bims-meglyc 2026-03-29 papers

Issue of 2026–03–29
seven papers selected by
Silvia Radenkovic, UMC Utrecht

Biomolecules. 2026 03 12. pii: 418. [Epub ahead of print]16(3):

Expanded Clinical Spectrum of Autosomal-Dominant STT3A-CDG.

Hamdan Al-Shahrani, Evelin Szabó, Caroline Staccone, Georgia MacDonald, Yutaka Furuta, Daniel Schecter, Andrew C Edmondson, Anne McRae, Josh Baker, Eva Morava, Rory J Tinker.

STT3A encodes the catalytic subunit of the oligosaccharyltransferase A (OST-A) complex and is classically linked to severe autosomal-recessive congenital disorder of glycosylation (CDG). To define the distinct autosomal-dominant disorder, we reviewed all published cases and integrated three previously unpublished individuals from the CDG natural history study. Across 21 individuals, abnormal transferrin glycosylation was present in nearly all individuals (20/21), and subtle facial dysmorphism was common (18/21). Neurodevelopmental involvement was frequent, including motor delay (13/21), learning difficulties (13/21), speech delay (12/21), and intellectual disability (10/21). Musculoskeletal manifestations were also common, including skeletal abnormalities (12/21), short stature (11/21), muscle cramps (8/21), and early-onset osteoarthritis in adults (6/21). Less frequent features included congenital heart defects (5/21) and coagulation factor deficiency (5/21). Importantly, the newly reported individuals expand dominant STT3A-CDG with previously unreported features, including anorectal malformation, morbid obesity, and clinically significant bleeding diathesis with von Willebrand factor and factor VIII deficiency. Biochemical signatures ranged from classic type I transferrin patterns to subtle or atypical abnormalities, emphasizing that near-normal transferrin testing does not exclude the diagnosis. Variants clustered in conserved catalytic regions, with recurrent p.Arg405 across de novo, inherited, and mosaic cases supporting a mutational hotspot and likely dominant-negative mechanism.

Keywords: STT3A; congenital disorder of glycosylation; dominant-negative; genotype–phenotype correlation; oligosaccharyltransferase

DOI: https://doi.org/10.3390/biom16030418

Front Genet. 2026 ;17 1813006

Editorial: Inborn errors of carbohydrate metabolism volume II.

José Elías García-Ortíz, Ida Vanessa Doederlein-Schwartz, Melania Abreu-González, Iván Martínez-Duncker.

Keywords: CDG (congenital disorder of glycosylation); GLUT1; LOPD; carbohydrate; inborn error (disorder) of metabolism; lysosomal storage disease (LSD); metabolism; polyglucosan

DOI: https://doi.org/10.3389/fgene.2026.1813006

Mol Genet Metab. 2026 Mar 03. pii: S1096-7192(26)00154-X. [Epub ahead of print]148(2): 109871

A patient with a rare metabolic disease and myo-inositol administration leading to a new treatment for epilepsy.

Gerard T Berry, E Naomi Vos, Didem Demirbas, William Brucker, Allissia Gilmartin, Maria K Lehtinen, Edward Yang, Sanjay P Prabhu, Jie Chen, Xiaoping Huang, Wanshu Qi, Michael J Bennett, Robin L Haynes, Lance Rodan, Annapurna Poduri, Phillip L Pearl, Alexander Rotenberg, Miao He, M Estela Rubio-Gozalbo.

Keywords: Congenital disorders of glycosylation; Defects of glycosylphosphatidylinositol (GPI) anchor synthesis; Developmental and epileptic encephalopathy; Myo-inositol

DOI: https://doi.org/10.1016/j.ymgme.2026.109871

Mol Genet Genomic Med. 2026 Mar;14(3): e70206

Reporting a Novel Disease Causing Variant in PGAP3 Associated With Hyperphosphatasia and Intellectual Disability: A Case Report and Comprehensive Literature Review.

