Classic Galactosemia: Study on the Late Prenatal Development of GALT Specific Activity in a Sheep Model

Abstract

Classic galactosemia results from deficient activity of galactose-1-phosphate uridylyltransferase (GALT), a key enzyme of galactose metabolism. Despite early diagnosis and early postnatal therapeutic intervention, patients still develop neurologic and fertility impairments. Prenatal developmental toxicity has been hypothesized as a determinant factor of disease. In order to shed light on the importance of prenatal GALT activity, several studies have examined GALT activity throughout development. GALT was shown to increase with gestational age in 7-28 weeks human fetuses; later stages were not investigated. Prenatal studies in animals focused exclusively on brain and hepatic GALT activity. In this study, we aim to examine GALT specific activity in late prenatal and adult stages, using a sheep model. Galactosemia acute target-organs-liver, small intestine and kidney-had the highest late prenatal activity, whereas the chronic target-organs-brain and ovary-did not exhibit a noticeable pre- or postnatal different activity compared with nontarget organs. This is the first study on GALT specific activity in the late prenatal stage for a wide variety of organs. Our findings suggest that GALT activity cannot be the sole pathogenic factor accounting for galactosemia long-term complications, and that some organs/cells might have a greater susceptibility to galactose toxicity. Anat Rec, 300:1570-1575, 2017. © 2017 Wiley Periodicals, Inc.

Impaired fertility and motor function in a zebrafish model for classic galactosemia

“…Additionally, knockout fish accumulated elevated concentrations of Gal-1-P, which was exacerbated upon exposure to exogenous galactose. Catalytic activity of galk1, gale, and ugp were also measured, and interestingly varied considerably in the various tissues, which probably reflect specific needs of the given organ (Adeva-Andany et al 2016 ; Coelho et al 2017 ; Walter and Fridovich-Keil 2014 ). In contrast with their specific activity which was essentially the same as in wildtype fish, galk1 and gale mRNA were significantly higher in ovary of knockout fish, suggesting that specific cellular signaling in knockout fish possibly increased galk1 and gale transcription, repressed galk1 and gale synthesis and/or increased galk1 and gale turnover.…”

Galactose 1‐phosphate accumulates to high levels in galactose‐treated cells due to low GALT activity and absence of product inhibition of GALK

“…Galactose required for glycosylation of glycoproteins and glycolipids in non-liver tissues can be produced via endogenous synthesis or turnover of galactose-containing macromolecules. 29 The liver is also the site where GALT mRNA is highest, [32][33][34] and thus the site where the greatest conversion from Gal-1P to Glc-1P takes place ( Figure 1A). The excess glucose is then stored as glycogen, allowing for release of glucose into the bloodstream when required by the body, possibly acting as a mechanism of glucose homeostasis.…”

The 1‐13C galactose breath test in GALT deficient patients distinguishes NBS detected variant patients but does not predict outcome in classical phenotypes

“…This might be due to their younger age, as we found a significant correlation between age and galactose oxidation capacity in patients with an identical genotype (homozygous p.Gln188Arg). Previous research also demonstrated that galactose oxidation capacity fluctuates in the first weeks of life and in an animal model, age‐dependent GALT activity was demonstrated in different tissues . At this moment, it is unclear if younger patients truly have a higher galactose oxidation capacity or whether other factors that vary with age have influenced the breath test results, such as body composition, temporary label trapping or differences in alternative disposal pathways, such as upregulation of the UDP‐glucose pyrophosphorylase pathway.…”