bims-meglyc 2026-09-13 papers

Issue of 2026–09–13
four papers selected by
Silvia Radenkovic, UMC Utrecht

J Inherit Metab Dis. 2026 Sep;49(5): e70240

Results From a Phase 2, Open-Label Study Evaluating the Safety, Tolerability, and Effect on Ataxia of GLM101 in Three Adult Patients With PMM2-CDG.

Mercedes Serrano, Florencia Epifani, Rose Marino, Peter McWilliams.

Phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG) is a rare, autosomal recessive disease caused by PMM2 deficiency, which impairs conversion of mannose-6-phosphate into mannose-1-phosphate (M1P) and disrupts N-linked glycosylation. It typically results in a multisystem disorder in which a prominent cerebellar syndrome, characterized by ataxia among other clinical manifestations, can be assessed using the International Cooperative Ataxia Rating Scale (ICARS). GLM101 is a liposomal M1P substrate replacement therapy in clinical development. We present results conducted both within and outside the protocol-defined schedule from three adult patients enrolled in a Phase 2 study evaluating the efficacy, safety, and tolerability of GLM101 (NCT05549219). PMM2-CDG patients received weekly infusions of 30 mg/kg GLM101 for 24 weeks. Ataxia was measured by ICARS as standard of care. Absolute and percent change from baseline were calculated. Additional results reported include global impression of change scales (caregiver and clinician) and safety. Three adult patients (1 M, 2 F) completed 24 weeks of treatment. The mean (SD) baseline ICARS was 50.7 (19.0) and mean (SD) change from baseline was -14.0 (7.2) and -17.7 (3.1) at Weeks 12 and 24, respectively. Improvements were seen across all ICARS subdomains. All patients and clinicians reported global clinical improvement. GLM101 was well tolerated with no serious adverse events. Infusion-associated reactions were reported in one patient, with no need to interrupt the therapy. Safety findings showed no adverse trends. In conclusion, GLM101 was well tolerated and demonstrated potential for meaningful clinical benefit. These findings support continued evaluation of GLM101 in patients with PMM2-CDG.

Keywords: GLM101; ICARS; PMM2‐CDG; ataxia; cerebellar syndrome; phosphomannomutase deficiency

DOI: https://doi.org/10.1002/jimd.70240

Brain. 2026 Sep 11. pii: awag304. [Epub ahead of print]

Mice with the mono-allelic p.R37H Dhdds variant show aberrant glycosylation and interneuron deficits.

Developmental delay and seizures with or without movement abnormalities (OMIM 617836) caused by heterozygous pathogenic variants in the DHDDS gene (DHDDS-CDG) is a rare genetic disease that belongs to the progressive encephalopathy spectrum. It results in cognitive delay in affected children, accompanied by myoclonus, seizures, ataxia and tremor, which worsens over time. DHDDS encodes a subunit of a DHDDS/NUS1 cis-prenyltransferase (cis-PTase), a branch point enzyme of the mevalonate pathway essential for N-linked glycosylation. We describe the first mouse model of this disease, DhddsR37H+/- strain, heterozygous for the human recurrent de novo c.110G>A:p.R37H pathogenic variant. DhddsR37H+/- mice present with seizures, myoclonus and memory deficits associated with reduced density or/and maturity of inhibitory interneurons in the cortex. Multiomics analyses of mouse CNS tissues, together with the enzymatic/structural characterization of the R37H DHDDS mutant protein, reveal that the variant produces a catalytically inactive enzyme and results in a brain dolichol deficit, aberrant glycosylation of brain glycoproteins, including those involved in synaptic transmission and major perturbations in the CNS proteome and lipidome. Acetazolamide, a carbonic anhydrase inhibitor clinically approved for treatment of glaucoma, epilepsy, and intracranial hypertension, and successfully used "off-label" to treat genetic movement disorders, reduces seizure susceptibility to pentylenetetrazol in DhddsR37H+/- mice, suggesting potential therapeutic value of using this drug in human DHDDS-CDG patients. Together, our results define cis-PTase as a master regulator of CNS development and function and establish that its monoallelic debilitating variants cause a novel congenital disorder of glycosylation associated with aberrant levels of neuronal proteins and lipids.

