eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia)

Author: Gerard T Berry, MD, Professor of Pediatrics, Children's Hospital of Boston
Coauthor(s): George A Anadiotis, DO, Consulting Staff, Division of Clinical and Biochemical Genetics, Department of Pediatric Rehabilitation and Development, Emmanuel Children's Hospital
Contributor Information and Disclosures

Updated: Oct 10, 2008

Introduction

Background

Hereditary galactosemia is among the most common carbohydrate metabolism disorders and can be a life-threatening illness during the newborn period.1,2,3 First described in a variant patient in 1935 by Mason and Turner, galactose-1-phosphate uridyltransferase (GALT) deficiency is the most common enzyme deficiency that causes hypergalactosemia.4 Removing lactose largely eliminates the toxicity associated with newborn disease, but long-term complications routinely occur, as reported by Komrower and Lee in 19705 and then delineated in a 1990 retrospective survey by Waggoner and associates.6

Pathophysiology

Hypergalactosemia is associated with the following 3 enzyme deficiencies:1

  • Galactokinase converts galactose to galactose-1-phosphate and is not a common deficiency.
  • Uridine diphosphate (UDP) galactose-4-epimerase epimerizes UDP galactose to UDP glucose and is also uncommon.
  • GALT is responsible for hereditary galactosemia and is the most common deficiency. This enzyme catalyzes conversion of galactose-1-phosphate and UDP glucose to UDP galactose and glucose-1-phosphate. Individuals with GALT deficiency manifest abnormal galactose tolerance.

Frequency

United States

Incidence is approximately 1 case per 40,000-60,000 persons.3

International

Incidence widely varies (ie, 1 case in 70,000 people in the UK but 1 case in 20,000 people in Ireland.) The disorder is thought to be much less common in Asians.

Mortality/Morbidity

Aside from the high mortality rate in newborn infants with sepsis caused by Escherichia coli, life expectancy has never been studied in patients with galactosemia. Most patients appear to reach adulthood following institution of a galactose-restricted diet.7,1

Race

Galactosemia occurs in all races; however, galactosemia variants are based on the exact gene defect.

  • Variants are most notable among the black population. Affected individuals may have approximately 10% of enzyme activity in the liver but no activity in the erythrocytes.2  The ability of an individual with the variant gene defect to tolerate ingestion of some milk may hinder diagnosis in states without newborn screening.
  • A likely benign variety is recognized, known as the Duarte variant. Neonates with this variant may or may not have positive (ie, abnormal) newborn screening test results, and most can tolerate normal diets. During infancy, but less so in childhood, these individuals may have elevated galactose metabolite levels.
  • Whether dietary galactose restriction is necessary or beneficial for patients with Duarte variant galactosemia is unknown. Many metabolic disease specialists take a conservative approach and recommend galactose restriction in the first year of life when milk intake is highest, but this restriction is based primarily on theoretical concerns of galactose toxicity in infants with the Duarte variant.8

Sex

Galactosemia equally affects males and females.

Age

Galactosemia is most often diagnosed in infancy by newborn screening because all states include galactosemia as part of their newborn screen. Variant forms of galactosemia can present later.

Clinical

History

  • In all states, galactosemia is detected with a positive (ie, abnormal) newborn screening test result.
  • Parents often complain to physicians about various feeding difficulties with their newborn, most notably, vomiting.9
  • Almost all infants on a lactose-containing diet manifest poor weight gain.

Physical

  • Untreated infants with severely deficient galactose-1-phosphate uridyltransferase (GALT) activity typically present with the following variable findings:
    • Poor growth within the first few weeks of life
    • Jaundice
    • Bleeding from coagulopathy
    • Liver dysfunction and/or hepatomegaly
    • Cataracts (sometimes as early as the first few days of life)
    • Lethargy
    • Hypotonia
    • Sepsis (E coli)
  • Surprisingly, ascites may also be detected during early infancy. In some patients, ascites are detected as early as the first few days of life.
  • In an infant or child with cataracts, galactosemia must be excluded. If unsure, consult an ophthalmologist because some cataracts, especially congenital cataracts, are visible only by using a slitlamp.
  • Vitreous hemorrhage is a known complication of galactosemia, although its prevalence is unknown.10  An enigmatic linkage of E coli sepsis with galactosemia is noted. Galactosemia should be high on the differential diagnosis of term infants with sepsis caused by infection with this pathogen.
  • Learning problems and speech and language deficits are common; language acquisition may be delayed.11,12,9,13
  • The most common findings in adults include hypergonadotropic hypogonadism or primary ovarian insufficiency in women, although some women have become pregnant, most notably blacks who probably have variant disease.14,15,16,17,1 Short stature and neurologic abnormalities (eg, tremor, ataxia, dystonia) also occur in a minority of patients.18,1
  • Rare reports of patients with severe galactosemia off of diet therapy since childhood have raised concerns about whether lactose restriction needs to be maintained after infancy.19,20

