Galactosemia Panel

Galactosemia is an inborn error of metabolism of galactose resulting in elevated levels of galactose and derivative metabolites, such as galactose-1-phosphate and galactitol. Galactosemia is caused by biallelic pathogenic variants in the GALT, GALK1, GALE, or GALM genes.

Galactosemia type I is caused by pathogenic variants in the GALT gene. Severity of galactosemia type I is quite variable, though it is generally categorized into three groups based on patient phenotype: classic, clinical variant, and Duarte variant galactosemia (Crushell et al. 2009. PubMed ID: 19418241; Berry 2017. PubMed ID: 20301691; Fridovich-Keil and Walter 2014). The most phenotypically severe presentation is observed in classic galactosemia patients, who may present shortly after birth with feeding problems, failure to thrive, hepatocellular damage, bleeding, and sepsis. In untreated infants, liver failure, sepsis, and even death may occur. In addition, even treated patients remain at risk for developmental delays and motor abnormalities. Females often develop premature ovarian insufficiency (Berry. 2017. PubMed ID: 20301691). The prevalence of classic galactosemia is estimated to range from ~1:10,000 to ~1:48,000 (Berry. 2017. PubMed ID: 20301691).

Galactosemia type II is caused pathogenic variants in the GALK1 gene. In the vast majority of affected patients, the only clinical and biochemical findings are bilateral cataracts, hypergalactosemia and increased urinary galactitol. However, a few patients have been reported with intellectual disability or pseudotumor cerebri (Fridovich-Keil and Walter 2014).

Epimerase Deficiency Galactosemia (EDG; sometimes called type III galactosemia) is caused pathogenic variants in the GALE gene. EDG is categorized into three main types (peripheral, intermediate and profound generalized) based on which cell types are affected. Many of these patients are reported to be clinically asymptomatic, with only the profound EDG patients having been reported to typically have an associated phenotype (Timson. 2006. PubMed ID: 16611573; Fridovich-Keil and Walter 2014).

An additional form of congenital galactosemia has been recently described. All patients presented with congenital hypergalactosemia. A few also presented with cataracts or transient cholestasis, but no other clinical features suggestive of hypergalactosemia due to defects in GALT, GALK1, or GALE. All were found to have biallelic variants in the GALM gene (Wada et al. 2019. PubMed ID: 30451973).

Today in countries that perform routine newborn screening, nearly all cases of GALT-associated classic galactosemia are detected shortly after birth. However, it may be more difficult to detect patients with clinical and biochemical variant galactosemias because the galactose level in such patients is not as high as in classic galactosemia patients, and results of breath testing may be normal (Berry 2017. PubMed ID: 20301691). In situations where the activity of the GALT enzyme is always tested or the patient is fed enough lactose, GALT-associated clinical and biochemical variant galactosemias should be detectable (Berry 2017. PubMed ID: 20301691; Fridovich-Keil and Walter 2014). In cases where the first round of screening is based on GALT enzyme activity alone, individuals with galactosemia due to variants in genes other than GALT may be missed (Berry 2017. PubMed ID: 20301691; Fridovich-Keil and Walter 2014).

Galactosemia is an autosomal recessive disorder. Pathogenic variants in the GALT gene are the primary genetic cause of galactosemia. Relatively small numbers of cases are caused by pathogenic variants in the GALK1 (galactokinase), GALE (UDP galactose-4’-epimerase), and GALM (galactose mutarotase) genes. GALT encodes the enzyme galactose-1-phosphate uridyltransferase.

Over 300 causative GALT variants have been reported to date (Human Gene Mutation Database; http://arup.utah.edu/database/GALT/GALT_display.php). Roughly 70% of these variants are missense, although nonsense, splicing, small insertions and deletion variants, in-frame amino acid deletions, and small indels have all been reported. While not an overall common cause of galactosemia type I, gross deletions in GALT have also been reported. It should be noted, however, that a 5.5 kb complex deletion has been reported to be common in individuals of Ashkenazi Jewish descent (Barbouth et al. 2006. PubMed ID: 16540753; Coffee et al. 2006. PubMed ID: 17079880).

Together, fewer than 100 causative variants have been reported in the remaining genes in this panel (GALK1, GALE, and GALM). Missense, nonsense, splicing, small insertions and deletion variants, in-frame amino acid deletions, and small indels have all been reported (Human Gene Mutation Database).

The four enzymes encoded by the GALT, GALK1, GALE, and GALM genes are responsible for the conversion of b-D-galactose to glucose-1-phosphate. In the first step, galactose mutarotase (GALM) converts b-D-galactose to a-D-galactose. Next, galactokinase (GALK1) phosphorylates a-D-galactose, producing galactose-1-phosphate. Galactose-1-phosphate uridyltransferase (GALT) then converts the galactose-1-phosphate and a molecule of UDP-glucose to glucose-1-phosphate and UDP-galactose. The glucose-1-phosphate can be used in other downstream metabolic pathways, such as glycolysis. The UDP galactose-4’-epimerase enzyme (GALE) recycles the UDP-galactose (generated in the previous reaction) back to UDP-glucose for re-use.

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Although the overall sensitivity of this test panel is not precisely known, most pathogenic variants reported for the genes in this panel are of the type which can be detected by sequencing with CNV analysis.

The most commonly affected gene in galactosemia patients is GALT. Between 91% and 99% of causative GALT variants have been reportedly detected by gene sequencing (Bosch et al. 2005. PubMed ID: 15841485; Kozák et al. 2000. PubMed ID: 10649501; Boutron et al. 2012. PubMed ID: 22944367). In addition, several exonic or whole-gene deletions have been reported in GALT (Human Gene Mutation Database). In general, these deletions have been observed in a single patient, although a ~5.5 kb complex deletion is common in those of Ashkenazi Jewish descent (Barbouth et al. 2006. PubMed ID: 16540753; Coffee et al. 2006. PubMed ID: 17079880; Berry 2017. PubMed ID: 20301691).

Although only a small number of GALK1 patients have been reported, studies of a total of twenty-one affected individuals have shown all of them to be homozygous or heterozygous for suspected causative GALK1 variants, suggesting a sensitivity of ~100% (Kolosha et al. 2000. PubMed ID: 10790206; Kalaydjieva et al. 1999. PubMed ID: 10521295).

It is difficult to estimate the clinical sensitivity of testing the GALE gene due to the low numbers of patients reported. Patients with peripheral GALE deficiency have been reported to carry at least one GALE variant (Park et al. 2005. PubMed ID: 16301867). 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. PubMed ID: 9973283).

Lastly, only a small number of patients with deficiencies in the galactose mutarotase enzyme have been reported. All reported patients were found to carry biallelic variants in the GALM gene, suggesting a sensitivity of ~100% in this patient population (Wada et al. 2019. PubMed ID: 30451973).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).