Abstract
BackgroundClassical galactosemia (CG) (OMIM #230400) is a rare disorder of carbohydrate metabolism, due to deficiency of galactose‐1‐phosphate uridyltransferase (EC 2.7.7.12). The pathophysiology of the long‐term complications, mainly cognitive, neurological, and female infertility remains poorly understood.ObjectivesThis study investigated (a) the association between specific IgG N‐glycosylation biomarkers (glycan peaks and grouped traits) and CG patients (n = 95) identified from the GalNet Network, using hydrophilic interaction ultraperformance liquid chromatography and (b) a further analysis of a GALT c.563A‐G/p.Gln188Arg homozygous cohort (n = 49) with correlation with glycan features with patient Full Scale Intelligence Quotient (FSIQ), and (c) with galactose intake.ResultsA very significant decrease in galactosylation and sialylation and an increase in core fucosylation was noted in CG patients vs controls (P < .005). Bisected glycans were decreased in the severe GALT c.563A‐G/p.Gln188Arg homozygous cohort (n = 49) (P < .05). Logistic regression models incorporating IgG glycan traits distinguished CG patients from controls. Incremental dietary galactose intake correlated positively with FSIQ for the p.Gln188Arg homozygous CG cohort (P < .005) for a dietary galactose intake of 500 to 1000 mg/d. Significant improvements in profiles with increased galactose intake were noted for monosialylated, monogalactosylated, and monoantennary glycans.ConclusionThese results suggest that N‐glycosylation abnormalities persist in CG patients on dietary galactose restriction which may be modifiable to a degree by dietary galactose intake.
Highlights
Classical galactosemia (CG) (OMIM 230400) is a rare disorder of carbohydrate metabolism caused by galactose-1-phosphate uridyltransferase (GALT) deficiency (EC 2.7.7.12).[1]
Significant improvements in profiles with increased galactose intake were noted for monosialylated, monogalactosylated, and monoantennary glycans. These results suggest that N-glycosylation abnormalities persist in CG patients on dietary galactose restriction which may be modifiable to a degree by dietary galactose intake
We identified a significant increase in core fucosylated neutral glycans and a significant decrease in core fucosylated and afucosylated bisected glycans in Immunoglobulin G (IgG) glycans from galactosemia adult Irish and Dutch CG patients[23], with subsequent clinical validation of an automated high-throughput IgG hydrophilic interaction ultraperformance liquid chromatography (HILIC-UPLC) method.[24]
Summary
Classical galactosemia (CG) (OMIM 230400) is a rare disorder of carbohydrate metabolism caused by galactose-1-phosphate uridyltransferase (GALT) deficiency (EC 2.7.7.12).[1]. Long-term complications persist in treated adult patients to include significant cognitive impairment, movement disorders, decreased bone mineral density, and infertility in females These complications are present regardless of genotype or age at the onset of treatment.[1,2,3,4,5,6] The accumulation of toxic galactose intermediates coupled with deficiency of UDP-hexose sugars is proposed to contribute to the development of these complications with possible disruption of glycosylation central to the post-translational modification of protein and lipids.[7,8] The current tests of measuring red blood cell (RBC) Gal-1-P and urinary galactitol levels, apart from predicting gross deviations from diet and monitoring initial decreases of RBC Gal-1-P in the neonate, do not reveal milder deviations or correlate with clinical outcome.[9,10,11,12]. Conclusion: These results suggest that N-glycosylation abnormalities persist in CG patients on dietary galactose restriction which may be modifiable to a degree by dietary galactose intake
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