Our recent discovery of autoantibodies (AuAbs) against folate receptors (FRs) in women with a pregnancy complicated by neural tube defects (NTDs) provides a mechanism by which folate uptake into the developing embryo via the FR could be compromised and explains why periconceptional supplementation with folic acid reduces the occurrence of NTDs. We have shown an association of these AuAbs with a cerebral folate deficiency syndrome (CFD) that develops 4 to 6 months after birth that is characterized by a low folate concentration in the cerebrospinal fluid. Clinical response to pharmacologic folate supplementation strongly suggests that folate deficiency in the brain due to AuAbs blocking folate uptake as the likely cause of this syndrome. Very little is known about the properties of these AuAbs and how best to prevent the onset or manage the progression of these disorders. Therefore, the objectives of this pilot proposal are to characterize the properties of these AuAbs, study their effects on cellular folate metabolism and to determine the optimal folate supplementation strategy that would effectively correct the metabolic deficiency. Towards achieving these objectives, the following specific aims are proposed:
Specific Aim 1 : To determine the properties of the autoantibodies to the folate receptors associated with the occurrence of NTDs and infantile onset CFD syndrome. The objectives of these studies will be to characterize the structural properties of the AuAbs by determining the binding affinity, specificity and the structural domains of FR involved in AuAb binding.
Specific Aim 2 : To determine the metabolic and cellular effects of the autoantibodies against folate receptors. The objectives of these studies will be to determine what effects these AuAbs have on cell replication, FR expression and turnover, intracellular folate status and metabolism and what metabolic, structural and functional abnormalities result from exposure to the AuAbs. Hematopoietic and neuronal cells in culture will provide in-vitro models to directly study the effects of these AuAbs at the cellular level These in-vrtro studies would also provide the models to evaluate the effects of the AuAbs at the cellular level and to determine what form and concentration of folate is most efficient in correcting the metabolic consequences. ? ?
| Shapira, Iuliana; Sequeira, Jeffrey M; Quadros, Edward V (2015) Folate receptor autoantibodies in pregnancy related complications. Birth Defects Res A Clin Mol Teratol 103:1028-30 |
| Hasselmann, Oswald; Blau, Nenad; Ramaekers, Vincent T et al. (2010) Cerebral folate deficiency and CNS inflammatory markers in Alpers disease. Mol Genet Metab 99:58-61 |
| Berrocal-Zaragoza, Maria Isabel; Fernandez-Ballart, Joan D; Murphy, Michelle M et al. (2009) Association between blocking folate receptor autoantibodies and subfertility. Fertil Steril 91:1518-21 |
| Molloy, Anne M; Quadros, Edward V; Sequeira, Jeffrey M et al. (2009) Lack of association between folate-receptor autoantibodies and neural-tube defects. N Engl J Med 361:152-60 |
| Ramaekers, Vincent T; Sequeira, Jeffrey M; Blau, Nenad et al. (2008) A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Dev Med Child Neurol 50:346-52 |
| Bonkowsky, Joshua L; Ramaekers, Vincent T; Quadros, Edward V et al. (2008) Progressive encephalopathy in a child with cerebral folate deficiency syndrome. J Child Neurol 23:1460-3 |
| Ramaekers, V T; Sequeira, J M; Artuch, R et al. (2007) Folate receptor autoantibodies and spinal fluid 5-methyltetrahydrofolate deficiency in Rett syndrome. Neuropediatrics 38:179-83 |
