bims-meglyc 2025-11-09 papers

Issue of 2025–11–09
five papers selected by
Silvia Radenkovic, UMC Utrecht

Am J Case Rep. 2025 Nov 03. 26 e948797

Novel PGM1 Mutation in Congenital Disorder of Glycosylation Type 1T: A Case Report of Liver Failure and Myopathy.

BACKGROUND Congenital disorders of glycosylation (CDG) are rare, inherited metabolic conditions caused by defects in glycoprotein synthesis. CDG Type 1T, associated with mutations in the phosphoglucomutase 1 (PGM1) gene, often presents with hepatic dysfunction, developmental delay, and multisystem involvement. Due to clinical overlap with other metabolic disorders, misdiagnosis is common, leading to delayed treatment. CASE REPORT We report a 20-month-old boy, born to consanguineous parents, who initially received a misdiagnosis of galactosemia following abnormal newborn screening. Despite dietary modifications, he developed persistent transaminitis, coagulopathy, hypotonia, and delayed motor milestones. Further evaluation revealed abnormal carbohydrate-deficient transferrin analysis, and whole exome sequencing identified a homozygous PGM1 variant of uncertain significance, supporting CDG Type 1T diagnosis. Liver biopsy demonstrated steatosis with bridging portal fibrosis. The patient was started on oral D-galactose supplementation (1.5 g/kg/day). Over a 51-day follow-up period, liver enzymes improved markedly, with AST declining from 1980 to 385 U/L and ALT from 695 to 210 U/L, alongside normalization of coagulation profiles. Muscle enzyme response was partial, with creatine kinase levels remaining mildly elevated, reflecting differential therapeutic effects across tissues. CONCLUSIONS This case underscores the diagnostic challenges of CDG Type 1T and emphasizes the importance of combining biochemical markers and genetic sequencing to achieve timely diagnosis. The identified PGM1 variant, although classified as a variant of uncertain significance, was strongly supported by clinical and biochemical findings. Significant hepatic improvement with D-galactose highlights the therapeutic potential of early targeted supplementation, although incomplete muscular response indicates the need for ongoing follow-up and exploration of adjunctive therapies.

DOI: https://doi.org/10.12659/AJCR.948797

BMJ Case Rep. 2025 Nov 04. pii: e268902. [Epub ahead of print]18(11):

Congenital disorder of glycosylation type IIb in an infant with developmental and epileptic encephalopathy.

R K Shwetabh, Anita Singh, Kausik Mandal, Kirti Naranje, Akanksha Verma.

We report a term infant presenting in early infancy with progressive developmental delay, feeding difficulties, recurrent seizures and failure to thrive. The infant initially exhibited symptoms from early neonatal age, including vomiting, lethargy and seizures, necessitating multiple hospitalisations. Progressive neurological deterioration, hepatomegaly, bilateral nephromegaly, hypothyroidism, gastro-oesophageal reflux disease and auditory neuropathy were noted. MRI showed cerebral atrophy and dilated ventricles. Extensive investigations ruled out infections, metabolic acidosis and structural brain malformations. Whole exome sequencing identified a homozygous missense mutation in the mannosyl-oligosaccharide glucosidase (MOGS) gene (c.2090T>C; p.Leu697Ser), previously reported in MOGS CDG (congenital disorder of glycosylation type IIb). A mannose-based diet led to partial improvement. This case highlights the importance of considering neurometabolic conditions such as CDG in infants with early-onset developmental and epileptic encephalopathy and multisystem involvement. Early diagnosis and supportive multidisciplinary care are vital for improving outcomes and guiding family counselling.

Keywords: Congenital disorders; Genetic screening / counselling; Neonatal intensive care; Neuro genetics

DOI: https://doi.org/10.1136/bcr-2025-268902

Front Genet. 2025 ;16 1678103

In vitro cell model to dilucidate the underlying molecular mechanism associated with ophthalmic manifestation of congenital disorders of glycosylation: studying an ALG2-CDG patient.

Marisa Angelica Cubilla, Ana Clara Sclausero, Mariano Bisbal, Carla Gabriela Asteggiano.

Introduction: Congenital Disorders of Glycosylation (CDG) are severe disruptions in the synthesis of glycoconjugates, resulting in inherited metabolic conditions. These multisystem diseases, typically inherited in an autosomal recessive manner, have an occurrence rate of approximately 1 in 20,000 to 1 in 50,000 live births. The clinical presentation of CDG is highly varied and complex, with neurological symptoms being predominant, affecting multiple organ systems. The process of glycosylation, a critical post-translational modification, is tightly controlled by proteins encoded by over 250 genes, and mutations in any of these genes are known to cause CDG. The discovery of new associated genes over recent years has accelerated; comprehensively characterizing these, especially rare ones, will aid in identifying novel therapeutic targets, improving prognostic evaluations, and developing effective treatments. In vitro models (such as cell lines or patient-derived "clinical-grade" cells) are essential for advancing CDG research. Notably, 60% of defects affecting N- or O-glycosylation impact the eyes, leading to photoreceptor degeneration and cell death. The 661W cell line, derived from immortalized mouse retinal cells and expressing specific ocular markers, serves as a valuable experimental model to study the ocular involvement in CDG.
Methods: In this study, we utilized the 661W cell line to explore the molecular consequences of a homozygous variant in the ALG2 gene (c.752G>T; p.Arg251Leu), which encodes the enzyme α-1,3-mannosyltransferase. Following transfection with a plasmid carrying the variants of the gene of interest ALG2 p.Arg251/p.Arg251, we carefully evaluated changes in gene expression using RT-PCR and Western blotting.
Results: Our results suggest that the 661W cell line may serve as a useful model for examining the potential impact of a specific mutation, supporting a possible link between the mutation's molecular effects and clinical disease progression.
Discussion: These findings could provide valuable insights to inform the development of targeted therapeutic strategies within the framework of personalized medicine.

