Glycogen Storage Myopathies
Glycogen storage diseases (GSDs) affecting skeletal muscle comprise a group of inherited metabolic disorders caused by defects in enzymes involved in glycogenolysis or glycolysis. Muscle relies on glycogen as the primary fuel source for short-term, high-intensity exercise: preexisting ATP is rapidly consumed, creatine phosphate provides a brief buffer, and then glycogenolysis and anaerobic glycolysis generate ATP for the first 1–2 minutes before aerobic pathways dominate. Disruption at any step along this pathway produces characteristic exercise intolerance, myalgia, contractures, and—in severe cases—rhabdomyolysis and myoglobinuria. All glycogen storage myopathies are autosomal recessive except for X-linked phosphorylase b kinase deficiency (GSD IX) and phosphoglycerate kinase 1 deficiency. With the advent of enzyme replacement therapy for Pompe disease and improved genetic diagnostics, early recognition of these disorders has become increasingly important.
Bottom Line
- Pompe disease (GSD II): Acid maltase (GAA) deficiency causes lysosomal glycogen accumulation; infantile-onset presents with cardiomegaly, profound hypotonia, and death by 1–2 years without enzyme replacement therapy; late-onset Pompe disease (LOPD) causes progressive limb-girdle weakness and diaphragmatic dysfunction; dried blood spot GAA activity is the screening test of choice
- McArdle disease (GSD V): Myophosphorylase deficiency is the most common glycogen storage myopathy; exercise intolerance with the characteristic second wind phenomenon, rhabdomyolysis risk, and no lactate rise on forearm exercise test; PYGM gene testing confirms diagnosis; management centers on aerobic conditioning and pre-exercise glucose
- Tarui disease (GSD VII): Phosphofructokinase deficiency causes exercise intolerance with hemolytic anemia; no second wind (out-of-wind phenomenon) and worsening with glucose intake distinguish it from McArdle disease
- Diagnostic approach: Forearm exercise test (no lactate rise with normal ammonia rise indicates glycogenolytic/glycolytic defect), muscle biopsy (PAS-positive vacuoles or subsarcolemmal glycogen), genetic testing panels, and dried blood spot for Pompe disease
- Treatment: Enzyme replacement therapy (alglucosidase alfa, avalglucosidase alfa) for Pompe disease; no specific pharmacotherapy for other glycogenoses—management relies on exercise modification, dietary strategies, and avoidance of triggers
Glycogen Metabolism in Skeletal Muscle
Glycogen is the principal storage form of glucose in skeletal muscle, comprising branched chains of glucose residues linked by α-1,4 and α-1,6 glycosidic bonds. Two sequential pathways convert glycogen to ATP:
- Glycogenolysis: Myophosphorylase cleaves α-1,4 bonds from the outer chains, releasing glucose-1-phosphate. The debranching enzyme (amylo-1,6-glucosidase) removes α-1,6 branch points, releasing free glucose. Phosphorylase b kinase activates myophosphorylase by phosphorylation
- Glycolysis: Glucose-1-phosphate is converted to glucose-6-phosphate by phosphoglucomutase, then proceeds through glycolysis. Phosphofructokinase (PFK) catalyzes the rate-limiting step: fructose-6-phosphate → fructose-1,6-bisphosphate. The pathway continues through aldolase, phosphoglycerate kinase, phosphoglycerate mutase, enolase, and lactate dehydrogenase
- Lysosomal pathway: A separate pathway involves acid α-glucosidase (acid maltase, GAA), which degrades glycogen within lysosomes. Deficiency in this enzyme causes Pompe disease—distinct from the cytoplasmic glycogenolytic defects
Defects in enzymes along either the glycogenolytic or glycolytic pathways prevent normal ATP generation during exercise, leading to exercise intolerance and, in many cases, muscle contractures (electrically silent on EMG, unlike cramps). The type of substrate used for ATP production varies with exercise intensity: fatty acid oxidation dominates at lower intensities (~60–65% maximal oxygen uptake), while glycolysis dominates at higher intensities (~80–100% maximal oxygen uptake).
