bims-meglyc 2024-04-28 papers

Issue of 2024–04–28
three papers selected by
Silvia Radenkovic, UMC Utrecht

Mol Genet Metab. 2024 Apr 10. pii: S1096-7192(24)00360-3. [Epub ahead of print]142(1): 108476

Clinical and biochemical footprints of congenital disorders of glycosylation: Proposed nosology.

Bobby G Ng, Hudson H Freeze, Nastassja Himmelreich, Nenad Blau, Carlos R Ferreira.

We have identified 200 congenital disorders of glycosylation (CDG) caused by 189 different gene defects and have proposed a classification system for CDG based on the mode of action. This classification includes 8 categories: 1. Disorders of monosaccharide synthesis and interconversion, 2. Disorders of nucleotide sugar synthesis and transport, 3. Disorders of N-linked protein glycosylation, 4. Disorders of O-linked protein glycosylation, 5. Disorders of lipid glycosylation, 6. Disorders of vesicular trafficking, 7. Disorders of multiple glycosylation pathways and 8. Disorders of glycoprotein/glycan degradation. Additionally, using information from IEMbase, we have described the clinical involvement of 19 organs and systems, as well as essential laboratory investigations for each type of CDG. Neurological, dysmorphic, skeletal, and ocular manifestations were the most prevalent, occurring in 81%, 56%, 53%, and 46% of CDG, respectively. This was followed by digestive, cardiovascular, dermatological, endocrine, and hematological symptoms (17-34%). Immunological, genitourinary, respiratory, psychiatric, and renal symptoms were less frequently reported (8-12%), with hair and dental abnormalities present in only 4-7% of CDG. The information provided in this study, including our proposed classification system for CDG, may be beneficial for healthcare providers caring for individuals with metabolic conditions associated with CDG.

Keywords: CDG; Glycans; Glycoproteins; Glycosaminoglycans; Glycosphingolipids; Glycosylphosphatidylinositol; IEMbase

DOI: https://doi.org/10.1016/j.ymgme.2024.108476

Front Genet. 2024 ;15 1373448

Case report: Novel NUS1 variant in a Chinese patient with tremors and intellectual disability.

Ruolin Li, Jiayi Yang, Jinfeng Ma, Aimei Zhang, Hongfang Li.

Introduction: Nuclear undecaprenyl pyrophosphate synthase 1 (NUS1) gene variants are associated with a range of phenotypes, including epilepsy, intellectual disability, cerebellar ataxia, Parkinson's disease, dystonia, and congenital disorders of glycosylation. Additionally, cases describing genotypes and clinical features are rare.
Case Presentation: Herein, we report the case of a 23-year-old Chinese female patient who presented with tremors, intellectual disability, and epilepsy. A history of carbon monoxide exposure, brain trauma, or encephalitis was not present in this case. Trio whole-exome sequencing analysis revealed a de novo pathogenic variant of c.750del in exon 4, leading to p.Leu251* amino acid substitution. Genetic analysis failed to identify the identical mutations in the remaining family members who underwent screening. The patient was diagnosed with a rare congenital disease, "congenital glycosylation disorder, type 1aa, autosomal dominant, type 55, with seizures (MRD-55)."
Conclusion: We provide further evidence for the role of variants in NUS1 in the development of tremors, epilepsy, and intellectual disabilities. These findings expand our understanding of the clinical phenotypes of NUS1 variants.

Keywords: amino acid substitution; case report; epilepsy; exome sequencing; intellectual disability; tremor; undecaprenyl pyrophosphate synthetase; young adult

DOI: https://doi.org/10.3389/fgene.2024.1373448

Genes (Basel). 2024 Apr 11. pii: 485. [Epub ahead of print]15(4):

Recessive GNE Mutations in Korean Nonaka Distal Myopathy Patients with or without Peripheral Neuropathy.

Nasrin Tamanna, Byung Kwon Pi, Ah Jin Lee, Sumaira Kanwal, Byung-Ok Choi, Ki Wha Chung.

Autosomal recessive Nonaka distal myopathy is a rare autosomal recessive genetic disease characterized by progressive degeneration of the distal muscles, causing muscle weakness and decreased grip strength. It is primarily associated with mutations in the GNE gene, which encodes a key enzyme of sialic acid biosynthesis (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase). This study was performed to find GNE mutations in six independent distal myopathy patients with or without peripheral neuropathy using whole-exome sequencing (WES). In silico pathogenic prediction and simulation of 3D structural changes were performed for the mutant GNE proteins. As a result, we identified five pathogenic or likely pathogenic missense variants: c.86T>C (p.Met29Thr), c.527A>T (p.Asp176Val), c.782T>C (p.Met261Thr), c.1714G>C (p.Val572Leu), and c.1771G>A (p.Ala591Thr). Five affected individuals showed compound heterozygous mutations, while only one patient revealed a homozygous mutation. Two patients revealed unreported combinations of combined heterozygous mutations. We observed some specific clinical features, such as complex phenotypes of distal myopathy with distal hereditary peripheral neuropathy, an earlier onset of weakness in legs than that of hands, and clinical heterogeneity between two patients with the same set of compound heterozygous mutations. Our findings on these genetic causes expand the clinical spectrum associated with the GNE mutations and can help prepare therapeutic strategies.

Keywords: GNE; Korean; Nonaka distal myopathy; biallelic mutations; whole-exome sequencing

DOI: https://doi.org/10.3390/genes15040485