Keywords: 661W cell model; ALG2-CDG; N-glycosylation; congenital disorders of glycosylation (CDG); congenital myasthenic syndrome (CMS); neuromuscular disorder; personalized medicine; photoreceptor

DOI: https://doi.org/10.3389/fgene.2025.1678103

Mol Genet Metab. 2025 Oct 24. pii: S1096-7192(25)00259-8. [Epub ahead of print]146(4): 109267

Clinical utility of untargeted urine oligosaccharide screening.

Gisele Bentz Pino, Marie A Quade, Matthew J Schultz, Amy L White, Dawn S Peck, April L Studinski Jones, Dimitar K Gavrilov, Devin Oglesbee, Silvia Tortorelli, Dietrich Matern, Patricia L Hall.

High-resolution urine oligosaccharide screening with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been clinically available for 10 years and has been used to help diagnose a wide spectrum of disorders. The untargeted nature of MALDI-TOF MS analysis gives it broad clinical utility. Here we report characteristic profiles for several disorders that had not previously been described using this method, including lysosomal disorders, congenital disorders of glycosylation, and glycogen storage disorders. In addition, we review the clinical performance of the assay in our laboratory and provide basic test performance information for each condition. A total of 4445 analyses performed with 4145 unique patient samples generated 139 confirmed and presumptive positive results and 16 false-positive results. The disorder with the highest rate of false positivity was Pompe disease, which has an oligosaccharide profile similar to that seen in formula-fed infants. The positive predictive value of urine oligosaccharide screening with MALDI-TOF MS was 89.7 % across all conditions. For 10 of the 16 conditions detected during the study period, no false-positive results occurred. No known false-negative results were reported for any of the targeted conditions. Urine oligosaccharide analysis with MALDI-TOF MS, which uses an accessible specimen type and offers quick turnaround time, is an effective initial screening method for patients with a clinical presentation suggestive of a lysosomal disorder.

Keywords: Biochemical testing; Lysosomal disorders; Urine oligosaccharides

DOI: https://doi.org/10.1016/j.ymgme.2025.109267

Biochem Biophys Res Commun. 2025 Oct 24. pii: S0006-291X(25)01539-6. [Epub ahead of print]790 152823

AAV9-mediated NGLY1 gene replacement suppresses non-epileptic convulsions in Ngly1-/- rats.

Makoto Asahina, Reiko Fujinawa, Hiroto Hirayama, Hiroshi Yukitake, Tadashi Suzuki.

N-glycanase 1 (NGLY1) deficiency is a rare autosomal-recessive neurological disorder characterized by neurological dysfunction and so far, has no effective therapy. A systemic Ngly1-/- rat model recapitulates many patient symptoms, including developmental delay, motor and cognitive deficits. Here we carried out further detailed phenotypic analyses for the Ngly1-/- rats, with particular focus on those easily translatable to patients' symptoms, i.e. sleep disturbances, EEG abnormalities and convulsive behaviors. EEG/EMG recordings revealed fragmented sleep and frequent spontaneous epileptiform discharges in Ngly1-/- rats. Continuous video-EEG monitoring confirmed a high incidence of convulsive events with/without epileptic discharge. At three weeks of age, Ngly1-/- rats received a single intracerebroventricular injection of AAV9-hNGLY1. We then examined whether central nervous system-targeted gene therapy using an adeno-associated virus serotype 9 carrying human NGLY1 (AAV9-hNGLY1) can rescue those phenotypes. While NGLY1 protein was robustly expressed in the brain with partial restoration of enzymatic deglycosylation activity, AAV9-hNGLY1-treated Ngly1-/- rats showed no significant improvement in EEG abnormalities or sleep disruption. In sharp contrast, AAV9-hNGLY1 significantly reduced the frequency of non-epileptic convulsive episodes. These findings expand the phenotypic characterization of the Ngly1-/- rat model to include sleep and seizure phenotypes and demonstrate that AAV9-mediated NGLY1 restoration can suppress overt motor convulsions. On the other hand, persistent EEG seizures and sleep disturbances indicate only a partial therapeutic benefit, underscoring the need for further refinement of gene therapy strategies, as well as additional therapeutic options, for NGLY1 deficiency.

Keywords: AAV gene-therapy; EEG abnormalities; NGLY1 deficiency; Ngly1(−/−) rat; Non-epileptic convulsion; Seizure; Sleep disorder

DOI: https://doi.org/10.1016/j.bbrc.2025.152823