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Disease Categories > Genetic Disease

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Galactosemia

Galactosemia is a disorder of carbohydrate metabolism caused by a deficiency of one of three enzymes (galactokinase, galactose-1-phosphate uridyltransferase, uridine diphosphate galactose-4-epimerase) involved in galactose metabolism. The most common form, known as classic galactosemia, refers to deficiency of galactose-1-phosphate uridyltransferase (GALT).

Epidemiology

Incidence – 1/60,000 for classic galactosemia, 1/30,000 for all variants combined
Age – classic galactosemia has neonatal onset, although some of its complications (developmental delays, speech dyspraxia, ataxia/tremors, ovarian failure) usually become evident later in life
Sex – equal distribution

Inheritance

Autosomal recessive
- Penetrance is 100% for severe GALT mutations
Classic (G/G) galactosemia is caused by two severe (G) GALT mutations
D/G galactosemia is caused by one severe and one mild (Duarte, D) GALT mutation
The Duarte (N314D) variant is present in 5% of Americans and reduces enzymatic activity by 50%; therefore, it is not considered a classic (G) GALT mutation
More than 190 GALT mutations have been reported

Pathophysiology

Classic galactosemia results in accumulation of galactose-1-phosphate, galactose, and its derivatives, galactitol, and galactonate
- The accumulation of these metabolites can cause organ dysfunction and cataracts
Accumulation of the same metabolites and possibly defective glycoconjugation might be involved in ovarian failure and speech dyspraxia
The GALT enzyme catalyzes the conversion of galactose-1-phosphate to uridylphosphate (UDP)-galactose
GALT enzyme activity
- 5% or less in classic disease (G/G)
- 25% in DG galactosemia (heterozygous for a Duarte and a severe mutation)
- 50% in individuals homozygous for Duarte mutation (D/D) or heterozygous for a G mutation (G/N)
- 75% in individuals heterozygous for Duarte (D/N)

Clinical Presentation of Classic Galactosemia

Symptoms usually manifest between 3 and 10 days post birth
Feeding problems, emesis, diarrhea, lethargy and failure to thrive
Hepatocellular damage – bleeding diathesis, abnormal liver function tests, hepatomegaly and jaundice
Untreated galactosemia often is complicated by gram-negative sepsis (E. coli in particular) and death
Elimination of galactose from the diet reverses growth failure, renal/hepatic dysfunction, and cataracts. However, patients can still have ovarian failure (primary or secondary amenorrhea), mental retardation, speech dyspraxia, ataxia and learning disabilities

Diagnosis

Laboratory testing
- Newborn screening for elevated galactose and/or reduced GALT enzyme activity may detect 100% of cases
- Enzyme activity in red blood cells can confirm the diagnosis
- Molecular genetic testing can further confirm the diagnosis and identify specific mutation(s), some of which (Q188R, K285N and others) have prognostic significance
- Measurement and periodic monitoring of galactose-1-phosphate levels should be performed on affected individuals
- Endogenous production of galactose may cause abnormally high values of galactose-1-phosphate even with dietary galactose restriction in patients with classic galactosemia

Differential Diagnosis

Sepsis
Liver disease from any cause (infectious, genetic, toxic)
Obstructive biliary disease
Other metabolic diseases (eg, urea cycle disorders)
Mitochondrial diseases

Treatment

Classic galactosemia (G/G) requires early and lifelong lactose restriction
Restrict diet to soy formulas as soon as possible
- Avoid casein hydrolysates (components in milk-based formulas) because they contain small quantities of bioavailable lactose
D/G galactosemia can be treated with galactose restriction in the first year of life
- These patients usually have no sequelae due to the variant form of galactosemia and can have an unrestricted diet after 12 months of life
The D/D genotype does not result in symptoms of galactosemia, thus, requires no treatment

