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Myopathies due to a defect in glucose or lipid metabolism

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Dott. Andrea Martinuzzi
Neurologist, Research Unit Manager
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Dott.ssa Cristina Stefan
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Dott. Enrico Trevisi
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Dott.ssa Elena Vinante
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Dott.ssa Eleonora Martini
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+39 0438 414242



Metabolic myopathies represent a complex and heterogeneous group of rare conditions that are marked by muscular disorders (weakness, exhaustion, episodes of acute myolysis with myoglobiluria) due to problems in the main energy metabolic pathways of the muscle. If the early and neonatal onset forms, which show severe metabolic dysfunction patterns, are excluded, the most common forms are the myophosphorylase defect for the glycolytic pathway (McArdle's disease, Glycogenosis type 5) and the metabolism pathway for the lipid defect of Carnitin Palmitoyl transferase 2 (CPT2).

Both forms show episodes of generalized damage of the muscle fibers in the young adult: in the first case they are triggered by acute and intense efforts and in the second case by fasting, fever and prolonged efforts.
The myophosphorylase defect is caused by mutations in both PYGM gene alleles (recessive form) that are constituted by a mutation in the first exon of the gene (R50X) in 40% of all cases.

Beside the crises triggered by short but intense and sudden efforts that often lead to the emission of dark urine (myoglobinuria), clinical manifestations may include myalgias, stress cramps, persistent elevation of CK and, in 20-30% of cases, constant weakness and muscular atrophy, particularly in the muscles of the shoulders and of the bust.

A particular mark of this form is the feeling of energy recovery that the patient feels as soon as he takes some rest for a few minutes, at the moment of exhaustion occuring after 5-7 minutes of intense exercise (phenomenon of the "Second Wind "). Even if the condition is benign, it is related to relevant disability and psychological conditions of difficulty.
The second condition, that’s sometimes confused with the first condition due to the similarity of deep clinical manifestations (accessory myoglobinuria), is caused by a reduced ability to use fats by the muscle for the lack of the specific cell transporter. The disease is caused by mutations in both CPT2 gene alleles. Also in this case a mutation (S113L) represents the most frequent cause.

The disorder occurs in the child or in the young adult with muscle damage that’s caused by stressful conditions (fever, fasting, prolonged efforts). Crises are accompanied by myoglobinuria and intense myalgias.
The disorder that is caused by these conditions may be unnoticed for a long time because of an underestimation or misinterpretation of acute episodes and the diagnostic delay can also last several years.

Both conditions do not currently have effective therapy, but both constitute important lifestyle indications and appropriate specialist follow-up.
The Institute team has been representing for years the focus point for the diagnostic definition and clinical management of patients with muscle glycogenosis, it is part of the members of the research consortium that has created the European Registry and the Italian Registry for muscle glycogenosis, it offers rehabilitative proposals and the experimentation of new treatment protocols including special diet regimens (e.g. the ketogenic diet) which could represent a valid aid in these forms.

The program offered for these patients includes a multi-professional global assessment that includes the bioenergetic assessment of exercise capacity, specialized neurological, physiatric, psychological, dietary, chineseological, occupational and social evaluation. In addition to the guarantee of an expert able to make comparison among these rare diseases, the main objective of the program is to put the patient and his/her family in a position to better manage the disorder by minimizing its consequences and its impact during the daily life. Randomized clinical trials aimed at testing new therapeutic approaches have been conducted and are developing.

Selected publications

1. Trevisan CP, Angelini C, Freddo L, Isaya MG, Martinuzzi A (1984). Myoglobinuria and carnitine-palmitoyl transferase (CPT) deficiency: studies with malonyl-CoA suggest absence of only CPT II. Neurology; 34:353-356

2. Martinuzzi A, Askanas V, Kobayashi T, Engel WK, Di Mauro S (1986). Expression of muscle gene specific isozymes of phosphorylase and creatine kinase in innervated cultured human muscle. J.Cell.Biol.; 103:1423-1429

3. Angelini C, Vergani L, Costa L, Martinuzzi A, Dunner E, Marescotti C, Nosadini R (1986). Use of carnitine in exercise physiology. Adv.Clin.Enzymol.; 4:103-110

4. Martinuzzi A, Askanas V, Kobayashi T, Engel WK, Gorsky J (1987). Developmental expression of the muscle specific isozyme of phosphoglycerate mutase in human muscle cultured in monolayer and innervated by fetal rat spinal cord. Exp.Neurol.; 96:365-377

5. Askanas V, Martinuzzi A, Engel WK, Kobayashi T, Stern LZ, Hsu L (1987). Accumulation of CK-MM is impaired in innervated and contracting cultured muscle fibers of Duchenne muscular dystrophy patients. Life Science; 41:927-933

6. Rösler KM, Askanas V, Engel WK, Martinuzzi A (1987). Effects of electrical stimulation and tetrodotoxin paralysis on expression of muscle specific isozymes of four enzymes in aneurally cultured rat muscle. Exp.Neurol.; 97:739-745

7. Askanas V, Hwan H, Alvarez R, Engel WK, Kobayashi T, Martinuzzi A, Hawkins EF (1987). De-novo neuromuscular junction formation in human muscle fibers cultured in monolayer and innervated by fetal rat spinal cord: ultrastructural and ultrastructural-cytochemical studies. J.Neurocytol.; 16:523-537

