Epimerase Deficiency Galactosemia via the GALE Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1449 GALE$810.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity
Clinical sensitivity is difficult to estimate because only a small number of patients have been reported. However, one study was performed on thirty-seven Korean newborns that were found to have, at a minimum, peripheral GALE deficiency (Park et al. 2005). All exons of the GALE gene from the seven individuals with the most severely reduced enzyme activity were sequenced; six of the seven were compound heterozygotes for predicted causative variants. The seventh was heterozygous for a nonsense variant; a second variant was not identified. The remaining 30 individuals were subsequently screened, via DNA sequencing, for the variants identified in the first seven individuals. Seventeen of the thirty were found to be heterozygous for one of the previously identified variants. No additional sequencing was performed on these individuals so it is possible they harbor an additional, unidentified GALE-variant. Additionally, all individuals reported with profound generalized epimerase deficiency galactosemia have been found, by DNA sequencing, to be homozygous for the Val94Met GALE variant (Fridovich-Keil and Walter 2014; Wohlers et al. 1999).

Overall, the analytical sensitivity of this test is expected to be high because all variants in the GALE gene reported to date are detectable via DNA sequencing.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 GALE$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity
To date, there have been no reported gross deletions or duplications in the GALE gene (Human Gene Mutation Database).

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Clinical Features
Epimerase Deficiency Galactosemia (EDG; sometimes called Type III Galactosemia) is caused by a defect in galactose metabolism, resulting in elevated levels of galactose and derivatives such as galactose-1-phosphate. EDG is categorized into three main types (peripheral, intermediate and profound generalized) based on which cell types are affected. In those with the peripheral form of the disease, GALE enzyme activity is deficient in erythrocytes and circulating white blood cells, but at or near normal levels in all other tissues. The vast majority of such individuals are asymptomatic and are not thought to require any treatment. Individuals with the intermediate form are also deficient in GALE enzyme activity in erythrocytes and circulating white blood cells; in addition, the GALE enzyme activity in all other tissues tested is less than fifty percent of the normal activity level. These individuals are also generally asymptomatic during infancy, although the long-term outcome of the intermediate form is not well understood. Only a small number of individuals diagnosed with the profound generalized form of EDG have been described, all of whom had severely decreased GALE enzyme activity. When fed on a regular milk diet, patients with this form of galactosemia develop clinical findings including hypotonia, poor feeding, vomiting, weight loss, jaundice, hepatomegaly, liver dysfunction, aminoaciduria and cataracts. Treatment of individuals with the intermediate and profound generalized EDG involves eliminating or severely limiting dietary sources of galactose, which resolves most acute symptoms (Timson 2006; Fridovich-Keil et al. 2013).

In addition to the three main types of Epimerase Deficiency Galactosemia, several reports have shown that some individuals with moderately to considerably reduced GALE activity in erythrocytes have developed juvenile-onset cataracts. In some of these patients, GALE activity in the lens was studied and found to be significantly reduced (Fridovich-Keil and Walter 2014).
In countries where newborn screening programs operate, such programs typically identify galactosemic individuals shortly after birth. However, in cases where the first round of screening is based on GALT enzyme activity, individuals with epimerase deficiency galactosemia, rather than GALT-deficient classical galactosemia, may be missed (Fridovich-Keil et al. 2013).
Epimerase Deficiency Galactosemia is caused by defects in the UDP-galactose 4’-epimerase enzyme, which is encoded by the GALE gene. This enzyme is part of the galactose metabolism pathway in many organisms and performs the last step in the Leloir pathway, converting UDP-Galactose to its C4 epimer, UDP-Glucose. In addition, this enzyme functions outside of the Leloir pathway to convert UDP-N-acetylgalactosamine to UDP-N-acetylglucosamine. Both GALE enzyme reactions are reversible, and all four of the UDP sugar products are important for the incorporation of galactose, glucose and hexosamines into complex polysaccharides, glycoproteins and glycolipids (Fridovich-Keil and Walter 2014; Thoden et al. 2000).

EDG is considered an autosomal recessive disorder (Fridovich-Keil et al. 2013), although many of the individuals described in the literature are apparent heterozygous for variants in the GALE gene (Maceratesi et al. 1998; Park et al. 2005). It is possible that these individuals harbor a type of variant not detected by the methods used (for example, promoter variants or large deletions). Alternatively, it is possible that a heterozygous, pathogenic variant in the GALE gene is sufficient to result in an abnormal biochemical profile. All known individuals that have been diagnosed with the profound generalized form of EDG have been homozygous for the variant Val94Met (Fridovich-Keil and Walter 2014; Walter et al. 1999; Wohlers et al. 1999).