Arash Salmaninejad, Mohammad Reza Seyedtaghia, Ali Hosseini Bereshneh, Nasrin Azizi, Reza Bayat, Somaye Esnaashari, Vahid Aminzadeh, Shahin Koohmanaee, Shahram Savad, Majid Mojarrad, Setila Dalili.

BACKGROUND: A rare autosomal recessive disorder known as hyperphosphatasia with impaired intellectual development syndrome (HPMRS), also referred to as Mabry syndrome, is caused by a deficiency in glycosylphosphatidylinositol (GPI). Elevated blood alkaline phosphatase (ALP) levels, cognitive impairment, and epileptic seizures are among its key features. These pathways are involved in the synthesis of GPI and the transfer of GPI anchor to the proteins, fatty acid remodeling, and transport of GPI-anchored proteins (GPI-APs).
METHODS: Using exome sequencing (ES), the cause of hyperphosphatasia and ID of an 11-year-old girl from non-consanguineous parents was solved, and the results confirmed by direct Sanger sequencing method.
RESULTS: ES identified a novel homozygous pathogenic variant, PGAP3 (NM_033419.5: c.202dupT, p.Cys68fs*2) that segregated within the family members. To the best of our knowledge at the time of writing this manuscript, this variant has not been reported in HPMRS in the literature.
CONCLUSION: Our findings indicate that the p.Cys68fs*2 variant may disrupt normal protein function and likely disrupt its interaction with its associated partner proteins, potentially leading to disruption of GPI biosynthesis. We present a novel pathogenic variant thus expanding the phenotypic and mutational spectrum of this extremely rare disorder. Elevated ALP assays and ES are valuable diagnostic tools for HPMRS. Additionally, a comprehensive literature review was conducted to expand the phenotypic and genotypic spectrum within the PGAP3 gene responsible for HPMRS.

Keywords: PGAP3 ; Mabry syndrome; glycosylphosphatidylinositol; hyperphosphatasia; intellectual disability

DOI: https://doi.org/10.1002/mgg3.70206

bioRxiv. 2026 Mar 04. pii: 2026.03.02.708854. [Epub ahead of print]

Disrupted O-GalNAc glycosylation as a mechanism and biomarker of SLC35A2 -associated epilepsy.

Rare germline and somatic variants in SLC35A2 cause a spectrum of severe glycosylation disorders that commonly present with epilepsy. SLC35A2 encodes the Golgi transporter for UDP-galactose, but how its deficiency leads to severe neurodevelopmental disorders is unknown. Using a mouse model deficient for Slc35a2 in the forebrain, we identified a specific defect in O-GalNAc glycan synthesis, while other galactose-containing glycoconjugates remained intact. O-GalNAc glycans were absent from their normal location within neuronal tracts of the corpus callosum, and truncated precursors accumulated in the cortex on critical extracellular matrix molecules. Cultured primary neurons lacking Slc35a2 showed impaired development, hyperexcitability, and impaired O-GalNAc glycosylation. Finally, human brain tissue from cases of SLC35A2 -associated intractable epilepsy displayed a strong correlation between variant burden and truncated O-GalNAc glycans. These findings provide a mechanistic link between genetic causes of SLC35A2 -associated epilepsy and protein O-glycosylation that can be targeted for biomarker and therapeutic development.

DOI: https://doi.org/10.64898/2026.03.02.708854

Int J Mol Sci. 2026 Mar 18. pii: 2767. [Epub ahead of print]27(6):

Clinical and Functional Characterization of Novel GALNT3 Mutations in a Chinese Child with Hyperphosphatemic Familial Tumoral Calcinosis.

