Classic Galactosemia - Galactosemia, Classic

Dx
Monitor
Background
Lab Tests

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

Sepsis
Liver disease from any cause (infectious, genetic, toxic)
Obstructive biliary disease
Other metabolic diseases (urea cycle disorders, citrullinemia type 2)
Mitochondrial diseases (mitochondrial DNA depletion syndrome)

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 Number	Comments
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)