Tarui Disease (GSD VII)

Tarui disease (GSD VII) is a rare autosomal recessive metabolic myopathy caused by mutations in the PFKM gene (chromosome 1), resulting in deficiency of the muscle isoform of phosphofructokinase (PFK) — the rate-limiting enzyme of glycolysis that catalyzes conversion of fructose-6-phosphate to fructose-1,6-bisphosphate.[1-2] Incidence is estimated at <1 per 1,000,000 live births, with higher prevalence in Japanese and Ashkenazi Jewish populations.[3-4] Four clinical subtypes exist: classical (most common), severe infantile, late-onset, and hemolytic.[5-6]

1. History

• Exercise intolerance is the hallmark — onset typically in childhood or second/third decade[1][7]
• Myalgia, muscle cramps, and stiffness provoked by short-duration, high-intensity, or isometric exercise[1][8]
• "Out-of-wind" phenomenon: worsening of exercise intolerance after carbohydrate-rich meals or glucose ingestion — a distinguishing feature from McArdle disease[1][9]
• Absence of "second wind" phenomenon (unlike McArdle disease, where symptoms improve after brief rest)[1]
• Nausea and vomiting commonly accompany exercise-induced crises[3-4]
• Dark or cola-colored urine after exertion (myoglobinuria)[5][8]
• Better exercise tolerance in the fasting state or with increased circulating free fatty acids[7][9]
• Ask about symptom onset age, frequency of episodes, relationship to meals, and family history of consanguinity

2. Alarm Features

• Myoglobinuria → risk of acute kidney injury/renal failure[5][10]
• Severe rhabdomyolysis with markedly elevated CK, hyperkalemia, compartment syndrome
• Severe infantile form: hypotonia at birth, cardiomyopathy, respiratory failure — typically fatal within the first year[5]
• Progressive fixed weakness in late-onset form, especially after age 50[3][7]
• Jaundice or signs of hemolytic crisis[5]
• Seizures reported in association with acute rhabdomyolysis episodes[10]

3. Medications

• No specific pharmacologic therapy exists for GSD VII[4][11]
• Avoid pre-exercise glucose/carbohydrate supplementation — worsens symptoms via the "out-of-wind" mechanism (glucose inhibits lipolysis, depriving muscle of alternative fatty acid fuel)[1][12-13]
• Avoid myotoxic drugs: cyclosporine and amiodarone have been reported to worsen myopathy significantly in GSD VII[14]
• Statins and other potentially myotoxic medications should be used with extreme caution
• Allopurinol may be considered for management of hyperuricemia/gout
• Creatine monohydrate has shown mild benefit in McArdle disease but is not established for GSD VII[12]

4. Diet

• Avoid high-carbohydrate meals before exercise — this is the single most important dietary intervention[7][9][13]
• Ketogenic diet (KD) implemented as a modified Atkins diet has shown long-term benefit in a 5-year case study: improved exercise tolerance, normalized ammonia levels, improved oxygen uptake and ventilatory parameters[11]
• High-fat diet provides alternative fuel (free fatty acids and ketones) that bypasses the glycolytic block[7][11]
• Adequate hydration is critical during and after exercise to reduce rhabdomyolysis and myoglobinuria risk
• Fasting state may paradoxically improve exercise performance by promoting lipolysis[7][9]
• KD should be implemented only under medical and nutritional supervision[11]
• The following figure from Haller & Lewis (NEJM, 1991) demonstrates the profound impact of substrate availability on exercise capacity — glucose infusion markedly impairs maximal work intensity and oxygen uptake compared to fasting or lipid infusion conditions:
• View full figure Figure 2. Maximal Work Intensity, Cardiac Output, and Respiratory Function during Maximal Cycle Exercise under the Three Sets of Study Conditions. The four patients are represented by the same symbols used in [[f001 [Figure 1]]]. Glucose-Induced Exertional Fatigue in Muscle Phosphofructokinase Deficiency. N Engl J Med. February 6, 1991.

