathies in patients older than 5 years in Denmark. Neurol Genet [Epub ahead of print].
  • Riaz M, Raz Y, van der Slujis B, Dickson G, van Engelen B, Vissing J, Raz V. Cytokine genes as potential biomarkers for muscle weakness in OPMD. Hum Mol Genet 2016; Aug 9. pii: ddw259. [Epub ahead of print].
  • Lindberg U, Witting N, Jørgensen SL, Vissing J, Rostrup E, Larsson HB, Kruuse C. Effects of sildenafil on cerebrovascular reactivity in patients with Becker muscular dystrophy. Neurotherapeutics 2017; 14(1): 182-190.
  • Ostergaard ST, Stojkovic T, Dahlqvist JR, Bouchet-Seraphin C, Nectoux J, Leturcq F, Cossée M, Solé G, Thomsen C, Krag T, Vissing J. Muscle involvement in limb girdle muscular dystrophy with GMPPB deficiency (LGMD2T). Neurol Genet 2016 Oct 11; 2(6):e112,
  • Løkken N, Hedermann G, Thomsen C, Vissing J. Contractile properties are disrupted in Becker muscular dystrophy, but not in limb girdle type 2I. Ann Neurol 2016; 80(3): 466-471.
  • Vissing J, Barresi R, Witting N, Ghelue Mv, Gammelgaard L, Bindoff LA, Straub V, Lochmüller H, Hudson J, Wahl CM, Arnardottir S, Dahlbom K, Jonsrud C, Duno M. A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy. Brain 2016; 139(8): 2154-2163.
  • Zaharieva et al. Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or “classical” congenital myopathy. Brain 2016; 139(3): 674-691.
  • Witting N, Werlauff U, Duno M, Vissing J. Prevalence and phenotypes of congenital myopathy due to α-actin 1 gene mutations. Muscle Nerve 2016; 53(3): 388-393.
  • Semplicini C, Vissing J, Dahlqvist JR, Stojkovic T, Bello L, Witting N, Duno M, Leturcq F, Bertolin C, D’Ambrosio P, Eymard B, Angelini C, Politano L, Laforet P, Pegoraro E. Clinical and genetic spectrum in limb-girdle muscular dystrophy type 2E. Neurology 2015; 84(17): 1772-1781.
  • Werlauff U, Petri H, Witting N, Vissing J. Frequency and phenotype of myotubular myopathy amongst Danish patients with congenital myopathy older than 5 years. J Neuromuscul Dis 2015; 2: 167–174.
  • Dahlqvist J, Orngreen M, Witting N, Vissing J. Endocrine function over time in patients with myotonic dystrophy type 1. Eur J Neurol 2015; 22(1): 116-122.
  • Ostergaard E, Weraarpachai W, Ravn K, Born AP, Jønson L, Duno M, Wibrand F, Shoubridge EA, Vissing J. Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity and short stature. J Med Genet 2015; 52(3): 203-207.
  • Løkken N, Born AP, Duno M, Vissing J. LAMA2-related myopathy; frequency among congenital and limb-girdle muscular dystrophies. Muscle Nerve 2015; 52(4): 547-553.
  • Petri H, Sveen ML, Thune JJ, Vissing C, Dahlqvist JR, Witting N, Bundgaard H, Køber L, Vissing J. Progression of cardiac involvement in patients with limb-girdle type 2 and Becker muscular dystrophies: A 9-year follow-up study. Int J Cardiol 2015; 182: 403-411.
  • Petri H, Ahtarovski K, Vejlstrup N, Vissing J, Witting N, Køber L, Bundgaard H. Myocardial fibrosis in patients with myotonic dystrophy type 1: a cardiovascular magnetic resonance study. J Cardiovasc Magn Reson 2014 Aug 1;16(1):59.
  • Lund M, Diaz LJ, Gørtz S, Feenstra B, Duno M, Juncker I, Eiberg H, Vissing J, Wohlfahrt J, Melbye M. Risk of cancer in relatives of patients with myotonic dystrophy: a population based cohort study. Eur J Neurol 2014; 21(9): 1192-1197.
