European Journal of Pediatrics

, Volume 154, Supplement 2, pp S97–S102 | Cite as

Galactosemia unsolved

  • Stanton Segal


Classic galactosemia is an enigmatic disorder that presents the challenge of unraveling the basis of the long-term complications of mental disability, speech defects, ovarian failure and neurologic syndromes which occur despite a galactose-restricted diet. A complete understanding of the pathobiochemistry and molecular genetics, and evaluation of the present theories for the poor long-term outcome, continuous intoxication, critical metabolite depletion and in utero damage is needed in order to design new therapeutic strategies. Answering this urgent question of how to treat galactosemic patients mandates enhanced clinical and basic research efforts.

Key words

Chronic intoxication Complications Endogenous galactose Galactose metabolism 



galactose-1-phosphate uridyltransferase






  1. 1.
    Allen JT, Holton JB, Lennox AC and Hodges IC (1988) Early morning urine galactitol levels in relation to galactose intake: a possible method of monitoring the diet in galactokinase deficiency. J Inherited Metab Dis 11: 243–245CrossRefPubMedGoogle Scholar
  2. 2.
    Bakker HD (1995) Galactosemia surveys. Eur J Pediatr 154 [Suppl 1]:Google Scholar
  3. 3.
    Bergren WR, Ng WG, Donnell GN (1972) Galactonic acid in galactosemia: identification in the urine. Science 176: 683–684Google Scholar
  4. 4.
    Berman W, Rogers S, Bautista J, Segal S (1979) Galactose metabolism in isolated perfused suckling-rat liver. Am J Physiol 5: E633-E637Google Scholar
  5. 5.
    Berry GT, Palmieri MJ, Heales S, Leonard JV, Segal S (1992) Red blood cell uridine sugar nucleotide levels in patients with classic galactosemia and other metabolic disorders. Metabolism 41: 783–787CrossRefPubMedGoogle Scholar
  6. 6.
    Berry GT, Palmieri M, Gross KC, Acosta PB, Henstenburg JA, Mazur A, Reynolds R, Segal S (1993) The effect of dietary fruits and vegetables on urinary galactitol excretion in galactose-1-phosphate uridyltransferase deficiency. J Inherited Metab Dis 16: 91–100CrossRefPubMedGoogle Scholar
  7. 7.
    Chen Y-T, Mattison DR, Feigenbaum L, Fukui H, Schulman JD (1981) Reduction in oocytes number following prenatal exposure to a diet high in galactose. Science 214: 1145–1147PubMedGoogle Scholar
  8. 8.
    Cuatrecasas P, Segal S (1966) Galactose conversion to d-xylulose: an alternate route of galactose metabolism. Science 153: 549–551PubMedGoogle Scholar
  9. 9.
    Dobbie JA, Holton JB, Clamp JR (1990) Defective galactosylation of proteins in cultured skin fibroblasts from galactosemic patients., Ann Clin Biochem 27: 274–275PubMedGoogle Scholar
  10. 10.
    Donnell GN, Bergren WR, Perry G, Koch R (1963) Galactose-1-phosphate in galactosaemia. Pediatrics 31: 802–810PubMedGoogle Scholar
  11. 11.
    Editorial (1982) “Clouds over galactosaemia”. Lancet 18: 1379–1380Google Scholar
  12. 12.
    Elsas LJ, II, Langley S, Paulk EM, Hjelm LN, Dembure PP (1995) A molecular approach to galactosemia. Eur J Pediatr 154 [Suppl 2]: S21-S27PubMedGoogle Scholar
  13. 13.
    Field TL, Reznikoff WS, Frey PA (1989) Galactose-1-phosphate uridyltransferase: identification of histidine-164 and histidine-166 as critical residues by site-directed mutagenesis. Biochemistry 28: 2094–2099CrossRefPubMedGoogle Scholar
  14. 14.
    Fishler K, Koch R, Donnell GN, Wenz E (1980) Developmental aspects of galactosemia from infancy to childhood. Clin Pediatr 19: 38–44Google Scholar
  15. 15.
    Flach JE, Reichardt JKV, Elsas LJ (1990) Sequence of a cDNA encoding human galactose-1-phosphate uridyltransferase. Mol Biol Med 7: 365–369PubMedGoogle Scholar
  16. 16.
    Friedman JH, Levy HL, Boustany RM (1989) Late onset neurologic syndromes in galactosemic siblings. Neurology 39: 741–742PubMedGoogle Scholar
