Skip to main content
SpringerLink
Log in

CSF 5-Methyltetrahydrofolate Serial Monitoring to Guide Treatment of Congenital Folate Malabsorption Due to Proton-Coupled Folate Transporter (PCFT) Deficiency

  • Case Report
  • Chapter
  • First Online:
JIMD Reports, Volume 24

Part of the book series: JIMD Reports ((JIMD,volume 24))

Abstract

Hereditary folate malabsorption is characterized by folate deficiency with impaired folate transport into the central nervous system (CNS). This disease is characterized by megaloblastic anemia of early appearance, combined immunodeficiency, seizures, and cognitive impairment. The anemia and immunologic disease are responsive but neurological signs are refractory to folic-acid treatment. We report a 7-year-old girl who has congenital folate deficiency and SLC46A1 gene mutation who is unable to transport folate from her gut to the circulatory system and consequently from the blood to the cerebrospinal fluid (CSF). As a result she developed undetectable 5-methyltetrahydrofolate levels in her plasma and CSF and became immunocompromised and quite ill. Intramuscular treatment with 5-formyltetrahydrofolate (folinic acid) was therapeutic at her presentation and has been successful preventing other signs and symptoms of hereditary folate malabsorption even at relatively low CSF levels. Although difficult, early detection and diagnosis of cerebral folate deficiency are important because folinic acid at a pharmacologic dose may normalize outcome in PCFT gene defects, as well as bypass autoantibody-blocked folate receptors and enter the cerebrospinal fluid by way of the reduced folate carrier. This route elevates the 5-methyltetrahydrofolate level within the central nervous system and can prevent the neuropsychiatric disorder. CSF levels of 5-methyltetrahydrofolate between 18 and 46 nmol/L may be sufficient to eradicate CNS disease.

Competing interests: None declared

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Atabay B, Turker M, Ozer EA, Mahadeo K, Diop-Bove N, Goldman ID (2010) Mutation of the proton-coupled folate transporter gene (PCFT-SLC46A1) in Turkish siblings with hereditary folate malabsorption. Pediatr Hematol Oncol 27(8):614–619

    Article  CAS  PubMed  Google Scholar 

  • Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G, Wickramasinghe SN, Everson RB, Ames BN (1997) Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A 94:3290–3295

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Borzutzky A, Crompton B, Bergamm AK, Giliani S, Baxi S, Martin M, Neufeld EJ, Notarangelo LD (2009) Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter. Clin Immunol 133(3):287–294

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cains S, Shepherd A, Nabiuni M, Owen-Lynch PJ, Miyan J (2009) Addressing a folate imbalance in fetal cerebrospinal fluid can decrease the incidence of congenital hydrocephalus. J Neuropathol Exp Neurol 68:404–416

    Article  PubMed  Google Scholar 

  • Chen C, Wagner C (1975) Folate transport in the choroid plexus. Life Sci 2049–2064

    Google Scholar 

  • Corbeel L, Van den Berghe G, Jaeken J, Van Tornout J, Eeckels R (1985) Congenital folate malabsorption. Eur J Pedoatr 143(4):284–290

    Article  CAS  Google Scholar 

  • Diop-Bove N, Kronn D, Goldman D (1993–2014) Gene reviews® [Internet]. University of Washington, Seattle,WA

    Google Scholar 

  • Diop-Bove N, Jain M, Scaglia F, Goldman ID (2013) A novel deletion mutation in the proton-coupled folate transporter (PCFT; SLCA6A1) in a Nicaraguan child with hereditary folate malabsorption. Gene 527(2):673–674

    Article  CAS  PubMed  Google Scholar 

  • Djukic A (2007) Folate-responsive neurological diseases. Pediatr Neurol 37:387–397

    Article  PubMed  Google Scholar 

  • Fernandes J, Saudubary JM, Den Berghe V (2012) Inborn metabolic diseases. Springer, Heidelberg

    Google Scholar 

  • Fournier I, Ploye F, Cottet-Emard JM, Brun J, Claustrat B (2002) Folate deficiency alters melatonin secretion in rats. J Nutr 132:2781–2784