Indications for Ordering

Tests generally appear in the order most useful for common clinical situations
Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Recommended Use	Limitations	Follow Up
Galactose-1-Phosphate in Red Blood Cells 0081296 Method: Gas Chromatography-Mass Spectrometry	Monitor response to and compliance with dietary treatment
Galactose-1-Phosphate Uridyltransferase 0080125 Method: Enzymatic	Measure GALT enzyme activity to determine disease status		GALT gene mutation analysis is recommended to determine the specific mutations in affected individuals
Galactosemia, (GALT) Enzyme Activity & 9 Mutations 0051175 Method: Enzymatic/Polymerase Chain Reaction/Single Nucleotide Extensions	Clarify an abnormal newborn screen for galactosemia; test neonates of an affected individual; carrier testing of parents of an affected individual Detects common GALT gene mutations (Q188R, S135L, K285N, T138M, L195P, Y209C, IVS2-2 A>G, N314D and L218L) as well as measuring GALT enzyme activity in red blood cells Analytical sensitivity and specificity is 99%	This test should not be used to monitor the dietary compliance of affected individuals Rare forms of galactosemia (caused by a deficiency of either galactokinase or galactose-4-epimerase) will not be detected	If the enzyme activity is in the affected range and two mutations are not detected, full gene sequencing is recommended to identify the causative GALT mutations
Galactosemia, GALT Gene Mutations 0051176 Method: Polymerase Chain Reaction/Single Nucleotide Extensions	Detects common GALT gene mutations (Q188R, S135L, K285N, T138M, L195P, Y209C, IVS2-2 A>G, N314D and L218L) Analytical sensitivity and specificity is 99%	Only the nine GALT mutations will be detected The fact that two specific mutations in the GALT gene are not detected does not eliminate the possibility of the disorder as it may be caused by rare GALT mutations not detected by this assay	If the enzyme activity is in the affected range and two mutations are not detected then, full gene sequencing is recommended to identify the causative GALT mutations
Galactosemia, GALT Gene Mutations, Fetal 0051270 Method: Polymerase Chain Reaction/Single Nucleotide Extensions	Detect 9 common fetal GALT gene mutations (Q188R, S135L, K285N, T138M, L195P, Y209C, and IVS2-2 A>G, N314D and L218L) Analytical sensitivity and specificity is 99%	Only the 9 GALT mutations will be detected Only families with 2 GALT mutations on this DNA panel should order this test	Cost-free result confirmation on neonatal cord blood post delivery is encouraged
Galactosemia (GALT) Sequencing 0051346 Method: Polymerase Chain Reaction/Sequencing	Sequencing of the entire GALT gene coding region and intron/exon borders Analytical sensitivity and specificity is 99% The clinical sensitivity for GALT sequencing is 98%	Deep intronic GALT mutations and large gene deletions or duplications will not be detected; analytical sensitivity may be compromised by rare primer site mutations	If 2 mutations are not detected in a known affected patient, GALT deletion/duplication analysis should be considered

General References

ARUP Laboratories: GALT Mutation Database. (Accessed 25 Feb 2008) (Link to resource)

Bosch AM. Classical galactosaemia revisited. J Inherit Metab Dis. 2006;29(4):516-525. (Link to PubMed)

Carreiro-Lewandowski E. Newborn screening: an overview. Clin Lab Sci. 2002;15(4):229-238. (Link to PubMed)

Clague A, Thomas A. Neonatal biochemical screening for disease. Clin Chim Acta. 2002;315(1-2):99-110. (Link to PubMed)

GeneTests: Galactosemia. (Accessed 25 Feb 2008) (Link to resource)

Ogier de Baulny H. Management and emergency treatments of neonates with a suspicion of inborn errors of metabolism. Semin Neonatol. 2002;7(1):17-26. (Link to PubMed)

Saudubray JM, Nassogne MC, de Lonlay P, Touati G. Clinical approach to inherited metabolic disorders in neonates: an overview. Semin Neonatol. 2002;7(1):3-15. (Link to PubMed)

Schweitzer-Krantz S. Early diagnosis of inherited metabolic disorders towards improving outcome: the controversial issue of galactosaemia. Eur J Pediatr. 2003;162 Suppl 1:S50-S53. (Link to PubMed)

References from the ARUP Institute for Clinical and Experimental Pathology®

Calderon FR, Nelson L, Dobrowolski P, Sinitsyna I, Phansalkar A, Longo N, Pasquali M, Mao R. Combination of enzyme analysis, allele-specific PCR and sequencing to detect mutations in the GALT gene. J Inherit Metab Dis. 2007;30(5):818-. (Link to PubMed)

Calderon FR, Phansalkar AR, Crockett DK, Miller M, Mao R. Mutation database for the galactose-1-phosphate uridyltransferase (GALT) gene. Hum Mutat. 2007;28(10):939-943. (Link to PubMed)

Jama M, Nelson L, Mao R, Lyon E. Simultaneous amplification, detection, and analysis of common mutations in the galactose-1-phosphate uridyl transferase gene. J Mol Diagn. 2007;9(5):618-623. (Link to PubMed)

Reviewed by

Longo, Nicola , M.D., Ph.D. Medical Director, Biochemical Genetics at ARUP Laboratories; Adjunct Associate Professor, Pediatrics and Pathology, University of Utah

Lyon, Elaine, Ph.D. Medical Director, Molecular Genetics at ARUP Laboratories; Associate Professor, Pathology, University of Utah

Mao, Rong , M.D. Co-Medical Director, Molecular Genetics at ARUP Laboratories; Assistant Professor, Pathology, University of Utah

Pasquali, Marzia , Ph.D., FACMG Medical Director, Biochemical Genetics and Supplemental Newborn Screening at ARUP Laboratories; Associate Professor, Clinical Pathology, University of Utah

Comprehensive Review: March 2008
Last Update: May 2008