Approach to the metabolic myopathies
- Basil T Darras, MD
Basil T Darras, MD
- Professor of Neurology
- Harvard Medical School
This topic review will provide an overview of the evaluation of the patient with a suspected metabolic myopathy. Detailed descriptions of the different disorders are presented separately. (See "Overview of inherited disorders of glucose and glycogen metabolism" and "Metabolic myopathies caused by disorders of lipid and purine metabolism" and "Mitochondrial myopathies: Clinical features and diagnosis".)
An overview of the biochemistry of energy metabolism in muscle is also discussed elsewhere. (See "Energy metabolism in muscle".)
OVERVIEW OF CLINICAL MANIFESTATIONS
The symptoms, signs, and laboratory abnormalities resulting from a metabolic myopathy vary with the underlying defect. Most patients with a metabolic myopathy (eg, glycogen storage diseases, carnitine palmitoyltransferase deficiency) have dynamic rather than static symptoms, and therefore usually complain of exercise intolerance or muscle pain and cramps with exercise. Nevertheless, other patients may develop progressive muscular weakness that is usually proximal (mimicking inflammatory myopathy or limb girdle muscular dystrophy), but is sometimes distal. In a smaller group of patients, both dynamic and static symptoms predominate (table 1).
Disorders of glycogen metabolism — Inherited disorders that result in abnormal storage of glycogen are known as glycogen storage diseases. These disorders have largely been categorized by number according to the chronology of recognition of the responsible enzyme defect (table 2). The age of onset varies from birth to adulthood. (See "Overview of inherited disorders of glucose and glycogen metabolism".)
In patients with defects of carbohydrate metabolism, muscle symptoms are induced by either brief isometric exercise, such as lifting heavy weights, or by less intense but sustained dynamic exercise, such as swimming, climbing stairs, or running. Acute muscle breakdown may lead to myoglobinuria, cramps, and muscle swelling.
- Tein I. Metabolic myopathies. Semin Pediatr Neurol 1996; 3:59.
- Darras BT, Friedman NR. Metabolic myopathies: a clinical approach; part I. Pediatr Neurol 2000; 22:87.
- Berardo A, DiMauro S, Hirano M. A diagnostic algorithm for metabolic myopathies. Curr Neurol Neurosci Rep 2010; 10:118.
- Haller RG, Vissing J. Spontaneous "second wind" and glucose-induced second "second wind" in McArdle disease: oxidative mechanisms. Arch Neurol 2002; 59:1395.
- Haller RG, Vissing J. No spontaneous second wind in muscle phosphofructokinase deficiency. Neurology 2004; 62:82.
- Haller RG, Lewis SF. Glucose-induced exertional fatigue in muscle phosphofructokinase deficiency. N Engl J Med 1991; 324:364.
- Hale DE, Bennett MJ. Fatty acid oxidation disorders: a new class of metabolic diseases. J Pediatr 1992; 121:1.
- Bell AW, Thompson GE. Free fatty acid oxidation in bovine muscle in vivo: effects of cold exposure and feeding. Am J Physiol 1979; 237:E309.
- Tein I, De Vivo DC, Bierman F, et al. Impaired skin fibroblast carnitine uptake in primary systemic carnitine deficiency manifested by childhood carnitine-responsive cardiomyopathy. Pediatr Res 1990; 28:247.
- Stanley CA, DeLeeuw S, Coates PM, et al. Chronic cardiomyopathy and weakness or acute coma in children with a defect in carnitine uptake. Ann Neurol 1991; 30:709.
- Melli G, Chaudhry V, Cornblath DR. Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine (Baltimore) 2005; 84:377.
- Mannix R, Tan ML, Wright R, Baskin M. Acute pediatric rhabdomyolysis: causes and rates of renal failure. Pediatrics 2006; 118:2119.
- van Adel BA, Tarnopolsky MA. Metabolic myopathies: update 2009. J Clin Neuromuscul Dis 2009; 10:97.
- Kollberg G, Moslemi AR, Lindberg C, et al. Mitochondrial myopathy and rhabdomyolysis associated with a novel nonsense mutation in the gene encoding cytochrome c oxidase subunit I. J Neuropathol Exp Neurol 2005; 64:123.