Pompe Disease (GSD II)
Pathophysiology
Pompe disease results from deficiency of acid α-glucosidase (GAA), a lysosomal enzyme encoded by the GAA gene on chromosome 17q25. Unlike other glycogenoses, glycogen accumulates within lysosomes rather than the cytoplasm. Progressive lysosomal distension disrupts autophagy, causes cellular dysfunction, and leads to muscle fiber destruction. The degree of residual GAA activity determines disease severity: complete absence causes infantile-onset disease, while partial deficiency (1–30% residual activity) produces late-onset forms.
Infantile-Onset Pompe Disease
Infantile-Onset Pompe Disease—Key Features
- Onset: First few months of life; virtually no residual GAA activity
- Cardinal features: Hypertrophic cardiomegaly (present in nearly all patients), profound generalized hypotonia ("floppy infant"), macroglossia, hepatomegaly, feeding difficulties, and failure to thrive
- Natural history: Without treatment, progressive cardiorespiratory failure leads to death by age 1–2 years
- CK: Markedly elevated (often >2000 U/L)
- Diagnosis: Newborn screening programs detect GAA deficiency on dried blood spot; confirmatory genetic testing identifies biallelic GAA pathogenic variants
- Treatment: Early initiation of enzyme replacement therapy (ERT) improves survival and motor outcomes; cardiac hypertrophy regresses with treatment; anti-drug antibodies (cross-reactive immunologic material [CRIM]-negative patients) require immunomodulation
Late-Onset Pompe Disease (LOPD)
Late-onset Pompe disease encompasses juvenile- and adult-onset forms, typically presenting between the first and sixth decades. The clinical phenotype is dominated by progressive skeletal muscle involvement:
- Limb-girdle weakness: Proximal greater than distal, affecting hip and shoulder girdle muscles; hip extensors and adductors are often affected early; mimics limb-girdle muscular dystrophy
- Diaphragmatic weakness: A hallmark feature; patients develop orthopnea, morning headaches, and excessive daytime sleepiness before limb weakness becomes severe; forced vital capacity (FVC) is the key monitoring parameter; supine FVC drops >10% compared with upright values
- Axial weakness: Paraspinal muscle involvement may cause rigid spine or camptocormia; scapular winging can occur
- CK: Mildly to moderately elevated (typically 2–10 × upper limit of normal)
- Tongue enlargement and calf pseudohypertrophy may be present
- EMG: Myopathic motor unit potentials with myotonic discharges, particularly in paraspinal muscles—myotonic discharges in LOPD occur without clinical myotonia
Diagnosing Late-Onset Pompe Disease
- Screening: Dried blood spot (DBS) GAA enzyme activity—a widely accessible, inexpensive screening test; abnormal results require confirmatory testing
- Confirmation: Genetic testing of the GAA gene identifies biallelic pathogenic variants; the c.-32-13T>G splice-site variant is the most common in European LOPD patients
- Muscle biopsy: PAS-positive vacuolar myopathy with acid phosphatase-positive material (lysosomal glycogen); however, biopsy may appear normal in up to 25% of LOPD patients, making it insufficient to exclude the diagnosis
- When to suspect Pompe disease: Any patient with unexplained limb-girdle weakness, diaphragmatic weakness out of proportion to limb weakness, mildly elevated CK, or myotonic discharges on EMG without clinical myotonia
- Urine glucose tetrasaccharide (Glc4): A biomarker of glycogen accumulation; elevated in Pompe disease; useful for monitoring treatment response
Enzyme Replacement Therapy for Pompe Disease
| Feature | Alglucosidase Alfa (Lumizyme/Myozyme) | Avalglucosidase Alfa (Nexviazyme) |
|---|---|---|
| FDA approval | 2006 (infantile-onset); 2010 (late-onset) | 2021 (late-onset, age ≥1 year) |
| Mechanism | Recombinant human GAA; uptake via mannose-6-phosphate (M6P) receptor | Engineered with ~15× higher M6P content → enhanced cellular uptake and lysosomal targeting |
| Dosing | 20 mg/kg IV every 2 weeks | 20 mg/kg IV every 2 weeks |
| Efficacy | Stabilizes or modestly improves respiratory function and ambulation; greatest benefit when started early | COMET trial: superior respiratory improvement (FVC) vs. alglucosidase alfa over 49 weeks; sustained benefits at ~3 years; #1 prescribed LOPD treatment as of 2025 |
| Monitoring | FVC (upright and supine), 6-minute walk test, CK, urine Glc4, anti-drug antibodies; infusion-associated reactions managed with premedication and rate adjustments | |
Emerging therapies: Gene therapy approaches (AAV-mediated GAA gene delivery) and substrate reduction therapy are under investigation. Cipaglucosidase alfa combined with miglustat (a chaperone that stabilizes the enzyme) has shown promise in clinical trials. Over 40 clinical trials for Pompe disease are currently active or recruiting.
