The molecular relationship between deficient UDP-galactose uridyl transferase (GALT) and ceramide galactosyltransferase (CGT) enzyme function: A possible cause for poor long-term prognosis in classic galactosemia

Lebea, Phiyani Justice; Pretorius, P. J.

doi:10.1016/j.mehy.2005.06.025

Cited by 25 publications

(22 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Galactosylation is abnormal in patients with GAL and may play a role in the CNS manifestations of GAL by means of (1) impaired galactosylation of cerebrosides and glycoproteins in the brain (30) and (2) a reduction in UDP-glucose/galactose contents in GALT-deficient cells (9).…”

Section: Discussionmentioning

confidence: 99%

Galactosemia, a Single Gene Disorder With Epigenetic Consequences

et al. 2010

View full text Add to dashboard Cite

Long-term outcomes of classic galactosemia (GAL) remain disappointing. It is unclear if the complications result mainly from prenatal-neonatal toxicity or persistent glycoprotein and glycolipid synthesis abnormalities. We performed gene expression profiling (T transcriptome) to characterize key-altered genes and gene clusters of four patients with GAL with variable outcomes maintained on a galactose-restricted diet, compared with controls. Significant perturbations of multiple cell signaling pathways were observed including mitogen-activated protein kinase (MAPK) signaling, regulation of the actin cytoskeleton, focal adhesion, and ubiquitin mediated proteolysis. A number of genes significantly altered were further investigated in the GAL cohort including SPARC (osteonectin) and S100A8 (S100 calcium-binding protein). The whole serum N-glycan profile and IgG glycosylation status of 10 treated patients with GAL were compared with healthy control serum and IgG using a quantitative high-throughput analytical HPLC platform. Increased levels of agalactosylated and monogalactosylated structures and decreases in certain digalactosylated structures were identified in the patients. The persistent abnormal glycosylation of serum glycoproteins seen with the microarray data indicates persisting metabolic dyshomeostasis and gene dysregulation in "treated" GAL. Strict restriction of dietary galactose is clearly life saving in the neonatal period; long-term severe galactose restriction may contribute to ongoing systemic abnormalities. (Pediatr Res 67: 286-292, 2010)

show abstract

Section: Discussionmentioning

confidence: 99%

Galactosemia, a Single Gene Disorder With Epigenetic Consequences

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Intellectual disability occurs in at least 50% of affected individuals (Waggoner et al 1990;Schweitzer et al 1993;Shield et al 2000;Doyle et al 2010;Waisbren et al 2012;Coss et al 2013;Rubio-Agusti et al 2013). Abnormal myelination was first documented in galactosaemia in 1971 (Haberland et al 1971;Lebea and Pretorius 2005). There is considerable variability in IQs documented between galactosaemia patients with scores ranging from very low to well above average.…”

Section: Congenital Disorders Of Glycosylationmentioning

confidence: 99%

Classical Galactosaemia and CDG, the N-Glycosylation Interface. A Review

et al. 2016

View full text Add to dashboard Cite

Classical galactosaemia is a rare disorder of carbohydrate metabolism caused by galactose-1-phosphate uridyltransferase (GALT) deficiency (EC 2.7.7.12). The disease is life threatening if left untreated in neonates and the only available treatment option is a long-term galactose restricted diet. While this is lifesaving in the neonate, complications persist in treated individuals, and the cause of these, despite early initiation of treatment, and shared GALT genotypes remain poorly understood. Systemic abnormal glycosylation has been proposed to contribute substantially to the ongoing pathophysiology. The gross N-glycosylation assembly defects observed in the untreated neonate correct over time with treatment. However, N-glycosylation processing defects persist in treated children and adults.Congenital disorders of glycosylation (CDG) are a large group of over 100 inherited disorders affecting largely N-and O-glycosylation.In this review, we compare the clinical features observed in galactosaemia with a number of predominant CDG conditions.We also summarize the N-glycosylation abnormalities, which we have described in galactosaemia adult and paediatric patients, using an automated high-throughput HILIC-UPLC analysis of galactose incorporation into serum IgG with analysis of the corresponding N-glycan gene expression patterns and the affected pathways.

show abstract

“…It has been suggested that long term complications may result from endogenous galactose synthesis (Berry et al 1993(Berry et al , 2004Ning et al 2000;Schadewaldt et al 2004a). Furthermore, as abnormalities in various glycoproteins have been reported, abnormal galactosylation may also be involved (Jaeken et al 1992;Lai et al 2003;Lebea and Pretorius 2005;Ornstein et al 1992;Prestoz et al 1997).…”

Section: Long-term Complicationsmentioning

confidence: 99%

“…This abnormal glycosylation may be related to the accumulation of galactose 1-phosphate, the precursor of UDPgalactose, which is the substrate for the galactosyltransferases that incorporate galactose into glycoproteins and glycolipids (Jaeken et al 1992;Lai et al 2003;Lebea and Pretorius 2005;Ornstein et al 1992;Prestoz et al 1997). In this respect it is important to mention that elevated intracellular concentrations of galactose 1-phosphate inhibit UDP-hexose pyrophosphorylase and thus may reduce the intracellular concentrations of UDP-hexoses (Lai et al 2003).…”

Section: Abnormal Glycosylationmentioning

confidence: 99%

Classical galactosaemia revisited

Bosch

2006

J of Inher Metab Disea

271

195

View full text Add to dashboard Cite

Classical galactosaemia (McKusick 230400) is an: autosomal recessive disorder of galactose metabolism, caused by a deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT; EC 2.7.712). Most patients present in the neonatal period, after ingestion of galactose, with jaundice, hepatosplenomegaly, hepatocellular insufficiency, food intolerance, hypoglycaemia, renal tubular dysfunction, muscle hypotonia, sepsis and cataract. The gold standard for diagnosis of classical galactosaemia is measurement of GALT activity in erythrocytes. Gas-chromatographic determination of urinary sugars and sugar alcohols demonstrates elevated concentrations of galactose and galactitol. The only therapy for patients with classical galactosaemia is a galactose-restricted diet, and initially all galactose must be removed from the diet as soon as the diagnosis is suspected. After the neonatal period, a lactose-free diet is advised in most countries, without restriction of galactose-containing fruit and vegetables. In spite of the strict diet, long-term complications such as retarded mental development, verbal dyspraxia, motor abnormalities and hypergonadotrophic hypogonadism are frequently seen in patients with classical galactosaemia. It has been suggested that these complications may result from endogenous galactose synthesis or from abnormal galactosylation. Novel therapeutic strategies, aiming at the prevention of galactose 1-phosphate production, should be developed. In the meantime, the follow-up protocol for patients with GALT deficiency should focus on early detection, evaluation and, if possible, early intervention in problems of motor, speech and cognitive development.

show abstract

The molecular relationship between deficient UDP-galactose uridyl transferase (GALT) and ceramide galactosyltransferase (CGT) enzyme function: A possible cause for poor long-term prognosis in classic galactosemia

Cited by 25 publications

References 23 publications

Galactosemia, a Single Gene Disorder With Epigenetic Consequences

Galactosemia, a Single Gene Disorder With Epigenetic Consequences

Classical Galactosaemia and CDG, the N-Glycosylation Interface. A Review

Classical galactosaemia revisited

Contact Info

Product

Resources

About