Developmental language disorder (DLD) is the most frequently occurring developmental disorder, affecting approximately 7% of the US population. Despite decades of research, the exact pathophysiology is unknown. Brain research with this population has shown altered anatomy including microgyria, dysplasia, ectopic vascularized neurons and glial scarring which appear to be due to some form of vascular anomaly. If vascular events are responsible for the brain lesions described, then it is possible that defective clearance of hemoglobin (Hb), a rich source of iron, might underlie the brain pathology and behavioral deficits of DLD. Haptoglobin (Hp) is a plasma protein which binds free Hb and speeds its removal through the reticuloendothelial system. Thus, we propose the defective removal of free Hb from the CNS, coupled with ensuing Hb-mediated CNS damage, may provide a molecular etiology for at least some cases of DLD. Our preliminary results show that the average plasma Hp levels were much lower in individuals with DLD compared to controls. In addition, 8-isoprostane, a plasma marker of in vivo oxidative stress was much higher in patients with DLD vs. normal controls. We plan to study the association between quantitative or qualitative deficiencies of plasma Hp, extent of oxidative stress and the occurrence of DLD. Specifically, we intend to determine plasma Hp levels and phenotypes, plasma 8-isoprostane in DLD and normal controls. We also propose to examine subjects? Hp phenotypes (Hp 1-1, 2-1, and 2-2) to determine whether a biologically less efficient phenotype (i.e. Hp 2-2) may exacerbate the effect of low Hp levels in DLD. A byproduct of Hp defects is the deposition of iron in tissue including the brain. We will look for evidence of iron deposits in brain tissue using magnetic resonance imaging. Finally, we will examine the outcome of these studies in relation to behavioral test results obtained on subjects to determine if either overall severity or specific domains of behavioral deficit are related to Hp status. Although it is unlikely that one biological factor will account for all cases of DLD, identification of such a factor in even a subgroup could lead to effective biological approaches.