McArdle Disease (GSD V)
Pathophysiology and Epidemiology
McArdle disease is caused by deficiency of myophosphorylase, encoded by the PYGM gene on chromosome 11q13. Myophosphorylase catalyzes the first step of glycogenolysis in muscle—cleaving α-1,4 glycosidic bonds to release glucose-1-phosphate. Its absence prevents glycogen breakdown, depriving muscle of its primary anaerobic fuel source. McArdle disease is the most common glycogen storage myopathy, with an estimated prevalence of 1 in 100,000. The most common pathogenic variant in European populations is p.R50X (previously reported as p.R49X).
Clinical Features
- Exercise intolerance: The hallmark symptom; patients experience myalgia, premature fatigue, and muscle stiffness during brief, intense activities (sprinting, climbing stairs, carrying heavy objects); symptoms typically begin in childhood but may not come to medical attention until adolescence or adulthood
- Second wind phenomenon: After ~10 minutes of sustained moderate exercise, patients experience marked improvement in exercise tolerance if they briefly rest and resume activity; this occurs because bloodborne glucose and free fatty acids become available for aerobic metabolism, bypassing the glycogenolytic block
- Muscle contractures: Exercise-induced, electrically silent (no motor unit potential firing on EMG), distinguishing them from ordinary muscle cramps; result from ATP depletion and failure of calcium reuptake into the sarcoplasmic reticulum
- Rhabdomyolysis and myoglobinuria: Occurs in approximately 50% of patients at some point; "cola-colored" urine after intense exercise; CK may exceed 100,000 U/L; acute kidney injury is a serious complication
- Fixed weakness: Approximately one-third of patients develop progressive proximal muscle weakness after age 40–50 years, even without discrete episodes
Diagnosing McArdle Disease
- Forearm exercise test (ischemic or non-ischemic): The patient squeezes a dynamometer for 1 minute (6 cycles of 9 seconds contraction, 1 second rest); serum lactate and ammonia measured at baseline and post-exercise; in McArdle disease, ammonia rises normally but lactate fails to rise—this flat lactate response with appropriate ammonia elevation is diagnostic of a glycogenolytic or glycolytic defect
- Genetic testing: PYGM sequencing is the preferred confirmatory test; over 150 pathogenic variants identified; commonly included in neuromuscular genetic panels
- Muscle biopsy: Subsarcolemmal glycogen accumulation (PAS-positive blebs); absent myophosphorylase staining on histochemistry; now largely replaced by genetic testing
- CK: Typically elevated between episodes (baseline 200–2000 U/L); markedly elevated during rhabdomyolysis
- EMG: Usually normal between episodes; may show myopathic changes in patients with fixed weakness; myotonic discharges are not a feature
Management of McArdle Disease
No specific pharmacotherapy exists for McArdle disease. Management is centered on lifestyle modification and trigger avoidance:
- Aerobic conditioning: Regular, supervised, moderate-intensity aerobic exercise (walking, cycling, swimming at 60–70% maximal heart rate) improves exercise capacity and oxidative metabolism; patients should "warm up" gradually to activate the second wind before increasing intensity
- Pre-exercise oral glucose or sucrose: Ingesting 30–40 g of simple carbohydrates 5–10 minutes before planned activity provides an exogenous glucose substrate, improving exercise tolerance and reducing symptom severity
- Avoid intense anaerobic exercise: Sprinting, heavy lifting, and isometric contractions carry the highest risk of rhabdomyolysis
