Article

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

ABSTRACT

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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    • "There is a specific inability to transport 5-MTHF across the blood–brain barrier, resulting in a host of neurological sequelae including seizures, delayed motor and cognitive development, autistic features, poor head growth, cerebellar ataxia, visual and hearing impairment, dyskinesia and spasticity (Pé rez-Dueñ as et al., 2011). An antibody-mediated process, with antibodies generated to FR, was thought to be responsible, but more recently mutations in FOLR1, the gene encoding FR, have been described in a number of cases of cerebral folate deficiency (Cario et al., 2009; Steinfeld et al., 2009). Other conditions associated with cerebral folate deficiency include dihydropteridine reductase deficiency; Rett's syndrome; Aicardi-Goutiere's syndrome ; hypomyelination with atrophy of the basal ganglia; Kearns-Sayre syndrome and several other mitochondrial respiratory chain diseases (Pé rez-Dueñ as et al., 2011). "

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    • "Cloning of FR complementary DNA has been described previously (Steinfeld et al., 2009). Mutations were introduced into human FR cloned into the expression vector pcDNA3.1( "
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