Diversity of approaches to classic galactosemia around the world: a comparison of diagnosis, intervention, and outcomes

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

BACKGROUND Classical 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. RESULTS Twenty 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 (r = - 0.68) and (r = - 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). CONCLUSIONS These 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

The history of rainfall data time-resolution in a wide variety of geographical areas

Collected rainfall records by gauges lead to key forcings in most hydrological studies. Depending on sensor type and recording systems, such data are characterized by different time-resolutions (or temporal aggregations), ta. We present an historical analysis of the time-evolution of ta based on a large database of rain gauge networks operative in many study areas. Globally, ta data were collected for 25,423 rain gauge stations across 32 geographic areas, with larger contributions from Australia, USA, Italy and Spain. For very old networks early recordings were manual with coarse time-resolution, typically daily or sometimes monthly. With a few exceptions, mechanical recordings on paper rolls began in the first half of the 20th century, typically with ta of 1 h or 30 min. Digital registrations started only during the last three decades of the 20th century. This short period limits investigations that require long time-series of sub-daily rainfall data, e.g, analyses of the effects of climate change on short-duration (sub-hourly) heavy rainfall. In addition, in the areas with rainfall data characterized for many years by coarse time-resolutions, annual maximum rainfall depths of short duration can be potentially underestimated and their use would produce errors in the results of successive applications. Currently, only 50% of the stations provide useful data at any time-resolution, that practically means ta = 1 min. However, a significant reduction of these issues can be obtained through the information content of the present database. Finally, we suggest an integration of the database by including additional rain gauge networks to enhance its usefulness particularly in a comparative analysis of the effects of climate change on extreme rainfalls of short duration available in different locations