5. Review of Systems

• Musculoskeletal: exercise intolerance, myalgia, cramps, muscle stiffness, fixed weakness (late-onset)
• Hematologic: jaundice, pallor (compensated hemolytic anemia)
• Renal: dark urine (myoglobinuria), decreased urine output
• GI: nausea, vomiting during exercise-induced crises
• Cardiac: palpitations, dyspnea (rare hypertrophic cardiomyopathy)[8]
• Rheumatologic: gout symptoms (hyperuricemia)

6. Collateral History and Family History

• Autosomal recessive inheritance — both parents are carriers[2][5]
• Inquire about consanguinity, which increases risk
• Family members with exercise intolerance, unexplained anemia, or gout
• Ethnic background: higher prevalence in Ashkenazi Jewish and Japanese populations[3-4]
• Siblings should be screened if index case is identified
• Assess for co-existing myoadenylate deaminase (AMPD) deficiency, which can exacerbate the phenotype[3]

7. Risk Factors

• Ashkenazi Jewish or Japanese ancestry[3-4]
• Parental consanguinity
• Family history of metabolic myopathy or unexplained hemolytic anemia
• High-carbohydrate diet worsens clinical manifestations
• High-intensity or isometric exercise triggers acute episodes[1][7]

8. Differential Diagnosis

• McArdle disease (GSD V) — most important mimic; distinguished by presence of second-wind phenomenon, absence of hemolytic anemia, and improvement with pre-exercise carbohydrate[1][3]
• Phosphoglycerate kinase (PGK) deficiency — the only other glycogenosis with combined myopathy and hemolytic anemia[3]
• Other glycolytic/glycogenolytic defects: GSD IX (phosphorylase kinase), GSD X (phosphoglycerate mutase), GSD XI (LDH-A)[13]
• Fatty acid oxidation disorders: CPT II deficiency, VLCAD deficiency — distinguished by symptoms during prolonged exercise/fasting rather than short intense exercise[15]
• Late-onset Pompe disease (GSD II) — progressive proximal weakness with respiratory insufficiency[15]
• Inflammatory myopathies (polymyositis, dermatomyositis) — if fixed weakness predominates
• Mitochondrial myopathies — elevated lactate at rest, multisystem involvement

9. Past Medical History

• Prior episodes of rhabdomyolysis or myoglobinuria
• History of unexplained anemia or jaundice
• Gout or hyperuricemia
• Renal impairment from recurrent myoglobinuria
• Cardiac history (rare hypertrophic cardiomyopathy)[8]
• Liver disease (relevant if considering myotoxic drugs)[14]
• Surgical history (anesthesia risk with metabolic myopathies)

10. Physical Exam

• Often normal between episodes, especially in patients <50 years[7]
• Vital signs: generally normal; tachycardia during acute rhabdomyolysis
• Muscle exam: usually no fixed weakness in classical form; proximal weakness may develop in late-onset form[5]
• Jaundice/scleral icterus: from compensated hemolysis[5][9]
• Muscle tenderness during or after acute episodes
• No muscle hypertrophy (unlike some cases of McArdle disease)
• Cardiac exam: rarely, signs of hypertrophic cardiomyopathy[8]
• Urine inspection: dark/cola-colored during myoglobinuria episodes

11. Lab Studies

• Creatine kinase (CK): elevated at baseline in most patients; markedly elevated during rhabdomyolysis[2][7]
• Reticulocyte count: elevated (compensated hemolysis)[3][7]
• Indirect bilirubin: elevated[3][9]
• Uric acid: elevated (hyperuricemia from myogenic purine degradation)[3][8]
• Urinalysis: myoglobinuria during acute episodes
• CBC: anemia may be absent due to compensation; look for reticulocytosis[7]
• BMP/renal function: monitor for AKI during rhabdomyolysis
• Haptoglobin: decreased (hemolysis marker)
• LDH: elevated
• Lactate and ammonia (during exercise testing): absent/blunted lactate rise with exaggerated ammonia response[1][13]

12. Imaging

• Muscle MRI: may show fatty replacement of muscle in advanced/late-onset cases; pattern includes anterior and posterior thigh involvement with selective sparing of medial compartment[14]
• Imaging is generally not required for diagnosis in classical presentation
• Echocardiography: indicated to screen for hypertrophic cardiomyopathy, particularly in infantile form or patients with cardiac symptoms[8]
• Renal ultrasound if concern for myoglobinuria-related kidney injury