- Hydration: Adequate fluid intake during and after exercise reduces rhabdomyolysis and renal injury risk
- Vitamin B6: Pyridoxine supplementation has been proposed (pyridoxal phosphate is a cofactor for myophosphorylase), though evidence of clinical benefit is limited
- Dietary strategy: A diet rich in complex carbohydrates, with adequate protein intake; avoid prolonged fasting before exercise
- Emerging therapies: Gene therapy approaches using AAV vectors to deliver PYGM are in preclinical development
Other Glycogen Storage Myopathies
GSD III (Debrancher Enzyme Deficiency, Cori-Forbes Disease)
GSD III is caused by deficiency of the glycogen debranching enzyme (amylo-1,6-glucosidase/4-α-glucanotransferase), encoded by the AGL gene. The most common subtype, GSD IIIa (~85% of cases), affects both liver and skeletal muscle, while GSD IIIb affects liver only:
- Hepatomyopathy: Childhood hepatomegaly, hypoglycemia, and growth retardation; liver disease often improves with age, while myopathy becomes more prominent in adulthood
- Myopathy: Progressive proximal weakness, exercise intolerance, and elevated CK; distal weakness can occur; EMG may show myopathic changes with myotonic discharges
- Cardiomyopathy: Occurs in GSD IIIa; hypertrophic cardiomyopathy may develop; cardiac monitoring is essential
- Peripheral neuropathy: Sensorimotor polyneuropathy has been reported in some patients with AGL variants
- Biopsy: Massive glycogen accumulation in subsarcolemmal and intermyofibrillar locations
- Management: High-protein diet (to provide gluconeogenic substrates), frequent meals, cornstarch supplementation, and cardiac surveillance
GSD VII (Tarui Disease, Phosphofructokinase Deficiency)
Tarui disease is caused by deficiency of muscle phosphofructokinase (PFK-M), encoded by the PFKM gene. PFK catalyzes the rate-limiting step of glycolysis (fructose-6-phosphate → fructose-1,6-bisphosphate):
- Exercise intolerance: Similar to McArdle disease—myalgia, contractures, and rhabdomyolysis with intense exercise
- "Out-of-wind" phenomenon: Unlike McArdle disease, patients do not experience a second wind; symptoms may paradoxically worsen after glucose or carbohydrate ingestion, because glucose raises insulin, which suppresses lipolysis and reduces availability of free fatty acids—the only remaining fuel source for muscle
- Hemolytic anemia: A distinguishing feature; PFK is also expressed in red blood cells; partial erythrocyte PFK deficiency causes chronic compensated hemolysis with reticulocytosis, elevated indirect bilirubin, and hyperuricemia
- Forearm exercise test: Flat lactate response (similar to McArdle disease)
- Biopsy: PAS-positive subsarcolemmal glycogen; polyglucosan bodies may be present
- Management: Avoid high-carbohydrate meals before exercise (unlike McArdle disease); ketogenic or high-fat diet may theoretically improve symptoms by increasing fatty acid availability; avoid intense anaerobic exercise
Other Glycogenoses and Related Disorders
| Disorder | Enzyme / Gene | Key Clinical Features |
|---|---|---|
| GSD IX (Phosphorylase b kinase deficiency) | Phosphorylase kinase / PHKA1 (X-linked muscle), PHKA2, PHKB, PHKG2 | Predominantly hepatic forms; muscle form (IXd) causes exercise intolerance and myopathy; notably, forearm exercise test may be normal (unlike other glycogenolytic defects) |
| GSD X (Phosphoglycerate mutase deficiency) | Phosphoglycerate mutase 2 / PGAM2 | Exercise intolerance, contractures, recurrent rhabdomyolysis; very rare; glycolytic pathway defect distal to PFK |
| GSD XII (Aldolase A deficiency) | Aldolase A / ALDOA | Exercise intolerance, rhabdomyolysis, hemolytic anemia (similar to GSD VII) |
