AUTHOR INFORMATION

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Authored by Gerard T Berry, MD, Professor of Pediatrics and Biochemistry, Thomas Jefferson University

Coauthored by George A Anadiotis, DO, Consulting Staff, Department of Pediatric Rehabilitation and Development, Division of Clinical and Biochemical Genetics, Emmanuel Children's Hospital

Gerard T Berry, MD, is a member of the following medical societies: American College of Medical Genetics, American Diabetes Association, American Society for Biochemistry and Molecular Biology, American Society of Human Genetics, Federation of American Society of Experimental Biology, Lawson-Wilkins Pediatric Endocrine Society, Sigma Xi, Society for Inherited Metabolic Disorders, Society for Pediatric Research, and Society for the Study of Inborn Errors of Metabolism

Edited by Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Head of Division of Metabolism, Department of Pediatrics, Oregon Health & Science University; Director, Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Hagop Youssoufian, MSc, MD, Medical Director, Adjunct Associate Professor, Clinical Discovery Department, Bristol-Myers Squibb; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Gerard T Berry, MD
Editor's Email:	Robert D Steiner, MD

eMedicine Journal, September 22 2006, VOLUME 7, Number 9

INTRODUCTION

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Background: Hereditary galactosemia is among the most common carbohydrate metabolism disorders and can be a life-threatening illness during the newborn period. 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. Removing lactose largely eliminates the toxicity associated with newborn disease, but long-term complications routinely occur, as reported by Komrower and Lee in 1970 and then delineated in a 1990 retrospective survey by Waggoner and associates.

Pathophysiology: Hypergalactosemia is associated with the following 3 enzyme deficiencies:

• 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:

• In the US: Incidence is approximately 1 case in 40,000-60,000 persons.

• Internationally: Incidence varies widely (ie, 1 case in 70,000 people in the UK but 1 case in 30,000 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.

Race: Galactosemia occurs in all races; however, galactosemia variants exist based upon 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. The ability of an individual with the variant gene defect to tolerate ingestion of some milk may hinder diagnosis in states without newborn screening. Remember, however, that some blacks may have severe classic galactosemia.

• A probably benign variety exists, 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 currently 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.

Sex: Galactosemia affects males and females equally.

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

CLINICAL

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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.



• Almost all infants on a lactose-containing diet manifest poor weight gain.

Physical:

• Untreated infants with severely deficient GALT activity typically present with the following variable findings:


• • Lethargy

  • Hypotonia

  • Jaundice

  • Liver dysfunction and/or hepatomegaly

  • Bleeding from coagulopathy

  • Sepsis

  • Cataracts (sometimes as early as the first few days of life)

  • Poor growth within the first few weeks of life
  
  
  
• Surprisingly, ascites also may 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. Galactosemia and E coli sepsis are associated. Galactosemia should be high on the differential diagnosis of term infants with sepsis caused by infection with this pathogen.



• Learning problems and speech/language deficits are common, and language acquisition may be delayed.



• The most common findings in adults include hypergonadotropic hypogonadism or primary ovarian failure in women, although some women have become pregnant, most notably blacks who probably have variant disease. Short stature and neurologic abnormalities (eg, tremor, ataxia) also occur in a minority of patients.

Causes: Classic galactosemia is caused by a severe deficiency in galactose-1-phosphate uridyltransferase. The deficiency is an autosomal recessive genetic condition. The gene for GALT is located at band 9p13.

DIFFERENTIALS

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

Other Problems to be Considered:

Respiratory chain disorders (usually associated with hyperlacticacidemia)
Fanconi-Bickel syndrome
Alpha1-antitrypsin deficiency
Sepsis
Tyrosinemia type 1

WORKUP

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Lab Studies:

• All states perform newborn screening.



• A positive (ie, abnormal) indication on the newborn screen must be followed by a quantitative erythrocyte 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 whites is the Q188R mutation. The S135L mutation is common in blacks.



• A urine-reducing substances test may help. This test’s results almost always are 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.

Other Tests:

• Infants who are galactosemic can become jaundiced. Hyperbilirubinemia often is 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.

TREATMENT

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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.

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 appear to tolerate lactose much better than children. The restriction of milk intake throughout life is controversial. Most metabolic specialists support a life-long diet therapy.



• 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 may have no effect on long-term complications of an affected fetus.

MEDICATION

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

FOLLOW-UP

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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 and/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, and/or liver dysfunction) before treatment for galactosemia is initiated may develop permanent liver, brain, and/or eye damage, although cataracts often are completely reversible. Even with appropriate dietary therapy, most patients have at least 1 long-term complication.

