Tetrahydrobiopterin May Be Transported into the Central Nervous System by the Folate Receptor α

Richard E. Frye, MD, PhD


The aim of this study was to determine if tetrahydrobiopterin (BH4), a cofactor that is essential for several critical neurometabolic pathways, is transported across the blood-brain barrier (BBB) using the same transport mechanism as folate. In this study we examined 30 children with ASD (mean age 7.5 years, standard deviation 3.2 years; 23% female). We studied autoantibodies that interfere with the binding of folate to the folate receptor α (FRα) – a receptor that is critically involved in the transport of folate across the BBB. The relationships between cerebrospinal fluid (CSF) BH4 concentrations with FRα autoantibody titers as well as with the interaction between CSF 5-methyltetrahydrofolate (5MTHF) concentration and FRα autoantibody titers were studied. CSF BH4 concentration was found to be lower in individuals with higher FRα blocking, but not binding, autoantibody serum titers, suggesting that interference with FRα dependent BBB transport interferes with BH4 transport across the BBB. This effect was not explained by lower CSF 5MTHF concentrations, thereby reducing the possibility that low CSF BH4 concentrations were secondary to low central folate. In addition, CSF BH4 concentration was inversely correlated with the interaction between CSF 5MTHF and FRα blocking autoantibody titers suggesting that BH4 competes with folate for FRα dependent transport across the BBB. These data suggest that FRα dependent transport mechanisms may be involved in the transportation of BH4 across the BBB.

[N A J Med Sci. 2013;6(3):117-120.   DOI:  10.7156/najms.2013.0603117]


tetrahydrobiopterin, folate receptor alpha, autoantibodies, cerebrospinal fluid, autism

Full Text:



Thony B, Auerbach G, Blau N. Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochem J. 2000;347(Pt 1):1-16.

Hyland K, Surtees RA, Heales SJ, Bowron A, Howells DW, Smith I. Cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population. Pediatr Res. 1993;34(1):10-14.

Ramaekers VT, Blau N. Cerebral folate deficiency. Dev Med Child Neurol. 2004;46(12):843-851.

Frye RE. Central tetrahydrobiopterin concentration in neurodevelopmental disorders. Front neurosci. 2010;4:52.

Frye RE, Huffman LC, Elliott GR. Tetrahydrobiopterin as a novel therapeutic intervention for autism. Neurotherapeutics. 2010;7(3):241-249.

Mataga N, Imamura K, Watanabe Y. L-threo-3,4-dihydroxyphenylserine enhanced ocular dominance plasticity in adult cats. Neurosci Lett. 1992;142(2):115-118.

Burton BK, Bausell H, Katz R, Laduca H, Sullivan C. Sapropterin therapy increases stability of blood phenylalanine levels in patients with BH4-responsive phenylketonuria (PKU). Mol Genet Metab. 2010;101(2-3):110-114.

Brand MP, Hyland K, Engle T, Smith I, Heales SJ. Neurochemical effects following peripheral administration of tetrahydropterin derivatives to the hph-1 mouse. J Neurochem. 1996;66(3):1150-1156.

Canevari L, Land JM, Clark JB, Heales SJ. Stimulation of the brain NO/cyclic GMP pathway by peripheral administration of tetrahydrobiopterin in the hph-1 mouse. J Neurochem. 1999;73(6):2563-2568.

Kapatos G, Kaufman S. Peripherally administered reduced pterins do enter the brain. Science. 1981;212(4497):955-956.

Miller L, Insel T, Scheinin M, Aloi J, Murphy DL, Linnoila M, Lovenberg W. Tetrahydrobiopterin administration to rhesus macaques. Its appearance in CSF and effect on neurotransmitter synthesis. Neurochem Res. 1986;11(2):291-298.

Thony B, Calvo AC, Scherer T, et al. Tetrahydrobiopterin shows chaperone activity for tyrosine hydroxylase. J Neurochem. 2008;106(2):672-681.

Kaufman S, Kapatos G, McInnes RR, Schulman JD, Rizzo WB. Use of tetrahydropterins in the treatment of hyperphenylalaninemia due to defective synthesis of tetrahydrobiopterin: evidence that peripherally administered tetrahydropterins enter the brain. Pediatrics. 1982;70(3):376-380.

Fernell E, Watanabe Y, Adolfsson I, et al. Possible effects of tetrahydrobiopterin treatment in six children with autism--clinical and positron emission tomography data: a pilot study. Dev Med Child Neurol. 1997;39(5):313-318.

Wollack JB, Makori B, Ahlawat S, et al. Characterization of folate uptake by choroid plexus epithelial cells in a rat primary culture model. J Neurochem. 2008;104(6):1494-1503.

Ramaekers VT, Rothenberg SP, Sequeira JM, Opladen T, Blau N, Quadros EV, Selhub J. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med. 2005;352(19):1985-1991.

Molloy AM, Quadros EV, Sequeira JM, Troendle JF, Scott JM, Kirke PN, Mills JL. Lack of association between folate-receptor autoantibodies and neural-tube defects. N Engl J Med. 2009;361(2):152-160.

Ramaekers VT, Blau N, Sequeira JM, Nassogne MC, Quadros EV. Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits. Neuropediatrics. 2007;38(6):276-281.

Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry. 2013;18(3):369-381.

Frye RE, DeLatorre R, Taylor HB, et al. Metabolic effects of sapropterin treatment in autism spectrum disorder: a preliminary study. Transl Psychiatry. 2013;3:e237.

APA. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.


  • There are currently no refbacks.