Manganese Toxicity (Manganism): A Comprehensive Review of Etiology, Toxicokinetics, Clinical Presentation, and Management
Manganese Toxicity (Manganism): A Comprehensive Review of Etiology, Toxicokinetics, Clinical Presentation, and Management
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Original abstract
Manganese (Mn) is an essential trace metal required as a catalytic cofactor for numerous indispensable biochemical processes, including mitochondrial oxidative phosphorylation, glutamine synthetase activity, and superoxide dismutase-mediated antioxidant defense. However, excessive exposure to manganese—whether through occupational inhalation in welding, mining, and smelting, environmental ingestion of contaminated well water, or iatrogenic administration via total parenteral nutrition—produces a distinctive neurotoxic syndrome known as manganism. This condition is characterized by early psychiatric manifestations (emotional lability, hallucinations, personality changes) followed by progressive extrapyramidal motor dysfunction that closely resembles idiopathic Parkinson disease, including bradykinesia, rigidity, postural instability, and gait abnormalities. The pathophysiology of manganism involves preferential accumulation of manganese within the basal ganglia—particularly the globus pallidus—mediated by divalent metal transporter-1 (DMT-1), transferrin-receptor complexes, and store-operated calcium channels. Cellular injury occurs through multiple converging mechanisms: mitochondrial dysfunction with reactive oxygen species generation, glutamate-mediated excitotoxicity secondary to glutamine synthetase inhibition, neuroinflammation with glial activation, and apoptotic cell death. Diagnosis requires high clinical suspicion combined with occupational and environmental exposure history, neurological examination, and supportive findings from T1-weighted magnetic resonance imaging demonstrating bilateral hyperintensity of the globus pallidus. Treatment centers on immediate removal from the exposure source, with chelation therapy using para-aminosalicylic acid (PAS) or EDTA showing variable efficacy, particularly when initiated early. Adjunctive measures include iron supplementation (exploiting competitive transport inhibition), antioxidant therapy (vitamin E, N-acetylcysteine), and symptomatic management, though levodopa demonstrates limited and transient benefit. Prognosis is generally favorable for younger patients following exposure cessation, though residual deficits in fine motor control, behavioral regulation, and cognitive function may persist, particularly in older individuals or those with prolonged exposure histories. Prevention through workplace respiratory protection, water quality monitoring, and prudent use of manganese-containing parenteral nutrition remains the cornerstone of public health strategy.