Folate Disorders

  • K. Narisawa

Summary

This chapter discusses three inborn errors of folate metabolism: congenital folate malabsorption, formiminotransferase deficiency, and dihydrofolate reductase deficiency. They appear to be inherited by an autosomal recessive mechanism.

Eight patients have been described with specific defects in the intestinal absorption of folates. All patients present with folate-responsive severe megaloblastic anemia in early infancy. The majority have mild to severe abnormalities of the CNS. Folic acid absorption tests resulted in flat curves and CSF folate concentration was very low even in the presence of high folate blood levels. Treatment should be early and intensive by parenteral doses of folates to prevent neurologic damage.

The formiminotransferase deficiency syndrome consists of two different types. Type 1 is characterized clinically by severe mental and physical retardation, neurological abnormalities, and muscular hypotonia. Forminoglutamic acid (FIGLU) excretion was increased in response to a histidine load. The treatment of these patients is difficult but it should be tried with pharmacologic doses of folic acid. Type 2 may be a clinically benign disorder. Patients excreted huge amounts of FIGLU. Large doses of folate reduced the FIGLU excretion in some patients.

The three patients reported with dihydrofolate reductase deficiency presented at birth and shortly after birth with congenital megaloblastic anemia. They responded to treatment with 5-formyltetrahydrofolate (5-formyl THF) whereas physiologic doses of folic acid were ineffective. The mutations varied per family.