    CAS  PubMed  Google Scholar 

  • Geller J, Kronn D, Jayabose S, Sandoval C (2002) Hereditary folate malabsorption: family report and review of the literature. Medicine (Baltimore) 81:51–68

    Article  CAS  Google Scholar 

  • Ghoshal K, Li X, Datta J, Bai S, Pogribny I, Pogribny M, Huang Y, Young D, Jacob ST (2006) A folate- and methyl-deficient diet alters the expression of DNA methyltransferases and methyl CpG binding proteins involved in epigenetic gene silencing in livers of F344 rats. J Nutr 136:1522–1527

    PubMed Central  CAS  PubMed  Google Scholar 

  • Green R, Miller J (1999) Folate deficiency beyond megaloblastic anemia: hyperhomocysteinemia and other manifestations of dysfunctional folate status. Semin Hematol 36:47–64

    CAS  PubMed  Google Scholar 

  • Hansen FJ, Blau N (2005) Cerebral folate deficiency: life-changing supplementation with folinic acid. Mol Genet Metab 84:371–373

    Article  CAS  PubMed  Google Scholar 

  • Henderson GB (1990) Folate-binding proteins. Annu Rev Nutr 10:319–335

    Article  CAS  PubMed  Google Scholar 

  • Holm J, Hansen SI, Hoier-Madsen M, Bostad L (1991) High-affinity folate binding in human choroid plexus: characterization of radioligand binding, immunoreactivity, molecular heterogeneity and hydrophobic domain of the binding protein. Biochem J 280:267–271

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jebnoun S, Kacem S, Mokrani C, Chabchoub A, Khrouf N, Zittoun J (2001) A family study of congenital malabsorption of folate. J Inherit Metab Dis 24:749–750

    Article  CAS  PubMed  Google Scholar 

  • Kishimoto K, Kobayashi R, Sano H, Suzuki D, Maruoka H, Yasuda K, Chida N, Yamada M, Kobayashi K (2014) Impact of folate therapy on combined immunodeficiency secondary to hereditary folate malabsorption. Clin Immunol 153(1):17–22. doi:10.1006/j.clim.2014.03.014

    Article  CAS  PubMed  Google Scholar 

  • Kronenberg G, Harms C, Sobol RW, Cardozo-Pelaez F, Linhart H, Winter B, Balkaya M, Gertz K, Gay SB, Cox D (2008) Folate deficiency induces neurodegeneration and brain dysfunction in mice lacking uracil DNA glycosylase. J Neurosci 28:7219–7230

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lanzkowsky P, Erlandson ME, Bezan AI (1969) Isolated defect of folic acid absorption associated with mental retardation and cerebral calcification. Blood 34:452–465

    CAS  PubMed  Google Scholar 

  • Lasry I, Berman B, Straussberg R, Sofer Y, Bessler H, Sharkia M, Glaser F, Jansen F, Drori S, Assaraf YG (2008) A novel loss-of-function mutation in the proton-coupled folate transporter from a patient with hereditary folate malabsorption reveals that Arg 113 is crucial for function. Blood 112:2055–2061

    Article  CAS  PubMed  Google Scholar 

  • Levitt M, Nixon PF, Pincus JH, Bertino JR (1971) Transport characteristics of folates in cerebrospinal fluid; a study utilizing doubly labeled 5-methyltetrahydrofolate and 5-formyltetrahydrofolate. J Clin Invest 50:1301–1308

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Linhart HG, Troen A, Bell GW, Cantu E, Chao WH, Moran E, Steine E, He T, Jaenisch R (2008) Folate deficiency induces genomic uracil misincorporation and hypomethylation but does not increase DNA point mutations. Gastroenterology 136:227–235

    Article  PubMed Central  PubMed  Google Scholar 

  • Lubhy AL, Eagle FJ, Roth E, Cooperman JM (1961) Relapsing megaloblastic anemia in an infant due to a specific defect in gastrointestinal absorption of folic acid. Am J Dis Child 102:482–483

    Google Scholar 

  • Mahadeo K, Min SH, Diop-Bove NK, Kronn D, Goldman ID (2010) Gene reviews [Internet], updated 2010 May 06. University of Washington, Seattle, WA

