bims-meglyc 2024-03-24 papers

Issue of 2024–03–24
five papers selected by
Silvia Radenkovic, UMC Utrecht

Heliyon. 2024 Mar 30. 10(6): e27438

PIGN c.776T>C (p.Phe259Ser) variant present in trans with a pathogenic variant for PIGN-congenital disorder of glycosylation: Bella-Noah syndrome.

Lyvia Neves Rebello Alves, Lívia Valle Dos Santos Silveira, Raquel Silva Dos Reis Trabach, Débora Dummer Meira, Eldamária de Vargas Wolfgramm Dos Santos, Iúri Drumond Louro.

Glycosylation is the most common protein and lipid post-translational modification in humans. Congenital disorders of glycosylation (CDG) are characterized by both genetic and clinical heterogeneity, presenting multisystemic manifestations, and in most cases are autosomal recessive in inheritance. The PIGN gene is responsible for the addition of phosphoethanolamine to the first mannose in the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, a highly conserved process that enables proteins to bind to the cell surface membrane. Here, we report a family with two siblings pediatric cases with the exact same compound heterozygous variants in PIGN. The (c.776T > C) variant of uncertain significance (VUS) together with a known pathogenic variant (c.932T > G), resulting in clinical features compatible with PIGN-related conditions, more specific the CDG. This is the first time that PIGN variant c.776T > C is reported in literature in individuals with PIGN-congenital disorder of glycosylation (PIGN-CDG), and the current submission in ClinVar by Invitae® is specifically of our case. Detailed clinical information and molecular analyses are presented. Here, we show for the first time two affected siblings with one pathogenic variant (c.932T > G) and the c.776T > C VUS in trans. In honor of the family, we propose the name Bella-Noah Syndrome for disorder.

Keywords: Congenital disorder of glycosylation; Epileptic seizures; Glycosylation; Hypotonia; PIGN-CDG

DOI: https://doi.org/10.1016/j.heliyon.2024.e27438

Neurogenetics. 2024 Mar 18.

Early onset epileptic and developmental encephalopathy and MOGS variants: a new diagnosis in the whole exome sequencing (WES) ERA : Report of a new patient and review of the literature.

Federica Teutonico, Clara Volpe, Alice Proto, Ilaria Costi, Ugo Cavallari, Paola Doneda, Maria Iascone, Luisella Sturiale, Rita Barone, Stefano Martinelli, Aglaia Vignoli.

Mannosyl-oligosaccharide glucosidase - congenital disorder of glycosylation (MOGS-CDG) is determined by biallelic mutations in the mannosyl-oligosaccharide glucosidase (glucosidase I) gene. MOGS-CDG is a rare disorder affecting the processing of N-Glycans (CDG type II) and is characterized by prominent neurological involvement including hypotonia, developmental delay, seizures and movement disorders. To the best of our knowledge, 30 patients with MOGS-CDG have been published so far. We described a child who is compound heterozygous for two novel variants in the MOGS gene. He presented Early Infantile Developmental and Epileptic Encephalopathy (EI-DEE) in the absence of other specific systemic involvement and unrevealing first-line biochemical findings. In addition to the previously described features, the patient presented a Hirschprung disease, never reported before in individuals with MOGS-CDG.

Keywords: Burst suppression; CDG-IIb; Congenital disorders of glycosylation; Early infantile Developmental and Epileptic Encephalopathy (EI-DEE); Hypotonia; MOGS; Spasms

DOI: https://doi.org/10.1007/s10048-024-00754-y

Stem Cell Res. 2024 Mar 08. pii: S1873-5061(24)00079-5. [Epub ahead of print]77 103381

Establishment of a human induced pluripotent stem cell line（SDQLCHi059-A）from a patient with congenital disorder of glycosylation carrying heterozygous mutation in MPI gene.

Bin Wang, Lu Yang, Min Gao, Haiyan Zhang, Yi Liu, Zhongtao Gai.

