Systemic gene dysregulation in classical Galactosaemia: Is there a central mechanism?

Coss, Karen P.; Treacy, Eileen P.; Cotter, Eoin J.; Knerr, Ina; Murray, David; Shin, Yoon S.; Doran, Peter

doi:10.1016/j.ymgme.2014.08.004

Cited by 29 publications

(57 citation statements)

References 59 publications

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“…Data (mean ± SD) for healthy pediatric controls (black circle) have been previously published by our group (7). Articles demonstrated that the expression of B4GALT1 was decreased by twofold in adults with galactosemia vs. healthy controls in DNA microarray analysis (24). We could also demonstrate that this finding remained significant for the subgroup of adult patients with neurological impairment (24).…”

Section: Discussionmentioning

confidence: 51%

“…Articles demonstrated that the expression of B4GALT1 was decreased by twofold in adults with galactosemia vs. healthy controls in DNA microarray analysis (24). We could also demonstrate that this finding remained significant for the subgroup of adult patients with neurological impairment (24). We here used 300 and 500 mg of daily galactose supplements in our study patients as this amount is close to the range of the endogenous galactose synthesis which is 0.53-1.05 mg/kg body weight per hour (25).…”

Section: Discussionmentioning

confidence: 99%

“…Along these lines, the hippocampus, in particular, expresses high levels of leptin receptors and its signaling cascade (33). The hippocampal formation is also a prime site for many neurodegenerative processes, and disruption of leptin signaling may have a role in cognitive defects and, possibly, neurological impairment in adults with galactosemia (24) In this study, we only studied prepubertal children (Tanner stage 1) over a short period of time to minimize the effects of sex hormone-related changes on the leptin axis. During puberty, the sOb-R levels decrease with increasing Tanner stages for girls and boys (12).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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Background: Classical galactosemia is caused by severe galactose-1-phosphate uridyltransferase deficiency. Despite life-long galactose-restriction, many patients experience long-term complications. Intoxication by galactose and its metabolites as well as over-restriction of galactose may contribute to the pathophysiology. We provided temporary low-dose galactose supplements to patients. We assessed tolerance and potential beneficial effects with clinical monitoring and measurement of biochemical, endocrine, and IgG N-glycosylation profiles. Methods: We enrolled 26 patients (8.6 ± 1.9 y). Thirteen were provided with 300 mg of galactose/day followed by 500 mg for 2 wk each (13 patient controls). results: We observed no clinical changes with the intervention. Temporary mild increase in galactose-1-phosphate occurred, but renal, liver, and bone biochemistry remained normal. Patients in the supplementation group had slightly higher leptin levels at the end of the study than controls. We identified six individuals as "responders" with an improved glycosylation pattern (decreased G0/G2 ratio, P < 0.05). There was a negative relationship between G0/G2 ratio and leptin receptor sOb-R in the supplementation group (P < 0.05). conclusion: Temporary low-dose galactose supplementation in children over 5 y is well tolerated in the clinical setting. It leads to changes in glycosylation in "responders". We consider IgG N-glycan monitoring to be useful for determining individual optimum galactose intake.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…16 It is established that before and after initiation of treatment, galactosaemia patients exhibit defects in both assembly and processing of N-glycans. [17][18][19][20][21] These defects resemble those observed in a number of congenital disorders of glycosylation (CDG) type I (N-glycan assembly defects) and II (N-glycan processing defects). 22 A combination of increased levels of galactose-1-phosphate (gal-1-p) and decreased UDP-hexose substrates causes ER stress and in turn disrupts glycosylation, [23][24][25][26][27] causing systemic genomic dysregulation.…”

Section: Introductionmentioning

confidence: 83%

“…22 A combination of increased levels of galactose-1-phosphate (gal-1-p) and decreased UDP-hexose substrates causes ER stress and in turn disrupts glycosylation, [23][24][25][26][27] causing systemic genomic dysregulation. 19,21 We have proposed that early-stage developmental and also later ongoing disruption of glycosylation and related gene expression pathways may have a role in modifying the observed clinical outcome in classical galactosaemia. Abnormal glycosylation during prenatal galactose intoxication is proposed to affect long-term neurological development.…”

