Second-tier test for confirming a diagnosis of galactosemia (indicated by

enzymatic testing or newborn screening)

Carrier testing family members of an affected individual of known genotype

(has mutations included in the panel)

Resolution of Duarte variant and Los Angeles variant genotypes

Classical galactosemia is an autosomal recessive disorder of galactose

metabolism caused by mutations in the galactose-1-phosphate

uridyltransferase gene (GALT). The complete or near complete deficiency

of the galactose-1-phosphate uridyltransferase (GALT) enzyme is life

threatening. If left untreated, complications include liver failure, sepsis,

mental retardation and death. Galactosemia is treated by a galactose-

free diet, which allows for rapid recovery from the acute symptoms and a

generally good prognosis. Despite adequate treatment from an early age,

children with galactosemia remain at increased risk for developmental

delays, speech problems, and abnormalities of motor function. Females

with galactosemia are at increased risk for premature ovarian failure. The

prevalence of classic galactosemia is approximately 1/30,000.  

Duarte variant galactosemia (compound heterozygosity for the Duarte

mutation, N314D, and a classic mutation) is generally associated with

higher levels of enzyme activity (5-20%) than classic galactosemia (<5%);

however, this may be indistinguishable by newborn screening assays.

Typically, individuals with Duarte variant galactosemia have a milder

phenotype but are also often treated with a low galactose diet during

infancy. The LA variant which consists of N314D and a second change,

L218L, is associated with higher levels of GALT enzyme activity than the

Duarte variant allele.

Newborn screening, which identifies potentially affected individuals by

measuring total galactose (galactose and galactose-1-phosphate) and/or

determining the activity of the GALT enzyme, varies from state to state. The

diagnosis of galactosemia is established by follow-up quantitative

measurement of GALT enzyme activity.  If enzyme levels are indicative of

carrier or affected status, molecular testing for common GALT mutations

may be performed. If 1 or both disease-causing mutations are not detected

by targeted mutation analysis and biochemical testing has confirmed the

diagnosis of galactosemia, sequencing of the GALT gene is available to

identify private mutation(s).

The GALT gene maps to 9p13. Several disease-causing mutations are

common in patients with classic galactosemia (G/G genotype). The most

frequently observed is the Q188R classic mutation. This mutation accounts

for 60% to 70% of classical galactosemia alleles. The S135L mutation is the

most frequently observed mutation in African Americans and accounts for

approximately 50% of the mutant alleles in this population. The K285N

mutation is common in those of eastern European descent and accounts

for 25% to 40% of the alleles in this population. The L195P mutation is

observed in 5% to 7%of classical galactosemia. The Duarte mutation

(N314D) is observed in 5% of the general United States population.

The above mutations, in addition to the Los Angeles variant, are included in

#84366 "Galactosemia Gene Analysis (6 Mutation Panel) and in #84360

"Galactosemia Confirmation Test, Blood". See "Galactosemia Testing

Algorithm" in Special Instructions for additional information.

An interpretive report will be provided.

An interpretative report will indicate if results support a diagnosis of

galactosemia (2 mutations identified) or if the patient is a carrier for

galactosemia (1 mutation identified).

Recommendations for additional testing may be provided. For

diagnostic purposes, results should be interpreted in the context of

biochemical results.

Many disorders may present with symptoms similar to those present in

galactosemia. Therefore, biochemical testing is recommended to

establish the diagnosis of galactosemia prior to DNA analysis.

Not all individuals affected with or carriers of galactosemia have the

mutations included in this panel. Therefore, absence of a mutation, does

not eliminate the possibility of the presence of a mutation in another

region of the gene. For carrier testing, it is important to first document the

presence of GALT mutations in an affected family member.

Any error in the diagnosis or in the pedigree provided to us, including

false paternity, could lead to erroneous interpretations of results.

Medical genetic consultation is available for all DNA diagnosis cases

and is particularly indicated in complex cases or in situations in which the

diagnosis is atypical or uncertain.

Rare polymorphisms exist that could lead to false-negative or false-

positive results. If results obtained do not match the clinical findings,

additional testing should be considered.

A previous bone marrow transplant from an allogenic donor will interfere

with testing.

1.   Elsas LJ 2nd, Lai K:  The molecular biology of galactosemia. Genet

      Med 1998 Nov-Dec;1(1):40-48

2.   Kaye CI, Committee on Genetics, Accurso F, et al:  Newborn screening

      fact sheets. Pediatrics 2006 Sep;118(3):e934-963

3.   Novelli G, Reichardt JK:  Molecular basis of disorders of human

      galactose metabolism: past, present, and future. Mol Genet Metab

      2000 Sep-Oct;71(1-2):62-65