Congenital disorder of glycosylation (CDG) is inherited metabolicdiseasecaused by defects in the genes important for the process of protein and lipidglycosylation. We established an induced pluripotent stem cell (iPSC) line from peripheral blood mononuclear cells of a 6-month-old boy with congenital disorder of glycosylation carrying heterozygous mutations c.1193 T > C (p.I398T) and c.376_384dup CCGCAGCAC (p.P126_H128 dupPQH) in MPI gene. This iPSC line was free of exogenous gene, expressed pluripotency markers, has normal karyotype, exhibited differentiation potential and harbored the same mutations found in the patient. This cell line will provide a reliable cell model for further studies on the potential therapeutic targets of CDG.

DOI: https://doi.org/10.1016/j.scr.2024.103381

Brain Dev. 2024 Mar 16. pii: S0387-7604(24)00042-1. [Epub ahead of print]

Metabolic etiologies in children with infantile epileptic spasm syndrome: Experience at a tertiary pediatric neurology center.

Merve Feyza Yüksel, Neslihan Doğulu, Miraç Yıldırım, Engin Köse, Ömer Bektaş, Fatma Tuba Eminoğlu, Serap Teber.

OBJECTIVE: Infantile epileptic spasm syndrome (IESS), including West syndrome (WS) and infantile spasm (IS), causes a challenging prognosis, particularly when associated with metabolic etiologies.
METHODS: This study, conducted at a tertiary pediatric neurology center, explored the prevalence and clinical features of inborn errors of metabolism in 112 children with IESS over 10 years.
RESULTS: Most patients presented with seizures, primarily flexor spasms, and the median age at onset was 5 months. Comprehensive clinical evaluation and neuroimaging revealed structural-acquired causes as the most common etiology. Notably, inborn errors of metabolism were identified in 5.4 % of cases, with six distinct diagnoses including nonketotic hyperglycinemia, pyridoxine-dependent epilepsy, primary coenzyme Q10 deficiency 7, congenital disorder of glycosylation type IIM, 6-pyruvoyl tetrahydrobiopterin synthase deficiency, and argininosuccinate lyase deficiency. The prevalence of inborn errors of metabolism in this cohort was consistent with global variations reported in the literature. Genetic testing, including karyotype analysis and whole exome sequencing, was performed in a subset of cases with no clear diagnosis, revealing abnormalities in approximately 50 % of cases. Adrenocorticotropic hormone emerged as the most frequently prescribed antiseizure medication.
CONCLUSION: This study provides insight into the diagnostic challenges associated with IESS and highlights the importance of metabolic investigations, especially in cases without a clear etiology. The findings emphasize the need for further genetic and metabolic studies to enhance prognostic accuracy and guide potential treatment options for children with IESS, particularly in populations with high rates of consanguinity.

Keywords: Children; Epilepsy; Inborn errors of metabolism; Infantile epileptic spasm syndrome; Metabolic etiology

DOI: https://doi.org/10.1016/j.braindev.2024.03.003

Nat Rev Cardiol. 2024 Mar 18.

Protein glycosylation in cardiovascular health and disease.

John C Chatham, Rakesh P Patel.

Protein glycosylation, which involves the attachment of carbohydrates to proteins, is one of the most abundant protein co-translational and post-translational modifications. Advances in technology have substantially increased our knowledge of the biosynthetic pathways involved in protein glycosylation, as well as how changes in glycosylation can affect cell function. In addition, our understanding of the role of protein glycosylation in disease processes is growing, particularly in the context of immune system function, infectious diseases, neurodegeneration and cancer. Several decades ago, cell surface glycoproteins were found to have an important role in regulating ion transport across the cardiac sarcolemma. However, with very few exceptions, our understanding of how changes in protein glycosylation influence cardiovascular (patho)physiology remains remarkably limited. Therefore, in this Review, we aim to provide an overview of N-linked and O-linked protein glycosylation, including intracellular O-linked N-acetylglucosamine protein modification. We discuss our current understanding of how all forms of protein glycosylation contribute to normal cardiovascular function and their roles in cardiovascular disease. Finally, we highlight potential gaps in our knowledge about the effects of protein glycosylation on the heart and vascular system, highlighting areas for future research.

DOI: https://doi.org/10.1038/s41569-024-00998-z