bims-meglyc 2026-10-11 papers

bims-meglyc

Biomed News

on Metabolic disorders affecting glycosylation

Issue of 2026–10–11
six papers selected by
Silvia Radenkovic, UMC Utrecht

Clinical and molecular spectrum of congenital disorders of glycosylation in 80 Egyptian patients.
Repurposing the HMG-CoA reductase inhibitor atorvastatin for SRD5A3-congenital disorder of glycosylation.
Multisystemic Clues and Diagnostic Gaps: A Comparative Analysis of Pediatric Congenital Disorders of Glycosylation Patients.
Liver Transplantation in Inborn Errors of Metabolism: A Retrospective Study of a National Experience.
Metabolomic, lipidomic, and N-glycomic analyses of a human cell model of Krabbe disease reveal treatable deficits in glycosylation and serine-ceramide metabolism.
Sphingomyelin synthase 2 deficiency suppresses airway mucus accumulation by altering sphingolipid flux and mucin glycosylation.

Hum Genet. 2026 Oct 09. pii: 84. [Epub ahead of print]145(1):

Clinical and molecular spectrum of congenital disorders of glycosylation in 80 Egyptian patients.

Mohamed S Abdel-Hamid, Sherif F Abdel-Ghafar, Mahmoud Y Issa, Walaa ElNaggar, Hasnaa M Elbendary, Karima Rafat, Nagwa Gaboon, Mahmoud M Noureldeen, Ziad N Rezk, Nour Elkhateeb, Laila Selim, Joseph G Gleeson, Maha S Zaki.

Congenital disorders of glycosylation (CDG) represent a diverse group of inborn errors of metabolism caused by defective glycosylation processes, usually characterized by multiorgan involvement and overlapping clinical symptoms. This study aimed to decipher the clinical and genetic landscape of CDG in Egypt to enumerate the most common CDG types and unveil potentially new candidate genes. The study included 80 patients from 57 families with molecular findings consistent with CDG. Consanguinity was noted in 90% of the families. The most common clinical features were global developmental delay (98%), dysmorphic facies (86%), hypotonia (85%), movement disorders (48%), and seizures (42%). Vision impairment, hepatic, skeletal, and hematological abnormalities were the most frequently encountered systemic manifestations. Structural brain anomalies were commonly observed in our cohort and included thin corpus callosum, cortical atrophy, white matter abnormalities, cerebellar atrophy, and cerebellar vermis hypoplasia. Biallelic variants were identified in 94% of patients, while 6% had variants in X-linked genes. A total of 53 variants were identified in 29 genes, of which 38 (72%) were novel. The most frequent variants were in SRD5A3 (16%), PMM2 (11%), ALG1 (10%), NGLY1 (7.5%), MGAT2 (6%), and ALG11 (5%). We identified two sibs with a homozygous missense variant in CAMLG, which has been recently described in only one case, supporting its role as a new CDG type. Additionally, we described a case with the recently reported UGGT1-CDG and proposed ALG10 as a potentially new CDG gene. Our study highlights the striking phenotypic and genotypic variability associated with CDG and broadens the spectrum of variants and causative genes.

DOI: https://doi.org/10.1007/s00439-026-02881-y
Commun Med (Lond). 2026 Jul 29. pii: 517. [Epub ahead of print]6(1):

Repurposing the HMG-CoA reductase inhibitor atorvastatin for SRD5A3-congenital disorder of glycosylation.

Hiba Daghar, Seul Kee Byeon, Claudia Maios, Jennifer Poon, James Doyle, Wasantha Ranatunga, Éric Samarut, Ethan O Perlstein, Eva Morava, Akhilesh Pandey, J Alex Parker, Kristin A Kantautas.

BACKGROUND: Steroid 5 alpha-reductase 3-related congenital disorder of glycosylation (SRD5A3-CDG) is a rare inherited disease characterized by neurological dysfunction, including ataxia, as well as developmental and visual impairments, with no approved treatments. The disease is caused by defects in dolichol biosynthesis, a pathway essential for protein glycosylation. However, the lack of suitable in vivo models has limited both mechanistic insight and therapeutic development.
METHODS: We generated a Caenorhabditis elegans model carrying a patient-relevant loss-of-function mutation and performed a motility-based phenotypic drug repurposing screen to identify compounds that improve disease-relevant phenotypes. Lead compounds were evaluated in behavioral, neuronal, and metabolomic assays in worms and in fibroblasts from four individuals with SRD5A3-CDG.
RESULTS: Here we show that SRD5A3-deficient worms exhibit developmental delay, neuronal dysfunction, and metabolic alterations consistent with dysregulation of the mevalonate pathway. The screen identifies multiple classes of compounds that improve motility, including the cholesterol-lowering drug atorvastatin. Atorvastatin improves multiple disease-relevant phenotypes in the worm model. In patient-derived fibroblasts, treatment partially restores the balance between polyprenol and dolichol, which is disrupted in SRD5A3-CDG.
CONCLUSIONS: These findings establish an in vivo model of SRD5A3-CDG and identify modulation of the mevalonate pathway as a potential therapeutic strategy. The results support further investigation of atorvastatin as a repurposed treatment and demonstrate an approach for combining model organism screening with human cell validation to accelerate rare disease drug discovery.

