Publications

April 4, 2025

Clinical and Molecular Features of Patients With Congenital Disorders of Glycosylation in Japan

Okamoto N, Kadoya M, Wada Y. JIMD Rep., April 4, 2025

Congenital disorders of glycosylation (CDG) are a heterogeneous group of diseases caused by defects in various steps of the glycosylation pathway. There are over 200 known human glycosylation-related disorders. Many of these defects lead to multisystemic manifestations, commonly involving the central nervous system, with symptoms ranging from mild to severe. The phenotypic presentation of CDG can vary significantly. Identifying altered protein glycosylation is crucial for accurate diagnosis. Our research institute has contributed to the CDG diagnostic support center in Japan, developing new analytical techniques utilizing mass spectrometry.

April 4, 2025

Increased Oxidative Stress and Autophagy in NGLY1 Patient iPSC-derived Neural Stem Cells

Shyr ZA, et al. Exp Cell Res., April 4, 2025

NGLY1 (N-glycanase) is a de-glycosylating enzyme that promotes clearance of misfolded glycan proteins. NGLY1 deficiency leads to a disease pathology with varied symptoms, including severe neurological defects. There are no therapeutic options currently available for the treatment of this rare disease. With the goal of finding potential therapeutic avenues, we performed comprehensive characterization of aberrant cellular stress pathways in a patient relevant model of NGLY1 deficiency.

April 3, 2025

Mannose Phosphate Isomerase Deficiency-Congenital Disorder of Glycosylation (MPI-CDG) Type 1b: Familial Case of Thrombophilia and Liver Disorder

Ducatez F, Minacori E, Vuillaumier Barrot S, Sauvêtre G, Dabaj I. Clin Chem., April 3, 2025

March 30, 2025

Beneficial effects of Glc-1,6-P2 modulation on mutant phosphomannomutase-2

Monticelli M, et al. Biochim Biophys Acta Mol Cell Res., March 30, 2025

The metabolite Glucose-1,6-bisphosphate (Glc-1,6-P2) plays a vital role in human metabolism, and is a crucial activator and stabilizer for phosphomannomutase-2 (PMM2) - mutations within this protein propagate the most common congenital disorder of glycosylation (PMM2-CDG). In vivo, Glc-1,6-P2 is hydrolysed by phosphomannomutase-1 (PMM1), predominantly in the brain, under the influence of inosine monophosphate (IMP). In the present study, we employed knock-out PMM1 in Arg141His/Phe119LeuPMM2 patient-derived fibroblasts and investigated the phenotypic improvement.

March 25, 2025

SEC24C deficiency causes trafficking and glycosylation abnormalities in an epileptic encephalopathy with cataracts and dyserythropoeisis

Bögershausen N, et al. JCI Insight. , March 25, 2025

As a major component of intracellular trafficking, the coat protein complex II (COPII) is indispensable for cellular function during embryonic development and throughout life. The four SEC24 proteins (A-D) are essential COPII components involved in cargo selection and packaging. A human disorder corresponding to alterations of SEC24 function is currently only known for SEC24D. Here, we report that biallelic loss of SEC24C leads to a syndrome characterized by primary microcephaly, brain anomalies, epilepsy, hearing loss, liver dysfunction, anemia, and cataracts in an extended consanguineous family with four affected individuals. [...] Moreover, a shift in the N-glycosylation pattern and deregulation of the N-glycosylation pathway suggest a possible secondary alteration of protein glycosylation, linking the described disorder with the congenital disorders of glycosylation.

March 22, 2025

Diagnostic and Therapeutic Approaches in Congenital Disorders of Glycosylation

Raynor A, Lebredonchel É, Foulquier F, Fenaille F, Bruneel A. Handb Exp Pharmacol., March 22, 2025

Congenital disorders of glycosylation (CDG) constitute an increasing group of inborn metabolic disorders, with more than 170 described diseases to date. A disturbed glycosylation process characterizes them, with molecular defects localized in distinct cell compartments. In CDG, N-glycosylation, O-glycosylation, glycosylation of lipids (including phosphatidylinositol) as well as the glycosaminoglycan synthesis can be affected. [...] after an introduction on glycosylation and CDG, we review current biomarkers and analytical techniques in the field. Furthermore, we illustrate their interests in the follow-up of proven therapeutic approaches including D-mannose in MPI-CDG, D-galactose in PGM1-CDG, and manganese (MnSO4) in TMEM165-CDG.

