Galactosemia, a single gene disorder with epigenetic consequences.
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.
Coman
David J
DJ
National Centre for Inherited Metabolic Disorders, Children's University Hospital, Dublin 1, Ireland.
Murray
David W
DW
Byrne
Jennifer C
JC
Rudd
Pauline M
PM
Bagaglia
Paola M
PM
Doran
Peter D
PD
Treacy
Eileen P
EP
D000328:Adult; D015415:Biomarkers / Q000097:blood; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D044127:Epigenesis, Genetic; D005260:Female; D005693:Galactosemias / Q000097:blood / Q000150:complications / Q000178:diet therapy / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D006023:Glycoproteins / Q000097:blood; D006031:Glycosylation; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011134:Polysaccharides / Q000097:blood; D011499:Protein Processing, Post-Translational / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
D015415:Biomarkers; D006023:Glycoproteins; D007074:Immunoglobulin G; D011134:Polysaccharides