DOI: https://doi.org/10.1038/s43856-026-01791-4
Pediatr Neurol. 2026 Sep 23. pii: S0887-8994(26)00300-0. [Epub ahead of print]185 89-94

Multisystemic Clues and Diagnostic Gaps: A Comparative Analysis of Pediatric Congenital Disorders of Glycosylation Patients.

Sabire Gokalp, Halil Tuna Akar, Ekin Ozsaydı Aktasoglu, Hacer Basan, Abdullah Sezer.

   BACKGROUND: Congenital disorders of glycosylation (CDG) comprise a diverse group of rare inherited metabolic diseases caused by defects in glycan biosynthesis and processing. Since glycoconjugates play a critical role in development and cellular integrity, disruptions in glycosylation can result in a wide range of multisystemic symptoms, often with prominent neurological involvement. Despite their clinical relevance, many CDG cases remain underdiagnosed due to the limited sensitivity of conventional biochemical tests. This study aims to further characterize the clinical, radiologic, and genetic findings.
METHODS: This study retrospectively analyzed nine pediatric patients diagnosed with CDG at a tertiary center. Clinical features, biochemical investigations, neuroimaging findings, and molecular genetic results were reviewed. Genetic confirmation was obtained using targeted next-generation sequencing or whole-exome sequencing.
RESULTS: The cohort revealed wide phenotypic variability, with predominant features including hypotonia, global developmental delay, epilepsy, and abnormal brain magnetic resonance imaging findings such as cerebral atrophy and white matter abnormalities. While transferrin isoelectric focusing revealed abnormal patterns in five patients, four patients had normal transferrin isoelectric focusing results despite harboring pathogenic variants. Several rare CDG subtypes were identified, including GALNT2-CDG, B4GALT1-CDG, and ST3GAL5-CDG.
CONCLUSIONS: Our study underscores the importance of considering CDG in the differential diagnosis of multisystemic neurodevelopmental disorders. It also highlights the limitations of regular biochemical screening in excluding CDG, emphasizing the essential role of early implementation of molecular testing. Our findings not only contribute to the expanding spectrum of CDG presentations in pediatric populations but also provide valuable insights into novel genotype-phenotype correlations.

Keywords:  Congenital disorders of glycosylation; Multisystemic involvement; Pediatric; Transferrin isoelectric focusing

DOI:  https://doi.org/10.1016/j.pediatrneurol.2026.09.015
Acta Paediatr. 2026 Oct 06.

Liver Transplantation in Inborn Errors of Metabolism: A Retrospective Study of a National Experience.

Adi Efron-Srour, Eyal Reller, Michal Gafner, Danit Javasky, Chen Barazani Chayat, Galit Tal, Orna Staretz-Chacham, Ronen Spiegel, Yael Mozer-Glassberg, Michal Rozenfeld Bar-Lev, Michael Gurevich, Orith Waisbourd-Zinman, Yuval E Landau.

   AIM: Over the past four decades, liver transplantation has been performed worldwide for metabolic diseases, mainly to ameliorate the metabolic defect. However, little has been described regarding the indications and outcomes of the procedure.
METHODS: Data were collected retrospectively from medical records of 28 paediatric patients with metabolic diseases who underwent liver transplantation in Israel since 2008, considering both metabolic and liver transplant outcomes.
RESULTS: The underlying diagnoses for liver transplantation included urea cycle defects, organic acidemias, aminoacidopathies, glycogen storage disease, congenital disorder of glycosylation and a mitochondrial disorder. The mean age at transplantation was 49.5 ± 49.8 months. The mean follow-up time was 53.1 ± 46.8 months. Metabolic crises per year decreased, from a mean 3.8 ± 3.9 pre-transplant to none post-transplant (p < 0.001), and hospitalization frequency decreased from 7.1 ± 5.4 to 1.6 ± 1.7 (p < 0.001). Both surgical and late-term complications were mostly similar to those of nonmetabolic paediatric liver transplantations. Only three patients exhibited new neurological issues after transplant, two of which were likely attributed to the neurotoxic effects of immunosuppression.
CONCLUSIONS: Liver transplantation is a promising alternative for the treatment of certain metabolic diseases, offering potential benefits in metabolic crises and hospitalization frequency, dietary restrictions, medication regimens and neurodevelopmental status.

