Kerb's Cycle Associated Disorders

I. INTRODUCTION

• Definition: The Krebs cycle (Tricarboxylic Acid/TCA cycle) is the central metabolic pathway in the mitochondrial matrix responsible for the final oxidation of carbohydrates, lipids, and amino acids.
• Physiologic Functions:
  • Energy Production: Generates high-energy electron carriers (NADH, FADH2) for the electron transport chain (oxidative phosphorylation).
  • Biosynthesis: Provides intermediates for the synthesis of amino acids (e.g., glutamate, aspartate), heme, and neurotransmitters.
• Pathophysiology of Defects:
  • Energy Failure: Impaired ATP production leads to multisystem involvement, primarily affecting high-energy organs (brain, heart, muscle).
  • Lactic Acidosis: Blockage of the cycle prevents the entry of pyruvate (via acetyl-CoA), shunting it toward lactate.
  • Toxic Accumulation: Build-up of specific organic acids (e.g., fumarate, alpha-ketoglutarate).

II. CLASSIFICATION OF DISORDERS

Primary defects involve enzymes within the cycle. Secondary defects involve anaplerotic enzymes required to replenish cycle intermediates.

1. Alpha-Ketoglutarate Dehydrogenase Deficiency

• Enzyme Complex: Similar to Pyruvate Dehydrogenase (PDH) and Branched-Chain Alpha-Ketoacid Dehydrogenase (BCKDH); composed of E1, E2, and E3 subunits.
• E3 Subunit Deficiency (Dihydrolipoamide Dehydrogenase Deficiency):
  • Genetics: Mutations in DLD gene.
  • Mechanism: The E3 subunit is shared among Alpha-KGDH, PDH, and BCKDH. Deficiency affects all three.
  • Biochemical Profile:
    • Elevated Lactate and Pyruvate (PDH defect).
    • Elevated Branched-chain ketoacids (BCKDH defect - MSUD-like).
    • Elevated Alpha-ketoglutarate (Krebs cycle defect).
  • Clinical Features:
    • Onset: Early infancy (2 months+).
    • Progressive neurologic deterioration.
    • Hypotonia, developmental delay, ataxia.
    • Leigh Syndrome: MRI findings of basal ganglia/brainstem necrosis.
  • Prognosis: Poor; early death is common.

2. Succinate Dehydrogenase (SDH) Deficiency

• Unique Role: Functions as both a Krebs cycle enzyme (oxidizing succinate to fumarate) and Complex II of the Electron Transport Chain.
• Genetics: Mutations in SDHA (nuclear gene).
• Clinical Phenotypes:
  • Leigh Syndrome: Severe infantile encephalopathy.
  • Cardiomyopathy: Hypertrophic or dilated cardiomyopathy is a distinct feature (unlike many other TCA defects).
  • Tumor Predisposition: SDH subunit mutations are associated with paragangliomas and pheochromocytomas (though typically adult presentations).

3. Succinyl-CoA Synthetase Deficiency

• Genetics: SUCLG1 or SUCLA2 mutations.
• Mechanism: Associated with Mitochondrial DNA (mtDNA) Depletion Syndrome. The enzyme interacts with nucleoside diphosphate kinase, essential for mtDNA maintenance.
• Clinical Features:
  • Severe encephalomyopathy.
  • Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like features.
  • Methylmalonic Aciduria: Mild elevations may occur due to metabolic proximity to succinyl-CoA.

4. Fumarase (Fumarate Hydratase) Deficiency

• Biochemistry: Block leads to elevated fumarate and succinate.
• Clinical Features:
  • Severe infantile encephalopathy.
  • Brain malformations (polymicrogyria, ventriculomegaly).
  • Distinctive facial dysmorphism.
• Metabolic Markers: Fumaric aciduria.

