Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism.
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.
Steinfeld
Robert
R
Department of Pediatrics and Pediatric Neurology, Georg August University Göttingen, Göttingen, Germany. rsteinfeld@med.uni-goettingen.de
Grapp
Marcel
M
Kraetzner
Ralph
R
Dreha-Kulaczewski
Steffi
S
Helms
Gunther
G
Dechent
Peter
P
Wevers
Ron
R
Grosso
Salvatore
S
Gärtner
Jutta
J
D000595:Amino Acid Sequence; D001692:Biological Transport; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D001931:Brain Mapping; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D058975:Folate Receptor 1; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009186:Myelin Sheath / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000628:therapy*; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D002352:Carrier Proteins; C548696:FOLR1 protein, human; D058975:Folate Receptor 1; D058973:Folate Receptors, GPI-Anchored; D026901:Membrane Transport Proteins; D050505:Mutant Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D005492:Folic Acid