    Google Scholar 

  • Malatack JJ, Moran MM, Moughan B (1999) Isolated congenital malabsorption of folic acid in a male infant: insights into treatment and mechanism of defect. Pediatrics 104(5 Pt 1):1133–1137

    Article  CAS  PubMed  Google Scholar 

  • Matherly LH, Goldman DI (2003) Membrane transport of folates. Vitam Horm 66:403–456

    Article  CAS  PubMed  Google Scholar 

  • Min SH, Oh SY, Karp GI, Poncz M, Zhao R, Goldman ID (2008) The clinical course and genetic defect in the PCFT gene in a 27-year-old woman with hereditary folate malabsorption. J Pediatr 153(3):435–437. doi:10.1016/j.jpeds.2008

    Article  CAS  PubMed  Google Scholar 

  • Nath BJ, Lindebaum J (1979) Persistence of neutrophil hypersegmentation during recovery from megaloblastic granulopoiesis. Ann Intern Med 90:757–760

    Article  CAS  PubMed  Google Scholar 

  • Pogribny IP, Karpf AR, James SR, Melnyk S, Han T, Tryndyak VP (2008) Epigenetic alterations in the brains of Fisher 344 rats induced by long-term administration of folate/methyl-deficient diet. Brain Res 1237:25–34

    Article  CAS  PubMed  Google Scholar 

  • Ponz M, Colman L, Herbert V, Schwartz E, Cohen AR (1898) Therapy of congenital folate malabsorption. J Pediatr 98(1):76–79

    Article  Google Scholar 

  • Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, Sandoval C (2006) Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127(5):917–928

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Rosenblatt DS, Fenton WA (2001) Inherited disorders of folate and cobalamin transport and metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 3897–3933

    Google Scholar 

  • Santiago-Borrero PJ, Santini R Jr, Perez-Santiago E, Maldonado NI (1973) Congenital isolated defect of folic acid absorption. J Pediatr 82:450–455

    Article  CAS  PubMed  Google Scholar 

  • Scriver AL, Beaudet WS, Sly D, Valle CR (1995) The metabolic and molecular bases of inherited disease, vol 3, 7th edn. McGraw Hill, New York

    Google Scholar 

  • Shin DS, Mahadeo K, Min SH, Diop-Bove N, Clayton P, Zhao R, Goldman ID (2011) Identification of novel mutations in the proton-coupled folate transporter (PCFT-SLC46A1) associated with hereditary folate malabsorption. Mol Genet Metab 103:33–37

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shinohara Y, Hasegawa H, Ogawa K, Tagoku K, Hashimoto T (2006) Distinct effects of folate and choline deficiency on plasma kinetics of methionine and homocysteine in rats. Metabolism 55:899–906

    Article  CAS  PubMed  Google Scholar 

  • Sofer Y, Harel L, Sharkia M, Amir J, Schoenfeld T, Straussberg R (2007) Neurological manifestations of folate transport defect: case report and review of the literature. J Child Neurol 22:783–786

    Article  PubMed  Google Scholar 

  • Steinschneider M, Sherbany A, Pavlakis S, Emerson R, Lovelace R, De Vivo DC (1990) Congenital folate malabsorption: reversible clinical and neurophysiologic abnormalities. Neurology 40:1315

    Article  CAS  PubMed  Google Scholar 

  • Su PC (1976) Congenital folate deficiency. New Engl J Med 294:1128

    CAS  PubMed  Google Scholar 

  • Suleiman SA, Spector R, Cancilla P (1981) Partial purification and characterization of a folate binding protein from human choroid plexus. Neurochem Res 6:331–341

    Article  Google Scholar 

  • Surtees R (2001) Cobalamin and folate responsive disorders. In: Baxter P (ed) Vitamin responsive conditions in pediatric neurology, International review of child neurology series. Mac Keith, London, pp 96–108

    Google Scholar 

  • Surtees R, Heales S, Bowron A (1993) Biochemical pathogenesis of subacute combined degeneration of the spinal cord and brain. J Inherit Metab Dis 16:762–770