Causes

  • Classic galactosemia is caused by a severe deficiency in GALT.
  • The deficiency is an autosomal recessive genetic condition.
  • The gene for GALT is located on chromosome 9p13.21,22

More on Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia)

Overview: Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia)
Differential Diagnoses & Workup: Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia)
Treatment & Medication: Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia)
Follow-up: Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia)
References
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References

  1. Berry GT, Segal S and Gitzelmann R. Disorders of Galactose Metabolism. In: Fernandes J, Saudubray M, van den Berghe G, Walter JH. Inborn Metabolic Diseases – Diagnosis and Treatment. 4. New York, NY: Springer-Verlag, Inc; 2006.

  2. Segal S. Galactosemia unsolved. Eur J Pediatr. 1995;154(7 Suppl 2):S97-102. [Medline].

  3. Fridovich-Keil J, Walter. Galactosemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill Medical Publishing Division; 2008:72.

  4. Mason HH, Turner ME. Chronic galactosemia: report of case with studies on carbohydrates. Am J Dis Child. 1935;50:359-74.

  5. Komrower GM, Lee DH. Long-term follow-up of galactosaemia. Arch Dis Child. Jun 1970;45(241):367-73. [Medline].

  6. Waggoner DD, Buist NR, Donnell GN. Long-term prognosis in galactosaemia: results of a survey of 350 cases. J Inherit Metab Dis. 1990;13(6):802-18. [Medline].

  7. Walter JH, Collins JE, Leonard JV. Recommendations for the management of galactosaemia. UK Galactosaemia Steering Group. Arch Dis Child. Jan 1999;80(1):93-6. [Medline].

  8. Garden AS, Davidson DC. Recommendations for the management of galactosaemia. Arch Dis Child. Mar 2000;82(3):266. [Medline].

  9. Antshel KM, Epstein IO, Waisbren SE. Cognitive strengths and weaknesses in children and adolescents homozygous for the galactosemia Q188R mutation: a descriptive study. Neuropsychology. Oct 2004;18(4):658-64. [Medline].

  10. Levy HL, Brown AE, Williams SE, de Juan E Jr. Vitreous hemorrhage as an ophthalmic complication of galactosemia. J Pediatr. Dec 1996;129(6):922-5. [Medline].

  11. Waisbren SE, Norman TR, Schnell RR, Levy HL. Speech and language deficits in early-treated children with galactosemia. J Pediatr. Jan 1983;102(1):75-7. [Medline].

  12. Nelson CD, Waggoner DD, Donnell GN, et al. Verbal dyspraxia in treated galactosemia. Pediatrics. Aug 1991;88(2):346-50. [Medline].

  13. Potter NL, Lazarus JA, Johnson JM, Steiner RD, Shriberg LD. Correlates of language impairment in children with galactosaemia. J Inherit Metab Dis. Aug 2008;31(4):524-32. [Medline].

  14. Kaufman FR, Kogut MD, Donnell GN, Goebelsmann U, March C, Koch R. Hypergonadotropic hypogonadism in female patients with galactosemia. N Engl J Med. Apr 23 1981;304(17):994-8. [Medline].

  15. Guerrero NV, Singh RH, Manatunga A, Berry GT, Steiner RD, Elsas LJ 2nd. Risk factors for premature ovarian failure in females with galactosemia. J Pediatr. Dec 2000;137(6):833-41. [Medline].

  16. Forges T, Monnier-Barbarino P. [Premature ovarian failure in galactosaemia: pathophysiology and clinical management]. Pathol Biol (Paris). Feb 2003;51(1):47-56. [Medline].

  17. Gubbels CS, Land JA, Rubio-Gozalbo ME. Fertility and impact of pregnancies on the mother and child in classic galactosemia. Obstet Gynecol Surv. May 2008;63(5):334-43. [Medline].

  18. Schweitzer S, Shin Y, Jakobs C, Brodehl J. Long-term outcome in 134 patients with galactosaemia. Eur J Pediatr. Jan 1993;152(1):36-43. [Medline].

