Epimerase Deficiency Galactosemia via the GALE Gene

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).

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.

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

This test provides full coverage of all coding exons of the GALE gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).