Haptoglobin Phenotypes in Epilepsy (Technical Briefs‪)‬

Seizures occur in ~5% of people, and recur in 20% of that 5% (1, 2). The etiologies of most seizures are unknown, and head trauma is implicated in only 5-10% of cases (3). Blood or blood components, specifically iron, may be etiologically important; intracranial injection of hemoglobin (4), lysed erythrocytes (5), iron-containing proteins (5), or iron salts (6) produced chronic focal spike activity in rodents and cats. Because microhemorrhagic events occur in the central nervous system of all people, inadequate clearance of iron-rich (7) hemoglobin might underlie development of some seizure disorders. Haptoglobin binds free hemoglobin and removes it from the circulation (8), thus preventing iron loss and kidney damage during hemolysis (9). Haptoglobin contains [beta]-(heavy; 40 kDa) and [alpha]-(light; [[alpha].sub.1] = 8.9 kDa and [[alpha].sub.2] = 16 kDa) chains. Humans are polymorphic for haptoglobin, with three major phenotypes: Hp 1-1, Hp 2-2, and the heterozygous Hp 2-1 (10). The [beta]-chains are identical in all, with variations dependent on different [alpha]-chains. Hp 1-1 expresses only the [alpha]1-chain and is the smallest form (86 kDa). Hp 2-1 and Hp 2-2 express [[alpha].sub.2]-chains, which can form polymers of 86-300 kDa (Hp 2-1) and up to 900 kDa (Hp 2-2) (10). Hp 1-1 is biologically the most effective in binding free hemoglobin and suppressing inflammatory responses associated with extracellular (free) hemoglobin (9). In contrast, Hp 2-2 is the least effective (11). The plasma concentrations of haptoglobin are highest in individuals with Hp 1-1 and lowest in those with Hp 2-2, with intermediate concentrations in Hp 2-1 individuals (9).