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Cerebral Folate Deficiency in Autism Spectrum Disorders by Richard Frye, MD, PhD, and Daniel Rossignol, MD

Cerebral Folate Deficiency in Autism Spectrum Disorders by Richard Frye, MD, PhD, and Daniel Rossignol, MD

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www.autsmone.orgREPRINTEDWITHPERMISSION
AUTISMSCIENCEDIGEST:THEJOURNALOFAUTISMONE
ISSUE02
9
The imporTance of folaTe
Folic acid (vitamin B9, also known as olate) is a water-soluble B vitamin thatis essential or numerous phsioloical sstems o the bod. Folate derives itsname rom the Latin word
  olium
, which means lea, to sini that the mainnatural source o this vitamin is rom lea veetables. However, in the modern western diet, the main source o olate is rom olate-ortied oods.Folic acid is the inactive, oxidized orm o the olate compounds. Te mainactive orm o olate in the bod is 5-methltetrahdroolate (5-MHF). Folicacid is converted to dihdroolate and then to tetrahdroolate (HF) b theenzme dihdroolate reductase. Tis reaction, which requires niacin (vitaminB3), can be inhibited b certain medications. 5-MHF is also convertedto HF b the enzme methlenetetrahdroolate reductase (MHFR).5-MHF is then converted back to HF throuh a cobalamin (vitaminB12) dependent enzme called methionine snthase, a process that recclesmethionine rom homocsteine.Folate is important or the
de novo
snthesis o purine and primidine nucleicacids that are the molecules rom which DNA and RNA are produced. DNAstores the enetic code and needs to be duplicated when a cell divides andreplicates. Tus, olate is extremel important durin cell replication, especiall prior to birth durin the development o the embro and etus. It is alsoessential durin earl lie when cells are rowin quickl.Te olate ccle interacts with the methionine ccle as well as thetetrahdrobiopterin production and salvae pathwas. Deciencies in olatescan lead to abnormalities in these pathwas. Te methionine ccle is essentialor the methlation o DNA, a process that is important in controllinene expression. etrahdrobiopterin is essential or the production o nitric oxide, a substance critical or the reulation o blood ow and or theproduction o the monoamine neurotransmitters, includin dopamine,serotonin, and norepinephrine. Production o these neurotransmitters andnitric oxide converts tetrahdrobiopterin to dihdropterin. Te conversiono tetrahdrobiopterin back to dihdropterin aain requires conversion o 5-MHF to HF. In addition, tetrahdrobiopterin is produced
de novo
usinthe precursor purine uanosine triphosphate, a substance that requires HF tobe produced.Several disorders have been linked to olate decienc. For example, sinceblood cells need to be constantl replenished, a lack o olate commonl leads toanemia, an insucienc o red blood cells. Folate decienc durin prenanc leads to etal neural tube deects such as spina bida.
Cerebral FolateDeFiCienCy in autismspeCtrum DisorDers
By RICHARD E. FRyE, MD, PHD,
1
AND DANIEL A. ROSSIgNOL, MD, FAAFP
2
aflitions:1
 
Division o Child and Adolescent Neurology and Children’s Learning Institute, Department o Pediatrics,University o Texas Health Science Center at Houston, Houston, TX, 77030, USA; and
 
2
InternationalChild Development Resource Center, 3800 West Eau Gallie Blvd., Melbourne, FL, 32934, USA.
souce of uppo: th eech w uppoed, n p, by he aum reech inue.
Tis article is a companion piece to the stor o Evan Carkhu, a child dianosed with autism who went man  ears with neither a medical dianosis nor an explanation or his medical condition. Here we explain the medicalscience o the underlin neurodevelopmental disorder with which he was eventuall dianosed, called cerebralolate decienc (CFD). As ou will read rom the description o his disorder in the accompanin article, Evanhad several atpical characteristics that led some phsicians down a wron path. Evan’s stor is an excellent exampleo a amil who would not ive up, and CFD is an excellent example o a disorder that was previousl thouht to berare but is now bein increasinl reconized to aect some children with autism.
 
AUTISMSCIENCEDIGEST:THEJOURNALOFAUTISMONE
ISSUE02
REPRINTEDWITHPERMISSIONwww.autsmone.org
 
RichaRd E. FRyE, Md, Phd,
received his MD/PhD romGeorgetown University. Hecompleted his pediatric residencyat University o Miami, and a childneurology residency and ellowshipin behavioral neurology andlearning disabilities at Children’sHospital Boston. Dr. Frye is boardcertifed in general pediatricsand in neurology with specialcompetency in child neurology.Currently at the University o TexasHealth Science Center at Houston,Dr. Frye studies brain structure andunction in neurodevelopmentaldisorders, mitochondrial dysunctionand metabolic disorders in autism,and novel autism treatments. Hehas published numerous papersand book chapters on childrenwith autism.
10
AUTISMSCIENCEDIGEST:THEJOURNALOFAUTISMONE
ISSUE02
REPRINTEDWITHPERMISSIONwww.autsmone.org
 
