Galactosemia

Clinical Background

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

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

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: Galactose-1-Phosphate in Red Blood Cells

ARUP #: 0081296

Methodology: Gas Chromatography-Mass Spectrometry

Use:

Monitor response to and compliance with dietary treatment

Test name: Galactose-1-Phosphate Uridyltransferase

ARUP #: 0080125

Methodology: Enzymatic

Use:

Measure GALT enzyme activity to determine disease status

Follow-up:

GALT gene mutation analysis is recommended to determine the specific mutations in affected individuals

Test name: Galactosemia, (GALT) Enzyme Activity & 9 Mutations

ARUP #: 0051175

Methodology: Enzymatic/Polymerase Chain Reaction/Single Nucleotide Extensions

Use:

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%

Limitations:

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

Follow-up:

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

Test name: Galactosemia, GALT Gene Mutations

ARUP #: 0051176

Methodology: Polymerase Chain Reaction/Single Nucleotide Extensions

Use:

Detects common GALT gene mutations (Q188R, S135L, K285N, T138M, L195P, Y209C, IVS2-2 A>G, N314D and L218L)

Analytical sensitivity and specificity is 99%

Limitations:

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

Follow-up:

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

Test name: Galactosemia, (GALT ) 9 Mutations, Fetal

ARUP #: 0051270

Methodology: Polymerase Chain Reaction/Single Nucleotide Extensions

Use:

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%

Limitations:

Only the 9 GALT mutations will be detected

Only families with 2 GALT mutations on this DNA panel should order this test

Follow-up:

Cost-free result confirmation on neonatal cord blood post delivery is encouraged

Test name: Galactosemia (GALT) Sequencing

ARUP #: 0051346

Methodology: Polymerase Chain Reaction/Sequencing

Use:

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%

Limitations:

Deep intronic GALT mutations and large gene deletions or duplications will not be detected; analytical sensitivity may be compromised by rare primer site mutations

Follow-up:

If 2 mutations are not detected in a known affected patient, GALT deletion/duplication analysis should be considered

References

General References

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

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

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

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

GeneTests: Galactosemia. (Accessed 25 Feb 2008)

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.

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.

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.

References from the ARUP Institute for Clinical and Experimental Pathology Research®

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-.

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.

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.

Medical Reviewers

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