| Phosphoglycerate kinase 1 deficiency | PGK1 / PGK1 (X-linked) | Myopathy with hemolytic anemia; may cause CNS involvement (seizures, intellectual disability); only X-linked glycolytic myopathy |
| Lactate dehydrogenase A deficiency (GSD XI) | LDHA / LDHA | Exercise intolerance, skin lesions; elevated pyruvate with low lactate after exercise |
| Adult polyglucosan body disease (APBD) | Glycogen branching enzyme / GBE1 | Onset after age 40; progressive spastic paraparesis, peripheral neuropathy, neurogenic bladder, sensory loss, and mild cognitive impairment; polyglucosan bodies in nerve and muscle; common GBE1 p.Y329S variant in Ashkenazi Jewish patients; no specific treatment |
Comparison of Major Glycogen Storage Myopathies
| Feature | GSD II (Pompe) | GSD V (McArdle) | GSD VII (Tarui) | GSD III (Cori-Forbes) |
|---|---|---|---|---|
| Enzyme | Acid α-glucosidase (GAA) | Myophosphorylase | Phosphofructokinase | Debranching enzyme |
| Gene | GAA | PYGM | PFKM | AGL |
| Pathway | Lysosomal | Glycogenolysis | Glycolysis | Glycogenolysis |
| Inheritance | AR | AR | AR | AR |
| Presentation | Progressive weakness, respiratory failure, cardiomyopathy (infantile) | Exercise intolerance, rhabdomyolysis | Exercise intolerance, rhabdomyolysis, hemolysis | Hepatomyopathy, progressive weakness |
| CK (baseline) | Mildly elevated | Moderately elevated | Moderately elevated | Moderately elevated |
| Second wind | Absent | Present | Absent (out-of-wind) | Absent |
| Hemolytic anemia | No | No | Yes | No |
| Cardiomyopathy | Yes (infantile) | No | No | Yes (hypertrophic) |
| Forearm exercise test | Normal | No lactate rise | No lactate rise | Blunted lactate rise |
| Specific treatment | ERT (alglucosidase alfa, avalglucosidase alfa) | None (exercise/diet) | None (exercise/diet) | None (diet/cardiac surveillance) |
Diagnostic Approach
Clinical Evaluation
The evaluation of suspected glycogen storage myopathy begins with a careful clinical history focused on the pattern and triggers of symptoms:
- Exercise intolerance pattern: Symptoms triggered by brief intense exercise suggest glycogenolytic/glycolytic defects (McArdle, Tarui); symptoms during prolonged exercise suggest fatty acid oxidation defects (a key differential)
- Second wind phenomenon: Specifically ask whether exercise becomes easier after a brief rest—highly suggestive of McArdle disease
- Dark urine: "Cola-colored" urine after exercise indicates myoglobinuria from rhabdomyolysis
- Glucose effect: Improvement with pre-exercise carbohydrate suggests McArdle disease; worsening suggests Tarui disease
- Family history: Usually negative (autosomal recessive inheritance), but affected siblings may be present
- Physical examination: Typically normal between episodes in glycogenolytic/glycolytic defects; proximal weakness and respiratory insufficiency suggest Pompe disease or late-stage McArdle disease
Laboratory and Diagnostic Testing
| Test | Utility | Key Findings |
|---|---|---|
| Serum CK | Screening; monitoring | Elevated at baseline in most glycogenoses; markedly elevated during rhabdomyolysis (>10,000 U/L) |
| Dried blood spot GAA activity | Pompe disease screening | Reduced acid α-glucosidase activity; false positives possible—requires confirmatory genetic testing |
| Forearm exercise test | Glycogenolytic/glycolytic defect | No lactate rise with normal ammonia rise → glycogen pathway defect; no rise of either → insufficient exercise effort; note: normal result in phosphorylase b kinase deficiency |
| Reticulocyte count, haptoglobin, uric acid | Hemolysis screening | Elevated reticulocytes, low haptoglobin, hyperuricemia suggest GSD VII, PGK1 deficiency, or aldolase A deficiency |