13. Special Tests

• Nonischemic forearm exercise test (NIFT): absent or blunted lactate rise with normal/exaggerated ammonia elevation — highly suggestive of glycolytic/glycogenolytic defect[1][13][16]
• Cycle ergometry with lactate/ammonia monitoring: a unique late lactate rise (10–30 min post-exercise) may help distinguish GSD VII from McArdle disease[17]

Muscle biopsy

• PAS-positive vacuoles (glycogen accumulation)[3][7]
• Polyglucosan (amylopectin-like material) alongside normal glycogen — a feature relatively unique to GSD VII[3]
• Negative PFK histochemical stain (though false negatives can occur)[3][6]
• Specimen must be flash-frozen immediately — PFK is notoriously labile[3]
• Genetic testing (PFKM gene): definitive diagnosis; whole exome sequencing (WES) or targeted gene panels[2][7]
• 31P-MRS: increased phosphocreatine/ATP ratio at rest, ATP depletion during exercise, absence of intracellular acidification[4]

14. ECG

• Generally normal in classical form
• Indicated if cardiac symptoms or suspicion of cardiomyopathy
• One case reported paroxysmal atrial fibrillation associated with hypertrophic cardiomyopathy[8]
• ECG screening reasonable in all confirmed cases given rare cardiac involvement

15. Assessment

Tarui disease is a rare but clinically significant metabolic myopathy with a complete glycolytic block at the PFK step.[13] The classical form is the most common and generally compatible with a normal lifespan if complications (rhabdomyolysis, renal failure) are avoided.[5][7] Key distinguishing features from McArdle disease include compensated hemolytic anemia, absence of second wind, and the pathognomonic "out-of-wind" phenomenon with carbohydrate ingestion.[1][3] The severe infantile form carries a poor prognosis with death typically in the first year.[5] Late-onset forms may be misdiagnosed as inflammatory myopathy or other neuromuscular conditions for years.[14]

Complications to consider

• Acute kidney injury from myoglobinuria
• Gout from chronic hyperuricemia
• Progressive myopathy (late-onset)
• Rare hypertrophic cardiomyopathy
• Drug-induced worsening (cyclosporine, amiodarone)[14]

16. Treatment Plan

• No specific pharmacologic cure exists[4][11]

Lifestyle modification is the cornerstone

• Avoid high-intensity isometric exercise; engage in gradual, progressive aerobic exercise[4][13]
• Pause and rest at onset of symptoms — pain and fatigue may improve once fatty acid oxidation increases[4]

Dietary management

• Avoid pre-exercise carbohydrates[12-13]
• Consider ketogenic or modified Atkins diet under medical supervision[11]
• High-fat, low-carbohydrate diet to promote fatty acid utilization

Acute rhabdomyolysis management

• Aggressive IV fluid resuscitation
• Monitor and correct electrolytes (potassium, calcium, phosphorus)
• Monitor renal function and urine output
• Alkalinization of urine if severe myoglobinuria
• Hyperuricemia: allopurinol if symptomatic gout or significantly elevated uric acid
• Genetic counseling for patient and family[2][5]
• Avoid myotoxic medications (cyclosporine, amiodarone, statins with caution)[14]

17. Disposition

Admit if

• Significant rhabdomyolysis (CK >5× ULN with myoglobinuria)
• Acute kidney injury or oliguria
• Severe electrolyte derangements (hyperkalemia)
• Hemolytic crisis
• Severe infantile form with respiratory distress or cardiomyopathy

Discharge if

• Mild exercise-induced symptoms with normal renal function
• CK trending down, adequate oral hydration
• No myoglobinuria
• Specialist consultation: neurology (neuromuscular), genetics/metabolic medicine, nephrology (if AKI), cardiology (if cardiomyopathy suspected), dietitian (for KD implementation)

