Galactosemia Type II (Galactokinase Deficiency) via the GALK1 Gene

Galactosemia Type II is caused by a defect in galactose metabolism, resulting in an elevated level of total galactose and derivative metabolites. In the vast majority of affected patients, the only clinical and biochemical findings are bilateral cataracts, galactosemia and increased urinary galactitol. However, a few patients have been reported with intellectual disability or pseudotumor cerebri. The onset of symptoms is usually within the first weeks or months of life. This disorder is treated by restricting dietary intake of galactose and lactose, and if treatment is started early, symptoms are preventable or reversible. However, in cases where treatment is not begun until after cataracts have already formed, the damage may not be reversible by dietary restriction and surgery may be required (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 alone, individuals with galactosemia type II rather than GALT-deficient classical galactosemia may be missed (Berry 2014; Fridovich-Keil and Walter 2014).

Galactosemia Type II is an autosomal recessive disorder, and GALK1 is the only gene in which defects are known to cause galactokinase deficiency (Fridovich-Keil and Walter 2014). To date, over 35 causative variants have been reported in the GALK1 gene (Kalaydjieva et al. 1999; Kolosha et al. 2000; Okano et al. 2001; Park et al. 2007; Stambolian et al. 1995; Human Gene Mutation Database). Roughly two-thirds are missense variants, although nonsense, frameshift and small insertion and deletion variants have also been reported. The variants are spread throughout the coding regions of GALK1, although they tend to be somewhat clustered near conserved functional regions in exons 1, 3 and 7 (Fridovich-Keil and Walter 2014). The Pro28Thr variant has been reported to be a founder mutation in individuals of Romani and southeastern European descent (Kalaydjieva et al. 1999). The relatively mild Ala198Val variant has been found to be common in Japanese and Korean patients and has been termed the Osaka variant (Okano et al. 2001). The Gln382* variant has been reported to be common in patients from Costa Rica (Kolosha et al. 2000). No other pathogenic variants have been reported to be particularly common.

Galactosemia Type II is caused by defects in the galactokinase protein, which is encoded by the GALK1 gene. This enzyme is part of the galactose metabolism pathway in many organisms and performs the first step in the Leloir pathway, converting galactose to galactose-1-phosphate. While the phosphorylation reaction performed by galactokinase is reversible, the reaction equilibrium leans heavily in favor of galactose-1-phosphate formation (Berry 2014; Fridovich-Keil and Walter 2014). In the absence of galactokinase activity, galactose builds up and is converted to other metabolites, including galactitol, at a higher rate than normal. Excess galactitol accumulation in the lens of the eye leads to osmotic irregularities, which is thought to be the cause of cataract formation (Okano et al. 2001; Fridovich-Keil and Walter 2014).

Using DNA sequencing, Kolosha et al. (2000) analyzed the GALK1 gene from thirteen probands with low levels of erythrocyte galactokinase activity. Causative variants were found in the homozygous or compound heterozygous state in all thirteen probands (100%). Additionally, Kalaydjieva et al. (1999) used DNA sequencing to analyze the GALK1 gene in eight galactokinase deficient Romani children, and found the same variant (c.82C>A, p.Pro28Thr) in the homozygous state in all eight (100%). Additionally, this same variant was identified in the heterozygous state in all unaffected family members.Overall, the analytical sensitivity of this test is expected to be high because all pathogenic variants in the GALK1 gene reported to date are detectable via DNA sequencing.

To date, there have been no reported gross deletions or duplications in the GALK1 gene (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the GALK1 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).