Keywords:  inborn errors of metabolism; liver transplant outcomes; metabolic crises; paediatric liver transplantation

DOI:  https://doi.org/10.1111/apa.70792
bioRxiv. 2026 Aug 13. pii: 2026.08.12.744295. [Epub ahead of print]

Metabolomic, lipidomic, and N-glycomic analyses of a human cell model of Krabbe disease reveal treatable deficits in glycosylation and serine-ceramide metabolism.

Rodrigo Starosta, Hannah Saeger, Johanna Ten Hoeve, S J Kim, Johan L K Van Hove, Xuntian Jiang, Miao He, Neal Bennett.

Krabbe disease is a rare autosomal recessive lysosomal disease caused by deficiency of galactocerebrosidase (GALC), leading to accumulation of galactosylceramide and formation of the toxic metabolite galactosylsphingosine (psychosine). While psychosine accumulation is well-established as a primary pathogenic mechanism, the broader metabolic consequences of GALC deficiency remain incompletely understood. In this study, we used stable isotope tracing to comprehensively characterize metabolic perturbations in a human oligodendrocellular Krabbe disease model. This approach revealed elevated de novo ceramide synthesis in GALC knock-out cells, characterized by increased incorporation of glucose-derived serine into ceramide biosynthetic pathways. This enhanced ceramide production was amenable to pharmacological intervention by tezacaftor, an inhibitor of sphingolipid Δ 4 -desaturate (DEGS); tezacaftor administration also normalized psychosine levels, raising the possibility of its use as substrate reduction therapy. Additionally, we identified significant disruption of UDP-hexose metabolism, manifesting as an overabundance of truncated and hypogalactosylated glycans. These findings suggest impaired protein glycosylation as a previously unrecognized pathogenic mechanism in Krabbe disease. Our findings reveal novel metabolic dysregulation in Krabbe disease extending beyond established psychosine toxicity. The identification of enhanced de novo ceramide synthesis presents a new therapeutic target, while the discovery of galactose-deficient glycosylation defects supports galactose supplementation as a potential therapeutic intervention. These metabolic insights provide new mechanistic understanding and therapeutic opportunities for this devastating neurodegenerative disorder.

DOI: https://doi.org/10.64898/2026.08.12.744295
Mol Cell Biochem. 2026 Oct 05.

Sphingomyelin synthase 2 deficiency suppresses airway mucus accumulation by altering sphingolipid flux and mucin glycosylation.

Harumi Sakae, Kento Sonoda, Hikari Nishisaka, Yuri Ogiso, Ryoma Miyazaki, Masaya Matsuda, Takeshi Nabe, Ken Watanabe, Toshiro Okazaki, Tomoyuki Furubayashi, Makoto Taniguchi, Kazuyuki Kitatani.

  Sphingomyelin synthase 2 (SMS2) produces sphingomyelin from ceramide. In this study, SMS2 deficiency reduced airway accumulation of glycosylated mucins, such as MUC5AC, in a murine model of asthma, prompting investigation of the molecular mechanisms in mucin-forming epithelial cells. In the cell model, SMS2 silencing promoted the conversion of ceramide to glucosylceramide, a precursor of complex glycosphingolipids. This alteration reduced MUC5AC glycosylation, suggesting the potential for biochemical competition between sphingolipids and MUC5AC for glycosylation. Supplying C6-ceramide, which increases biochemical glycosylation for sphingolipids, reduced glycosylated MUC5AC, but this effect was absent in glucosylceramide synthase-silenced cells. These findings indicate that SMS2 deficiency alters sphingolipid metabolism, reducing MUC5AC glycosylation and maturation, underscoring the role of sphingolipid dynamics in modulating mucus production.

Keywords:  Ceramide; Glycosylation; Mucus; Sphingolipids; Sphingomyelin; Sphingomyelin synthase

DOI:  https://doi.org/10.1007/s11010-026-05753-1