18. Follow Up / Return Precautions

• Follow-up with neuromuscular specialist and metabolic medicine within 2–4 weeks of diagnosis or acute episode
• Periodic monitoring: CK, renal function, uric acid, CBC with reticulocyte count, bilirubin
• Echocardiography at baseline and periodically to screen for cardiomyopathy[8]
• Return immediately for: dark/cola-colored urine, decreased urine output, severe muscle pain unresponsive to rest, chest pain, palpitations, or progressive weakness

Patient counseling

• Avoid strenuous/isometric exercise; titrate activity to tolerance
• Do not eat high-carbohydrate meals before physical activity
• Carry a medical alert identification and emergency letter explaining the condition[18]
• Hydrate well before, during, and after exercise
• Expected course: classical form is generally stable with appropriate lifestyle modification; late-onset form may develop progressive weakness after age 50[5][7]
• Genetic counseling: 25% recurrence risk for siblings; carrier testing available for family members[5]

References

1. Hereditary myopathies associated with hematological abnormalities. — Beecher G, Fleming MD, Liewluck T. Muscle & Nerve. 2022.

2. Case Report: Comprehensive Exploration of a Novel PFKM Mutation in Glycogen Storage Disease Type VII. — Chen Y, Wang X, Ji N, et al. Frontiers in Genetics. 2024.

3. Muscle glycogenoses. — DiMauro S, Lamperti C. Muscle & Nerve. 2001.

4. Inborn Errors of Energy Metabolism Associated with Myopathies. — Das AM, Steuerwald U, Illsinger S. Journal of Biomedicine & Biotechnology. 2009.

5. Glycogen storage disease type VII. — National Library of Medicine (MedlinePlus) 2014.

6. PFKM Gene Defect and Glycogen Storage Disease GSDVII With Misleading Enzyme Histochemistry. — Auranen M, Palmio J, Ylikallio E, et al. Neurology. Genetics. 2015.

7. Diagnostic evaluation of rhabdomyolysis. — Nance JR, Mammen AL. Muscle & Nerve. 2015.

8. Clinical Features and New Molecular Findings in Muscle Phosphofructokinase Deficiency (GSD Type VII). — Musumeci O, Bruno C, Mongini T, et al. Neuromuscular Disorders : NMD. 2012.

9. Glucose-Induced Exertional Fatigue in Muscle Phosphofructokinase Deficiency. — Haller RG, Lewis SF. The New England Journal of Medicine. 1991.

10. Muscle Phosphofructokinase Deficiency (Tarui's Disease): Report of a Case. — Lin HC, Young C, Wang PJ, Shen YZ. Journal of the Formosan Medical Association = Taiwan Yi Zhi. 1999.

11. Beneficial Effects of Ketogenic Diet on Phosphofructokinase Deficiency (Glycogen Storage Disease Type VII). — Similä ME, Auranen M, Piirilä PL. Frontiers in Neurology. 2020.

12. Myopathies Related to Glycogen Metabolism Disorders. — Tarnopolsky MA. Neurotherapeutics : The Journal of the American Society for Experimental NeuroTherapeutics. 2018.

13. Diagnosis and management of metabolic myopathies. — Bhai SF, Vissing J. Muscle & Nerve. 2023.

14. Late and Severe Myopathy in a Patient With Glycogenosis VII Worsened by Cyclosporine and Amiodarone. — Filosto M, Cotti Piccinelli S, Pichiecchio A, et al. Frontiers in Neurology. 2018.

15. Pearls & Oy-Sters: A Curable Myopathy Manifesting as Exercise Intolerance and Respiratory Failure. — Silva AMS, Mendonça RH, Soares DC, et al. Neurology. 2018.

16. Laboratory diagnosis of metabolic myopathies. — Vladutiu GD. Muscle & Nerve. 2002.

17. Unique Exercise Lactate Profile in Muscle Phosphofructokinase Deficiency (Tarui Disease); Difference Compared With McArdle Disease. — Piirilä P, Similä ME, Palmio J, et al. Frontiers in Neurology. 2016.

18. Glycogen Storage Diseases. — Hannah WB, Derks TGJ, Drumm ML, et al. Nature Reviews. Disease Primers. 2023.