The metabolic map into the pathomechanism and treatment of PGM1-CDG

Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA). On the basis of the decreased galactosylation in glycan chains, galactose was administered to individuals with PGM1-CDG and was shown to markedly reverse most disease-related laboratory abnormalities. The disease and treatment mechanisms, however, have remained largely elusive. Here, we confirm the clinical benefit of galactose supplementation in PGM1-CDG-affected individuals and obtain significant insights into the functional and biochemical regulation of glycosylation. We report here that, by using tracer-based metabolomics, we found that galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their sugar metabolism, and as such replenishes the depleted levels of galactose-1-P, as well as the levels of UDP-glucose and UDP-galactose, the nucleotide sugars that are required for ER- and GA-linked glycosylation, respectively. To this end, we further show that the galactose in UDP-galactose is incorporated into mature, de novo glycans. Our results also allude to the potential of monosaccharide therapy for several other CDG

Born into an isolating world: family-centred care for babies born to mothers with COVID-19Research in context

Summary: Background: The benefits of facilitating breastmilk feeding and close contact between mother and neonate (family-centred care; FCC) in the perinatal period are well-established. The aim of this study was to determine how the delivery of FCC practices were impacted for neonates born to mothers with perinatal SARS-CoV-2 infection during the COVID-19 pandemic. Methods: Neonates born to mothers with confirmed SARS-CoV-2 infection during pregnancy were identified from the ‘EsPnIC Covid paEdiatric NeonaTal REgistry’ (EPICENTRE) multinational cohort between 10 March 2020 and 20 October 2021. The EPICENTRE cohort collected prospective data on FCC practices. Rooming-in and breastmilk feeding practice were the main outcomes, and factors influencing each were determined. Other outcomes included mother-baby physical contact prior to separation and the pattern of FCC components relative to time and local site guidelines. Findings: 692 mother-baby dyads (13 sites, 10 countries) were analysed. 27 (5%) neonates were positive for SARS-CoV-2 (14 (52%) asymptomatic). Most sites had policies that encouraged FCC during perinatal SARS-CoV-2 infection for most of the reporting period. 311 (46%) neonates roomed-in with their mother during the admission. Rooming-in increased over time from 23% in March–June 2020 to 74% in January–March 2021 (boreal season). 330 (93%) of the 369 separated neonates had no FCC physical contact with their mother prior, and 319 (86%) were asymptomatic. Maternal breastmilk was used for feeding in 354 (53%) neonates, increasing from 23% to 70% between March–June 2020 and January–March 2021. FCC was most impacted when mothers had symptomatic COVID-19 at birth. Interpretation: This is the largest report of global FCC practice during the COVID-19 pandemic to date. The COVID-19 pandemic may have impacted FCC despite low perinatal transmission rates. Fortunately, clinicians appear to have adapted to allow more FCC delivery as the COVID-19 pandemic progressed. Funding: The National Health and Medical Research Council (Australia): Grant ID 2008212 (DGT), Royal Children’s Hospital Foundation: Grant ID 2019–1155 (EJP), Victorian Government Operational Infrastructure Support Program