Glycolysis associated disorders

I. INTRODUCTION

• Definition: Glycolysis (Embden-Meyerhof pathway) is the sequence of enzymatic reactions in the cytosol that converts glucose into pyruvate, generating free energy (ATP) and NADH.
• Physiologic Importance:
  • Erythrocytes: Relies exclusively on glycolysis for energy (ATP) to maintain membrane ion pumps and shape. Failure leads to hemolysis.
  • Skeletal Muscle: Major source of ATP during intense anaerobic exercise. Failure leads to myopathy, cramps, and rhabdomyolysis.
  • Brain: Highly dependent on glucose metabolism; defects can cause severe encephalopathy.
• Biochemical Fate: Under aerobic conditions, pyruvate enters the Krebs cycle. Under anaerobic conditions (or defects in downstream respiration), pyruvate is converted to lactate by Lactate Dehydrogenase (LDH).

II. CLASSIFICATION OF DISORDERS

Glycolytic defects are rare autosomal recessive disorders (except Phosphoglycerate Kinase deficiency, which is X-linked). They typically present with Hemolytic Anemia or Myopathy.

A. Defects causing Predominantly Hemolytic Anemia

1. Pyruvate Kinase (PK) Deficiency (Most common).
2. Hexokinase Deficiency.
3. Glucose Phosphate Isomerase (GPI) Deficiency.
4. Triosephosphate Isomerase (TPI) Deficiency (also neurologic).

B. Defects causing Predominantly Myopathy (Muscle Glycogenoses)

These are often classified as Glycogen Storage Diseases (GSDs) because they block glycogen utilization.

1. Phosphofructokinase Deficiency (GSD Type VII / Tarui Disease).
2. Phosphoglycerate Mutase Deficiency (GSD Type X).
3. Lactate Dehydrogenase Deficiency (GSD Type XI).
4. Phosphoglycerate Kinase Deficiency (GSD IX variant - also causes hemolysis).
5. Aldolase A Deficiency (GSD Type XII).

III. SPECIFIC CLINICAL SYNDROMES

1. Phosphofructokinase Deficiency (GSD Type VII / Tarui Disease)

• Enzyme: Muscle Phosphofructokinase (PFK-M). This is the rate-limiting step of glycolysis.
• Epidemiology: Prevalent in Japanese and Ashkenazi Jewish populations.
• Clinical Features:
  • Exercise Intolerance: Early onset fatigue, severe muscle cramps, and myoglobinuria after vigorous exercise.
  • "Out-of-Wind" Phenomenon: Symptoms worsen with activity. Unlike McArdle disease (GSD V), there is no "Second Wind" phenomenon because the metabolic block prevents the utilization of glucose derived from glycogen or blood; fatty acids cannot compensate adequately during high-intensity anaerobic demand.
  • Hemolysis: Compensated hemolytic anemia (mild) due to partial PFK deficiency in RBCs.
  • Hyperuricemia: Common, exacerbated by exercise (myogenic).
• Dietary Effect: Symptoms may worsen after a high-carbohydrate meal (glucose inhibits lipolysis, further reducing available fuel).

2. Phosphoglycerate Kinase (PGK) Deficiency

• Genetics: X-linked Recessive.
• Clinical Features: A multisystem disorder involving three key tissues:
  • Muscle: Exercise intolerance, cramps, myoglobinuria.
  • Blood: Chronic nonspherocytic hemolytic anemia.
  • CNS: Seizures, intellectual disability, stroke.
• Variants: Presentation varies from pure myopathy to pure anemia or combined forms.

3. Phosphoglycerate Mutase Deficiency (GSD Type X)

• Enzyme: M-subunit (Muscle-specific) of Phosphoglycerate Mutase (PGAM-M).
• Epidemiology: Rare; majority of reported patients are Black.
• Clinical Features:
  • Pure myopathy phenotype similar to GSD V (McArdle).
  • Exercise intolerance, cramps, myalgia.
  • Recurrent myoglobinuria.
  • No hepatomegaly or cardiac involvement.

4. Lactate Dehydrogenase (LDH) Deficiency (GSD Type XI)

• Enzyme: M-subunit of Lactate Dehydrogenase (LDH-A).
• Clinical Features:
  • Exercise intolerance, muscle cramps, myoglobinuria.
  • Dermatologic: Characteristic erythematous skin rash (seen in some families).
  • Biochemical Paradox: During ischemic exercise, venous pyruvate increases significantly, but lactate does not rise (conversion blocked).

5. Pyruvate Kinase (PK) Deficiency

• Pathophysiology: Defect in the final step of glycolysis (PEP $\to$ Pyruvate), generating ATP. ATP depletion leads to RBC membrane rigidity and splenic destruction.
• Clinical Features:
  • Chronic Nonspherocytic Hemolytic Anemia (CNSHA).
  • Neonatal jaundice (risk of kernicterus).
  • Splenomegaly, gallstones (pigment stones).
  • Note: 2,3-BPG levels are elevated (proximal to block), causing a right-shift in the O2-dissociation curve (improved O2 delivery), making anemia better tolerated.

6. Triosephosphate Isomerase (TPI) Deficiency

• Severity: Most severe glycolytic defect; often lethal in early childhood.
• Clinical Features:
  • Severe hemolytic anemia.
  • Progressive Neuromuscular Dysfunction: Dystonia, tremor, spasticity, spinal motor neuron degeneration.
  • Cardiomyopathy.
  • Susceptibility to infections.

IV. DIAGNOSTIC INVESTIGATIONS

A. Screening Tests

1. Complete Blood Count (CBC): Anemia, reticulocytosis (if hemolysis is present).
2. Creatine Kinase (CK): Elevated at rest or massively elevated after exercise (in myopathic forms).
3. Urinalysis: Myoglobinuria (cola-colored urine) after exercise.

B. Functional Testing: Ischemic Forearm Exercise Test

Used to differentiate glycolytic defects from other myopathies.

• Procedure: Blood drawn for lactate and ammonia before and after ischemic exercise.
• Normal: Rise in both Lactate and Ammonia.
• Glycolytic Defects (GSD V, VII, X, XI): Flat Lactate curve (no rise) with a normal rise in Ammonia.
  • Note: In LDH deficiency (GSD XI), Pyruvate rises but Lactate does not.

C. Confirmatory Testing

1. Enzyme Assay: Spectrophotometric measurement in RBCs, leukocytes, or muscle biopsy tissue.
2. Molecular Genetics: Gene sequencing (Single gene or NGS Panels) is the gold standard.

V. MANAGEMENT

1. General Measures:
   • Avoidance of precipitating factors (strenuous anaerobic exercise).
   • Hydration during episodes of myoglobinuria to prevent renal failure.
2. Hemolytic Anemia:
   • Folic acid supplementation.
   • Blood transfusions as needed.
   • Splenectomy (beneficial in PK deficiency and GPI deficiency; less effective in others).
3. Myopathic Forms:
   • Dietary Modification: High protein diet may provide alternative substrates.
   • Glucose Supplementation: Oral sucrose/glucose before exercise improves tolerance in McArdle (GSD V) but is contraindicated/ineffective in Tarui (GSD VII) due to inhibition of alternative fuel sources.
4. Genetic Counseling: For autosomal recessive/X-linked recurrence risks.