bims-meglyc 2026-05-03 papers

Issue of 2026–05–03
five papers selected by
Silvia Radenkovic, UMC Utrecht

Am J Med Genet A. 2026 Apr 27.

Early-Onset Epileptic Encephalopathy and Neurodevelopmental Regression Associated With ST3GAL5 Deficiency.

Sabire Gokalp, Elif Guler, Mustafa Kilic.

GM3 synthase deficiency (GM3SD), also known as salt and pepper developmental regression syndrome, is a rare autosomal recessive congenital disorder of glycosylation caused by biallelic pathogenic variants in ST3GAL5. It is characterized by early onset epileptic encephalopathy, severe neurodevelopmental impairment, and sensory deficits. Routine metabolic screening tests are frequently non-specific, which may contribute to delayed diagnosis. We report a Turkish male infant who presented in early infancy with developmental delay and hypotonia, followed by early onset, refractory epilepsy and progressive neurodevelopmental regression. Feeding dysfunction progressed to complete loss of swallowing, necessitating gastrostomy and tracheostomy. Neuroimaging demonstrated diffuse cerebral atrophy and ventriculomegaly, and audiological evaluation revealed bilateral sensorineural hearing loss. Extensive metabolic investigations, including screening for congenital disorders of glycosylation, were non-diagnostic. Whole-exome sequencing identified a novel homozygous frameshift variant in ST3GAL5 (NM_003896.4: c.726_732del, p.(Met242Ilefs*35)), classified as likely pathogenic, confirming the diagnosis of GM3SD. During follow-up, renal calculi and hepatobiliary abnormalities, including biliary sludge, gallstones, and transaminase elevation, were observed. This case highlights the severe neurological course and diagnostic challenges associated with ST3GAL5-related GM3SD and underscores the critical role of comprehensive genetic testing in infants with unexplained epileptic encephalopathy and developmental regression. Although renal and hepatobiliary abnormalities are not considered characteristic features of GM3SD, their occurrence during long-term follow-up emphasizes the need for careful multisystem surveillance in severely affected patients.

Keywords: GM3 synthase deficiency; ST3GAL5; congenital disorders of glycosylation; epileptic encephalopathy; salt and pepper developmental regression syndrome

DOI: https://doi.org/10.1002/ajmg.a.70174

bioRxiv. 2026 Apr 18. pii: 2026.04.17.719256. [Epub ahead of print]

A drug repurposing screen reveals dopamine signaling as a candidate therapeutic pathway for PIGA-CDG.

Miriam Cecilia Aziz, Jennie Wilson, Clement Y Chow.

PIGA-CDG is a congenital disorder of glycosylation caused by pathogenic partial loss-of-function variants in the PIGA gene. PIGA encodes an enzyme responsible for the catalytic transfer of N-acetylglucosamine to phosphatidylinositol during the first step of glycosylphosphatidylinositol anchor biosynthesis. Loss of this enzyme has a widespread phenotypic impact, but primarily results in neurological symptoms including seizures, intellectual disability, and developmental delay. Currently, treatments are limited and focus on symptom management. We developed an eye model of PIGA-CDG that has a reduced eye size. We screened a library of 98% 1,520 FDA/EMA-approved compounds to find drugs that improved the small eye phenotype. This screen revealed numerous drugs that improved eye size, including those that targeted dopamine signaling and cyclooxygenases. Using pharmacological and genetic approaches, we show that modulating dopamine signaling improves the eye size. Genetic inhibition of dopamine 2 receptor signaling and dopamine reuptake improve both the eye model and neurologically relevant PIGA-CDG phenotypes, including seizures and locomotor deficits. We also pharmacologically and genetically validate cyclooxygenase targeting drugs in the eye model. These findings reveal novel biology underlying PIGA-CDG and point towards candidate therapeutic approaches.

DOI: https://doi.org/10.64898/2026.04.17.719256

Matrix Biol. 2026 Apr 28. pii: S0945-053X(26)00053-3. [Epub ahead of print] 102011

C-terminally clustered UGDH hypomorphic variants reveal subtle mechanisms of cellular and developmental disruption.

Jamuar syndrome (Developmental and Epileptic Encephalopathy 84, OMIM# 618792) is a rare autosomal recessive congenital disorder of glycosylation (CDG), caused by variations in the gene encoding UDP-glucose dehydrogenase (UGDH). Although a number of UGDH variants have been functionally characterized, there is an incomplete catalogue of variants and their impacts on development. Here, we present functional data characterizing new missense variants from three unrelated individuals who were D379N homozygous, Y356D homozygous, and compound heterozygous A436G/R442W, respectively. UGDH activity was low to undetectable in patient-derived fibroblasts bearing either UGDH D379N or UGDH A436G/R442W, relative to WT fibroblasts, despite robust UGDH expression in both. Measurement of nucleotide sugar levels revealed a significant decrease in the UGDH product, UDP-glucuronate, and consequent reductions in hyaluronan production, Notch1 levels, and rate of O-and N-linked glycan synthesis, consistent with loss of UGDH activity. These features support the designation of UGDH D379N and UGDH A436G as causative variants in Jamuar Syndrome. We expressed and purified UGDH D379N, A436G, R442W, R443H, and Y356D variants to examine underlying molecular mechanisms. Kinetic properties and structural stability assays selectively revealed significant changes in conformational dynamics that manifested strong effects on endogenous inhibitor binding and product inhibition. The results suggest that alterations to the C-terminal domain impact activity of UGDH in cells by impairing its cofactor exchange rate and diminishing quaternary association. These effects would be maximized at developmental milestones in which hypoxia drives morphological change, since NADH accumulation would then decrease glycosaminoglycan production, with profound developmental consequences.

