Classic Galactosemia - Galactosemia, Classic

  • Diagnosis
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Follow-up of an abnormal newborn screening test for galactosemia
  • Neonatal testing for an affected individual’s sibling
  • Carrier testing for parents of an affected individual
  • Evaluation of a patient for galactosemia

Laboratory Testing

  • Newborn screening for elevated galactose and reduced galactose-1-phosphate uridyltransferase (GALT) enzyme activity detects almost 100% of cases
  • Enzyme activity in red blood cells can be used for screening
  • GALT molecular genetic testing will confirm the diagnosis
    • Genotype/phenotype correlations aid in prognostication
    • For more information on GALT mutations and polymorphisms, refer to ARUP's GALT gene database
  • Auxiliary testing
    • CBC, liver function tests, electrolytes, PT/PTT, arterial blood gas, ammonia (to assist in acute management if patient is symptomatic)

Differential Diagnosis

  • Measurement and periodic monitoring of galactose-1-phosphate in red blood cells 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

Galactosemia is a disorder of carbohydrate metabolism caused by a deficiency of one of three enzymes (galactokinase, galactose-1-phosphate uridyltransferase [GALT], uridine diphosphate galactose-4-epimerase) involved in galactose metabolism. Classic galactosemia, the most common form, is caused by a deficiency of GALT due to mutations in the GALT gene. Other rare forms of galactosemia may be caused by deficiencies of either galactokinase or galactose-4-epimerase.

Epidemiology

  • Incidence (classic)
    • Caucasians – ~1/30,000-60,000
    • Varies in other populations
  • Age – classic galactosemia has neonatal onset (3-14 days post-birth)
  • Sex – M:F, equal

Inheritance

  • Autosomal recessive
  • Seven pathogenic alleles (G) detected with the following frequency in individuals with classic galactosemia in the U.S. (GeneReviews)
    • Q188R – 49%
      • Causal mutation in 70% of individuals of northern European descent
    • S135L – 7% of total
      • Causal mutation in 50% of individuals of African American descent
    • K285N – 4%
      • Predominant causal mutation in individuals of German, Austrian, and Croatian descent
    • T138M – unknown frequency
    • L195P – 2%
    • Y209C – 1%
    • IVS2-2 A>G – almost exclusively found individuals of Hispanic descent

Pathophysiology

  • Classic galactosemia results in accumulation of galactose-1-phosphate, galactose, and its derivatives, galactitol and galactonate
    • Accumulation of these metabolites can cause growth failure, renal and liver dysfunction, and cataracts
    • Metabolite accumulation and possibly defective glycoconjugates may be involved in ovarian failure and speech dyspraxia
  • GALT enzyme catalyzes conversion of galactose-1-phosphate to uridyl phosphate-galactose
  • GALT enzyme activity
    • Enzyme ranges can overlap between genotypes

Clinical Presentation

  • Symptoms usually manifest between 3-14 days of age
    • Most common presenting symptoms in untreated infants
      • Hepatocellular damage
      • Food intolerance
      • Sepsis
    • Other symptoms
      • Failure to thrive
      • Lethargy
      • Seizures
    • Sequelae in treated affected individuals
      • Speech problems
      • Premature ovarian insufficiency
      • Intellectual impairment
      • Neurologic deficits
      • Cataracts
  • If diagnosis not made at birth, liver disease and brain damage may become irreversible

Treatment

  • Classic galactosemia requires early and lifelong lactose restriction
  • Restrict diet to soy formulas as soon as possible
    • Avoid products containing casein hydrolysates (components in milk-based formulas) because they contain small quantities of bioavailable lactose
  • DG 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
  • DD genotype does not result in symptoms of galactosemia and does not require treatment
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.