| Genetic testing panel | Definitive diagnosis | Metabolic myopathy / rhabdomyolysis panels include GAA, PYGM, PFKM, AGL, GBE1, PGAM2, and other relevant genes; whole-exome sequencing if panel is negative |
| Muscle biopsy | When genetic testing is inconclusive | PAS-positive vacuoles (Pompe); subsarcolemmal glycogen blebs (McArdle, Tarui); absent myophosphorylase staining (McArdle); polyglucosan bodies (GSD IV/APBD); enzyme histochemistry guides diagnosis |
| EMG | Supportive | Myotonic discharges without clinical myotonia (Pompe); may be normal in McArdle; myopathic MUPs in chronic stages |
Forearm Exercise Test Protocol
- Place an IV catheter and obtain baseline serum lactate and ammonia
- Patient squeezes a hand dynamometer (or tennis ball) at maximal effort for 6 cycles (9 seconds squeeze, 1 second rest) over 60 seconds
- Measure serum lactate and ammonia at 1 minute post-exercise (some protocols include additional time points)
- Normal result: Both lactate and ammonia rise ≥3× above baseline
- Glycogenolytic/glycolytic defect: Ammonia rises but lactate does not
- Myoadenylate deaminase deficiency: Lactate rises but ammonia does not
- Insufficient effort: Neither rises—test must be repeated
- Non-ischemic protocol preferred (no blood pressure cuff); ischemic protocol increases rhabdomyolysis risk and should be avoided in patients with known glycogenoses
- Note: With the availability of genetic testing, forearm exercise testing is performed less frequently but remains useful for clarifying variants of uncertain significance in PYGM
Differential Diagnosis
Glycogen storage myopathies must be distinguished from other causes of exercise intolerance and recurrent rhabdomyolysis:
- Fatty acid oxidation disorders: Carnitine palmitoyltransferase II (CPT II) deficiency is the most common cause of recurrent rhabdomyolysis in adults; symptoms triggered by prolonged exercise, fasting, illness, or cold exposure (rather than brief intense exertion); elevated long-chain acylcarnitines on blood acylcarnitine profile
- Mitochondrial myopathies: Exercise intolerance with lactic acidosis; may have multisystem features (ptosis, ophthalmoplegia, hearing loss, cardiomyopathy); serum GDF-15 and FGF21 are screening biomarkers
- Muscular dystrophies: "Pseudometabolic" presentations with exertional rhabdomyolysis can occur in dystrophinopathies (DMD), dysferlinopathy (DYSF), FKRP-related LGMD, and anoctaminopathy (ANO5); persistently elevated interictal CK and genetic testing distinguish these
- RYR1-related myopathies: May present with exertional rhabdomyolysis and susceptibility to malignant hyperthermia
- Acquired causes: Medications (statins, alcohol), toxins, infections (including COVID-19), extreme exercise, crush injuries, and electrolyte disturbances must be excluded before pursuing genetic workup
When to Pursue Genetic Testing for Rhabdomyolysis (RHABDO Criteria)
- R — Recurrent episodes of exertional rhabdomyolysis
- H — HyperCKemia persists ≥8 weeks after the event
- A — Accustomed (not extreme or unusual) physical exercise triggered the episode
- B — Blood CK >50× the upper limit of normal
- D — Drugs, medications, or other exogenous factors cannot sufficiently explain the severity
- O — Other family members affected or other exertional symptoms (cramps, myalgia)
- Any one of these criteria warrants consideration of genetic testing for an underlying metabolic myopathy or muscular dystrophy
Prognosis and Long-Term Management
The prognosis of glycogen storage myopathies varies substantially by disorder and subtype:
- Pompe disease: Untreated infantile-onset is fatal by age 1–2 years; ERT has dramatically improved survival and motor outcomes, though long-term decline can still occur despite treatment. Late-onset Pompe disease is slowly progressive; ERT stabilizes or improves respiratory and motor function, with avalglucosidase alfa showing superior outcomes compared with first-generation ERT
- McArdle disease: Life expectancy is normal; quality of life depends on education about exercise modification and trigger avoidance; progressive myopathy may develop in the fourth to fifth decade; rhabdomyolysis with acute kidney injury is the most serious acute complication
- Tarui disease: Similar prognosis to McArdle disease, with additional management of hemolytic complications
- GSD III: Liver disease generally improves in adulthood; myopathy and cardiomyopathy require ongoing surveillance; hepatocellular adenoma and carcinoma are rare long-term hepatic complications
- APBD: Progressive neurologic decline; no disease-modifying treatment currently available; supportive management for spasticity, bladder dysfunction, and neuropathic symptoms
For all glycogen storage myopathies, patients should carry a medical alert identification, and anesthetic teams should be informed of the diagnosis prior to any surgical procedure. In McArdle and Tarui diseases, succinylcholine should be avoided due to the risk of severe contractures and hyperkalemia. General anesthesia may provoke rhabdomyolysis in susceptible individuals, and postoperative monitoring of CK and renal function is essential.
References
- Milone M. A pattern recognition approach to myopathy. Continuum (Minneap Minn) 2025;31(5):1244–1269.
- Kushlaf H. Muscle channelopathies and rhabdomyolysis. Continuum (Minneap Minn) 2025;31(5):1409–1436.
- Haller RG, Vissing J. Spontaneous "second wind" and glucose-induced second "second wind" in McArdle disease: oxidative mechanisms. Arch Neurol 2002;59(9):1395–1402.
- Kishnani PS, Corzo D, Nicolino M, et al. Recombinant human acid alpha-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology 2007;68(2):99–109.
- Diaz-Manera J, Kishnani PS, Kushlaf H, et al. Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial. Lancet Neurol 2021;20(12):1012–1026.
- van der Ploeg AT, Clemens PR, Corzo D, et al. A randomized study of alglucosidase alfa in late-onset Pompe's disease. N Engl J Med 2010;362(15):1396–1406.
- Scalco RS, Gardiner AR, Pitceathly RD, et al. Rhabdomyolysis: a genetic perspective. Orphanet J Rare Dis 2015;10:51.
- Nogales-Gadea G, Santalla A, Brull A, et al. The pathogenomics of McArdle disease—genes, enzymes, models, and therapeutic implications. J Inherit Metab Dis 2015;38(2):221–230.
- Toscano A, Musumeci O. Tarui disease and distal glycogenoses: clinical and genetic update. Acta Myol 2007;26(2):105–107.
- Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genet Med 2006;8(5):267–288.
- Vissing J, Haller RG. The effect of oral sucrose on exercise tolerance in patients with McArdle's disease. N Engl J Med 2003;349(26):2503–2509.
- Kruijt N, Laforet P, Vissing J, et al. 276th ENMC International Workshop: recommendations on optimal diagnostic pathway and management strategy for patients with acute rhabdomyolysis worldwide. Neuromuscul Disord 2025;50:105344.
- Stahl K, Rastelli E, Schoser B. A systematic review on the definition of rhabdomyolysis. J Neurol 2020;267(4):877–882.
- Lucia A, Nogales-Gadea G, Perez M, et al. McArdle disease: what do neurologists need to know? Nat Clin Pract Neurol 2008;4(10):568–577.
- Mancuso M, Filosto M, Tsujino S, et al. Muscle glycogenosis and mitochondrial hepatopathy in an infant with mutations in both the myophosphorylase and deoxyguanosine kinase genes. Arch Neurol 2003;60(10):1445–1447.