Potential Role Of Oxidative Damage In Neurological Manifestations Of Acute Intermittent Porphyria

Accumulation of 5-aminolevulinic acid (ALA) is the main defect in acute porphyria and the most likely potential candidate to cause acute neurological manifestations during an acute porphyric attack via multiple direct and indirect mechanisms. ALA is a potential endogenous source of reactive oxygen species (ROS). After administration of ALA or inducers of ALA-synthase in vitro conditions or in animal models, the main pro-oxidants detected have been superoxide, hydrogen peroxide, hydroxyl radicals, and 4,5-dioxovaleric acid (DOVA), which has produced oxidative damage (OD) to lipids, proteins, and DNA. At the organelle level, ALA-induced OD affects the permeability of the biological membranes, probably as a result of protein polymerization and lipid peroxidation. In vitro exposure to ALA has caused OD to Schwann cells and inhibited myelin formation. Magnetic resonance imaging (MRI) of patients with acute intermittent porphyria (AIP) who suffer from severe reversible posterior encephalopathy syndrome (PRES) during the acute attack shows features of impaired permeability of the blood-brain barrier (BBB); this could be the result of oxidative stress (OS) allowing neurotoxins such as ALA to damage neurons. Peripheral demyelination found in heterozygote or homozygote patients with AIP could be caused by direct OD caused by ALA, which produces pro-oxidants that may affect Schwann cells and myelin. Because ALA is not the most potent pro-oxidant, the OD is only a minor contributor to the neurological manifestations of AIP in general. It could, however, explain the fact that encephalopathy and peripheral demyelination are present only during severe attacks of AIP, in which the high level of serum ALA results in significant auto-oxidation.