No genes other than GALE are known to cause Epimerase Deficiency Galactosemia. To date, twenty-two missense variants and one nonsense variant have been reported, spread throughout the GALE gene (Liu et al. 2012; Park et al. 2005; Timson, 2006; Human Gene Mutation Database). Few large-scale studies of the GALE gene in various affected populations have been published, and in most studies to date the reported variants seem to be private with the exception of the Val94Met variant. However, in a study of Korean individuals diagnosed with peripheral EDG, three variations (Arg169Trp, Arg239Trp and Gly302Glu) were reported to be the most prevalent (Park et al. 2005).
Testing Strategy
This test involves bidirectional Sanger sequencing using genomic DNA of all coding exons of the GALE gene plus ~20 bp of flanking non-coding DNA on each side. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.
Indications for Test
Patients identified as galactosemic via newborn screening or other biochemical testing, especially individuals with elevated total galactose (galactose + galactose-1-phosphate) and normal GALT enzyme activity levels, are good candidates for this test (Fridovich-Keil et al. 2013). Those exhibiting clinical symptoms such as hypotonia, poor feeding, vomiting, weight loss, jaundice, hepatomegaly, liver dysfunction, aminoaciduria and cataracts upon galactose ingestion are also good candidates for this test. Lastly, family members of patients who have known GALE variants are candidates. We will also sequence the GALE gene to determine carrier status.


Official Gene Symbol OMIM ID
GALE 606953
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
UDPglucose-4-Epimerase Deficiency 230350

Related Tests

Galactosemia Type I via the GALT Gene
Galactosemia Type I via the GALT Gene, 5.5 kb Common Deletion
Galactosemia Type II via the GALK1 Gene


Genetic Counselors
  • Fridovich-Keil J, Bean L, He M, Schroer R. 2013. Epimerase Deficiency Galactosemia. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 21290786
  • Fridovich-Keil J.L., Walter J.H. 2014. Galactosemia. In: Valle D, Beaudet A.L., Vogelstein B, et al., editors. New York, NY: McGraw-Hill. OMMBID.
  • Human Gene Mutation Database (Bio-base).
  • Liu Y, Bentler K, Coffee B, Chhay JS, Sarafoglou K, Fridovich-Keil JL. 2012. A Case Study of Monozygotic Twins Apparently Homozygous for a Novel Variant of UDP-Galactose 4’-epimerase (GALE). JIMD Reports, DOI 10.1007/8904_2012_153. PubMed ID: 23430501
  • Maceratesi P, Daude N, Dallapiccola B, Novelli G, Allen R, Okano Y, Reichardt J. 1998. Human UDP-Galactose 4’ Epimerase (GALE) Gene and Identification of Five Missense Mutations in Patients with Epimerase-Deficiency Galactosemia. Mol. Genet. Metab. 63:26-30. PubMed ID: 9538513
  • Park  H-D, Park KU, Kim JQ, Shin CH, Yang SW, Lee DH, Song Y-H, Song J. 2005. The molecular basis of UDP-galactose-4-epimerase (GALE) deficiency galactosemia in Korean patients. Genet. Med., 7:646-649. PubMed ID: 16301867
  • Thoden JB, Wohlers TM, Fridovich-Keil JL, Holden HM. 2000. Crystallographic Evidence for Tyr 157 Functioning as the Active Site Base in Human UDP-Galactose 4-Epimerase. Biochemistry, 39:5691-5701. PubMed ID: 10801319
  • Timson DJ. 2006. The Structural and Molecular Biology of Type III Galactosemia. IUBMB Life, 58:83-89. PubMed ID: 16611573
  • Walter JH, Roerts REP, Beesley GTN, Wraith JE, Cleary MA, Holton JB, MacFaul R. 1999. Generalised uridine diphosphate galactose-4-epimerase deficiency. Arch. Dis. Child, 80:374-376. PubMed ID: 10086948
  • Wohlers TM, Christacos NC, Harreman MT, Fridovich-Keil JL. 1999. Identification and Characterization of a Mutation, in the Human UDP-Galactose-4-Epimerase Gene, Associated with Generalized Epimerase-Deficiency Galactosemia. Am. J. Hum. Genet. 64:462-470. PubMed ID: 9973283
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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Ordering Options

myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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