March 20, 2025

A Novel Homozygous Missense Variant of PIGT Related to Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 with Elevated of Serum ALP Level in a Thai Newborn Patient

Klangjorhor J, et al. Int J Mol Sci. , March 20, 2025

Phosphatidylinositol glycan class T (PIGT) is part of the glycosylphosphatidylinositol transamidase (GPI-TA) complex, crucial for various cell functions. Biallelic pathogenic variants in PIGT are associated with Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 (MCAHS3), a rare neonatal hypotonia syndrome characterized by dysmorphic features and seizures. Diagnosing neonatal hypotonia, which has diverse congenital and acquired causes, is challenging, particularly in syndromic monogenic cases. Next-generation sequencing is essential for accurate diagnosis. This study reports a term newborn with hypotonia, dysmorphic features, seizures, and severe skeletal issues, including a humeral fracture at birth, consistent with MCAHS3.

March 20, 2025

Computational profiling of molecular biomarkers in congenital disorders of glycosylation Type-I and binding analysis of Ginkgolide A with P4HB

Rahiyab M, Khan I, Ali SS, Hussain Z, Ali S, Iqbal A. Comput Biol Med., March 20, 2025

Congenital disorders of glycosylation (CDG) comprise a diverse group of genetic diseases characterized by aberrant glycosylation that leads to severe multi-systematic effects. Despite advancements in understanding the underlying molecular mechanisms, curative options remain limited. This study employed computational methods to identify key molecular biomarkers for CDG-I and examine the pharmacological effects of Ginkgolide A (GA), a potent bioactive natural compound. We analyzed the GSE8440 microarray dataset to discover differentially expressed genes (DEGs) in patients compared to healthy individuals with CDG-I utilizing GEO2R.

March 19, 2025

Goal attainment in PMM2-CDG: A new approach measuring meaningful clinical outcomes

Verberkmoes S, et al. Mol Genet Metab., March 19, 2025

Patient-centered outcomes, including patient-reported outcomes (PROs), are increasingly important in healthcare and research, though their use in rare diseases remains limited. In disorders with significant phenotypic variation, selecting appropriate outcome measures is crucial to ensuring the relevance of clinical trials for the patient population. Phosphomannomutase 2-CDG (PMM2-CDG) involves a complex genotype-phenotype relationship, making it challenging to predict clinical outcomes and select reliable measures for clinical trials. Caused by biallelic pathogenic variants in the PMM2, PMM2-CDG displays highly variable clinical severity, underscoring the need for personalized outcome measures. One such so far unexplored, individualized approach is Goal Attainment Scaling (GAS), which allows patients to set and track personal goals over time. We evaluated 93 PMM2-CDG patients enrolled in the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) Natural History study, classifying patient goals using the International Classification of Functioning, Disability, and Health (ICF) model, and assessing goal achievement prospectively.

March 18, 2025

Knockout of the fcsk gene in zebrafish causes neurodevelopmental defects

Liu ZX, Zou TT, Liu HH, Jia HB, Zhang XQ. Zool Res., March 18, 2025

Congenital disorders of glycosylation (CDG) are a cluster of monogenic disorders resulting from defects in glycosylation. FCSK encodes fucokinase, an enzyme that catalyzes the phosphorylation of L-fucose to generate fucose-1-phosphate, an important step in fucosylation. Mutations in FCSK lead to CDG with an autosomal recessive inheritance pattern, primarily manifesting as developmental delay, hypotonia, and brain abnormalities. However, no fcsk mutant animal models have yet been established. This study constructed the first fcsk knockout ( fcsk -/-) zebrafish model using CRISPR/Cas9 technology. Notably, fcsk -/- zebrafish exhibited impaired growth, characterized by delayed epiboly and DNA accumulation during early embryonic development, as well as brain atrophy in adulthood.