Enzymatic/Polymerase Chain Reaction/Single Nucleotide Extensions
Related Tests
Enzymatic/Liquid Chromatography-Tandem Mass Spectrometry
May be used as initial screening test to diagnose individuals with classic galactosemia
Polymerase Chain Reaction/Single Nucleotide Extensions
Use to clarify genotype when enzyme activity is known
Sequencing
Use when GALT enzyme activity is consistent with galactosemia, and the nine pathogenic variant panel fails to identify two causative variants
Polymerase Chain Reaction/Single Nucleotide Extensions
Useful for prenatal diagnosis of GALT variant only if proband has known pathogenic variant
Contact an ARUP genetic counselor before ordering this test for special instructions.
Gas Chromatography-Mass Spectrometry (GC-MS)
Monitor levels, response, and compliance with dietary restriction for individuals with an established diagnosis
Polymerase Chain Reaction/Sequencing
Useful when a familial variant identifiable by sequencing is known
Galactosemia can result in life-threatening complications including feeding problems, failure to thrive, hepatocellular damage, bleeding, and E. coli sepsis in untreated infants. If a lactose-restricted diet is provided during the first 10 days of life, the neonatal signs usually quickly resolve and the complications of liver failure, sepsis, and neonatal death are prevented; however, despite adequate treatment from an early age, children with classic galactosemia remain at increased risk for developmental delays, speech problems (termed childhood apraxia of speech and dysarthria), and abnormalities of motor function.
Disease Overview
Incidence
1/30,000-60,000 live births in White individuals
- Other ethnicities vary
Age of Onset
- Typically asymptomatic at birth
- Develop escalating symptoms within 3-14 days of birth following exposure to a milk-based diet
Symptoms
- Most common presenting symptoms in untreated infants
- Hepatocellular damage
- Food intolerance
- Sepsis
- Death
- Other symptoms
- Failure to thrive
- Lethargy
- Seizures
- If infant with disease is left untreated, liver and brain damage are irreversible
- Sequelae in treated affected individuals
- Speech problems
- Premature ovarian insufficiency
- Intellectual impairment
- Neurologic deficits
- Cataracts
Etiology
- Galactose-1-phosphate uridyltransferase (GALT) is an enzyme involved in galactose utilization
- Other enzyme deficiencies are rare
- Deficiency results in accumulation of galactose-1-phosphate, galactitol, and galactonate
- Genotype/phenotype correlation helps in prognostication
Genetics
Gene
GALT
Inheritance
Autosomal recessive
Penetrance
100% for classic galactosemia
Structure/Function
- Located on chromosome 9p13
- 11 exons
- Encodes for GALT enzyme involved in galactose metabolism
Variants
- Over 300 known pathogenic variants detectable by full gene sequencing
- Seven pathogenic alleles (G) detected with the following frequency in individuals with classic galactosemia in the U.S.
- Q188R: 49%
- Causal variant in 70% of individuals of northern European descent
- S135L: 7%
- Causal variant in 50% of individuals of African American descent
- K285N: 4%
- Predominant causal variant in individuals of German, Austrian, and Croatian descent
- T138M: unknown frequency
- L195P: 2%
- Y209C: 1%
- IVS2-2 A>G: almost exclusively found in individuals of Hispanic descent
- Q188R: 49%
- Other frequently identified variants
- Duarte variant (N314D): 5% of the general U.S. population
- Associated with moderate decrease in GALT activity
- LA variant (N314D linked to L218L allele)
- Associated with a mild increase in GALT expression
- Duarte variant (N314D): 5% of the general U.S. population
Test Interpretation
Galactose-1-Phosphate Uridyltransferase
Clinical Sensitivity
Classic galactosemia: >99%
Results
- Individuals affected with classic galactosemia usually have ≤0.7 U/g Hb
- Normal enzyme activity is ≥19.4 U/g Hb
- Enzyme ranges can overlap between genotypes
- Follow-up genetic testing for characterization of pathogenic variants is recommended
Galactosemia, (GALT) 9 Mutations
Clinical Sensitivity
Classic galactosemia: 80% in White individuals, and reduced in other ethnicities
Results
- Detection of two severe variants (G/G)
- Classic galactosemia
- One pathogenic variant and one Duarte variant (D/G)
- Duarte-variant galactosemia
- One pathogenic variant (G/N)
- Individual is at least a carrier of classic galactosemia
- In the presence of markedly reduced GALT activity, patient may have classic galactosemia with a variant not detected by the nine variant panel
- Individual is at least a carrier of classic galactosemia
- No pathogenic variants
- Galactosemia or carrier status cannot be excluded
- Refer to enzyme activity for follow-up testing
Galactosemia (GALT), Sequencing
Sensitivity/Specificity
- Clinical sensitivity (classic galactosemia): 98%
- Analytical sensitivity and specificity: 99%
Results
- Detection of two severe variants (G/G)
- Classic galactosemia
- One pathogenic variant and one Duarte variant (D/G)
- Duarte-variant galactosemia
- One pathogenic variant (G/N)
- Individual is at least a carrier of classic galactosemia
- In the presence of markedly reduced GALT activity, patient may have classic galactosemia with a variant not detected by the nine variant panel
- No pathogenic variants
- Galactosemia or carrier status cannot be excluded
- Refer to enzyme activity for follow-up testing
Limitations
- GALT enzyme activity ranges overlap, so molecular testing is necessary to clarify genotype
- Variants other than the nine GALT panel variants specified above will not be evaluated on the Galactosemia (GALT) 9 Mutations panel
- Other rare forms of galactosemia caused by deficiency of galactokinase (GALK) or galactose-4 epimerase (GALE) will not be identified
- Rare diagnostic errors can occur due to primer-site variants
- Regulatory region variants, deep intronic variants, and large deletions/duplications will not be detected
References
-
GeneReviews Classic Galactosemia and Clinical Variant Galactosemia - Galactosemia
Berry GT. Classic Galactosemia and Clinical Variant Galactosemia. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Mar 2017; Accessed: Feb 2020]
Online
Preferred initial test for the diagnosis of classic galactosemia or carrier status