- Kwon JH, Kim JS. Rhabdomyolysis in a patient with MELAS syndrome. Eur Neurol 2003; 50:123.
- McFarland R, Taylor RW, Chinnery PF, et al. A novel sporadic mutation in cytochrome c oxidase subunit II as a cause of rhabdomyolysis. Neuromuscul Disord 2004; 14:162.
- Tein I, DiMauro S, DeVivo DC. Recurrent childhood myoglobinuria. Adv Pediatr 1990; 37:77.
- Tonin P, Lewis P, Servidei S, DiMauro S. Metabolic causes of myoglobinuria. Ann Neurol 1990; 27:181.
- Rosenberg H, Davis M, James D, et al. Malignant hyperthermia. Orphanet J Rare Dis 2007; 2:21.
- Dlamini N, Voermans NC, Lillis S, et al. Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis. Neuromuscul Disord 2013; 23:540.
- Aboumousa A, Hoogendijk J, Charlton R, et al. Caveolinopathy--new mutations and additional symptoms. Neuromuscul Disord 2008; 18:572.
- Quinlivan R, Jungbluth H. Myopathic causes of exercise intolerance with rhabdomyolysis. Dev Med Child Neurol 2012; 54:886.
- Griggs R, Mendell J, Miller R. Metabolic myopathies. In: Evaluation and Treatment of Myopathies, Griggs R, Mendell J, Miller R (Eds), FA Davis, Philadelphia 1995. p.247.
- Zutt R, van der Kooi AJ, Linthorst GE, et al. Rhabdomyolysis: review of the literature. Neuromuscul Disord 2014; 24:651.
- Das AM, Steuerwald U, Illsinger S. Inborn errors of energy metabolism associated with myopathies. J Biomed Biotechnol 2010; 2010:340849.
- Vockley J. The changing face of disorders of fatty acid oxidation. Mayo Clin Proc 1994; 69:249.
- Mortensen PB, Gregersen N. The biological origin of ketotic dicarboxylic aciduria. II. In vivo and in vitro investigations of the beta-oxidation of C8-C16-dicarboxylic acids in unstarved, starved and diabetic rats. Biochim Biophys Acta 1982; 710:477.
- DiMauro S, Tsujino S. Nonlysosomal glycogenoses. In: Myology, Engel A, Banker B (Eds), McGraw-Hill, New York 1994. p.1554.
- Hogrel JY, Laforêt P, Ben Yaou R, et al. A non-ischemic forearm exercise test for the screening of patients with exercise intolerance. Neurology 2001; 56:1733.
- Kazemi-Esfarjani P, Skomorowska E, Jensen TD, et al. A nonischemic forearm exercise test for McArdle disease. Ann Neurol 2002; 52:153.
- Hanisch F, Eger K, Bork S, et al. Lactate production upon short-term non-ischemic forearm exercise in mitochondrial disorders and other myopathies. J Neurol 2006; 253:735.
- Lindner A, Reichert N, Eichhorn M, Zierz S. Acute compartment syndrome after forearm ischemic work test in a patient with McArdle's disease. Neurology 2001; 56:1779.
- Bruno C, Hays AP, DiMauro S. Glycogen storage diseases of muscle. In: Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician's Approach, Jones HR Jr, De Vivo DC, Darras BT (Eds), Butterworth Heinemann, Philadelphia 2003. p.813.
- Ørngreen MC, Schelhaas HJ, Jeppesen TD, et al. Is muscle glycogenolysis impaired in X-linked phosphorylase b kinase deficiency? Neurology 2008; 70:1876.
- Haller RG. Fueling around with glycogen: the implications of muscle phosphorylase b kinase deficiency. Neurology 2008; 70:1872.
- DiMauro S, Garone C, Naini A. Metabolic myopathies. Curr Rheumatol Rep 2010; 12:386.
- OVERVIEW OF CLINICAL MANIFESTATIONS
- Disorders of glycogen metabolism
- Disorders of lipid metabolism
- Mitochondrial disorders
- Myoglobinuria and rhabdomyolysis
- EVALUATION AND DIAGNOSIS
- Symptom assessment
- Serum and urine testing
- - Lipid metabolism defects
- Semi-ischemic exercise test
- Muscle biopsy
- Molecular genetic techniques
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS