bims-meglyc 2025-07-27 papers

Issue of 2025–07–27
four papers selected by
Silvia Radenkovic, UMC Utrecht

Mol Genet Metab. 2025 Jul 18. pii: S1096-7192(25)00187-8. [Epub ahead of print]146(1-2): 109196

Phenotypic and genotypic description of GMPPA-congenital disorder of glycosylation: A review of 26 cases.

Ruqaiah Altassan, Sarah K Aldhahri, Georgia Macdonald, Rameen Shah, Eva Morava.

GMPPA-Congenital Disorder of Glycosylation (CDG) is an ultra-rare autosomal recessive CDG caused by pathogenic variants in GMPPA that affects the N-linked glycosylation pathway. Affected individuals present with three major symptoms: achalasia, alacrima, and impaired intellectual development during infancy. Current management of GMPPA-CDG is targeted to address patients' symptoms. To date, 23 individuals have been reported with GMPPA-CDG. This paper reviews the clinical, biochemical and genetic characteristics of the reported 23 patients and adds 3 patients with GMPPA-CDG. We also describe the effect of oral N-acetylglucosamine (GlcNAc) supplementation in 3 patients. Besides alacrima, achalasia and developmental/ intellectual disability, we noted in these patients also variable growth impairment, facial dysmorphism, hyperkeratosis, hypohidrosis, anodontia, and hearing deficit. Under treatment with GlcNAc (4-6 g/day), we noted improved tear production in our 3 patients. Given its effect on different developmental pathways, we emphasize the need for multidisciplinary care for this multisystem disorder. We did not find a genotype/phenotype correlation in our cohort of 26 patients.

Keywords: AAMR; Achalasia, short stature; Alacrima; CDG; Impaired intellectual development syndrome; N-acetyl-glucoseamine

DOI: https://doi.org/10.1016/j.ymgme.2025.109196

Cureus. 2025 Jun;17(6): e86531

Persistent Neutropenia and Atopy in an Adolescent: A Subtle Presentation of Phosphoglucomutase 3 Deficiency.

Madalena Fonseca, Francisco Abrantes, Sara Pinho, Isabel Esteves, Catarina Salgado, Carolina Gonçalves, Anabela Ferrão.

Phosphoglucomutase 3 (PGM3) deficiency (OMIM (Online Mendelian Inheritance in Man) #615816) is a rare autosomal recessive congenital disorder of glycosylation that disrupts multiple glycosylation pathways, with few cases reported in the literature. It leads to a broad clinical spectrum ranging from hyper-IgE syndrome (HIES)-like features to severe combined immunodeficiency (SCID). We report a case of a 17-year-old female of Brazilian origin, referred to our center in Portugal for investigation of persistent neutropenia. Her medical history included recurrent infections in early childhood, severe eczema, and autism spectrum disorder. She exhibited persistent neutropenia and T-cell lymphopenia, with elevated IgE levels. Genetic analysis using a next-generation sequencing panel for primary immunodeficiencies identified compound heterozygous likely pathogenic variants in PGM3: a missense variant (c.1475C>T, p.(Thr492Ile)) and a complete gene deletion in the other allele, confirming the diagnosis of PGM3 deficiency. Chronic neutropenia was the main finding that prompted the genetic investigation. Although it is not a defining feature of PGM3 deficiency, it has been reported in nearly half of the cases. In this patient, the clinical presentation has been comparatively milder than the severe phenotypes described in the literature, which highlights the phenotypic variability of this condition and the need for clinical suspicion, even when classical features are absent. The genetic diagnosis has important implications for clinical follow-up and enables appropriate genetic counseling. This case illustrates the clinical variability of PGM3 deficiency and reinforces the role of genetic testing in clarifying the diagnosis, guiding management, and informing long-term follow-up in rare inborn errors of immunity.

Keywords: chronic neutropenia; congenital disorder of glycosylation; eczema; inborn errors of immunity; pgm3 deficiency

DOI: https://doi.org/10.7759/cureus.86531

JCI Insight. 2025 Jul 22. pii: e180752. [Epub ahead of print]10(14):

A hypomorphic Mpi mutation unlocks an in vivo tool for studying global N-glycosylation deficiency.

Elisa B Lin, Steve Meregini, Zhao Zhang, Avishek Roy, Tandav Argula, James M Mitchell, William J Israelsen, Sara Ludwig, Jamie Russell, Jiexia Quan, Sara Hildebrand, Evan Nair-Gill, Bruce Beutler, Jeffrey A SoRelle.

Glycans are one of the 4 major macromolecules essential for life and are the most abundant family of organic molecules. However, in contrast with DNA and RNA, glycan structures have no template; this results in limited tools to study this challenging macromolecule with a diversity of glycan structures. A central bottleneck in studying glycosylation in vivo is that inhibitors and complete KOs are lethal. In a forward genetic screen, we identified a viable, hypomorphic mutation at a conserved site in mannose phosphate isomerase (Mpi) that causes a multisystemic phenotype affecting RBCs, liver, stomach, intestines, skin, size, fat, and fluid balance in mice. The phenotype could be rescued with mannose. Analyses of glycopeptides in mice with this mutation showed a 500% increase in unoccupied N-glycan sites. This is equivalent to a "glycan knockdown," which would be useful for examining the role of glycans in biology and disease. Therefore, we report an in vivo tool to study global N-glycosylation deficiency with tissue-specific targeting and a rescue mechanism with mannose.

Keywords: Gastroenterology; Genetic diseases; Genetics; Glycobiology; Mouse models

DOI: https://doi.org/10.1172/jci.insight.180752