cerebral folaTe deficiency: a recenTly described neurodevelopmenTal disorder
One decade ao, Ramaekers and colleaues
described a new neurodevelopmental disorder called cerebral olate deciency (CFD). Tey described ve patients with normal neurodevelopment until our to six monthso lie. Durin the second hal o the rst year o lie, these patients demonstrateddevelopmental reression and proressively developed neuroloical symptoms,includin irritability, psychomotor retardation, ataxia, dyskinesias, pyramidalsins, visual loss, and seizures. Patients also demonstrated acquired microcephaly.5-MHF was ound to be normal in the serum and red blood cells but was low in the cerebrospinal fuid. Tis new disorder was named CFD to describe thelack o olate specically in the central nervous system (CNS).
cerebral folaTe TransporTers
o understand CFD, it is necessar to understand that the CNS is a protectedarea o the bod. Te blood-brain barrier hihl reulates the entr o substances into the CNS. For the active orm o olate (5-MHF) to enterthe CNS, it must be transported across the blood-brain barrier b one o twospecialized carriers. Te primar carrier uses a specialized olate receptor knownas olate receptor 1 (FR1). Trouh this sstem, 5-MHF binds to FR1, whichis located on the apical side (blood vessel side) o epithelial cells o the choroidplexus. FR1 then transports 5-MHF to the basolateral side o the epithelialcells. On the basolateral side o the cell, 5-MHF is released into the CNS. Tistransport process requires ener in the orm o an adenosine-5’-triphosphate(AP) dependent mechanism. FR1 is then reccled back to the apical side o the cell to pick up more 5-MHF.A secondar carrier o olate throuh the blood-brain barrier is the reducedolate carrier (RFC). Te RFC has a lower anit or olic acid and 5-MHFthan the FR1 sstem but has a hiher anit or 5-ormltetrahdroolate,also known as olinic acid or leucovorin. Te RFC is also responsible ortransportin 5-MHF into neurons once it has entered the CNS.I blood concentrations o olate are hih enouh, olate ma also diuseacross the blood-brain barrier without a carrier.
causes of cerebral folaTe deficiency
examined the ene that encodes FR1 to investiate whether or not enetic mutations accounted or dsunction in the transporto 5-MHF into the CNS but could not identi an such mutations. In 2004,Ramaekers and Blau
expanded their case series to 20 patients, none o whom were ound to have a mutation in the FR1 ene. However, these researchers didnd non-unctional FR1 receptors in the patients’ cerebrospinal uid, leadin tothe hpothesis that some tpe o molecule, potentiall an autoantibod, mihtbe irreversibl bindin to the FR1 protein, causin it to become dsunctionalor bindin olate. In 2005, Ramaekers and colleaues
identied hih-anit blockin autoantibodies aainst FR1 in the serum o 25 o 28 children withCFD. Tese autoantibodies were not ound in ae-matched control subjects.More recentl, Mollo and colleaues
described an additional blockin FR1autoantibod (termed a “bindin” antibod), but this autoantibod has et to beassociated with an patholoical disease. Interestinl, althouh the majorit o cases o individuals with these autoantibodies have not been reported to havean obvious inammator conditions, FR1 autoantibodies have been associated with juvenile rheumatoid arthritis.
In 2006, CFD was linked to mitochondrial disease in a case report o a child with an incomplete orm o Kearns-Sare sndrome.
Further case reports andcase series later expanded the association between CFD and mitochondrialdisorders to include complex I decienc,
and complex IV hperunction,
as well as a wide variet o mitochondrial disorders in bothchildren and adults.
In most o these cases, the autoantibodies to FR1 werenot ound, suestin that it was the lack o AP availabilit secondar tomitochondrial dsunction that resulted in the impaired transportation o 5-MHF into the CNS.
cerebral folaTe deficiency andauTism specTrum disorders
Seven o the 20 children portraed in the second case series describin CFD were reported to have an autism spectrum disorder (ASD),
while ve o the28 patients rst described to have the FR1 autoantibod were ound to havelow-unctionin autism with neuroloical eatures.
Further case reports
and case series
have expanded the description o CFD in children with idiopathic autism. Overall, these reports suest that earl-onset low-unctionin autism with neuroloical decits is characteristic o children withboth autism and CFD. Interestinl, Rett sndrome, a disorder considered tobe a part o the dianostic roup o autism spectrum disorders, has also beenreported to have reduced 5-MHF levels in the cerebrospinal uid.
It should be noted that only some children with autism who have CFDhave been reported to possess FR1 autoantibodies.
Because these reportso children with idiopathic autism and Rett syndrome include children withand without the FR1 autoantibody, this suests that actors other thanthe FR1 autoantibody miht be important or the development o CFD inthese children. Althouh not specically investiated, it is possible that many children with CFD and idiopathic autism or Rett syndrome who do not havethe FR1 autoantibody may have mitochondrial disease. Indeed, as previously noted, mitochondrial disease appears to be associated with CFD,
and thereappears to be an increased prevalence o mitochondrial disease in children withidiopathic autism as compared to the eneral population.
At least one caseseries has linked children with mitochondrial disease and reressive-type autismto CFD.
Interestinly, Rett syndrome has also been linked to mitochondrialabnormalities in both an animal model
and a case report.
o a lesserextent, children with idiopathic autism miht also maniest dysunction o the mitochondria without necessarily ulllin the criteria or strictly denedmitochondrial disease.
Tus, it is possible that mitochondrial dysunctioncould contribute to the development o CFD in children with idiopathic autism.
examinedthe ene that encodes FR1to investiate whether or notenetic mutations accountedor dsunction in the transporto 5-MHF into the CNS butcould not identi an suchmutations.