A 38-year-old woman from rural Maharashtra presents with progressive fatigue, muscle weakness, and recurrent episodes of myoglobinuria following strenuous exercise. Laboratory investigations reveal elevated serum lactate (8 mmol/L, normal 0.5–2.2), normal blood glucose, and normal ammonia levels. Muscle biopsy shows ragged-red fibres. Genetic testing confirms a homozygous mutation in the succinate dehydrogenase (SDH) gene. Which of the following best explains the accumulation of lactate in this patient?

Explanation

## Pathophysiology of SDH Deficiency **Key Point:** Succinate dehydrogenase (Complex II) catalyzes the oxidation of succinate to fumarate in the TCA cycle and is the only membrane-bound enzyme of the cycle, also participating in the electron transport chain. ### Mechanism of Lactate Accumulation When SDH is deficient: 1. **Blocked TCA cycle progression** — succinate cannot be oxidized to fumarate, causing a metabolic bottleneck. 2. **Impaired NAD+ regeneration** — the downstream steps of the TCA cycle (fumarate → malate → oxaloacetate) are necessary to regenerate NAD+ from NADH. 3. **Pyruvate shunting to lactate** — without sufficient NAD+, pyruvate cannot be efficiently oxidized via pyruvate dehydrogenase. Instead, pyruvate is reduced to lactate by lactate dehydrogenase (LDH) to regenerate NAD+ for glycolysis to continue. 4. **Lactate accumulation** — the result is lactic acidosis and elevated serum lactate. ### Why This Is a Mitochondrial Disorder Ragged-red fibres indicate mitochondrial dysfunction. SDH deficiency impairs both TCA cycle function and oxidative phosphorylation, leading to energy depletion in high-demand tissues (muscle, brain). **Clinical Pearl:** Lactate accumulation with normal ammonia and normal blood glucose rules out urea cycle defects and glycogen storage diseases, respectively. The ragged-red fibres and exercise-induced myoglobinuria are hallmarks of mitochondrial cytopathy. **High-Yield:** SDH deficiency causes a unique pattern: **lactic acidosis + normal glucose + normal ammonia + ragged-red fibres**. This triad points to impaired NAD+ regeneration in the TCA cycle. ```mermaid flowchart TD A[Glucose]:::action --> B[Pyruvate] B --> C{NAD+ available?}:::decision C -->|Yes| D[Pyruvate → Acetyl-CoA]:::action C -->|No| E[Pyruvate → Lactate]:::action D --> F[Acetyl-CoA → Citrate]:::action F --> G[Citrate → Isocitrate → α-KG → Succinyl-CoA]:::action G --> H[Succinate]:::outcome H --> I[SDH: Succinate → Fumarate]:::action I -->|Blocked| J[NAD+ not regenerated]:::urgent I -->|Normal| K[Fumarate → Malate → OAA]:::action K --> L[NAD+ regenerated]:::outcome J --> E L --> C ``` **Mnemonic:** **SLANG** — **S**uccinate dehydrogenase deficiency → **L**actate accumulation → **A**bnormal **N**AD+ regeneration → **G**lyceraldehyde-3-phosphate dehydrogenase cannot proceed efficiently.