Metabolic and mitochondrial myopathies

Metabolic and mitochondrial myopathies
Understanding of the pathophysiology underlying the metabolic myopathies provides unique insights into the normal regulation of muscle metabolism. We have developed several dietary treatment strategies for these conditions, and developed diagnostic tests. In collaboration with Queen Square in London, we investigate the effect of valproic acid in McArdle disease, with the intent to increase gene expression of dormant isoforms of phosphorylase to rescue the phenotype. In collaboration with Hôpital Pitié-Salpêtrière in Paris, we investigate the effect of treating patients with McArdle disease with triheptanoin, to spark combustion of fats. We are also partners in the creation and of a registry for muscle glycogenoses (EUROMAC, (http://euromacregistry.eu/). Several ongoing studies at our center focus on describing the energy defect and pathophysiology of more newly described muscle glycogenosis.

Pathophysiology, diagnostics and treatment of mitochondrial myopathies have been a focus in our center for many years. We have developed new diagnostic exercise tests for mitochondrial myopathies, and have in the past and are currently testing different compounds that may have a beneficial effect in the disorders. We are currently also studying mitochondrial dynamics to training with aging, and whether age-related muscle loss (sarcopenia) can be treated.


References for metabolic myopathies

  • Voermans NC, Preisler N, Madsen KL, Janssen M, Kusters B, Bakar NA, Conte F, Maas D, Groothuis JT, Nusman F, Engelen Bv, Scherpenzeel Mv, Vissing J, Lefeber DJ. PGM1 deficiency: Effect of treatment with galactose. Neuromuscul Disord 2017; [Epub ahead of print].
  • Preisler N, Laforet P, Madsen KL, Prahm KP, Hedermann G, Vissing CR, Galbo H, Vissing J. Skeletal muscle metabolism is impaired during exercise in glycogen storage disease type III. Neurology 2015; 84(17): 1767-1771.
  • Ørngreen MC, Jeppesen TD, Taivassalo T, Hauerslev S, Preisler N, Heinecke K, Haller RG, Vissing J, van Hall G. Lactate and energy metabolism during exercise in patients with blocked glycogenolysis (McArdle disease). J Clin Endocrinol Metab 2015; 100(8): E1096-E1104.
  • Witting N, Duno M, Piraud M, Vissing J. Severe axial myopathy in McArdle disease. JAMA Neurology 2014; 71(1): 88-90.
  • Orngreen MC, Madsen KL, Preisler N, Andersen G, Vissing J, Laforêt P. Bezafibrate in skeletal muscle fatty oxidation disorders: a randomized clinical trial. Neurology 2014; 82(7): 607-613.
  • Andreassen CS, Schlütter JM, Vissing J, Andersen H. Effect of enzyme replacement therapy on isokinetic strength for all major muscle groups in four patients with Pompe disease – a long-term follow-up. Mol Genet Metab 2014; 112(1): 40-43.
  • Andreassen CS, Schlütter JM, Vissing J, Andersen H. Effect of enzyme replacement therapy on isokinetic strength for all major muscle groups in four patients with Pompe disease – a long-term follow-up. Mol Genet Metab 2014 Mar 5. pii: S1096-7192(14)00087-0. doi: 10.1016/j.ymgme.2014.02.015
  • Orngreen MC, Madsen KL, Preisler N, Andersen G, Vissing J, Laforêt P. Bezafibrate does not improve fat oxidation in patients with disorders of fat metabolism; a double blind, randomized clinical trial. Neurology 2014; 82(7): 607-613
  • Preisler N, Lukacs Z, Vinge L, Madsen KL, Husu E, Hansen RS, Duno M, Andersen H,Laub M, Vissing J. Late-onset Pompe disease is prevalent in unclassified limb-girdle muscular dystrophies. Mol Metab Genet 2013: 110(3):287-289.