  • Lund M, Diaz LJ, Ranthe MF, Petri H, Duno M, Juncker I, Eiberg H, Vissing J, Bundgaard H, Wohlfahrt J, Melbye M. Cardiac involvement in myotonic dystrophy: a nationwide cohort study. Eur Heart J 2014; 35(32): 2158-2164.
  • Petri H, Witting N, Ersbøll MK, Sajadieh A, Helweg-Larsen S, Duno M, Vissing J, Kober L, Bundgaard H. High prevalence of cardiac involvement in patients with myotonic dystrophy type 1; a cross-sectional cohort study. Int J Cardiol 2014; 174(1): 31-36.
  • Witting N, Mensah A, Kober L, Bundgaard H, Petri H, Duno M, Milea D, Vissing J. Ocular, bulbar, limb and cardiopulmonary involvement in oculopharyngeal muscular dystrophy. Acta Neurol Scand 2014; 130(2): 125-130.
  • Citirak G, Witting N, Duno M, Werlauff U, Petri H, Vissing J. Frequency and phenotype of patients carrying TPM2 and TPM3 gene mutations in a cohort of 94 patients with congenital myopathy. Neuromuscul Disord 2014; 24(4): 325-330.
  • Mosbech MB, Olsen AS, Neess D, Ben-David O, Klitten LL, Larsen J, Sabers A, Vissing J, Nielsen JE, Hasholt L, Klein AD, Tsoory MM, Hjalgrim H, Tommerup N, Futerman AH, Møller RS, Færgeman NJ. Reduced ceramide synthase 2 activity causes progressive myoclonic epilepsy. Ann Clin Transl Neurol 2014; 1(2): 88-98.
  • Werlauff U, Højbjerg A, Firla-Holme R, Steffensen BF, Vissing J. Fatigue in patients with spinal muscular atrophy type II and congenital myopathies; evaluation of the fatigue severity scale. Qual Life Res 2014: 23(5); 1479-1488.
  • Witting N, Duno M, Piraud M, Vissing J. Severe axial myopathy in McArdle disease. JAMA Neurology 2014; 71(1): 88-90.
  • Citirak G, Witting N, Duno M, Werlauff U, Petri H, Vissing J. Frequency and phenotype of patients carrying TPM2 and TPM3 gene mutations in a cohort of 94 patients with congenital myopathy. Neuromuscul Disord 2014; 24(4): 325-330.
  • Vissing CR, Preisler N, Husu E,Prahm K, Vissing J. Aerobic training in patients with myopathy and hyperCKemia caused by anoctamin 5 deficiency. Muscle Nerve 2013 Nov 6. doi: 10.1002/mus.24112.
  • Riisager M, Duno M, Hansen FJ, Krag TO, Vissing CR, Vissing J. A new mutation of the Fukutin gene causing late onset of Limb Girdle Muscular Dystrophy. Neuromuscl Disord 2013; 23(7): 562-567.
  • Witting N, Duno M, Petri H, Krag T, Bundgaard H, Kober L, Vissing J. Anoctamin 5 muscular dystrophy in Denmark; genotype, phenotype, prevalence, cardiology and muscle protein expression. J Neurol 2013; 260(8): 2084-2093.
  • Andersen G, Orngreen MC, Preisler N, Colding-Jørgensen E, Clausen T,Duno M, Jeppesen TD, Vissing J. Muscle phenotype in patients with Myotonic Dystrophy type 1. Muscle Nerve 2013; 47: 409-415.
  • Böhm J, Biancalana V, DeChene ET, Bitoun M, Pierson CR, Schaefer E, Karasoy H, Dempsey MA, Klein F, Dondaine N, Kretz C, Haumesser N, Poirson C, Toussaint A, Greenleaf RS, Barger MA, Mahoney LJ, Kang PB, Zanoteli E, Vissing J, Witting N, Echaniz-Laguna A, Wallgren-Pettersson C, Dowling J, Merlini L, Oldfors A, Bomme-Ousager L, Melki J, Krause A, Jern C, Oliveira ASB, Petit F, Jacquette A, Chaussenot A, Mowat D, Leheup B, Cristofano M, Aldea JP, Michel F, Furby A, Llona JEB, van Coster R, Bertini E, Urtizberea JA, Drouin-Garraud V, Béroud C, Prudhon B, Bedford HM, Mathews K, Erby LAH, Smith SA, Roggenbruck J, Crowe CA, Spitale AB, Johal SC, Amato AA, Demmer LA, Jonas J, Darras BT, Bird TD, Laurino M, Welt SI, Trotter C, Guicheney P, Das S, Mandel J-L, Beggs AH, Laporte J. Mutation spectrum in the large GTPase dynamin 2 (DNM2) and genotype/phenotype correlation in autosomal dominant centronuclear myopathy. Hum Mutat 2012; 33: 949-959.