Keywords

Anemia Methionine Histidine Pyrimidine Homocysteine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Rosenblatt DS (1989) Inherited disorders of folate transport and metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease, 6th edn. McGraw-Hill, New York, pp 2049–2064Google Scholar
  2. 2.
    Erbe RW (1979) Genetic aspects of folate metabolism. Adv Hum Genet 9: 293–354PubMedGoogle Scholar
  3. 3.
    Santiago-Borrero PJ, Santini R Jr, Perez-Santiago E, Maldonado N (1973) Congenital isolated defect of folic acid absorption. J Pediatr 82: 450–455PubMedCrossRefGoogle Scholar
  4. 4.
    Lanzkowsky P, Erlandson ME, Bezan AI (1969) Isolated defect of folic acid absorption associated with mental retardation and cerebral calcification. Blood 34: 452–465PubMedGoogle Scholar
  5. 5.
    Luhby 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: 482–483Google Scholar
  6. 6.
    Luhby AL, Cooperman JM (1967) Congenital megaloblastic anemia and progressive central nervous system degeneration. Further clinical and physiological characterization and therapy of syndrome due to inborn error of folate transport. 77th Annual Meeting of the American Pediatric Society, Atlantic City, NJ, USAGoogle Scholar
  7. 7.
    Konomi H, Kuwajima K, Yanagihara M, Kamoshita S, Narisawa K (1978) A case of congenital folic acid malabsorption with infantile spasms. Brain Dev 3: 234–235Google Scholar
  8. 8.
    Poncz M, Colman N, Herbert V, Schwartz E, Cohen AR (1981) Therapy of congenital folate malabsorption. J Pediatr 98: 76–79PubMedCrossRefGoogle Scholar
  9. 9.
    Corbeel L, van den Berghe G, Jaeken J, van Tornout J, Eeckels R (1985) Congenital folate malabsorption. Eur J Pediatr 143: 284–290PubMedCrossRefGoogle Scholar
  10. 10.
    Spector R, Lorenzo AV (1975) Folate transport by the choroid plexus in vitro. Science 187: 540–542PubMedCrossRefGoogle Scholar
  11. 11.
    Luhby AL, Cooperman JM, Pesci-Bourel A (1965) A new inborn error of metabolism: folic acid responsive megaloblastic anemia, ataxia, mental retardation and convulsions. Annual Meeting of the American Pediatric Society, Atlantic City, NJ, USAGoogle Scholar
  12. 12.
    Su PC (1976) Congenital folate deficiency. N Engl J Med 294: 1128PubMedGoogle Scholar
  13. 13.
    Beaudet R, MacKenzie RE (1976) Formiminotransferase-cyclodeaminase from porcine liver. A octomeric enzyme containing bifunctional polypeptides. Biochim Biophys Acta 453: 151–161PubMedCrossRefGoogle Scholar
  14. 14.
    Arakawa TS (1970) Congenital defects in folate utilization. Am J Med 48: 594–598PubMedCrossRefGoogle Scholar
  15. 15.
    Shin YS, Reiter S, Zeiger O, Brunstler I, von Rucker AV (1986) Orotic aciduria, homocystinuria, formiminoglutamic aciduria and megaloblastosis associated with the formiminotransferase/cyclodeaminase deficiency. Adv Exp Med Biol 195: 71–76PubMedCrossRefGoogle Scholar
  16. 16.
    Niederwieser A, Matasovic A, Steinmann B, Baerlocher K, Kempken B (1976) Hydantoin5-propionic aciduria in folic acid nondependent formiminoglutamic aciduria observed in two siblings. Pediatr Res 10: 215–219PubMedCrossRefGoogle Scholar
  17. 17.
    Duran M, Ketting D, de Bree PK, van Sprang FJ, Wadman SK et al (1981) A case of formiminoglutamic aciduria, clinical and biochemical studies. Eur J Pediatr 136: 319–323PubMedCrossRefGoogle Scholar
  18. 18.
    Arakawa TS, Ohara K, Kudo Z, Tada K, Hayashi T, Mizuno T (1963) Hyperfolic acidemia with formiminoglutamic aciduria following histidine loading, suggested for a case of congenital deficiency in formiminotransferase. Tohoku J Exp Med 80: 370–382PubMedCrossRefGoogle Scholar
  19. 19.
    Russel A, Statter M, Abzug S (1977) Methionine-dependent formiminoglutamic acid transferase deficiency: human and experimental studies in its therapy. Hum Hered 27: 205–206CrossRefGoogle Scholar
  20. 20.
    Niederwieser A, Giliberti P, Matasovic A, Plusnik S, Steinmann B, Baerlocher K (1974) Folic acid non-dependent formiminoglutamic aciduria in two siblings. Clin Chim Acta 54: 293–316PubMedCrossRefGoogle Scholar
  21. 21.
    Perry TL, Applegarth DA, Evans ME, Hansen S (1975) Metabolic studies of a family with massive formiminoglutamic aciduria. Pediatr Res 9: 117–122PubMedCrossRefGoogle Scholar
  22. 22.
    Beck B, Christensen E, Brandt N (1981) Formiminoglutamic aciduria in a slightly retarded boy with chronic obstructive lung disease. J Inherited Metab Dis 4: 225–228PubMedCrossRefGoogle Scholar
  23. 23.
    Herman RH, Rosensweig NS, Stifel FB, Herman YF (1969) Adult formiminotransferase deficiency: a new entity. Clin Res 17: 304Google Scholar
  24. 24.
    Tabor H, Wyngarden L (1959) The enzymatic formation of formiminotetrahydrofolic acid, 5,10-methenyltetrahydrofolic acid and 10-formyl-tetrahydrofolic acid in the metabolism of formiminoglutamic acid. J Biol Chem 234: 1830–1846PubMedGoogle Scholar
  25. 25.
    Arakawa TS, Tamura T, Higashi O, Ohara K, Tanno K et al (1968) Formiminotransferase deficiency syndromes associated with megaloblastic anemia responsive to pyridoxine or folic acid. Tohoku J Exp Med 94: 3–16PubMedCrossRefGoogle Scholar
  26. 26.
    Walters TR (1967) Congenital megaloblastic anemia responsive to N’-formyltetrahydrofolic acid administration. J Pediatr 70: 686–687Google Scholar
  27. 27.
    Tauro GP, Danks DM, Rowe PB, van der Weyden MB, Schwarz MA, Collins VL, Nael BW (1976) Dihydrofolate reductase deficiency causing megaloblastic anemia in two families. N Engl J Med 294: 466–470PubMedCrossRefGoogle Scholar
  28. 28.
    Hoffbrand AV, Tripp E, Jackson BFA, Luck WE, Frater-Schroder M (1984) Hereditary abnormal transcobalamin II previously diagnosed as congenital dihydrofolate reductase deficiency. N Engl J Med 310: 789–790PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1990

Authors and Affiliations

  • K. Narisawa

There are no affiliations available

Personalised recommendations