bims-meglyc 2024-05-12 papers

Issue of 2024–05–12
five papers selected by
Silvia Radenkovic, UMC Utrecht

Mol Genet Metab. 2024 Apr 23. pii: S1096-7192(24)00356-1. [Epub ahead of print]142(2): 108472

ALG13-Congenital Disorder of Glycosylation (ALG13-CDG): Updated clinical and molecular review and clinical management guidelines.

Rameen Shah, Erik A Eklund, Silvia Radenkovic, Mustafa Sadek, Ibrahim Shammas, Sanne Verberkmoes, Bobby G Ng, Hudson H Freeze, Andrew C Edmondson, Miao He, Tamas Kozicz, Ruqaiah Altassan, Eva Morava.

ALG13-Congenital Disorder of Glycosylation (CDG), is a rare X-linked CDG caused by pathogenic variants in ALG13 (OMIM 300776) that affects the N-linked glycosylation pathway. Affected individuals present with a predominantly neurological manifestation during infancy. Epileptic spasms are a common presenting symptom of ALG13-CDG. Other common phenotypes include developmental delay, seizures, intellectual disability, microcephaly, and hypotonia. Current management of ALG13-CDG is targeted to address patients' symptoms. To date, less than 100 individuals have been reported with ALG13-CDG. In this article, an international group of experts in CDG reviewed all reported individuals affected with ALG13-CDG and suggested diagnostic and management guidelines for ALG13-CDG. The guidelines are based on the best available data and expert opinion. Neurological symptoms dominate the phenotype of ALG13-CDG where epileptic spasm is confirmed to be the most common presenting symptom of ALG13-CDG in association with hypotonia and developmental delay. We propose that ACTH/prednisolone treatment should be trialed first, followed by vigabatrin, however ketogenic diet has been shown to have promising results in ALG13-CDG. In order to optimize medical management, we also suggest early cardiac, gastrointestinal, skeletal, and behavioral assessments in affected patients.

Keywords: ALG13-CDG; Congenital disorders of glycosylation; Epileptic spasm; Seizure disorder; X-linked CDG

DOI: https://doi.org/10.1016/j.ymgme.2024.108472

Am J Med Genet A. 2024 May 08. e63660

Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys.

Manjushree Shanmugasundaram, Amanda Wang, Megan Morand, Colin Bixler, Sangeeta Jain, Joseph Ray.

Congenital disorders of glycosylation (CDG) are a group of rare autosomal recessive genetic disorders caused by pathogenic variants in genes coding for N-glycosylated glycoproteins, which play a role in folding, degrading, and transport of glycoproteins in their pathway. ALG12-CDG specifically is caused by biallelic pathogenic variants in ALG12. Currently reported features of ALG12-CDG include: developmental delay, hypotonia, failure to thrive and/or short stature, brain anomalies, recurrent infections, hypogammaglobulinemia, coagulation abnormalities, and genitourinary abnormalities. In addition, skeletal abnormalities resembling a skeletal dysplasia including shortened long bones and talipes equinovarus have been seen in more severe neonatal presentation of this disorder. We report on a case expanding the phenotype of ALG12-CDG to include bilateral, multicystic kidneys in a neonatal demise identified with homozygous pathogenic variants in the ALG12 gene at c.1001del (p.N334Tfs*15) through clinical trio exome sequencing.

Keywords: ALG12; bilateral multicystic kidneys; congenital disorders of glycosylation

DOI: https://doi.org/10.1002/ajmg.a.63660

Mol Genet Genomic Med. 2024 May;12(5): e2445

Novel insight into FCSK-congenital disorder of glycosylation through a CRISPR-generated cell model.

Maryam Fazelzadeh Haghighi, Hossein Jafari Khamirani, Jafar Fallahi, Ali Arabi Monfared, Korosh Ashrafi Dehkordi, Seyed Mohammad Bagher Tabei.

BACKGROUND: FCSK-congenital disorder of glycosylation (FCSK-CDG) is a recently discovered rare autosomal recessive genetic disorder with defective fucosylation due to mutations in the fucokinase encoding gene, FCSK. Despite the essential role of fucokinase in the fucose salvage pathway and severe multisystem manifestations of FCSK-CDG patients, it is not elucidated which cells or which types of fucosylation are affected by its deficiency.
METHODS: In this study, CRISPR/Cas9 was employed to construct an FCSK-CDG cell model and explore the molecular mechanisms of the disease by lectin flow cytometry and real-time PCR analyses.
RESULTS: Comparison of cellular fucosylation by lectin flow cytometry in the created CRISPR/Cas9 FCSK knockout and the same unedited cell lines showed no significant change in the amount of cell surface fucosylated glycans, which is consistent with the only documented previous study on different cell types. It suggests a probable effect of this disease on secretory glycoproteins. Investigating O-fucosylation by analysis of the NOTCH3 gene expression as a potential target revealed a significant decrease in the FCSK knockout cells compared with the same unedited ones, proving the effect of fucokinase deficiency on EGF-like repeats O-fucosylation.
CONCLUSION: This study expands insight into the FCSK-CDG molecular mechanism; to the best of our knowledge, it is the first research conducted to reveal a gene whose expression level alters due to this disease.

Keywords: FCSK ; CRISPR/Cas9; congenital disorder of glycosylation; fucokinase

DOI: https://doi.org/10.1002/mgg3.2445

Nat Rev Genet. 2024 May 09.

Genetics of glycosylation in mammalian development and disease.

Pamela Stanley.

Glycosylation of proteins and lipids in mammals is essential for embryogenesis and the development of all tissues. Analyses of glycosylation mutants in cultured mammalian cells and model organisms have been key to defining glycosylation pathways and the biological functions of glycans. More recently, applications of genome sequencing have revealed the breadth of rare congenital disorders of glycosylation in humans and the influence of genetics on the synthesis of glycans relevant to infectious diseases, cancer progression and diseases of the immune system. This improved understanding of glycan synthesis and functions is paving the way for advances in the diagnosis and treatment of glycosylation-related diseases, including the development of glycoprotein therapeutics through glycosylation engineering.

DOI: https://doi.org/10.1038/s41576-024-00725-x

J Inherit Metab Dis. 2024 May 05.

Human genetic defects of sphingolipid synthesis.

Patricia Dubot, Frédérique Sabourdy, Thierry Levade.

Sphingolipids are ubiquitous lipids, present in the membranes of all cell types, the stratum corneum and the circulating lipoproteins. Autosomal recessive as well as dominant diseases due to disturbed sphingolipid biosynthesis have been identified, including defects in the synthesis of ceramides, sphingomyelins and glycosphingolipids. In many instances, these gene variants result in the loss of catalytic function of the mutated enzymes. Additional gene defects implicate the subcellular localization of the sphingolipid-synthesizing enzyme, the regulation of its activity, or even the function of a sphingolipid-transporter protein. The resulting metabolic alterations lead to two major, non-exclusive types of clinical manifestations: a neurological disease, more or less rapidly progressive, associated or not with intellectual disability, and an ichthyotic-type skin disorder. These phenotypes highlight the critical importance of sphingolipids in brain and skin development and homeostasis. The present article reviews the clinical symptoms, genetic and biochemical alterations, pathophysiological mechanisms and therapeutic options of this relatively novel group of metabolic diseases.

Keywords: ceramide; glycosphingolipid; ichthyosis; neurodevelopment; peripheral neuropathy; sphingomyelin

DOI: https://doi.org/10.1002/jimd.12745