  19. Schadewaldt P, Lilburn M, Wendel U, Lee P. Unexpected outcome in untreated galactosaemia. Molecular Genetics and Metabolism. 2004;81:255-57.

  20. Panis B, Bakker JA, Sels JP, Spaapen LJ, van Loon LJ, Rubio-Gozalbo ME. Untreated classical galactosemia patient with mild phenotype. Mol Genet Metab. Nov 2006;89(3):277-9. [Medline].

  21. Elsas L, Fridovich-Keil J, Leslie N. Galactosemia: a molecular approach to the enigma. In: International Pediatrics. 1993:101-9.

  22. Elsas LJ 2nd, Langley S, Paulk EM, et al. A molecular approach to galactosemia. Eur J Pediatr. 1995;154(7 Suppl 2):S21-7. [Medline].

  23. Arn PH. Galactosemia. Curr Treat Options Neurol. Jul 2003;5(4):343-345. [Medline].

  24. Berry GT. Galactosemia and amenorrhea in the adolescent. Ann N Y Acad Sci. 2008;1135:112-7. [Medline].

  25. Bosch AM. Classical galactosaemia revisited. J Inherit Metab Dis. Aug 2006;29(4):516-25. [Medline].

  26. Forges T, Monnier-Barbarino P, Leheup B, Jouvet P. Pathophysiology of impaired ovarian function in galactosaemia. Hum Reprod Update. Sep-Oct 2006;12(5):573-84. [Medline].

  27. Gibson JB. Gonadal function in galactosemics and in galactose-intoxicated animals. Eur J Pediatr. 1995;154(7 Suppl 2):S14-20. [Medline].

  28. Holton JB, Leonard JV. Clouds still gathering over galactosaemia. Lancet. Nov 5 1994;344(8932):1242-3. [Medline].

  29. Komrower GM. Clouds over galactosemia. Lancet. Jan 22 1983;1(8317):190. [Medline].

  30. Komrower GM. Galactosaemia - thirty years on the experience of a generation. J Inherit Metab Dis. 1982;5(Suppl 2):96-104.

  31. Leslie ND. Insights into the pathogenesis of galactosemia. Annu Rev Nutr. 2003;23:59-80. [Medline].

  32. Ridel KR, Leslie ND, Gilbert DL. An updated review of the long-term neurological effects of galactosemia. Pediatr Neurol. Sep 2005;33(3):153-61. [Medline].

  33. Schweitzer-Krantz S. Early diagnosis of inherited metabolic disorders towards improving outcome: the controversial issue of galactosaemia. Eur J Pediatr. Dec 2003;162 Suppl 1:S50-3. [Medline].

  34. Segal S. Komrower Lecture. Galactosaemia today: the enigma and the challenge. J Inherit Metab Dis. Aug 1998;21(5):455-71. [Medline].

  35. Segal S, Berry G. Disorders of galactose metabolism. In: The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill; 1995:967-1000.

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Further Reading

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Keywords

galactose-1-phosphate uridyltransferase deficiency, GALT, hypergalactosemia, classic galactosemia, GALT deficiency, Escherichia coli, E coli, sepsis, Duarte variant, liver dysfunction, hepatomegaly, cataract, hypotonia, ascites, learning disorder, delayed language acquisition, language deficit, speech deficit, hypergonadotropic hypogonadism, primary ovarian insufficiency

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Contributor Information and Disclosures

Author

Gerard T Berry, MD, Professor of Pediatrics, Children's Hospital of Boston
Gerard T Berry, MD is a member of the following medical societies: American College of Medical Genetics, American Diabetes Association, American Society of Human Genetics, Federation of American Societies for Experimental Biology, Lawson-Wilkins Pediatric Endocrine Society, Sigma Xi, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Coauthor(s)

George A Anadiotis, DO, Consulting Staff, Division of Clinical and Biochemical Genetics, Department of Pediatric Rehabilitation and Development, Emmanuel Children's Hospital
George A Anadiotis, DO is a member of the following medical societies: American Medical Association and American Society of Human Genetics
Disclosure: Nothing to disclose.

Medical Editor

Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Deputy Director, Oregon Clinical and Translational Research Institute
Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research
Disclosure: Genzyme Honoraria Speaking and teaching; Genzyme Grant/research funds Other; Shire Honoraria Speaking and teaching; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Speaking and teaching; Biomarin Consulting fee Consulting

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Hagop Youssoufian, MD, MSc, Vice President of Clinical Research, ImClone Systems Incorporated
Hagop Youssoufian, MD, MSc is a member of the following medical societies: American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Human Genetics
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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