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

Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia)

Gerard T Berry, MD, Professor of Pediatrics, Children's Hospital of Boston
George A Anadiotis, DO, Consulting Staff, Division of Clinical and Biochemical Genetics, Department of Pediatric Rehabilitation and Development, Emmanuel Children's Hospital

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

Differential Diagnoses

Fructose 1-Phosphate Aldolase Deficiency (Fructose Intolerance)
Galactokinase Deficiency
Hemochromatosis, Neonatal

Workup

Laboratory Studies

All states perform newborn screening.
A positive (ie, abnormal) indication on the newborn screen must be followed by a quantitative erythrocyte galactose-1-phosphate uridyltransferase (GALT) analysis by a laboratory that routinely performs biochemical genetic testing and consultation.
A GALT isoelectric-focusing electrophoresis test helps distinguish variant forms such as the Duarte defect. GALT genotyping may provide a specific molecular diagnosis. The most common GALT allele in Caucasians is the Q188R mutation. The S135L mutation is common in blacks.²²
A urine-reducing substances test may help. This test's results are almost always abnormal (ie, positive) in infants with galactosemia who are ingesting lactose. This is a tube test rather than a dipstick test and must be differentiated from the routine urine dipstick test for glucose.

Imaging Studies

Patients with galactosemia may exhibit white matter abnormalities on MRI of brain.
Pseudotumor cerebri has been detected in the newborn period.

Other Tests

Infants with galactosemia can become jaundiced. Hyperbilirubinemia is often unconjugated but can become conjugated later.
Urine examination reveals evidence of albuminuria and, later, a generalized aminoaciduria. Eliminating lactose-containing formula from the diet quickly resolves the albuminuria.

Histologic Findings

Fatty infiltration and inflammatory changes initially may occur in the liver.
Portal hypertension and pseudoacinar formation occur in later stages.
Cirrhosis occurs in the final stage and is indistinguishable from other causes.

Treatment

Medical Care

The mainstay of medical care in the postnatal period is to immediately discontinue ingestion of lactose-containing formula.
This ameliorates the acute toxicity associated with the neonatal period but does not prevent all long-term complications.
Clotting abnormalities may be cryptic and require fresh frozen plasma treatments.¹⁰

Consultations

Refer children to appropriate language and speech centers to optimize treatment for learning problems.
Refer women to an endocrinologist or reproductive gynecologist for appropriate treatment for ovarian failure.
No standardized treatment for short stature has been established, and the etiology is unknown in many instances.
Because dietary therapy is necessary, refer patients to a dietitian who has experience with metabolic disorders.
Consultation with a biochemical geneticist (ie, metabolic disease specialist) is advisable for diagnostic laboratory evaluation, monitoring, and clinical care for patients with galactosemia.

Diet

Prescribe a galactose-restricted diet for infants who are galactosemic. Older patients may tolerate lactose better than infants. The restriction of milk intake throughout life is controversial. However, most metabolic specialists support a life-long diet therapy.⁷
Totally eliminating galactose is difficult because it is present in a wide variety of foods (eg, infant foods, fruits, vegetables), especially in the macromolecular form.
Dietary restrictions during pregnancy, as well as prospectively during postnatal life, may have no effect on long-term complications of an affected fetus.

Medication

Drug therapy currently is not a component of the standard of care for this condition. See Treatment.

Follow-up

Further Inpatient Care

During the initial hospitalization for a child with symptomatic severe classic galactosemia, the major concerns are sepsis, bleeding, liver dysfunction, and brain swelling. Treat these conditions as they would be treated in patients who do not have galactosemia.
Immediate and total removal of galactose from the diet is the only specific treatment for a patient with galactosemia that differs from treatments for patients with sepsis or liver dysfunction from other causes.

Prognosis

If untreated, severe classic galactosemia is a life-threatening disorder. Fortunately, most states and developed countries screen for galactosemia in the newborn period, and affected infants are treated before they become very ill.
Infants with galactosemia who are severely ill (eg, those with sepsis, coagulopathy, liver dysfunction) before treatment for galactosemia is initiated may develop permanent liver, brain, and/or eye damage (although cataracts are often completely reversible).
Most patients with severe galactosemia who do not receive treatment often do not survive the newborn period.
Even with appropriate dietary therapy, most patients have at least 1-2 long-term complications.

Patient Education

Dietary therapy requires both parental and patient education. Involve children in their dietary management as soon as appropriate.

Miscellaneous

Medicolegal Pitfalls

Failure to respond appropriately to a positive (ie, abnormal) neonatal screening test result
Failure to restrict galactose in the diet of an affected infant
Failure to follow up a positive (ie, abnormal) screening test result with a quantitative galactose-1-phosphate uridyltransferase (GALT) analysis
Failure to test for or consider galactosemia in the clinical setting due to the mistaken assumption that all children are screened for galactosemia or that the screening test is 100% accurate and foolproof

Special Concerns

Although the initial toxicity of infancy is resolved by a galactose-restricted diet, long-term complications require regular follow-up with a physician.

References

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

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.

Further Reading