www.autsmone.orgREPRINTEDWITHPERMISSION
AUTISMSCIENCEDIGEST:THEJOURNALOFAUTISMONE
ISSUE02
11
cerebral folaTe deficiency: a recenTly described neurodevelopmenTal disorder
One decade ao, Ramaekers and colleaues
1
described a new neurodevelopmental disorder called cerebral olate deciency (CFD). Tey described ve patients with normal neurodevelopment until our to six monthso lie. Durin the second hal o the rst year o lie, these patients demonstrateddevelopmental reression and proressively developed neuroloical symptoms,includin irritability, psychomotor retardation, ataxia, dyskinesias, pyramidalsins, visual loss, and seizures. Patients also demonstrated acquired microcephaly.5-MHF 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 specically 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 hihl reulates the entr o substances into the CNS. For the active orm o olate (5-MHF) 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). Trouh this sstem, 5-MHF binds to FR1, whichis located on the apical side (blood vessel side) o epithelial cells o the choroidplexus. FR1 then transports 5-MHF to the basolateral side o the epithelialcells. On the basolateral side o the cell, 5-MHF is released into the CNS. Tistransport process requires ener in the orm o an adenosine-5’-triphosphate(AP) dependent mechanism. FR1 is then reccled back to the apical side o the cell to pick up more 5-MHF.A secondar carrier o olate throuh the blood-brain barrier is the reducedolate carrier (RFC). Te RFC has a lower anit or olic acid and 5-MHFthan the FR1 sstem but has a hiher anit or 5-ormltetrahdroolate,also known as olinic acid or leucovorin. Te RFC is also responsible ortransportin 5-MHF into neurons once it has entered the CNS.I blood concentrations o olate are hih enouh, olate ma also diuseacross the blood-brain barrier without a carrier.
causes of cerebral folaTe deficiency 
Ramaekers’ roup
1
examined the ene that encodes FR1 to investiate whether or not enetic mutations accounted or dsunction in the transporto 5-MHF into the CNS but could not identi an such mutations. In 2004,Ramaekers and Blau
2
expanded their case series to 20 patients, none o whom were ound to have a mutation in the FR1 ene. However, these researchers didnd non-unctional FR1 receptors in the patients’ cerebrospinal uid, leadin tothe hpothesis that some tpe o molecule, potentiall an autoantibod, mihtbe irreversibl bindin to the FR1 protein, causin it to become dsunctionalor bindin olate. In 2005, Ramaekers and colleaues
3
identied hih-anit blockin autoantibodies aainst FR1 in the serum o 25 o 28 children withCFD. Tese autoantibodies were not ound in ae-matched control subjects.More recentl, Mollo and colleaues
4
described an additional blockin FR1autoantibod (termed a “bindin” antibod), but this autoantibod has et to beassociated with an patholoical disease. Interestinl, althouh the majorit o cases o individuals with these autoantibodies have not been reported to havean obvious inammator conditions, FR1 autoantibodies have been associated with juvenile rheumatoid arthritis.
5
In 2006, CFD was linked to mitochondrial disease in a case report o a child with an incomplete orm o Kearns-Sare sndrome.
6
Further case reports andcase series later expanded the association between CFD and mitochondrialdisorders to include complex I decienc,
Alpers’ disease
8
and complex IV hperunction,
9
as well as a wide variet o mitochondrial disorders in bothchildren and adults.
10
In most o these cases, the autoantibodies to FR1 werenot ound, suestin that it was the lack o AP availabilit secondar tomitochondrial dsunction that resulted in the impaired transportation o 5-MHF into the CNS.
cerebral folaTe deficiency andauTism specTrum disorders
Seven o the 20 children portraed in the second case series describin CFD were reported to have an autism spectrum disorder (ASD),
2
while ve o the28 patients rst described to have the FR1 autoantibod were ound to havelow-unctionin autism with neuroloical eatures.
3
Further case reports
9,11
 and case series
12,13,14
have expanded the description o CFD in children with idiopathic autism. Overall, these reports suest that earl-onset low-unctionin autism with neuroloical decits is characteristic o children withboth autism and CFD. Interestinl, Rett sndrome, a disorder considered tobe a part o the dianostic roup o autism spectrum disorders, has also beenreported to have reduced 5-MHF levels in the cerebrospinal uid.
15,16
It should be noted that only some children with autism who have CFDhave been reported to possess FR1 autoantibodies.
3,13
Because these reportso children with idiopathic autism and Rett syndrome include children withand without the FR1 autoantibody, this suests that actors other thanthe FR1 autoantibody miht be important or the development o CFD inthese children. Althouh not specically investiated, 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,
6-10
and thereappears to be an increased prevalence o mitochondrial disease in children withidiopathic autism as compared to the eneral population.
17,18
At least one caseseries has linked children with mitochondrial disease and reressive-type autismto CFD.
9
Interestinly, Rett syndrome has also been linked to mitochondrialabnormalities in both an animal model
19
and a case report.
20
o a lesserextent, children with idiopathic autism miht also maniest dysunction o the mitochondria without necessarily ulllin the criteria or strictly denedmitochondrial disease.
18
Tus, it is possible that mitochondrial dysunctioncould contribute to the development o CFD in children with idiopathic autism.
Ramaekers’ roup
 
examinedthe ene that encodes FR1to investiate whether or notenetic mutations accountedor dsunction in the transporto 5-MHF into the CNS butcould not identi an suchmutations.

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