Galactose‐1‐phosphate uridyltransferase deficiency: A literature review of the putative mechanisms of short and long‐term complications and allelic variants

Viggiano, Emanuela; Politano, Luisa; Burlina, Alberto

doi:10.1111/cge.13030

Cited by 22 publications

(28 citation statements)

References 113 publications

(281 reference statements)

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“…The impact of abnormal glycosylation on the physiological function of different glycoproteins and glycolipids has been considered a contributing factor to galactosemia complications (Liu et al 2012;C o s se ta l .2014a, b). Recent in vitro and in vivo studies have also demonstrated the increase in oxidative stress and downregulation of PI3K/Akt pathway in response to the impaired GALT function (Jumbo-Lucioni et al 2013;Balakrishnan et al 2016), although the understanding of the complex interplay between these different mechanisms is still limited (Viggiano et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Biochemical changes and clinical outcomes in 34 patients with classic galactosemia

Yuzyuk

Viau

Andrews

et al. 2018

J of Inher Metab Disea

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Impaired activity of galactose-1-phosphate uridyltransferase (GALT) causes galactosemia, an autosomal recessive disorder of galactose metabolism. Early initiation of a galactose-restricted diet can prevent or resolve neonatal complications. Despite therapy, patients often experience long-term complications including speech impairment, learning disabilities, and premature ovarian insufficiency in females. This study evaluates clinical outcomes in 34 galactosemia patients with markedly reduced GALT activity and compares outcomes between patients with different levels of mean galactose-1-phosphate in red blood cells (GAL1P) using logistic regression: group 1 (n = 13) GAL1P ≤1.7 mg/dL vs. group 2 (n = 21) GAL1P ≥ 2 mg/dL. Acute symptoms at birth were comparable between groups (p = 0.30) with approximately 50% of patients presenting with jaundice, liver failure, and failure-to-thrive. However, group 2 patients had significantly higher prevalence of negative long-term outcomes compared to group 1 patients (p = 0.01). Only one of 11 patients >3 yo in group 1 developed neurological and severe behavioral problems of unclear etiology. In contrast, 17 of 20 patients >3 yo in group 2 presented with one or more long-term complications associated with galactosemia. The majority of females ≥15 yo in this group also had impaired ovarian function with markedly reduced levels of anti-Müllerian hormone. These findings suggest that galactosemia patients with higher GAL1P levels are more likely to have negative long-term outcome. Therefore, evaluation of GAL1P levels on a galactose-restricted diet might be helpful in providing a prognosis for galactosemia patients with rare or novel genotypes whose clinical presentations are not well known.

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Section: Introductionmentioning

confidence: 99%

Biochemical changes and clinical outcomes in 34 patients with classic galactosemia

Yuzyuk

Viau

Andrews

et al. 2018

J of Inher Metab Disea

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“…Life-long galactose restricted diet is the only treatment currently available for this condition. Although this treatment is life-saving in the neonate, long-term complications including cognitive impairment, neurological and speech abnormalities, and fertility problems in female patients, persist in treated adult patients despite early diagnosis and initiation of treatment [ 1 – 8 ]. Ovarian damage and subfertility with primary ovarian insufficiency (POI) is a major complication for females causing a very significant disease burden.…”

Section: Introductionmentioning

confidence: 99%

Fertility in classical galactosaemia, a study of N-glycan, hormonal and inflammatory gene interactions