Yuan Gao, Cai Zhang, Shimin Wu, Yanqin Ying, Ling Hou, Yan Liang, Xiaoping Luo.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disorder characterized by hyperphosphatemia and ectopic calcifications. Mutations in GALNT3, which encodes a key enzyme responsible for O-glycosylation of FGF23, represent a major genetic cause of HFTC. This modification is essential for the stability and secretion of FGF23. We investigated a 4-year and 6-month-old Chinese girl with HFTC to characterize the clinical features, identify the causative variants, and explore the underlying pathogenic mechanism. Whole-exome sequencing followed by Sanger validation identified novel compound heterozygous variants in GALNT3 (c.659T>A, p.Ile220Asn and c.1850C>A, p.Ser617*). The patient exhibited hyperphosphatemia with a biochemical profile consistent with FGF23 deficiency, including extremely low intact FGF23 and elevated C-terminal fragments. Functional studies using Western blotting and wheat germ agglutinin affinity chromatography demonstrated that the mutant GALNT3 caused a severe defect in FGF23 O-glycosylation, leading to impaired secretion of intact FGF23. Glycosylated FGF23 was detected only in the medium of cells expressing wild-type GALNT3. These findings indicate that defective O-glycosylation results in failure of FGF23 secretion and functional inactivation. This study expands the mutational spectrum of GALNT3 and provides mechanistic insight into the role of GALNT3 in phosphate homeostasis.

Keywords: GALNT3; O-glycosylation; compound heterozygous mutation; hyperphosphatemic familial tumoral calcinosis; phosphate metabolism; protein secretion

DOI: https://doi.org/10.3390/ijms27062767

J Clin Med. 2026 Mar 21. pii: 2395. [Epub ahead of print]15(6):

Modifier-Sensitive Phenotypic Divergence in XMEN Disease (MAGT1 Deficiency): Neurodegenerative and Immuno-Hematologic Trajectories.

Ragip Fatih Kural, Zuleyha Galata, Reyhan Gumusburun, Ceyda Tunakan Dalgic, Nur Soyer, Havva Yazıcı, Ayse Nur Yuceyar, Aslı Subasıoglu, Irem Evcili, Bilgi Gungor, Kasım Okan, Mehmet Soylu, Cihat Uzunkopru, Omur Ardeniz.

Background: X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia (XMEN) disease is a rare inborn error of immunity caused by loss-of-function mutations in MAGT1, leading to impaired N-linked glycosylation. Although chronic EBV viremia is a hallmark of XMEN disease, the mechanisms underlying its marked clinical heterogeneity remain poorly understood. Methods: We performed an in-depth clinical, immunological, and genetic characterization of two siblings carrying a pathogenic MAGT1 variant (c.369_370insCC; p.Gly124fs), validated and deposited in ClinVar (SCV007293792). Assessments included whole-exome sequencing, multiparametric flow cytometry focusing on NKG2D expression, and longitudinal clinical follow-up. Results: Despite shared absence of NKG2D expression, the siblings exhibited strikingly divergent phenotypes. One sibling developed progressive neurodegeneration with central nervous system atrophy. The other presented with a complex immuno-hematologic phenotype, including EBV-positive Hodgkin lymphoma, recurrent autoimmune cytopenias, and lymphoma-associated thrombotic microangiopathy, representing a novel clinical association in XMEN disease. Comparative immunophenotyping revealed shared defects in B-cell maturation but distinct T-cell differentiation patterns. To contextualize neurological variability, we propose a descriptive, hypothesis-generating three-category conceptual classification comprising early-onset neurodevelopmental forms, adult-onset neurodegenerative manifestations, and secondary immune-mediated or vascular involvement of the nervous system. Conclusions: These findings demonstrate profound intrafamilial heterogeneity in XMEN disease and suggest a model in which modifier-sensitive factors influence organ-specific disease expression. The observation of lymphoma-associated thrombotic microangiopathy and the proposed descriptive neurological classification provide a conceptual framework that may help guide tailored, multidisciplinary surveillance beyond the primary genetic defect.

Keywords: EBV-driven lymphoma; MAGT1 deficiency; XMEN disease; immunohematology; inborn errors of immunity; neurodegeneration; tailored surveillance; thrombotic microangiopathy

DOI: https://doi.org/10.3390/jcm15062395