bims-meglyc 2025-11-16 papers

Issue of 2025–11–16
five papers selected by
Silvia Radenkovic, UMC Utrecht

Front Pediatr. 2025 ;13 1651524

Novel SSR4 gene splice variant leads to congenital disorder of glycosylation, type Iy.

Background: Congenital disorders of glycosylation (CDG) are a group of multi-systemic genetic disorders. Over 100 monogenic human diseases were known related with defects in glycosylation process. Defects of SSR4 gene lead to a rare X linked pattern of CDG which has been rarely reported.
Method: We reported a Chinese boy with developmental delay, microcephaly, and epileptic seizures. Whole exome sequencing and Sanger sequencing were performed in the family.
Result: A novel maternal splice variant c.351+1del in SSR4 gene was identified by trio-exome sequencing, and confirmed by Sanger sequencing. The functional effect of the variant was further investigated by minigene. The minigene results showed three abnormal splice forms: (1) 1 bp deletion in 3' end of exon 4; (2) 42 bp deletion in 3' end of exon 4; (3) skipping of exon 4. All three forms resulted in truncated proteins. c.351+1del in SSR4 gene causes congenital disorder of glycosylation, type Iy, consisted with the proband's phenotype. Up to date, all of the pathogenic SSR4 gene variants were null variants. The most variants were reported in exon 4. Patients (within or between families) carrying the same variants exhibited phenotypic heterogeneity.
Conclusion: The current study expanded the pathogenic variant spectrum of SSR4 gene and revealed the impact of c.351+1del on SSR4 splicing. Standardizing the transcript and naming conventions of variants were crucial for the study of SSR4 genotypes and phenotypes.

Keywords: SSR4; congenital disorder of glycosylation; minigene; transcript; whole exome sequencing

DOI: https://doi.org/10.3389/fped.2025.1651524

BMC Musculoskelet Disord. 2025 Nov 14. 26(1): 1049

Clinical, pathological and genetic characteristics of GNE myopathy: a single-center observational study.

Jinliang Deng, Ning Wang, Yuhao Wu, Ziyan Hao, Hongran Wu, Shaojuan Ma, Juyi Liu, Guang Ji, Xueqin Song.

INTRODUCTION: GNE myopathy is a rare autosomal recessive hereditary myopathy resulting in impaired sialic acid biosynthesis. The features of this condition include distal muscle weakness with relatively preserved quadriceps femoris strength and the presence of rimmed vacuoles in muscle fibers.
METHODS: We performed a retrospective clinical analysis of patients diagnosed with GNE myopathy at our hospital from 2017 to 2024.
RESULT: All six patients exhibited weakness in the distal lower limbs. Rimmed vacuoles were observed in the muscle fibers of five patients. Additionally, several relatively uncommon clinical manifestations were identified in this study, including Beevor's sign, respiratory dysfunction, ragged red fibers, and elevated acid phosphatase enzyme activity. Genetic analysis revealed five novel variants in the GNE gene: c.1691G > T (p.G564V), c.1877 C > G (p.A626G), c.935_936insAA (p.H312fs), c.1247 A > T (p.K416M), and c.974 C > T (p.A325V). Furthermore, three patients carried the hotspot variant p.D207V.
CONCLUSION: The clinical and histopathological findings underscore the distinctive characteristics and heterogeneity of the disease. Significantly, this study broadens the mutational spectrum of GNE myopathy by identifying five novel variants.

Keywords: Distal muscle weakness; GNE myopathy; Rimmed vacuoles

DOI: https://doi.org/10.1186/s12891-025-09282-8

Neurology. 2025 Dec 09. 105(11): e214425

Urine Sorbitol and Xylitol for the Diagnosis of Sorbitol Dehydrogenase Deficiency-Related Neuropathy.