Keywords: DHDDS ; NUS1 ; cis-prenyltransferase; glycosylation defects; inhibitory interneurons; progressive encephalopathy

DOI: https://doi.org/10.1093/brain/awag304

Clin Case Rep. 2026 Sep;14(9): e73083

Identification of the Genomic Etiology of Unexplained Congenital Problems in Pediatric Patients: First Reported Case With Coffin-Siris Syndrome and Sialuria From India.

Aparna Bhanushali, Archana Kawalakatt, Smita Kulkarni, Preethi Nair, Ankita Mali, Ashlesha Pradhan, Anirvan Chatterjee.

Coffin-Siris syndrome (CSS) (OMIM:614608) is a rare genetic disorder characterized by global developmental delay (GDD), speech impediment, coarse facial features, and hypoplastic or absent fifth fingernails/toenails. Genetic variants in the SMARCB1 gene are associated with CSS, benign tumors (schwannomas), and rhabdoid tumor predisposition syndrome. Genetic variants in the GNE gene are associated with the autosomal dominant sialuria (OMIM#269921), a rare inborn error of metabolism resulting in high levels of free sialic acid. Here we present case reports of two siblings: patient 1 (10 years) and patient 2 (2 years). While both siblings showed GDD and dysmorphic features such as hypotelorism and large ears, patient #1 exhibited additional phenotypes. Whole exome sequencing identified a heterozygous pathogenic variant, NM_003073.5:c.1096C>T (p.Arg366Cys), in the SMARCB1 gene in both siblings. In addition, patient 1 harbored a heterozygous likely pathogenic variant, NM_005476.7:c.2086G>A (p.Val696Met), in the GNE gene, which was absent in patient 2. The co-occurrence of the GNE variant may contribute to the increased severity of the phenotype in patient 1. This study is the first report worldwide of the co-occurrence of two extremely rare disorders. These findings highlight the complexity of genomic contributions while also emphasizing the value of genomic sequencing for congenital problems.

Keywords: Coffin–Siris syndrome; Coffin–Siris syndrome‐3; GNE; India; SMARCB1; global developmental delay; sialuria; unexplained‐congenital; whole exome sequencing

DOI: https://doi.org/10.1002/ccr3.73083

Biochim Biophys Acta Gen Subj. 2026 Sep 09. pii: S0304-4165(26)00097-8. [Epub ahead of print]1870(12): 130997

B3GNT5-associated glycosylation remodeling in tumor-associated macrophages supports TGF-β-related glioma progression.

Zhe Dai, Ying Wang, Inka Brockhausen, Yin Gao.

Tumor-associated macrophages (TAMs) are abundant in the glioma microenvironment, but the glycosylation changes linked to their pro-tumorigenic functions remain unclear. β1,3-N-acetylglucosaminyltransferase 5 (B3GNT5), an enzyme involved in lacto/neolacto-series glycosphingolipid biosynthesis, has been associated with poor prognosis in glioma. Here, analyses of bulk transcriptomic, single-cell RNA-sequencing, and spatial transcriptomic datasets showed that B3GNT5 was enriched mainly in glioma-associated TAMs rather than in tumor cells. B3GNT5-high TAMs displayed M2-like features that were enriched at later stages of macrophage differentiation. In a macrophage-glioma coculture model, glioma-derived soluble signals increased B3GNT5 expression in macrophages. B3GNT5 silencing altered lectin-detectable cell-surface glycosylation and reduced macrophage-mediated glioma cell proliferation and invasion. B3GNT5 was associated with B4GALT1 expression, and co-immunoprecipitation and immunofluorescence assays indicated detectable B3GNT5-B4GALT1 association. Further experiments showed that B3GNT5 silencing reduced coculture-induced ITGB1/integrin β1 and TGF-β1 expression. Knockdown of TGFB1, ST6GAL1, or ITGB1 in macrophages attenuated TAM-induced Smad2 phosphorylation in glioma cells, while adenoviral ITGB1 overexpression partially restored TGF-β1 expression after B3GNT5 or ST6GAL1 depletion. These findings suggest that B3GNT5-associated glycosylation remodeling supports TAM-mediated, TGF-β-related glioma progression.

Keywords: B3GNT5; B4GALT1; Glioma; Glycosylation remodeling; Integrin β1; TGF-β signaling; Tumor-associated macrophages

DOI: https://doi.org/10.1016/j.bbagen.2026.130997