Folate Receptor Alpha Defect Causes Cerebral Folate Transport Deficiency: A Treatable Neurodegenerative Disorder Associated with Disturbed Myelin Metabolism

Department of Pediatrics and Pediatric Neurology, Georg August University Göttingen, Göttingen, Germany.
The American Journal of Human Genetics (Impact Factor: 10.93). 10/2009; 85(3):354-63. DOI: 10.1016/j.ajhg.2009.08.005
Source: PubMed


Sufficient folate supplementation is essential for a multitude of biological processes and diverse organ systems. At least five distinct inherited disorders of folate transport and metabolism are presently known, all of which cause systemic folate deficiency. We identified an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 (FOLR1) gene coding for folate receptor alpha (FRalpha). Three patients carrying FOLR1 mutations developed progressive movement disturbance, psychomotor decline, and epilepsy and showed severely reduced folate concentrations in the cerebrospinal fluid (CSF). Brain magnetic resonance imaging (MRI) demonstrated profound hypomyelination, and MR-based in vivo metabolite analysis indicated a combined depletion of white-matter choline and inositol. Retroviral transfection of patient cells with either FRalpha or FRbeta could rescue folate binding. Furthermore, CSF folate concentrations, as well as glial choline and inositol depletion, were restored by folinic acid therapy and preceded clinical improvements. Our studies not only characterize a previously unknown and treatable disorder of early childhood, but also provide new insights into the folate metabolic pathways involved in postnatal myelination and brain development.

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    • "Consequently, negligible MeTHF enters brain directly from blood [62]. Consistent with this model is that human KO’s of either FRα or PCFT manifest central folate deficiency (CFD) states, characterized by very low CSF folate concentrations and severe neurological disease or death [63-65]. Early treatment with mega-doses of reduced folates ameliorates CFD, however, and when started early enough, prevents CNS damage [64]. "
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    • "Obstruction to CSF flow or drainage results in a failure of cortical cells to release 10-formyl tetrahydrofolate, which we believe acts as a folate binding and transporter protein in CSF, and to an arrest in cell cycle and consequential deficient cortical development [23,24,26]. Folate supply to the cerebral cortex can be affected independently of supply to the rest of the CNS and body and result in various cerebral folate deficiencies underlying a variety of neurological conditions that can be alleviated by specific folate supplements [20,22,26,57,61,72-81]. In addition to this folate supply to the developing cortex, there is a complex mix of growth factors and other important proteins in developmental CSF that are affected by CSF drainage and obstruction which remain to be tested for direct effects on the process of cortical development (unpublished data). "
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    • "In the majority of CFD patients, circulating FOLR1 auto-antibodies of the blocking type have been identified in serum and have been suspected to prevent the binding of MTHF to the membrane-attached FOLR1 of choroid plexus [13]. Recently, in patients without FOLR1 autoimmunity a genetic defect of the FOLR1 gene has been found [14] [15]. "
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