Patient Education:

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

MISCELLANEOUS

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Medical/Legal 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 or child



• Failure to follow up a positive (ie, abnormal) screening test result with a quantitative 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:

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

TEST QUESTIONS

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CME Question 1: A physician examines an infant who has a positive (ie, abnormal) result for galactosemia on the newborn screening test and institutes a lactose-free formula. What is the physician’s next most appropriate step?

A: Order an ophthalmologic examination.
B: Repeat the newborn screen.
C: Direct studies to check ovarian function.
D: Send blood for an erythrocyte galactose-1-phosphate uridyltransferase (GALT) analysis.
E: None of the above

The correct answer is D: In a stable newborn infant with a positive screen who has been placed on the appropriate diet, a blood GALT assay is the next most appropriate step. This is the criterion standard test because a repeat newborn screening test provides no new information. The other tests can be performed when the diagnosis is confirmed.

CME Question 2: Which of the following is not a finding in adults with galactosemia?

A: Speech/language or cognitive defects
B: Distinct coarse facial features
C: Primary ovarian failure
D: Short stature
E: Tremor

The correct answer is B: All the findings except coarse facial features are associated with galactosemia. Coarse facial features are most prominent in the clinical spectrum of mucopolysaccharide disorders such as Hurler syndrome.

Pearl Question 1 (T/F): Escherichia coli sepsis is associated with galactosemia.

The correct answer is True: Galactosemia and E coli sepsis are associated. Galactosemia should be high on the differential diagnosis of term infants with sepsis caused by infection with this pathogen.

Pearl Question 2 (T/F): Hypergonadotropic hypogonadism and primary ovarian failure are the most common endocrine abnormalities in adult women with galactosemia.

The correct answer is True: The most common findings in adults include hypergonadotropic hypogonadism or primary ovarian failure in women, although some women have become pregnant, most notably blacks who probably have variant disease. Short stature and neurologic abnormalities (eg, tremor, ataxia) also occur.

Pearl Question 3 (T/F): The most common enzymatic deficiency causing galactosemia is galactokinase deficiency.

The correct answer is False: Galactose-1-phosphate uridyltransferase deficiency is the most common cause of galactosemia.

Pearl Question 4 (T/F): Among Native Americans, a gene variant is responsible for 10% enzyme activity in the liver but no activity in the erythrocytes.

The correct answer is False: This gene variant is most commonly found in black Americans.

BIBLIOGRAPHY

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• Arn PH: Galactosemia. Curr Treat Options Neurol 2003 Jul; 5(4): 343-345[Medline].
• Bosch AM: Classical galactosaemia revisited. J Inherit Metab Dis 2006 Jul 11;[Medline].
• Elsas L, Fridovich-Keil J, Leslie N: Galactosemia: a molecular approach to the enigma. In: International Pediatrics. 1993:101-9.
• 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].
• Garden AS, Davidson DC: Recommendations for the management of galactosaemia. Arch Dis Child 2000 Mar; 82(3): 266[Medline].
• Gibson JB: Gonadal function in galactosemics and in galactose-intoxicated animals. Eur J Pediatr 1995; 154(7 Suppl 2): S14-20[Medline].
• Holton JB, Leonard JV: Clouds still gathering over galactosaemia. Lancet 1994 Nov 5; 344(8932): 1242-3[Medline].
• Nelson CD, Waggoner DD, Donnell GN, et al: Verbal dyspraxia in treated galactosemia. Pediatrics 1991 Aug; 88(2): 346-50[Medline].
• Ridel KR, Leslie ND, Gilbert DL: An updated review of the long-term neurological effects of galactosemia. Pediatr Neurol 2005 Sep; 33(3): 153-61[Medline].
• Schweitzer S, Shin Y, Jakobs C, Brodehl J: Long-term outcome in 134 patients with galactosaemia. Eur J Pediatr 1993 Jan; 152(1): 36-43[Medline].
• Schweitzer-Krantz S: Early diagnosis of inherited metabolic disorders towards improving outcome: the controversial issue of galactosaemia. Eur J Pediatr 2003 Dec; 162 Suppl 1: S50-3[Medline].
• Segal S, Berry G: Disorders of galactose metabolism. In: The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill; 1995:967-1000.
• Segal S: Komrower Lecture. Galactosaemia today: the enigma and the challenge. J Inherit Metab Dis 1998 Aug; 21(5): 455-71[Medline].
• Segal S: Galactosemia unsolved. Eur J Pediatr 1995; 154(7 Suppl 2): S97-102[Medline].
• 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].
• Walter JH, Collins JE, Leonard JV: Recommendations for the management of galactosaemia. UK Galactosaemia Steering Group. Arch Dis Child 1999 Jan; 80(1): 93-6[Medline].

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