8. Vita G, Askanas V, Martinuzzi A, Engel WK (1988). Histoenzymatic profile of the human muscle cultured in monolayer and innervated de novo by fetal rat spinal cord. Muscle & Nerve; 11:1-9

9. Martinuzzi A, Askanas V, Kobayashi T, Engel WK (1988). Asynchronous regulation of muscle specific isozymes of creatine kinase, glycogen phosphorylase, lactic dehydrogenase and phosphoglycerate mutase in innervated and non-innervated cultured human muscle. Neurosci. Lett.; 89:216-222

10. Angelini C, Vergani L, Martinuzzi A (1992). Clinical and biochemical aspects of carnitine deficiency and insufficiency: transport defects and inborn errors of ß-oxidation. Crit.Rev.Clin.Lab.Sci.; 29: 217-242

11. Martinuzzi A, Vergani L, Carrozzo R, Fanin M, Bartoloni L, Askanas V, Engel WK, Angelini C (1993). Expression of muscle-type glycogen phosphorylase in innervated and aneural cultured muscle of patients with myophosphorylase deficiency. J.Clin.Invest.; 92:1774-178012.

12. Tsujino S, Shanske S, Martinuzzi A, Heiman-Patterson T, DiMauro S (1995). Two novel missense mutations in Caucasian patients with myophosphorylase deficiency (McArdle's disease). Hum.Mutat.; 6:276-27713.

13. Siciliano G, Rossi B, Martini A, Angelini C, Martinuzzi A, Lodi R, Zaniol P, Barbiroli B, Muratorio A (1994). Myophosphorylase deficiency affects muscle mitochondrial respiration as shown by 31P-MR spectroscopy in a case with associated multifocal encephalopathy. J.Neurol.Sci.; 128:84-9114.

14. Martinuzzi A, Tsujino S, Vergani L, Schievano G, Cadaldini M, Bartoloni L, Fanin M, Siciliano G, Shanske S, Di Mauro S, Angelini C (1996). Molecular characterization of myophosphorylase deficiency in a group of patients from Northern Italy. J.Neurol. Sci.; 137: 14-19 15.

15. Martinuzzi A, Schievano G, Vergani L, Pegoraro E, Fanin M, Schiraldi C, Siciliano G, Vita G, Toscano A, Angelini C (1996). Diagnosis and therapy of myophosphorylase deficiency: experience with a group of Italian patients. Basic and Appl. Myol.; 6: 107-11416.

16. Martinuzzi A, Schievano G, Nascimbeni A, Fanin M (1999). McArdle's disease: the unsolved mystery of the reappearing enzyme. Am. J. Pathol.;154: 1893-189717.

17. Martinuzzi A, Sartori E, Fanin M, Angelini C, Siciliano G, Mongini T, Tonin P, Tomelleri G, Toscano A, Merlini L, Bindoff LA, Bertelli S (2003). Phenotype modulators in myophosphorylase deficiency. Ann. Neurol.; 53:497-50218.

18. Bruno C, Cassandrini D, Martinuzzi A, Toscano A, Moggio M, Moranti L, Servidei S, Mongini T, Angelini C, Musumeci O, Comi GP, Lamperti C, Filosto M, Zara F, Minetti C (2006). McArdle Disease: The Mutation Spectrum of PYGM in a Large Italian Cohort. Human Mutation; 27(7): 71819.

19. Martinuzzi A, Liava A, Trevisi E, Frare M, Tonon C, Malucelli E, Manners D, Kemp G, Testa C, Barbiroli B, Lodi R (2008); Randomized placebo-controlled double-mind pilot trial of Ramipril in McArdle’s disease; Muscle & Nerve, 37(3):350-35720.

20. Kemp Graham J, Tonon C, Malucelli E, Testa C, Liava A, Manners D, Trevisi E, Martinuzzi A, Barbiroli B, Lodi R (2009); Cytosolic PH buffering during exercise and recovery in skeletal muscle of patients with McArdle’s disease; European Journal of Applied Physiology, 105(5): 687-69421.

21. Malucelli E, Iotti S, Manners D, Testa C, Martinuzzi A, Barbiroli B, Lodi R (2011). The role of PH on the thermodynamics and kinetics of muscle biochemistry: an in vivo study by P-MRS in patients with myophosphorylase deficiency. Biochimica et Biophysica Acta-Bioenergetics; 1807(9):1244-124922.

22. Quinlivan R, Martinuzzi A, Schoser B. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V). Cochrane Database Syst Rev. 2014 Nov 12;11:CD003458. doi: 10.1002/14651858.CD003458.pub5. Review. PMID: 25391139.


  • Prof Ros Quinlivan, UCL London, UK
  • Prof. John Vissing, Department Of Clinical Medicine, University of Copenhagen
  • Prof. Antonio Toscano, Main Regional Center for Rare Neuromuscular Diseases, Department of di Clinical and Experimental Medicine, University of Messina
  • Prof. Gabriele Siciliano, Department of Clinical and Experimental Medicine, University of Pisa


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