Metabolic myopathies (McArdle, Pompe, CPT II deficiency)
Metabolic myopathies are inherited defects of muscle energy metabolism; the most common adult forms, McArdle disease (myophosphorylase deficiency) and carnitine palmitoyltransferase II deficiency, cause exercise-induced cramps, weakness, and myoglobinuric rhabdomyolysis, while acid maltase deficiency (Pompe disease) causes progressive proximal and respiratory weakness. Diagnosis rests on creatine kinase, the forearm exercise lactate test, enzyme assay, and genetic testing; treatment is aggressive fluids for rhabdomyolysis, sucrose before exercise in McArdle disease, avoidance of fasting, and enzyme replacement with alglucosidase alfa in Pompe disease.
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What this article covers
- Overview
Definition: metabolic myopathies are inherited deficiencies of key muscle energy pathways, glycogen breakdown and fatty acid oxidation, that cause exercise intolerance, myalgia, cramps, and…
- Epidemiology
McArdle disease: autosomal recessive; patients typically present in adolescence or early adulthood with exertional cramps and red urine.
- Risk factors
Strenuous exercise: the dominant trigger of muscle breakdown in McArdle disease and CPT II deficiency, especially high-intensity exertion.
- Pathophysiology
McArdle disease, no muscle glycogenolysis: deficiency of the skeletal muscle isoform of glycogen phosphorylase prevents muscle glycogen breakdown, so no glucose 6-phosphate enters glycolysis and lactate does not rise with exercise.
- Clinical features
Exercise intolerance with cramps and weakness: the hallmark of McArdle disease and CPT II deficiency is exercise-induced muscle pain, cramping, and weakness, often with an otherwise normal examination between attacks.
- Differential diagnosis
Exertional heat stroke: rhabdomyolysis with core temperature above 40 C (104 F) and central nervous system dysfunction; see heat stroke.
- Diagnosis
Basis of diagnosis: there is no clinical criteria set; the diagnosis is confirmed by demonstrating the specific enzyme deficiency or its pathogenic variant in a patient with a compatible phenotype…
- Management
First, treat an acute attack as rhabdomyolysis: start aggressive IV isotonic fluid (0.9% sodium chloride initially), titrated to a urine output of more than 200-300 mL/hr, and continue with serial…
- Complications
Acute kidney injury: heme pigment from myoglobin causes tubular toxicity, renal vasoconstriction, and cast obstruction, with a fractional excretion of sodium below 1% and pigmented granular casts.
- Prognosis
Infantile Pompe disease: death usually occurs in infancy from cardiac and respiratory failure; enzyme replacement therapy improves symptoms and survival.
- Prevention
Newborn screening: the Pompe enzyme assay is included in many newborn screening programs, allowing diagnosis in infancy.
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- Rhabdomyolysis
Rhabdomyolysis is necrosis of skeletal muscle with release of myoglobin, creatine kinase, and intracellular electrolytes into the circulation, diagnosed by a serum creatine kinase at least five times the upper limit of normal (typically over 1500 U/L) with a urine dipstick positive for blood but no red cells on microscopy; treatment is aggressive isotonic intravenous fluid to a urine output of 200 to 300 mL/h and correction of hyperkalemia, with acute kidney injury from pigment nephropathy the dominant complication.
- Mitochondrial myopathies
Mitochondrial myopathies are inherited disorders of oxidative phosphorylation, most caused by maternally transmitted mitochondrial DNA mutations, that preferentially disable skeletal muscle, brain, retina, and heart. Named syndromes include MELAS, MERRF, Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia, and Leigh syndrome. Diagnosis proceeds from lactate and muscle biopsy to genetic testing; management is supportive, built around seizure control and toxin avoidance.
- Limb-girdle muscular dystrophy
Limb-girdle muscular dystrophy is an inherited, slowly progressive dystrophy of the shoulder and pelvic girdle muscles caused by mutations in sarcolemmal and excitation-contraction coupling proteins such as caveolin and dysferlin. It is confirmed by genetic testing after an elevated creatine kinase and a myopathic EMG, and care centers on respiratory and cardiac surveillance, noninvasive ventilation once daytime hypercapnia appears, heart failure therapy for cardiomyopathy, and avoidance of succinylcholine.
- Polymyositis
Polymyositis is an idiopathic inflammatory myopathy causing symmetric, subacute proximal muscle weakness with no rash, driven by endomysial CD8-positive T-cell invasion of non-necrotic, MHC class I-expressing muscle fibers. It is a diagnosis of exclusion confirmed by muscle biopsy, and first-line treatment is high-dose prednisone with a steroid-sparing agent such as methotrexate or azathioprine started concurrently.
- Drug-induced myopathy
Drug-induced myopathy spans a spectrum from asymptomatic creatine kinase elevation to rhabdomyolysis and is caused by statins (most common), glucocorticoids, colchicine, hydroxychloroquine, zidovudine, amiodarone, alcohol, and cocaine, each with a distinct mechanism, time course, and presentation. The critical distinction is toxic myopathy that resolves with drug withdrawal versus statin-associated anti-HMGCR necrotizing myopathy, which persists after discontinuation and requires immunosuppression.
- Hyperkalemia
Hyperkalemia is a serum potassium level above 5.0 mEq/L, most often from decreased kidney excretion, transcellular shifts, or excess intake, with levels above 6.0-6.5 mEq/L or any ECG change constituting a medical emergency from the risk of fatal arrhythmia. Treatment sequences cardiac membrane stabilization with calcium, transcellular potassium shifting with insulin/dextrose and albuterol, then definitive potassium removal with binders, diuretics, or dialysis.