BACKGROUND AND OBJECTIVES: Sorbitol dehydrogenase (SORD) deficiency, due to biallelic loss-of-function variants in the SORD gene, is a recently recognized cause of autosomal recessive hereditary neuropathy. Specific diagnosis is difficult on clinical grounds alone, and molecular genetic testing of SORD is complicated by the presence of a pseudogene. Biochemical testing of serum sorbitol is suggested as a potential biomarker. We report a novel urine biochemical profile of elevated excretion of sorbitol and a second polyol, xylitol, to aid in the identification of individuals with SORD-related neuropathy.
METHODS: Patients with confirmed or suspected SORD-related neuropathy were recruited by clinicians from 7 academic medical centers and 1 nonprofit specialty care center. Urine was analyzed by a clinically validated, gas chromatography-mass spectrometry assay to measure sorbitol and xylitol excretion. Over 700 reference samples were evaluated from residual clinical samples. Clinical and molecular findings were gathered using a standardized questionnaire.
RESULTS: Nineteen individuals with a clinical and genetic diagnosis of SORD-related neuropathy (median age 31 years, 47% female) and 715 reference samples were used to determine the initial performance of this index urine test. The median sorbitol excretion in affected individuals was 638 mmol/mol creatinine (1st percentile of disease range = 456; reference median = 7, reference 99th percentile = 198). The median xylitol excretion was 1,577 mmol/mol creatinine (1st percentile of disease range = 1,242; reference median = 7, reference 99th percentile = 102). In this patient cohort, the combination of sorbitol and xylitol yielded 100% sensitivity and specificity for SORD-related neuropathy. Four additional individuals who had clinical phenotypes compatible with SORD-related neuropathy had abnormal urine sorbitol/xylitol profile, 2 with genotypes involving a variant of unknown significance in SORD and 2 with a single heterozygous pathogenic SORD variant detected, whereas normal urine sorbitol/xylitol levels were observed in 11 asymptomatic, heterozygous carriers.
DISCUSSION: These data demonstrate the clinical utility of urine sorbitol and xylitol analysis in the screening and diagnosis of SORD deficiency-related neuropathy. In addition, this is the first description of elevated xylitol in SORD deficiency as a clinically informative biomarker, which may increase the specificity of biochemical testing.

DOI: https://doi.org/10.1212/WNL.0000000000214425

Neuromuscul Disord. 2025 Oct 25. pii: S0960-8966(25)00985-X. [Epub ahead of print]56-57 106258

Novel missense variants associated with GNE myopathy.

GNE myopathy is a rare autosomal recessive skeletal muscle disorder characterized by progressive distal muscle weakness, typically starting in the lower legs and gradually involving proximal muscle groups. It is an autosomal recessive disease, caused by biallelic variants in GNE. To date, over 350 causative GNE variants have been reported, however, establishing genotype-phenotype correlation remains difficult due to clinical heterogeneity and limited patient numbers. In this study, we describe 20 unrelated European families with a diagnosis of GNE myopathy and biallelic GNE variants identified in either homozygosity or compound heterozygosity. While the majority of variants observed in our cohort have been previously reported, we identified five novel missense variants: p.(G355R), p.(A679T), p.(I709T), p.(V727G), and p.(V744I). Using in silico prediction tools and ACMG/AMP criteria, we classified p.(G355R) and p.(V727G) as likely pathogenic. The clinical features of our cohort were consistent with the classical presentation of GNE myopathy. Our findings contribute new genotype data and support ongoing efforts to refine variant interpretation in GNE myopathy. This study expands the mutational spectrum of GNE and reinforces the phenotypic consistency across diverse populations.

Keywords: GNE myopathy; foot drop; neuromuscular disease; rare disease; rimmed vacuoles; sialic acid

DOI: https://doi.org/10.1016/j.nmd.2025.106258

Glycobiology. 2025 Nov 06. pii: cwaf061. [Epub ahead of print]35(11):

The Glyco-Switch of life: O-GlcNAcylation in cell fate decision.

Ao Wang, Matthew Young, Jiaoyang Jiang.

O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a unique type of protein glycosylation that intricately links cellular metabolism to various signaling pathways. This reversible, nutrient-sensitive modification dynamically regulates a wide range of biological processes, including apoptosis, cell proliferation, and differentiation. Recent studies have made substantial progress in elucidating the pivotal roles of O-GlcNAcylation in modulating key oncogenes and signaling cascades. Aberrant O-GlcNAc cycling has been associated with a variety of pathological conditions, including cancer, metabolic disorders, and neurodegenerative diseases, underscoring its critical influence on cell fate decisions. In this review, we will highlight recent advances in understanding how O-GlcNAcylation modulates major cell fate regulating pathways, including nuclear factor kappaB (NF-κB), Notch, G protein-coupled receptor (GPCR) signaling, and transforming growth factor beta (TGF-β). We propose that O-GlcNAcylation integrates extracellular signals with intracellular metabolic states, functioning as an essential "Glyco-Switch" sensor that modulates cell fate decisions in both physiological and pathological contexts.

Keywords: G protein–coupled receptor (GPCR) signaling; Notch; O-GlcNAcylation; cell fate decision; nuclear factor kappaB (NF-κB)

DOI: https://doi.org/10.1093/glycob/cwaf061