  17. 17.
    Gibson JB (1995) Gonadal function in galactosemics and galactose toxic animals. Eur J Pediatr 154 [Suppl 1]:Google Scholar
  18. 18.
    Gitzelmann R (1969) Formation of galactose-1-phosphate from uridine diphosphate galactose in erythrocytes from patients with galactosemia. Pediatr Res 3: 279–286PubMedGoogle Scholar
  19. 19.
    Gitzelmann R (1995) Galactose-1-phosphate. Eur J Pediatr 154 [Suppl 1]:Google Scholar
  20. 20.
    Gitzelmann R, Hansen RG (1974) Galactose biogenesis and disposal in galactosemics. Biochim Biophys Acta 372: 374–378Google Scholar
  21. 21.
    Gitzelmann R, Curtius HC, Muller M (1966) Galactitol excretion in the urine of a galactokinase-deficient man. Biochem Biophys Res Commun 22: 437–444CrossRefGoogle Scholar
  22. 22.
    Gitzelmann R, Curtius HC, Schneller I (1967) Galactitol and galactose-1-phosphate in the lens of a galactosemic infant. Exp Eye Res 6: 1–3PubMedGoogle Scholar
  23. 23.
    Gitzelmann R, Hansen RG, Steinmann B (1975) Biogenesis of galactose, a possible mechanism of self-intoxication. In: Hommes, Van den Berg (eds) Normal and pathological development of energy metabolism. Academic Press, London, pp 25–37Google Scholar
  24. 24.
    Goldfarb S, Ziyadeh FN, Fern EFO, Simmons DA (1991) The effect of polyol pathway inhibition and dietary myoinositol on glomerular hemodynamic function in experimental diabetes mellitus in the rat. Diabetes 40: 465–471PubMedGoogle Scholar
  25. 25.
    Greene DA, DeJesus PV Jr, Winegrad AI (1975) Effects of insulin and dietary myoinositol on impaired peripheral motor nerve conduction velocity in acute streptozotocin diabetes. J Clin Invest 55: 1326–1336PubMedGoogle Scholar
  26. 26.
    Gross KC, Acosta PB (1991) Fruits and vegetables are a source of galactose: implications in planning the diets of patients with galactosaemia. J Inherited Metab Dis 14: 253–258CrossRefPubMedGoogle Scholar
  27. 27.
    Haworth JC, Ford JD, Younoszai MK (1969) Effect of galactose toxicity on growth of the rat fetus and brain. Pediatr Res 3: 441–447PubMedGoogle Scholar
  28. 28.
    Heidenreich R (1995) Regulation of galactose-1-phosphate uridyltransferase gene expression. Eur J Pediatr 154 [Suppl 2]: S28-S32Google Scholar
  29. 29.
    Henderson MJ, Holton JB (1983) Further observations in a case of uridine diphosphate galactose-4-epimerase deficiency with a severe clinical presentation. J Inherited Metab Dis 6: 17–20PubMedGoogle Scholar
  30. 30.
    Holton JB (1990) Galactose disorders. An overview. J Inherited Metab Dis 13: 476–486CrossRefPubMedGoogle Scholar
  31. 31.
    Holton JB (1995) Effects of galactosemia in utero. Eur J Pediatr 154 [Suppl 2]: S77-S81Google Scholar
  32. 32.
    Hsia DY-Y, Walker F (1961) Variability in the clinical manifestations of galactosemia. J Pediatr 59: 872–883PubMedGoogle Scholar
  33. 33.
    Irons M, Levy HL, Pueschel S, Castree K (1985) Accumulation of galactose-1-phosphate in the galactosaemic fetus despite maternal milk avoidance. J Pediatr 107: 261–263PubMedGoogle Scholar
  34. 34.
    Jakobs C, Schweitzer S, Dorland B (1995) Galactitol in galactosemia. Eur J Pediatr 154 [Suppl 2]: S50-S52PubMedGoogle Scholar
  35. 35.
    Jakobs C, Kleijer WJ, Bakker HD, Van Gennip AH, Przyrembel H, Niermeijer MF (1988) Dietary restriction of maternal lactose intake does not prevent accumulation of galactitol in the amniotic fluid of fetuses affected with alactosaemia. Prenat Diagn 8: 641–645PubMedGoogle Scholar
  36. 36.
    Kaufman FR, Kogut MD, Donnell GN, Goebelsmann U, March C, Koch R (1981) Hypergonadotropic hypogonadism in female patients with galactosemia. N Engl J Med 304: 994–998PubMedGoogle Scholar
  37. 37.