Galactosemia (GALT) Enzyme Activity and 9 Mutations 0051175
Method: Enzymatic/Polymerase Chain Reaction/Single Nucleotide Extensions

Limitations 

Test should not be used to monitor dietary compliance of affected individuals

Only 9 common GALT mutations will be evaluated

Rare forms of galactosemia (caused by a deficiency of either galactokinase or galactose-4-epimerase) will not be detected

Follow-up 

If enzyme activity is in the affected range and 2 mutations are not detected, GALT gene sequencing is recommended to identify the causative mutations

Galactose-1-Phosphate Uridyltransferase 0080125
Method: Enzymatic

Limitations 

Rare forms of galactosemia (caused by a deficiency of either galactokinase or galactose-4-epimerase) will not be detected

Enzyme test cannot predict GALT carrier status

Follow-up 

GALT gene mutation analysis is recommended to determine the specific mutations in affected individuals as enzyme activity ranges overlap

Galactosemia, (GALT) 9 Mutations 0051176
Method: Polymerase Chain Reaction/Single Nucleotide Extensions

Limitations 

Only 9 common GALT mutations will be evaluated

Rare forms of galactosemia (caused by a deficiency of either galactokinase or galactose-4-epimerase) will not be detected

Follow-up 

If enzyme activity is in the affected range and 2 mutations are not detected, GALT gene sequencing is recommended to identify the causative mutations

Galactosemia (GALT), Sequencing 2006697
Method: Sequencing

Limitations 

Large GALT 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

Galactose-1-Phosphate in Red Blood Cells 0081296
Method: Gas Chromatography-Mass Spectrometry

Galactosemia (GALT) 9 Mutations, Fetal 0051270
Method: Polymerase Chain Reaction/Single Nucleotide Extensions

Limitations 

Only 9 common GALT mutations will be evaluated

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

Follow-up 

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

General References

Berry G. Classic Galactosemia and Clinical Variant Galactosemia. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Apr 2014; Accessed: Nov 2015]

Bosch AM. Classical galactosaemia revisited. J Inherit Metab Dis. 2006; 29(4): 516-25. PubMed

Crushell E, Chukwu J, Mayne P, Blatny J, Treacy EP. Negative screening tests in classical galactosaemia caused by S135L homozygosity. J Inherit Metab Dis. 2009; 32(3): 412-5. PubMed

Cuthbert C, Klapper H, Elsas L. Diagnosis of inherited disorders of galactose metabolism. Curr Protoc Hum Genet. 2008; Chapter 17: Unit 17.5. PubMed

Freer DE, Ficicioglu C, Finegold D. Newborn screening for galactosemia: a review of 5 years of data and audit of a revised reporting approach. Clin Chem. 2010; 56(3): 437-44. 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. 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): 939-43. PubMed

Diaz GA, Krivitzky LS, Mokhtarani M, Rhead W, Bartley J, Feigenbaum A, Longo N, Berquist W, Berry SA, Gallagher R, Lichter-Konecki U, Bartholomew D, Harding CO, Cederbaum S, McCandless SE, Smith W, Vockley G, Bart SA, Korson MS, Kronn D, Zori R, Merritt L, Nagamani SC, Mauney J, Lemons C, Dickinson K, Moors TL, Coakley DF, Scharschmidt BF, Lee B. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology. 2013; 57(6): 2171-9. PubMed

Jama M, Nelson L, Pont-Kingdon G, 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): 618-23. PubMed

Jumbo-Lucioni PP, Garber K, Kiel J, Baric I, Berry GT, Bosch A, Burlina A, Chiesa A, Pico ML, Estrada SC, Henderson H, Leslie N, Longo N, Morris AA, Ramirez-Farias C, Schweitzer-Krantz S, Scheweitzer-Krantz S, Silao CL, Vela-Amieva M, Waisbren S, Fridovich-Keil JL. Diversity of approaches to classic galactosemia around the world: a comparison of diagnosis, intervention, and outcomes. J Inherit Metab Dis. 2012; 35(6): 1037-49. PubMed

Tang M, Facchiano A, Rachamadugu R, Calderon F, Mao R, Milanesi L, Marabotti A, Lai K. Correlation assessment among clinical phenotypes, expression analysis and molecular modeling of 14 novel variations in the human galactose-1-phosphate uridylyltransferase gene. Hum Mutat. 2012; 33(7): 1107-15. PubMed

Medical Reviewers

Last Update: August 2016