  • Preisler N, Laforêt P, Echaniz-Laguna A, Orngreen MC, Lonsdorfer-Wolf E, Doutreleau S, Geny B, Stojkovic, T, Piraud M, Petit FM, Vissing J. Fat and carbohydrate metabolism during exercise in phosphoglucomutase type 1 deficiency. J Clin Endocrinol Metab 2013; 98: E1235-1240.
  • Preisler N, Pradel A, Husu E, Madsen KL, Becquemin MH, Mollet A, Labrune P, Petit F, Hogrel JY, Jardel C, Maillot F, Vissing J, Laforêt P. Exercise intolerance in glycogen storage disease type III: Weakness or energy deficiency? Mol Genet Metab 2013; 109(1): 14-20.
  • . Madsen KL, Preisler N, Orngreen MC, Andersen SP, Olesen JH, Lund AM, Vissing J. Patients with medium-chain acyl-Coenzyme A-dehydrogenase deficiency have impaired oxidation of fat during exercise but no effect of L-carnitine supplementation. J Clin Endocrinol Metab 2013; 98(4):1667-1675
  • Preisler N, Laforêt P, Madsen KL, Hansen RS, Lukacs, Z, Orngreen MC, Lacour A, Vissing J. Fat and carbohydrate metabolism during exercise in late-onset Pompe disease. Mol Genet Metab 2012; 107; 462-468.
  • Preisler N, Orngreen MC, Echaniz-Laguna A, Laforet P, Lonsdorfer-Wolf E, Doutreleau S, Geny B, Akman HO, Dimauro S, Vissing J. Muscle phosphorylase kinase deficiency; a neutral metabolic variant or a disease? Neurology 2012; 78: 265-268.
  • Laforêt P, Orngreen MC, Preisler N, Andersen G, Vissing J. Blocked muscle fat oxidation during exercise in neutral lipid storage disease. Arch Neurol 2012; 69: 530-533.
  • Quinlivan R, Buckley J, James M, Twist A, Ball S, Duno M, Vissing J, Bruno C, Cassandrini D, Roberts M, Winer J, Rose M, Sewry C. McArdle disease: A clinical review. J Neurol Neurosurg Psychiatry 2010; 81: 1182-1188.
  • . 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.
  • Duno M, Quinlivan R, Vissing J, Schwartz M. High-resolution melting facilitates mutation screening of Andersen ST, Jeppesen TD, Taivassalo T, Sveen ML, Heinicke K, Haller RG, Vissing J. Effect of changes in fat availability on exercise capacity in McArdle disease. Arch Neurol 2009; 66: 762-766.
  • PYGM in patients with McArdle disease. Ann Hum Genet 2009; 73: 292-297.
  • Ørngreen MC, Jeppesen TD, Andersen ST, Taivassalo T, Hauerslev S, Preisler N, Haller RG, van Hall G, Vissing J. Fat metabolism during exercise in patients with McArdle disease. Neurology 2009; 72: 718-724.
  • Naini A, Toscano A, Musumeci O, Vissing J, Akman HO, DiMauro S. Muscle phosphoglycerate mutase (PGAM) deficiency revisited. Arch Neurol 2009; 66(3): 394-398.
  • Andersen ST, Vissing J. Carbohydrate- and protein-rich diets in McArdle disease: Effects on exercise capacity. J Neurol Neurosurg Psychiatry 2008; 79: 1359-1363.
  • Andersen ST, Haller, RG, Vissing J. Effect of oral sucrose shortly before exercise on work capacity in McArdle disease. Arch Neurol 2008; 65: 786-789.
  • Diggelen O, DiMauro S, Vissing J. Is muscle glycogenolysis impaired in X-linked phosphorylase b kinase deficiency? Neurology 2008; 70: 1876-1882.
  • Andersen ST, Dunø M, Schwartz M, Vissing J. Do carriers of PYGM mutations have symptoms of McArdle disease? Neurology 2006; 67: 716-718.
  • Haller RG, Wyrick P, Taivassalo T, Vissing J. Aerobic conditioning: An effective therapy in McArdle disease. Ann Neurol 2006; 59: 922-928.
  • 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.