    Kaufman FR, Ng WN, Xu YK et al (1989) Treatment of patients (PTS) with classical galactosemia (G) with oral uridine. (Abstract) Pediatr Res 25: 834Google Scholar
  38. 38.
    Keevill NJ, Holton JB, Allen JT (1993) The investigation of UDPGlucose and UDPGalactose concentration in red blood cells of patients with classical galactosaemia. Clin Chim Acta 221: 135–142CrossRefPubMedGoogle Scholar
  39. 39.
    Kinoshita JH (1965) Cataract in galactosemia. Invest Ophthalmol 4:786–799PubMedGoogle Scholar
  40. 40.
    Kinoshita JH (1990) Prevention of retinal vessel changes associated with diabetic retinopathy in galactose-fed dogs by aldose reductase inhibitors. Arch Ophthalmol 108:1301–1309PubMedGoogle Scholar
  41. 41.
    Komrower GM (1982) Galactosemiathirty years on. The experience of a generation. J Inherited Metab Dis 5:96–104CrossRefGoogle Scholar
  42. 42.
    Leslie ND, Immerman EB, Flach JE, Florez M, Fridovich-Keil JL, Elsas LJ (1992) The human galactose-1-phosphate uridyltransferase gene. Genomics 14:474–480CrossRefPubMedGoogle Scholar
  43. 43.
    Litman N, Kanter A, Fineberg L (1975) Galactokinase deficiency presenting as pseudotumor cerebri. J Pediatr 86:410–412PubMedGoogle Scholar
  44. 44.
    Lo W, Packman S, Nash S, Schmidt K, Ireland S, Diamond I, Ng W, Donnell G (1984) Curious neurologic sequelae in galactosemia. Pediatrics 73:309–312PubMedGoogle Scholar
  45. 45.
    Mason HH, Turner ME (1935) Chronic galactosemia. Am J Dis Child 50:359–374Google Scholar
  46. 46.
    Maxwell ES (1957) The enzymic interconversion of uridine diphosphogalactose and uridine diphosphoglucose. J Biol Chem 229:139–151PubMedGoogle Scholar
  47. 47.
    Naughton E (1993) Galactosemia surveys. Eur J PediatrGoogle Scholar
  48. 48.
    Ng WG, Xu YK, Kaufman FR, Donnell GN (1989) Deficit of uridine diphosphate galactose in galactosaemia. J Inher Metab Dis 12:257–266CrossRefGoogle Scholar
  49. 49.
    Ornstein KS, McGuire EJ, Berry GT, Roth S, Segal S (1992) Abnormal galactosylation of complex carbohydrates in fibroblasts from patients with galactose-1-phosphate uridyltransferase deficiency. Pediatr Res 31:508–511PubMedGoogle Scholar
  50. 50.
    Pesch L, Segal S, Topper YJ (1960) Progesterone effects on galactose metabolism in prepubertal patients with congenital galactosemia and in rats maintained on high galactose diets. J Clin Invest 39:178–184PubMedGoogle Scholar
  51. 51.
    Quan Ma R, Wells WW (1965) The distribution of galactitol in tissues of rats fed galactose. Biochem Biophys Res Commun 20:486–490CrossRefPubMedGoogle Scholar
  52. 52.
    Quan Ma R, Wells HJ, Wells WW (1966) Galactitol in the tissues of a galactosemic child. Am J Dis Child 112:477–478PubMedGoogle Scholar
  53. 53.
    Rancour NJ, Hawkins ED, Wells WW (1979) Galactose oxidation in liver. Arch Biochem Biophys 193:232–241CrossRefPubMedGoogle Scholar
  54. 54.
    Reichardt JKV, Berg P (1988) Cloning and characterization of a cDNA encoding human galactose-1-phosphate uridyltransferase. Mol Biol Med 5:107–122PubMedGoogle Scholar
  55. 55.
    Reichardt JKV, Woo SLC (1991) Molecular basis of galactosemia: mutations and polymorphisms in the gene encoding human galactose-1-phosphate uridyltransferase. Proc Natl Acad Sci USA 88:2633–2637PubMedGoogle Scholar
  56. 56.
    Reichardt JKV, Packman S, Woo SL (1991) Molecular characterization of two galactosemia mutations: correlation of mutations with highly conserved domains in galactose-1-phosphate uridyltransferase. Am J Hum Genet 49:860–867PubMedGoogle Scholar
  57. 57.
    Roe TF, Ng WG, Bergren WR, Donnell GN (1973) Urinary galactitol in galactosemic patients. Biochem Med 7:266–273CrossRefPubMedGoogle Scholar
  58. 58.
    Rogers S, Segal S (1984) Enhanced galactose metabolism in isolated perfused livers of folate-treated suckling rats. Metabolism 33:634–640CrossRefPubMedGoogle Scholar