  • Gavassini BF, Carboni N, Nielsen JE, Danielsen ER, Thomsen C, Svenstrup K, Bello L, Maioli MA, Marrosu G, Ticca AF, Mura M, Marrosu MG, Soraru G, Angelini C, Vissing J, Pegoraro E. Clinical and molecular characterization of limb girdle muscular dystrophy due to LAMA2 mutations. Muscle Nerve 2011; 44: 703-709.
  • Stojkovic T,Vissing J, Petit F,Piraud M,Orngreen MC, Andersen G,Claeys KG,Wary C,Hogrel JY,Laforêt P. Muscle glycogenosis due to phosphoglucomutase 1 deficiency. N Engl J Med 2009; 361: 425-427.
  • Vissing J,Duno M,Schwartz M,HallerRG. Splice mutations preserve myophosphorylase activity that ameliorates the phenotype in McArdle disease. Brain 2009; 132: 1545-1552.
  • Ostergaard E, Hansen FJ, Sorensen N, Duno M, Vissing J, Larsen PL, Faeroe O, Thorgrimsson S, Wibrand F, Christensen E, Schwartz M. Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations. Brain 2007; 130: 853-861.
  • Jeppesen TD, Schwartz M, Frederiksen AL, Wibrand F, Olsen DB, Vissing J. Muscle phenotype and mutation load in 51 persons with the 3243A>G mitochondrial DNA mutation. Arch Neurol 2006; 63: 1701-1706.
  • Andersen ST, Dunø M, Schwartz M, Vissing J. Do carriers of PYGM mutations have symptoms of McArdle disease? Neurology 2006; 67: 716-718.
  • Sveen ML,Schwartz M,Vissing J. High prevalence and phenotype-genotype correlations of limb girdle muscular dystrophy type 2I in Denmark. Ann Neurol 2006; 59: 808-815.
  • Schwartz M, Hertz JM, Sveen ML, Vissing J. LGMD2I presenting with a characteristic Duchenne or Becker dystrophy phenotype. Neurology 2005; 64: 1635-1637.
  • Ørngreen MC, Dunø M, Christensen E, Sacchetti M, Schwartz M, Vissing J. Fuel utilization in subjects with carnitine palmitoyltransferase II gene mutations. Ann Neurol 2005; 57: 60-66.
  • Dunø M, Colding-Jørgensen E, Grunnet M, Jespersen T, Vissing J, Schwartz M. Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype. Eur J Hum Genet 2004; 12: 738-743.
  • Kraytsberg Y, Schwartz M, Brown TA, Ebralidse K, Kunz WS, Clayton DA, Vissing J, Khrapko K. Recombination of human mitochondrial DNA. Science 2004; 304: 981
  • JeppesenTD, Schwartz M, Hansen K,Danielsen ER, Wibrand F, Vissing J. Late onset of stroke-like episode associated with a 3256C→T point mutation of mitochondrial DNA. J Neurol Sci 2003; 214: 17-20.
  • Jeppesen TD, Schwartz M, Olsen DB, Vissing J. Oxidative capacity correlates with muscle mutation load in mitochondrial myopathy. Ann Neurol 2003; 54: 86-92.
  • Colding-Jørgensen E, Dunø M, Schwartz M, Vissing J. Decrement of compound muscle action potential is related to mutation type in myotonia congenita. Muscle Nerve 2003; 27: 449-455.
  • Schwartz M, Vissing J. Paternal inheritance of mitochondrial DNA. N Engl J Med 2002; 347: 576-580.