  • Vissing J, Quistorff B, Haller RG. Effect of fuels on exercise capacity in muscle phosphoglycerate mutase deficiency. Arch Neurol 2005; 62: 1440-1443.
  • Ørngreen MC, Nørgaard MG, Sacchetti M, van Engelen BG, Vissing J. Fuel utilization in patients with very long-chain acyl-CoA dehydrogenase deficiency. Ann Neurol 2004; 56: 279-282.
  • Haller RG, Vissing J. No spontaneous second wind in muscle phosphofructokinase deficiency. Neurology 2004; 62: 82-86.
  • . Vissing J, Haller RG. The effect of oral sucrose on exercise tolerance in patients with McArdle’s disease. N Engl J Med 2003; 349: 2503-2509.
  • Vissing J, Haller RG. A diagnostic cycle test for McArdle’s disease. Ann Neurol 2003; 54: 539-542.
  • Ørngreen MC, Ejstrup R, Vissing J. Effect of diet on exercise tolerance in carnitine palmitoyltransferase II deficiency. Neurology 2003; 61: 559-561.
  • Ørngreen MC, Olsen DB, Vissing J. Exercise tolerance in carnitine palmitoyltransferase II deficiency with IV and oral glucose. Neurology 2002; 59: 1046-1051.
  • Haller RG, Vissing J. Spontaneous “second wind” and glucose-induced second “second wind” in McArdle disease – Oxidative mechanisms. Arch Neurol 2002; 59: 1395-1402.
  • Kazemi-Esfarjani P, Skomorowska E, Jensen TD, Haller RG, Vissing J. A nonischemic forearm exercise test for McArdle disease. Ann Neurol 2002; 52: 153-159.
  • Nielsen JN, Wojtaszewski JFP, Haller RG, Hardie G, Kemp B, Richter EA, Vissing J. Role of 5’AMPactivated protein kinase in glycogen synthase activity and glucose utilization: insights from patients with McArdle’s disease. J Physiol (Lond) 2002; 541: 979989.
  • Nielsen JN, Vissing J, Wojtaszewski JFP, Haller RG, Begum N, Richter EA. Decreased insulin action in skeletal muscle from patients with McArdle’s disease. Am J Physiol (Endocrinol Metab) 2002; 282: E1267-E1275.
  • Vissing J, MacLean DA, Vissing SF, Saltin B, Haller RG. The exercise metaboreflex is maintained in the absence of muscle acidosis: insights from muscle microdialysis in humans with McArdle’s disease. J Physiol 2001; 537: 641-649.
  • Vissing J, Schmalbruch H, Haller RG, Clausen T. Muscle phosphoglycerate mutase deficiency with tubular aggregates: Effect of dantrolene. Ann Neurol 1999; 46: 274-277.
  • MacLean D, Vissing J, Vissing SF, Haller RG. Oral branched chain amino acids do not improve exercise capacity in McArdle disease. Neurology 1998; 51: 1456-1459.
  • Vissing J, Vissing SF, MacLean DA, Saltin B, Quistorff B, Haller RG. Sympathetic activation in exercise is not dependent on muscle acidosis: Direct evidence from studies in metabolic myopathies. J Clin Invest 1998; 101: 1654-1660.

References for mitochondrial myopathies

  • Soldath P, Wegener M, Sander B, Rosenberg T, Duno M, Wibrand F, Vissing J. Leber hereditary optic neuropathy due to a new ND1 mutation. Ophthal Genet In press.
  • Hedermann G, Løkken N, Dahlqvist JR, Vissing J. Dysphagia is prevalent in patients with CPEO and single, large-scale deletions in mtDNA. Mitochondrion 2016; 32: 27-30.
  • Guo S, Esserlind AL, Andersson Z, Frederiksen AL, Olesen J, Vissing J, Ashina M. Prevalence of migraine in persons with the 3243A>G mutation in mitochondrial DNA. Eur J Neurol 2016; 23(1): 175-181.