5. Pyruvate Carboxylase (PC) Deficiency (Anaplerotic Defect)

• Role: Converts pyruvate to oxaloacetate. Essential for replenishing TCA cycle intermediates (anaplerosis) and gluconeogenesis.
• Clinical Types:
  • Type A (North American): Lactic acidosis, developmental delay, survival into childhood.
  • Type B (French/Severe): Neonatal onset.
    • Biochemical Triad: Severe Lactic Acidosis + Hyperammonemia + Hypercitrullinemia.
    • Mechanism of Hyperammonemia: Oxaloacetate depletion $\to$ reduced aspartate $\to$ urea cycle failure.
    • Outcome: Coma, early death (usually <3 months).
  • Type C (Benign): Recurrent mild acidosis, normal development.

III. CLINICAL FEATURES

A. Neurologic (Dominant Presentation)

• Leigh Syndrome (Subacute Necrotizing Encephalomyelopathy): Common radiologic phenotype.
• Global Developmental Delay: Regression of milestones.
• Seizures: Intractable epilepsy.
• Movement Disorders: Dystonia, ataxia, choreoathetosis (basal ganglia involvement).
• Hypotonia: Severe central hypotonia ("floppy infant").

B. Extraneurologic

• Cardiac: Hypertrophic or dilated cardiomyopathy (especially SDH and Fumarase defects).
• Hepatic: Liver failure/dysfunction (PC deficiency).
• Metabolic: Recurrent severe metabolic acidosis (Lactic acidosis), especially during catabolic stress (fever, fasting).

IV. INVESTIGATIONS

A. Initial Screen

• Blood Gas: High anion gap metabolic acidosis.
• Lactate/Pyruvate: Elevated lactate; increased L:P ratio (>20) typically indicates respiratory chain defect, but Krebs defects also cause significant lactic acidosis.
• Ammonia: Elevated in PC deficiency (Type B).
• Glucose: Hypoglycemia (gluconeogenesis impairment in PC deficiency).

B. Metabolic Metabolites (Urine Organic Acids)

• Alpha-Ketoglutarate Deficiency: Elevated alpha-ketoglutarate, lactate, pyruvate, branched-chain hydroxyacids.
• Fumarase Deficiency: Massive excretion of fumaric acid.
• PC Deficiency: Elevated lactate, pyruvate, alanine, ketone bodies.

C. Imaging (MRI Brain)

• Leigh Syndrome: Bilateral symmetric T2 hyperintensities in basal ganglia (putamen, globus pallidus), thalamus, and brainstem.
• Structural Defects: Corpus callosum agenesis or cysts (specific to PDH/PC defects).

D. Confirmation

• Molecular Genetics: Whole Exome Sequencing (WES) or targeted gene panels (DLD, SDHA, FH, PC).
• Enzymatic Assay: Fibroblasts or muscle biopsy (largely replaced by genetics).

V. MANAGEMENT

A. Acute Management

• Correction of Acidosis: Bicarbonate or citrate administration.
• Anabolism: IV Dextrose to reverse catabolism (caution in ketogenic defects, but Krebs defects usually require glucose).
• Ammonia Control: Nitrogen scavengers / dialysis for PC Type B.

B. Long-Term/Chronic Management

• Dietary Modification:
  • High Lipid/Ketogenic Diet: Potentially useful for PDH defects, but controversial in Krebs defects (as the cycle is blocked downstream).
  • High Carbohydrate/Protein: For PC deficiency (prevents gluconeogenic stress).
• Anaplerotic Therapy:
  • Triheptanoin (C7 oil): Provides propionyl-CoA/succinyl-CoA to bypass early cycle blocks and replenish intermediates.
  • Aspartate/Citrate: Supplementation in PC deficiency to replenish oxaloacetate pool.
• Cofactor Supplementation ("Mitochondrial Cocktail"):
  • Thiamine (B1): For Alpha-KGDH (E1 subunit).
  • Lipoic Acid: For E3 subunit defects.
  • Biotin: For Pyruvate Carboxylase deficiency.

VI. PROGNOSIS

• Generally poor for severe infantile forms (Type B PC deficiency, severe Leigh syndrome).
• High mortality in infancy/early childhood due to respiratory failure or intractable acidosis.
• Milder forms (e.g., PC Type A) may survive with significant neurodevelopmental disability.