Test Code: 9543

Galactosemia (Galactokinase Deficiency): GALK1 Gene Sequencing
Test Code: 9543
Turnaround time: 5 weeks

CONDITION DESCRIPTION

Galactokinase (GALK) deficiency is one of the three known forms of galactosemia, along with galactose-1-phosphate uridylyltransferase (GALT) deficiency (classic galactosemia) and UDP-galactose-4-epimerase (GALE) deficiency [1-2]. GALK deficiency is an autosomal recessive disorder characterized by an elevation of blood galactose concentration and diminished galactose-1-phosphate concentration, leading to production of alternative metabolic products such as galactitol [3]. Galactokinase-deficiency may present in the neonatal period with cataracts; no other clinical complications have been consistently associated with GALK-deficiency [2]. GALK deficiency should be considered in individuals with cataracts, elevated red cell galactose, galactosuria, or elevated urinary galactitol and normal GALT enzyme activity. GALK activity is used to rule-out variant galactosemia due to galactokinase deficiency which should not be confused with classical galactosemia secondary to GALT deficiency, or epimerase- deficiency galactosemia secondary to GALE deficiency. The vast majority of patients with biochemical diagnosis of GALK deficiency have mutations in the GALK1 (17q25) gene [4-6]. Gene sequence analysis is available to test for mutations in the GALK1 gene in patients with a biochemical diagnosis of GALK deficiency (test code: 9543). For patients with mutations not identified by full gene sequencing, a separate deletion/duplication assay is available using a targeted CGH array (test code: 4148).

References:

  • Fridovich-Keil JL. Galactosemia: the good, the bad, and the unknown. J Cell Physiol 2006, 209(3):701-5.
  • Holton et al. Galactosemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill, New York, pp. 1559-1561 (2001).
  • Gitzelmann R. Deficiency of erythrocyte galactokinase in a patient with galactose diabetes, Lancet 2:670-671, 1965.
    Sangiuolo et al. Biochemical Characterization of Two GALK1 Mutations in Patients with Galactokinase Deficiency. Hum Mutat 2004 Apr;23(4):396-403
  • Park et al. Molecular and biochemical characterization of the GALK1 gene in Korean patients with galactokinase deficiency. Mol Genet Metab. 2007. 91:234-8
  • Timson and Reece. Functional analysis of disease-causing mutations in human galactokinase Eur J Biochem. 2003. 270:1767-74
  • Thoden and Holden. The Molecular Architecture of Human N-Acetylgalactosamine Kinase. J Biol Chem. 280(38):32784-32791, 2005.
  • Kolosha et al. Novel mutations in 13 probands with galactokinase deficiency. Hum Mutat. 2000;15(5):447-53.

GENES
GALK1

INDICATIONS
This test is indicated for:

  • Individuals with elevated blood galactose but with normal GALT and GALE enzyme activities.
  • Carrier testing for individuals with a family history of GALK deficiency.

METHODOLOGY

PCR amplification of 8 exons contained in the GALK1 gene is performed on patient genomic DNA. Direct sequencing of amplification products is performed in both the forward and reverse directions using automated fluorescence dideoxy sequencing methods. Patient gene sequences are compared to a normal reference sequence. Sequence variations are then classified as mutations, benign variants unrelated to disease or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members. This assay does not interrogate the promoter region, deep intronic regions or other regulatory elements. Large deletions are not detected by this analysis.

DETECTION

The vast majority of patients with clinical and biochemical diagnosis will have an abnormal DNA test. Clinical Sensitivity: 26/26 mutations identified in 13 patients [8], 4/4 mutations identified in 2 patients [9].

Analytical Sensitivity: ~99%

Detection is limited to duplications and deletions. Array CGH will not detect point mutations or intronic mutations. Results of molecular analysis must be interpreted in the context of the patient’s clinical and/or biochemical phenotype.

SPECIMEN REQUIREMENTS

Submit only 1 of the following specimen types
* Preferred specimen type: Whole Blood

Type: Whole Blood
Specimen Requirements:
In EDTA (purple top) or ACD (yellow top) tube: Infants (2 years): 3-5 ml
Older Children & Adults: 5-10 ml

Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.

Type: Saliva
Specimen Requirements:
OrageneTM Saliva Collection kit (available through CEN4GEN) used according to manufacturer instructions.

Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.

SPECIAL INSTRUCTIONS
Submit copies of diagnostic biochemical test results with the sample. Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed by another third party provider, please submit a copy of the sequencing report with the test requisition.

RELATED TESTS

  • GALT and GALE Gene Sequencing for transferase deficient and epimerase deficient galactosemia
  • Custom Diagnostic Mutation Analysis (test code: 6875) is available to family members if mutations are identified by sequencing.
  • A Deletion/Duplication Assay is available separately for individuals where mutations are not identified by sequence analysis. Refer to the test requisition or contact the laboratory for more information.