  • Rafiq J, Duno M, Østergaard E, Ravn K, Vissing CR, Wibrand F, Vissing J. Exercise intolerance and myoglobinuria associated with a novel maternally inherited MT-ND1 mutation. JIMD Rep 2016; 25: 65-70.
  • Lund M, Melbye M, Diaz LJ, Duno M, Wohlfahrt J, Vissing J. Mitochondrial dysfunction and risk of cancer. Br J Cancer 2015; 112: 1134-1140.
  • 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.
  • Levison L, Dunø M, Risom L, Toft PB, Vissing J. Differences in genetic defects morphology of eye- and limb muscles in mitochondrial myopathy. Acta Ophthalmol 2015; 93(4): e306-308.
  • Born AP, Duno M, Rafiq J, Risom L, Wibrand F, Ostergaard E, Vissing J. A mitochondrial tRNAMet mutation causing developmental delay, exercise intolerance and limb girdle phenotype with onset in early childhood. Eur J Paediatr Neurol 2015; 19(1): 69-71.
  • Rue N, Vissing J, Galbo H. Insulin resistance and increased cytokine levels in patients with mitochondrial myopathy. J Clin Endocrinol Metab 2014; 99(10): 3757-3765.
  • Jeppesen TD, Duno M, Risom L, Schwartz M, Wibrand F, Rafiq J, Jakobsen J, Andersen H, Krag T, Vissing J. A novel de novo mutation of the mitochondrial tRNAlys gene mt.8340G>A associated with pure myopathy. Neuromuscl Disord 2014; 24(2): 162-166.
  • Jeppesen TD, Orngreen MC, van Hall G, Vissing J. Lactate metabolism during exercise in patients with mitochondrial myopathy. Neuromuscl Disord 2013; 23(8): 629-636.
  • Ghelli A, Marchesini A, Tropeano CV, Calvaruso MA, Iommarini L, Porcelli AM, Zanna C, Nardo VD, Martinuzzi A, Wibrand F, Vissing J, Kurelac I, Gasparre G, Selamoglu N, Daldal F, Rugolo M. The Cytochrome B p.278Y>C mutation causative of a multisystem disorder enhances superoxide production and alters supramolecular interactions of respiratory chain complexes. Hum Mol Genet 2013; 22: 2141-2151.
  • Krag TO, Hauerslev S, Jeppesen TD, Duno M, Schwartz M, Vissing J. Muscle
  • Vissing CR, Duno M, Olesen JH, Rafiq J, Risom L, Christensen E, Wibrand F, Vissing J. Recurrent myoglobinuria and deranged acylcarnitines due to a mutation in the mtDNA MT-CO2 gene. Neurology 2013; 80: 1908-1910.
  • Jeppesen TD, Vissing J, González- Alonso J. Influence of erythrocyte oxygenation and intravascular ATP on resting and exercising skeletal muscle blood flow in humans with mitochondrial myopathy. Mitochondrion 2012; 12: 414-422.
  • Wibrand F, Jeppesen TD, Frederiksen AL, Olsen DB, Duno M, Schwartz M, Vissing J. Limited diagnostic value of enzyme analysis in patients with mitochondrial tRNA mutations. Muscle Nerve 2010; 41; 607-613.
  • Jeppesen TD,Duno M,Schwartz M,Krag T,Rafiq J, Wibrand F,Vissing J. Short- and long-term effects of endurance training in patients with mitochondrial myopathy. Eur J Neurol 2009; 16: 1336-1339.
  • Frederiksen AL, Jeppesen TD, Vissing J, Schwartz M, Kyvik KO, Schmitz O, Poulsen PL, Andersen PH. High prevalence of impaired glucose homeostasis and myopathy in a- and oligosymptomatic 3243A>G mtDNA mutation-positive subjects. J Clin Endocrinol Metab 2009; 94: 2872-2879.
  • Jeppesen TD, Ørngreen MC, van Hall G, Haller RG, Vissing J. Fat metabolism during exercise in patients with mitochondrial disease. Arch Neurol 2009; 66(3): 365-370.
