What are the categories and management of metabolic myopathies?

Metabolic Myopathies: Categories and Management

Primary Categories

Metabolic myopathies are divided into three main categories based on the specific metabolic pathway affected: glycogen storage diseases (GSDs), fatty acid oxidation defects (FAODs), and mitochondrial myopathies due to respiratory chain dysfunction. 1, 2, 3

Category	Key Disorders	Clinical Presentation	Diagnostic Features	Management
Glycogen Storage Diseases	• GSD Type II (Pompe disease) • GSD Type III • GSD Type V (McArdle disease) • Phosphofructokinase deficiency • Phosphoglycerate kinase deficiency • Phosphoglycerate mutase deficiency	• High-intensity exercise intolerance • Exercise-induced cramps and myalgias • "Second wind" phenomenon • Recurrent myoglobinuria • Fixed proximal weakness (Pompe)	• Elevated CK (95% in Pompe, though some adults normal) • Abnormal forearm ischemic exercise test • Muscle biopsy: glycogen accumulation • Genetic testing	• Pompe: Enzyme replacement therapy (alglucosidase alfa) [4,5] • Avoid fasting >4-6 hours [4] • Maintain euglycemia (glucose >70 mg/dL) [4] • High-protein diet with frequent meals [4] • Avoid succinylcholine in surgery [4]
Fatty Acid Oxidation Defects	• Carnitine palmitoyltransferase (CPT) deficiency • Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency • Trifunctional protein (TFP) deficiency • Multiple acyl-CoA dehydrogenase deficiency (MADD)	• Endurance exercise intolerance • Fasting-induced symptoms • Myoglobinuria during prolonged activity • Metabolic crises with hypoglycemia • Multisystem involvement in infants (liver, heart, brain)	• Normal or mildly elevated CK between episodes • Markedly elevated CK during rhabdomyolysis • Urine organic acids • Acylcarnitine profile • Muscle biopsy: lipid accumulation	• Avoid prolonged fasting and strenuous endurance exercise [5,3] • High-carbohydrate, low-fat diet [3] • Frequent meals (every 3-4 hours) [3] • MADD: Riboflavin supplementation [5] • Carnitine supplementation in select cases [3]
Mitochondrial Myopathies	• Respiratory chain complex deficiencies (I-V) • Mitochondrial DNA deletions/mutations • MNGIE (mitochondrial neurogastrointestinal encephalomyopathy) • Primary coenzyme Q10 deficiency	• Endurance exercise intolerance • Progressive proximal weakness • Multisystem involvement (CNS, cardiac, endocrine) • Ptosis and ophthalmoplegia • Lactic acidosis	• Elevated lactate (resting and post-exercise) • Muscle biopsy: ragged red fibers on Gomori trichrome • COX-negative fibers • Subsarcolemmal mitochondrial accumulation • mtDNA or nDNA genetic testing	• Primary CoQ10 deficiency: CoQ10 supplementation (high-dose) [5,3] • MNGIE: Allogeneic hematopoietic stem cell transplantation or liver transplantation [5] • Aerobic exercise training (low-intensity) [3] • Avoid mitochondrial toxins (valproate, aminoglycosides) [3] • Supportive: treat cardiac arrhythmias, diabetes [4]

Diagnostic Algorithm

Initial Clinical Assessment

The pattern of exercise intolerance distinguishes categories: GSDs cause symptoms during brief, high-intensity activity (sprinting, lifting), while FAODs and mitochondrial disorders manifest during prolonged, low-intensity endurance activities or fasting states. 1, 2, 3

• GSDs: "Second wind" phenomenon (improvement after 10 minutes of exercise), exercise-induced cramps without weakness between episodes 1, 6
• FAODs: Symptoms triggered by fasting, prolonged exercise, fever, or illness; multisystem involvement in severe infantile forms 2, 3
• Mitochondrial: Progressive fixed weakness, multisystem features (ptosis, ophthalmoplegia, hearing loss, diabetes, cardiac conduction defects), maternal inheritance pattern 4, 7, 3

Exercise Testing

• Forearm ischemic exercise test: Abnormal in GSDs (flat lactate curve with normal ammonia rise); normal lactate rise in FAODs and mitochondrial disorders 1, 6
• Cycle ergometry with lactate measurement: Excessive lactate elevation suggests mitochondrial dysfunction 4, 6
• Non-ischemic forearm exercise test: Preferred to avoid rhabdomyolysis risk; similar diagnostic yield 6

Laboratory Evaluation

• Creatine kinase: Elevated in most metabolic myopathies (particularly during episodes), though may be normal between attacks in FAODs 7, 2
• Urine myoglobin: Positive during rhabdomyolysis episodes 2, 3
• Acylcarnitine profile: Diagnostic for specific FAODs 2, 3
• Urine organic acids: Abnormal in FAODs and some mitochondrial disorders 2, 3
• Lactate/pyruvate ratio: Elevated in mitochondrial disorders 2, 3

Muscle Biopsy

Muscle biopsy remains the gold standard for confirming metabolic myopathy diagnosis and differentiating between categories. 4, 7

• GSDs: Periodic acid-Schiff (PAS)-positive glycogen accumulation, absent or reduced specific enzyme activity 2
• FAODs: Oil Red O staining shows lipid accumulation 2
• Mitochondrial: Ragged red fibers on Gomori trichrome, COX-negative fibers, subsarcolemmal mitochondrial proliferation 4, 7, 2

Genetic Testing

• Targeted gene panels for suspected category based on clinical phenotype 2, 5
• Next-generation sequencing (whole exome or genome) when diagnosis unclear 5
• Mitochondrial DNA sequencing for suspected mitochondrial disorders 2, 3

Critical Management Principles

Acute Crisis Management

• Rhabdomyolysis: Aggressive IV hydration (maintain urine output >200 mL/hour), monitor for renal failure and compartment syndrome 3
• Hypoglycemia (GSDs, FAODs): IV dextrose to maintain glucose >70 mg/dL 4
• Metabolic acidosis: Correct underlying trigger, supportive care 3

Surgical/Anesthesia Precautions

• Avoid succinylcholine in all metabolic myopathies due to rhabdomyolysis risk 4
• Maintain normoglycemia perioperatively with IV dextrose infusion (D10 preferred) 4
• Monitor for respiratory complications given potential diaphragmatic weakness 4
• Assess coagulation in GSD III due to potential cirrhosis 4

Pregnancy Considerations

• Maintain strict euglycemia throughout pregnancy in GSDs to prevent fetal demise 4
• Avoid fasting and ketosis 4
• Monitor hepatic adenomas (may enlarge with hormonal changes) 4
• Plan delivery at tertiary center with metabolic team coordination 4

Common Pitfalls

• Distinguishing metabolic myopathy from deconditioning: Both show reduced VO2 peak, but deconditioning has leftward-shifted heart rate-VO2 relationship with normal lactate response and no muscle pain 4
• Normal CK between episodes: Does not exclude FAOD; must measure during symptomatic period or after controlled exercise challenge 2, 3
• Mitochondrial disorders in adults: Frequency of 1/8000 makes them the most common metabolic myopathy; 19% of adults labeled as chronic intestinal pseudo-obstruction actually have mitochondrial disease 4, 7
• Cardiac involvement: Screen for cardiomyopathy and conduction defects in mitochondrial disorders, GSD II (Pompe), and GSD III 4