    Article  CAS  PubMed  Google Scholar 

  • Urbach J, Abrahamov A, Grossowicz N (1987) Congenital isolated folic acid malabsorption. Arch Dis Child 62:78–80

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang Q, Li X, Ding Y, Liu Y, Qin Y, Yang Y (2014) The first Chinese case report of hereditary folate malabsorption with a novel mutation on SLC46A1. Brain Dev. doi:10.1016/j.braindev.2014.01.010

    Google Scholar 

  • Whitehead VM (2006) Acquired and inherited disorders of cobalamin and folate in children. Br J Haematol 134(2):125–136

    Article  CAS  PubMed  Google Scholar 

  • Wright AJ, Finglas PM, Dainty JR et al (2003) Single oral doses of 13C forms of pteroylmonoglutamic acid and 5-formyltetrahydrofolic acid elicit differences in short-term kinetics of labelled and unlabelled folates in plasma: potential problems in interpretation of bioavailability studies. Br J Nutr 90:363–371

    Article  CAS  PubMed  Google Scholar 

  • Wu D, Pardridge WM (1999) Blood–brain barrier transport of reduced folic acid. Pharm Res 16:415–419

    Article  CAS  PubMed  Google Scholar 

  • Zhao R, Min SH, Qiu A, Sakaris A, Goldberg GL, Sandoval C, Malatack JJ, Rosenblatt DS, Goldman ID (2007) The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption. Blood 110:1147–1152

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhao R, Min SH, Wang Y, Campanella E, Low PS, Goldman ID (2009) A role for the proton-coupled folate transporter (PCFT-SLC46A1) in folate receptor-mediated endocytosis. J Biol Chem 284:4267–4274

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhao R, Akabas MH, Goldman ID (2012) Identification of a functionally critical GXXG motif and its relationship to the folate binding site of the proto-coupled folate transporter (PCFT-SLC46A1). Am J Physiol Cell Physiol 303(6):C673–C681

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zittoun J, Zittoun R (1999) Modern clinical testing strategies in cobalamin and folate deficiency. Semin Hematol 36:35–46

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Division of Pediatric Neurology, Boston Medical Center, Boston University Medical School, Boston, MA, USA

    A. Torres

  2. Department of Neurology, Divisions of Hematology and Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    S. A. Newton, B. Crompton, A. Borzutzky, E. J. Neufeld, L. Notarangelo & G. T. Berry

Authors
  1. A. Torres
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. A. Newton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. Crompton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Borzutzky
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. J. Neufeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. Notarangelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G. T. Berry
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G. T. Berry .

Editor information

Editors and Affiliations

  1. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  2. Division of Metabolism and Children’s Research Centre, University Children’s Hospital Zuri, Zurich, Switzerland

    Matthias Baumgartner

  3. Tulane University Medical School, New Orleans, Louisiana, USA

    Eva Morava

  4. Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, Minnesota, USA

    Marc Patterson

  5. Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, United Kingdom

    Shamima Rahman

  6. Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany

    Verena Peters

Additional information

Communicated by: Georg Hoffmann

Compliance with Ethics Guidelines

Compliance with Ethics Guidelines

Conflict of Interest:

Alcy Torres, Stephanie A. Newton, Brian Crompton, Arturo Borzutzky, Ellis J. Neufeld, Luigi Notarangelo, and Gerard T. Berry declare that they have no conflict of interest.

Informed Consent

Informed consent was not obtained from the family as lumbar punctures for CSF testing were considered to be a part of routine care for patients with this potentially very serious encephalopathic illness.

Rights and permissions

Reprints and permissions

Copyright information

© 2015 SSIEM and Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Torres, A. et al. (2015). CSF 5-Methyltetrahydrofolate Serial Monitoring to Guide Treatment of Congenital Folate Malabsorption Due to Proton-Coupled Folate Transporter (PCFT) Deficiency. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 24. JIMD Reports, vol 24. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_445

Download citation

  • DOI: https://doi.org/10.1007/8904_2015_445

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-48226-1

  • Online ISBN: 978-3-662-48227-8

  • eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)

Publish with us

Policies and ethics

Search

Navigation