  • Jeppesen TD, Schwartz M, Colding-Jorgensen E, Krag T, Hauerslev S, Vissing J. Phenotype and clinical course in a family with a new de novo Twinkle gene mutation. Neuromuscul disord 2008; 18: 306-309.
  • Yavuz H, Özel A, Christensen M, Christensen E, Schwartz M, Elmacı M, Vissing J. Treatment of mitochondrial neurogastrointestinal encephalomyopathy with dialysis. Arch Neurol 2007; 64: 435-438
  • Jeppesen TD, Quistorff B, Wibrand F, Vissing J. 31P-MRS of muscle is not a sensitive diagnostic test for mitochondrial myopathy. J Neurol 2007; 254: 29-37.
  • 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,Olsen DB,Wibrand F,Krag T,Dunø M,Hauerslev S,Vissing J. Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. Brain 2006; 129: 3402-3412.
  • 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.
  • Frederiksen AL, Andersen PH, Kyvik KO, Jeppesen TD, Vissing J, Schwartz M. Tissue specific distribution of the 3243A>G mtDNA mutation. J Med Genet 2006; 43: 671-677.
  • Østergaard E, Wibrand F, Ørngreen MC, Vissing J, Horn N. Impaired energy metabolism and abnormal muscle histology in mut\– methylmalonic aciduria. Neurology 2005; 65: 931-934.
  • . 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
  • Schwartz M, Vissing J. No evidence for paternal inheritance of mtDNA in patients with sporadic mtDNA mutations. J Neurol Sci 2004; 218: 99-101.
  • Olsen DB, Langkilde AR,Ørngreen MC, Rostrup E, Schwartz M, Vissing J. Muscle structural changes in mitochondrial myopathy relate to genotype. J Neurol 2003; 250: 1328-1334.
  • 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.
  • Antonicka H, Ogilvie I, Taivassalo T, Haller RG, Vissing J, Kennaway NG, Shoubridge EA. Identification and characterization of a common set of Complex I assembly intermediates in mitochondria from patients with Complex I deficiency. J Biol Chem 2003; 278: 43081-43088.
  • Jeppesen TD, Schwartz M, Olsen DB, Vissing J. Oxidative capacity correlates with muscle mutation load in mitochondrial myopathy. Ann Neurol 2003; 54: 86-92.
  • Goethem GV, Schwartz M, Löfgren A, Dermaut B, Van Broeckhoven C, Vissing J. Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy. Eur J Hum Genet 2003; 11: 547-549.
  • Jeppesen TD, Olsen DB, Vissing J. Cycle ergometry is not a sensitive diagnostic test for mitochondrial myopathy. J Neurol 2003; 250: 293-299.
  • Taivassalo T, Jensen TD, Kennaway N, DiMauro S, Vissing J, Haller RG. The spectrum of exercise intolerance in mitochondrial myopathies: a study of 40 patients. Brain 2003; 126: 413-423.
  • Vissing J, Ravn K, Danielsen ER, Wibrand F, Dunø M, Wevers RA, Schwartz M. Multiple mtDNA deletions with features of MNGIE. Neurology 2002; 59: 926-929.
  • Schwartz M, Vissing J. Paternal inheritance of mitochondrial DNA. N Engl J Med 2002; 347: 576-580.
  • Jensen TD, Kazemi- Esfarjani P, Skomorowska E, Vissing J. A forearm exercise screening test for mitochondrial myopathy. Neurology 2002; 58: 1533-1538.
  • Wibrand F, Ravn K, Schwartz M, Rosenberg T, Horn N, Vissing J. Multisystem disorder associated with a missense mutation in the mitochondrial cytochrome b gene. Ann Neurol 2001; 50: 540-543.
  • Steensberg A, Vissing J, Pedersen BK. Lack of IL-6 production during exercise in patients with mitochondrial myopathy. Eur J Appl Physiol 2001; 84: 155157.
  • Vissing J, Gansted U, Quistorff B. Exercise intolerance in mitochondrial myopathy is not related to lactic acidosis. Ann Neurol 2001; 49: 672-676.