Classic Galactosemia - Galactosemia, Classic

Diagnosis

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

Monitoring

  • 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

Clinical Background

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

Indications for Laboratory Testing

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

Preferred initial test to diagnose classic galactosemia

Evaluates 9 common GALT gene mutations (Q188R, S135L, K285N, T138M, L195P, Y209C, IVS2-2 A>G, N314D, and L218L) and measures GALT enzyme activity in red blood cells

Clinical sensitivity approaches 80% for classic galactosemia in Caucasians; lower in other ethnic groups

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

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

May be used as initial screening test to diagnose individuals with classic galactosemia

Sensitivity >99% for classic galactosemia

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

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

Use to clarify genotypes when enzyme activity is known

Evaluates 9 common GALT gene mutations (Q188R, S135L, K285N, T138M, L195P, Y209C, IVS2-2 A>G, N314D, and L218L)

Clinical sensitivity approaches 80% in Caucasians; lower in other ethnic groups

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

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

Sequencing of the entire GALT gene coding region and intron/exon borders

Clinical sensitivity for GALT sequencing is 98%

Large GALT 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

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

Monitor initial accumulation, response, and compliance with dietary treatment for patients with an established diagnosis

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

Evaluates 9 GALT gene mutations (Q188R, S135L, K285N, T138M, L195P, Y209C, IVS2-2 A>G, N314D, and L218L)

Clinical sensitivity approaches 80% in Caucasians; lower in other ethnic groups

Only 9 common GALT mutations will be evaluated

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

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

Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Management (if symptomatic)

Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Management (if symptomatic)

Partial Thromboplastin Time 0030235
Method: Electromagnetic Mechanical Clot Detection

Management (if symptomatic)

Prothrombin Time 0030215
Method: Electromagnetic Mechanical Clot Detection

Management (if symptomatic)

Electrolyte Panel 0020410
Method: Quantitative Ion-Selective Electrode/Enzymatic

Management (if symptomatic)

Ammonia, Plasma 0020043
Method: Colorimetry

Management (if symptomatic)