Keywords: UDP-glucose dehydrogenase; congenital disorders of glycosylation; developmental epileptic encephalopathy; enzyme kinetics; glycosaminoglycan; hyaluronan

DOI: https://doi.org/10.1016/j.matbio.2026.102011

Front Biosci (Landmark Ed). 2026 Mar 31. 31(4): 46961

Discovering the Hidden Power of NGLY1: Orchestrating Immune Cell Functions and Autoimmune Diseases.

Christina B Brunner, Melissa C Schubbert, Maximilian M Siewert, Michèle Ohnemüller, Frederic Kuwert, Ulla I M Gerling-Driessen, Katharina Pracht.

The enzyme N-glycanase 1 (NGLY1) regulates autophagic processes and endoplasmic reticulum (ER)-associated proteasomal degradation by de-N-glycosylation of misfolded glycoproteins. Mutations of NGLY1 that result in a loss of protein function cause congenital disorder of deglycosylation 1 (CDDG1), also known as NGLY1 deficiency. NGLY1 deficiency is associated with severe dysregulation of mitochondria and proteasomal degradation, which primarily manifests as impairments in the nervous system. However, recent studies also linked NGLY1 function to cellular processes associated with immunity and autoimmune diseases, such as rheumatoid arthritis. NGLY1 plays a distinct role in mitochondrial homeostasis, thereby potentially regulating interferon responses, cellular stress responses and innate immunity. It also controls the stability of the programmed cell death protein-1 (PD-1) receptor on T lymphocytes and cancer cells, influencing tumor immune evasion. Importantly, NGLY1 was shown to process foreign peptides destined for presentation on major histocompatibility complex (MHC) molecules, a process that enables cytotoxic T lymphocytes to identify pathogens or mutated cells. Finally, altered levels of NGLY1 may impair B lymphocytes, especially the formation and function of antibody-secreting cells. In this review, we aim to compile findings from the last three decades and explore the connections between NGLY1-controlled processes and immune cell function. Understanding NGLY1-mediated mechanisms may provide new insights into the modulation of immune responses and the development of therapeutic strategies for immune-related disorders.

Keywords: B-lymphocytes; NGLY1; T-lymphocytes; congenital disorders of deglycosylation (CDDG); endoplasmic reticulum-associated degradation; immune system; inflammation; mitochondria; rheumatoid arthritis (RA)

DOI: https://doi.org/10.31083/FBL46961

bioRxiv. 2026 Apr 14. pii: 2026.04.10.717608. [Epub ahead of print]

Patient iPSC-Derived Cartilage Organoids Reveal Defective ECM Deposition and Altered Chondrogenic Trajectory in Saul-Wilson Syndrome.

Sonal Mahajan, Sara Ancel, Giuliana Ascone, Rajdeep Kaur, Juancarlos Torres, Rabi Murad, Yu Xin Wang, Carlos R Ferreira, Hudson H Freeze.

Saul-Wilson syndrome (SWS) is a skeletal dysplasia characterized by primordial dwarfism and progeroid features caused by a recurrent dominant COG4 variant (p.G516R). We previously showed that this mutation accelerates Golgi retrograde trafficking and disrupts glycosylation of the proteoglycan decorin, while zebrafish models revealed defects in chondrocyte elongation and intercalation. We have also shown that the SW1353 chondrosarcoma cells carrying the SWS variant exhibit reduced secretion of extracellular matrix (ECM) components. While these results indicate a critical function of COG4 in Golgi processing, the developmental process leading to skeletal dysplasia in SWS patients remains unknown. Here, we generated patient-derived iPSC cartilage organoids (SWS organoids), modeling early human chondrogenesis. SWS organoids failed to produce cartilage structures and displayed poor expression of chondrogenic markers. Time-course RNA-seq analysis of the chondrogenic process revealed reduced activation of gene networks involved in skeletal development, ECM organization, ossification, and glycosaminoglycan metabolism. Spatial multiomic analysis of protein and glycosylation by CODEX and GLYPH imaging revealed an altered chondrogenic trajectory, persistence of mesenchymal states, global glycosylation changes, and reduced deposition of chondroitin sulfate proteoglycans. These results indicate that the COG4 mutation disrupts ECM glycosylation and chondrogenic commitment, and that SWS organoids model early defects in cartilage formation underlies impaired skeletal growth in SWS.
Highlights: Patient iPSC-derived cartilage organoids model development defects in Saul-Wilson syndromeSWS organoids show defective extracellular matrix deposition and attenuated chondrogenic gene expressionGlycan profiling reveals global glycosylation defects and deficient proteoglycan GAG chainsAn early developmental impairment in chondrogenesis alters skeletal formation in Saul-Wilson syndrome.

DOI: https://doi.org/10.64898/2026.04.10.717608