Colhoun

Rubio-Gozalbo

Bosch

et al. 2018

Orphanet J Rare Dis

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BackgroundClassical Galactosaemia (CG) (OMIM #230400) is a rare inborn error of galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). Long-term complications persist in treated patients despite dietary galactose restriction with significant variations in outcomes suggesting epigenetic glycosylation influences. Primary Ovarian Insufficiency (POI) is a very significant complication affecting females with follicular depletion noted in early life. We studied specific glycan synthesis, leptin system and inflammatory gene expression in white blood cells as potential biomarkers of infertility in 54 adults with CG adults (27 females and 27 males) (age range 17–51 yr) on a galactose-restricted diet in a multi-site Irish and Dutch study. Gene expression profiles were tested for correlation with a serum Ultra-high Performance Liquid Chromatography (UPLC)-Immunoglobulin (IgG)-N-glycan galactose incorporation assay and endocrine measurements.ResultsTwenty five CG females (93%) had clinical and biochemical evidence of POI. As expected, the CG female patients, influenced by hormone replacement therapy, and the healthy controls of both genders showed a positive correlation between log leptin and BMI but this correlation was not apparent in CG males. The strongest correlations between serum leptin levels, hormones, G-ratio (galactose incorporation assay) and gene expression data were observed between leptin, its gene and G-Ratios data (rs = − 0.68) and (rs = − 0.94) respectively with lower circulating leptin in CG patients with reduced IgG galactosylation. In CG patients (males and females analysed as one group), the key glycan synthesis modifier genes MGAT3 and FUT8, which influence glycan chain bisecting and fucosylation and subsequent cell signalling and adhesion, were found to be significantly upregulated (p < 0.01 and p < 0.05) and also the glycan synthesis gene ALG9 (p < 0.01). Both leptin signalling genes LEP and LEPR were found to be upregulated (p < 0.01) as was the inflammatory genes ANXA1 and ICAM1 and the apoptosis gene SEPT4 (p < 0.01).ConclusionsThese results validate our previous findings and provide novel experimental evidence for dysregulation of genes LEP, LEPR, ANXA1, ICAM1 and SEPT4 for CG patients and combined with our findings of abnormalities of IgG glycosylation, hormonal and leptin analyses elaborate on the systemic glycosylation and cell signalling abnormalities evident in CG which likely influence the pathophysiology of POI.

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“…2 Symptoms such as failure to thrive, poor feeding, vomiting, diarrhea, jaundice, hepatomegaly, present themselves in newborns with galactosemia. 3 Untreated galactosemia can lead to liver disease, renal tubular dysfunction, Escherichia coli sepsis, and neonatal death. 4 Newborn screening for galactosemia largely eliminates neonatal death through early identification and prompt treatment with a galactose-free diet.…”

Section: Introductionmentioning

confidence: 99%

Identification of neuronal structures and pathways corresponding to clinical functioning in galactosemia

Ahtam

Waisbren

Anastasoaie

et al. 2020

J of Inher Metab Disea

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Classic galactosemia (OMIM# 230400) is an autosomal recessive disorder due to galactose-1-phosphate uridyltransferase deficiency. Newborn screening and prompt treatment with a galactose-free diet prevent the severe consequences of galactosemia, but clinical outcomes remain suboptimal. Five men and five women with classic galactosemia (mean age = 27.2 ± 5.47 years) received comprehensive neurological and neuropsychological evaluations, electroencephalogram (EEG) and magnetic resonance imaging (MRI). MRI data from nine healthy controls (mean age = 30.22 ± 3.52 years) were used for comparison measures. Galactosemia subjects experienced impaired memory, language processing, visual-motor skills, and increased anxiety. Neurological examinations revealed tremor and dysarthria in six subjects. In addition, there was ataxia in three subjects and six subjects had abnormal gait. Mean full scale IQ was 80.4 ± 17.3. EEG evaluations revealed right-sided abnormalities in five subjects and bilateral abnormalities in one subject. Compared to age-and gender-matched controls, subjects with galactosemia had reduced volume in left cerebellum white matter, bilateral putamen, and left superior temporal sulcus. Galactosemia patients also had lower fractional anisotropy and higher radial diffusivity values in the dorsal and ventral language networks compared

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Galactose‐1‐phosphate uridyltransferase deficiency: A literature review of the putative mechanisms of short and long‐term complications and allelic variants

Cited by 22 publications

References 113 publications

Biochemical changes and clinical outcomes in 34 patients with classic galactosemia

Biochemical changes and clinical outcomes in 34 patients with classic galactosemia

Fertility in classical galactosaemia, a study of N-glycan, hormonal and inflammatory gene interactions

Identification of neuronal structures and pathways corresponding to clinical functioning in galactosemia

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