Galactosemia, a Single Gene Disorder With Epigenetic Consequences

Abstract

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)

Effects of temporary low-dose galactose supplements in children aged 5–12 y with classical galactosemia: a pilot study

“…Despite newborn screening and early treatment with a lifelong galactose-restricted diet, a high percentage of patients experience long-term complications, including cognitive impairment, speech and language abnormalities, tremor, ataxia, osteopenia, and over 80% of females have premature ovarian insufficiency (2)(3)(4). The pathophysiology is complex and comprises toxic build-up of galactose and its metabolites galactose-1-phosphate (Gal-1-P) and galactitol, altered glycoprotein and glycolipid production, disruption of multiple cell signaling pathways, and gene dysregulation (5,6). …”

Leptin Levels in Children and Adults with Classic Galactosaemia

“…Recent results from our group, as well as others, have demonstrated abnormal N-glycan processing and assembly in individuals with Gal (Coss et al 2012a;Coman et al 2010). This might affect G-protein-coupled receptors, including the insulin-like peptide relaxin receptors LGR7 and LGR8 which have roles in reproductive tissue remodelling.…”

“…due to direct toxic effects of galactose and its metabolites or due to hypoglycosylation; (2) altered dynamics of follicle development, e.g. due to dysregulated balance of apoptosis and survival pathways in the folliculogenesis; (3) perturbated gene expression pattern along with metabolic dyshomeostasis; and (4) altered follicle maturation due to reduced biopotency of nurturing factors such as FSH or others (Coman et al 2010;Rubio-Gozalbo et al 2010;Fridovich-Keil et al 2011;Coss et al 2012a). We have described earlier that, consistent with the international experience, 91.2% of females with Gal suffer from hypergonadotropic hypogonadism along with pubertal delay and fertility issues (Coss et al 2012b).…”

“…They may comprise, for example, toxic effects of accumulated galactose and its metabolites, disturbances in glycoprotein and glycolipid synthesis, altered cell signalling pathways and dysregulated gene expression (Coman et al 2010;Coss et al 2012a). FSH levels are often found to be elevated in females with Gal but biologic activity of gonadotropins was described as essentially normal (Kaufman et al 1981;Berry 2008).…”

“…Leptin acts on multiple brain regions including the brain stem, hypothalamus, hippocampus and ventral tegmental area by activating the cytokine type 1 leptin receptor which is coupled to the JAK2 signalling mechanism (Trinko et al 2011). As we have reported dysregulation of multiple central cell signalling pathways in Gal (Coman et al 2010), we proposed to study circulating leptin levels in children and adults with Gal.…”