Section: Introductionmentioning

confidence: 99%

Classical galactosaemia: novel insights in IgG N-glycosylation and N-glycan biosynthesis

et al. 2016

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Classical galactosaemia (OMIM #230400), a rare disorder of carbohydrate metabolism, is caused by a deficient activity of galactose-1-phosphate uridyltransferase (EC 2.7.7.12). The pathophysiology of the long-term complications, mainly cognitive, neurological and female fertility problems remains poorly understood. The lack of validated biomarkers to determine prognosis, monitor disease progression and responses to new therapies, pose a huge challenge. We report the detailed analysis of an automated robotic hydrophilic interaction ultra-performance liquid chromatography N-glycan analytical method of high glycan peak resolution applied to serum IgG. This has revealed specific N-glycan processing defects observed in 40 adult galactosaemia patients (adults and adolescents), in comparison with 81 matched healthy controls. We have identified a significant increase in core fucosylated neutral glycans (Po0.0001) and a significant decrease in core fucosylated (Po0.001), non-fucosylated (Po0.0001) bisected glycans and, of specific note, decreased N-linked mannose-5 glycans (Po0.0001), in galactosaemia patients. We also report the abnormal expression of a number of related relevant N-glycan biosynthesis genes in peripheral blood mononuclear cells from 32 adult galactosaemia patients. We have noted significant dysregulation of two key N-glycan biosynthesis genes: ALG9 upregulated (Po0.001) and MGAT1 downregulated (Po0.01) in galactosaemia patients, which may contribute to its ongoing pathophysiology. Our data suggest that the use of IgG N-glycosylation analysis with matched N-glycan biosynthesis gene profiles may provide useful biomarkers for monitoring response to therapy and interventions. They also indicate potential gene modifying steps in this N-glycan biosynthesis pathway, of relevance to galactosaemia and related N-glycan biosynthesis disorders.

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Pathophysiology and targets for treatment in hereditary galactosemia: A systematic review of animal and cellular models

Haskovic

Coelho

Bierau

et al. 2020

J of Inher Metab Disea

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Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an inborn error of carbohydrate metabolism caused by deficient activity of any of the galactose metabolising enzymes. The current standard of care, a galactoserestricted diet, fails to prevent long-term complications. Studies in cellular and animal models in the past decades have led to an enormous progress and advancement of knowledge. Summarising current evidence in the pathophysiology underlying hereditary galactosemia may contribute to the identification of treatment targets for alternative therapies that may successfully prevent long-term complications. A systematic review of cellular and animal studies reporting on disease complications (clinical signs and/or biochemical findings) and/or treatment targets in hereditary galactosemia was performed. PubMed/MEDLINE, EMBASE, and Web of Science were searched, 46 original articles were included. Results revealed that Gal-1-P is not the sole pathophysiological agent responsible for the phenotype observed in galactosemia. Other currently described contributing factors include accumulation of galactose metabolites, uridine diphosphate (UDP)-hexose alterations and subsequent impaired glycosylation, endoplasmic reticulum (ER) stress, altered signalling pathways, and oxidative stress. SSIEM 392J Inherit Metab Dis. 2020;43:392-408. wileyonlinelibrary.com/journal/jimd pyrophosphorylase (UGP) up-regulation, uridine supplementation, ER stress reducers, antioxidants and pharmacological chaperones have been studied, showing rescue of biochemical and/or clinical symptoms in galactosemia. Promising co-adjuvant therapies include antioxidant therapy and UGP up-regulation. This systematic review provides an overview of the scattered information resulting from animal and cellular studies performed in the past decades, summarising the complex pathophysiological mechanisms underlying hereditary galactosemia and providing insights on potential treatment targets. K E Y W O R D Sanimal models, cellular models, hereditary galactosemia, pathophysiology, treatment targets

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Systemic gene dysregulation in classical Galactosaemia: Is there a central mechanism?

Cited by 29 publications

References 59 publications

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

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

Classical galactosaemia: novel insights in IgG N-glycosylation and N-glycan biosynthesis

Pathophysiology and targets for treatment in hereditary galactosemia: A systematic review of animal and cellular models

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