  59. 59.
    Sardharwalla IB, Wraith JE, Bridge C, Fowler B, Roberts SA (1987) A patient with severe type epimerase-deficiency galactosemia. Abstract 25th Annual Symposium of the Society for the Study of Inborn Errors of MetabolismGoogle Scholar
  60. 60.
    Schweitzer S, Shin Y, Jakobs C and Brodehl J (1993) Long-term outcome in 134 patients with galactosaemia. Eur J Pediatr 152:36CrossRefPubMedGoogle Scholar
  61. 61.
    Segal S (1969) The negro variant of congenital galactosemia. In: Hsia DY (ed) Galactosemia. Thomas, Springer-field IL, pp 176–185Google Scholar
  62. 62.
    Segal S (1989) Disorders of galactose metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited diseases, 6th edn. McGraw Hill, New York, pp 453–480Google Scholar
  63. 63.
    Segal S (1995) Defective galactosylation in galactosemia: is low cell UDP-galactose an explanation? Eur J Pediatr 154 [Suppl 2]:S65-S71Google Scholar
  64. 64.
    Segal S, Bernstein H (1963) Observations on cataract formation in the newborn offspring of rats fed a high-galactose diet. J Pediatr 62:363–370PubMedGoogle Scholar
  65. 65.
    Segal S, Blair A (1961) Some observations on the metabolism of D-galactose in normal man. J Clin Invest 40:2016–2025Google Scholar
  66. 66.
    Segal S, Cuatrecasas P (1968) The oxidation of 14C galactose by patients with congenital galactosemia: evidence for a direct oxidative pathway. Am J Med 44:340–471CrossRefGoogle Scholar
  67. 67.
    Segal S, Blair A, Roth H (1965) The metabolism of galactose by patients with congenital galactosemia. Am J Med 38:62–70CrossRefPubMedGoogle Scholar
  68. 68.
    Segal S, Rogers S, Holtzapple P (1971) Liver galactose-1-phosphate uridyl-transferase: activity in normal and galactosemic subjects. J Clin Invest 50:627–641PubMedGoogle Scholar
  69. 69.
    Segal S, Rutman JY, Frimpter GW (1979) Galactokinase deficiency and mental retardation. J Pediatr 95:750–752PubMedGoogle Scholar
  70. 70.
    Steinmann B, Gitzelmann R, Zachmann M (1981) Hypogonadism and galactosaemia. N Engl J Med 305:464–465PubMedGoogle Scholar
  71. 71.
    Stewart M, Kurien M, Sherman W, Cotlier E (1968) Inositol changes in nerve and lens of galactose fed rats. J Neurochem 15:941–946PubMedGoogle Scholar
  72. 72.
    Tsai CM, Holmberg N, Ebner KE (1970) Purification, stabilization, and properties of bovine mammary UDP-galactose 4-epimerase.. Arch Biochem Biophys 136:233–244CrossRefPubMedGoogle Scholar
  73. 73.
    Van Heyningen R (1959) Formation of polyols by the lens of the rat with “sugar” cataracts. Nature 184:194–195Google Scholar
  74. 74.
    Yue DK, Hanwell MA, Satchell PN, Handelsman DJ, Turtle JR (1984) The effects of aldose reductase inhibition on nerve sorbitol and myo-inositol in diabetic and galactosemic rats. Metabolism 33:1119–1122CrossRefPubMedGoogle Scholar
  75. 75.
    Wada E (1986) Galactonolactone in experimental galactosemic animals. Arch Biochem Biophys. 251:215–221CrossRefPubMedGoogle Scholar
  76. 76.
    Waggoner DD, Buist NRM, Donnell GN (1990) Long-term prognosis in galactosemia: Results of a survey of 350 cases. J Inherited Metab Dis 13:802–818CrossRefPubMedGoogle Scholar
  77. 77.
    Warfield AS, Segal S (1978) Myo-inositol and phosphatidylinositol in synaptosomes from galactose-fed rats. Proc Natl Acad Sci 75:45–68PubMedGoogle Scholar
  78. 78.
    Wells HJ, Wells WW (1967) Galactose toxicity and myo-inositol metabolism in the developing rat brain. Biochemistry 6:1168–1173CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • Stanton Segal
    • 1
  1. 1.Division of Biochemical Development and Molecular DiseasesChildren's Hospital of PhiladelphiaPhiladelphiaUSA

Personalised recommendations