Frontiers in congenital disorders of glycosylation consortium, a cross-sectional study report at year 5 of 280 individuals in the natural history cohort

Abstract

Objective: Our report describes clinical, genetic, and biochemical features of participants with a molecularly confirmed congenital disorder of glycosylation (CDG) enrolled in the Frontiers in Congenital Disorders of Glycosylation (FCDGC) Natural History cohort at year 5 of the study. Methods: We enrolled individuals with a known or suspected CDG into the FCDGC Natural History Study, a multicenter prospective and retrospective natural history study of all genetic causes of CDG. We conducted a cross-sectional analysis of baseline study visit data from participants with confirmed CDG who were consented into the FCDGC Natural History Study (5U54NS115198) from October 2019 to November 2023. Results: Three hundred thirty-three subjects consented to the FCDGC Natural History Study. Of these, 280 unique individuals had genetic data available that was consistent with a diagnosis of CDG. These 280 individuals were enrolled into the study between October 8, 2019 and November 29, 2023. One hundred forty-one (50.4%) were female, and 139 (49.6%) were male. Mean and median age at enrollment was 10.1 and 6.5 years, respectively, with a range of 0.22 to 71.4 years. The cohort encompassed individuals with disorders of N-linked protein glycosylation (57%), glycosylphosphatidylinositol anchor disorder (GPI anchor) (15%), disorders of Golgi homeostasis, trafficking and transport (12%), dolichol metabolism disorders (5%), disorders of multiple pathways (6%), and other (5%). The most frequent presenting symptom(s) leading to diagnosis were developmental delay/disability (77%), followed by hypotonia (56%) and feeding difficulties (42%). Mean and median time between first related symptom and diagnosis was 2.7 and 0.8 years, respectively. One hundred percent of individuals in our cohort had developmental differences/disabilities at the time of their baseline visit, followed by 97% with neurologic involvement, 91% with gastrointestinal (GI)/liver involvement, and 88% with musculoskeletal involvement. Severity of disease in individuals was scored on the Nijmegen Progression CDG Rating Scale (NPCRS) with 27% of scores categorized as mild, 44% moderate, and 29% severe. Of the individuals with N-linked protein glycosylation defects, 83% of those with data showed a type 1 pattern on carbohydrate deficient transferrin (CDT) analysis including 82/84 individuals with PMM2-CDG, 6% a type 2 pattern, 1% both type 1 and type 2 pattern and 10% a normal or nonspecific pattern. One hundred percent of individuals with Golgi homeostasis and trafficking defects with data showed a type 2 pattern on CDT analysis, while Golgi transport defect showed a type II pattern 73% of the time, a type 1 pattern for 7%, and 20% had a normal or nonspecific pattern. Most of the variants documented were classified as pathogenic or likely pathogenic using ACMG criteria. For the majority of the variants, the predicted molecular consequence was missense followed by nonsense and splice site, and the majority of the diagnoses are inherited in an autosomal recessive pattern but with disorders of all major nuclear inheritance included. Discussion: The FCDGC Natural History Study serves as an important resource to build future research studies, improve clinical care, and prepare for clinical trial readiness. Herein is the first overview of CDG participants of the FCDGC Natural History Study. © 2024 Elsevier Inc.

• author: Lam, Christina ; Eklund, E.A. and Morava, E.
• author collaboration: et al.
• organization: Paediatrics (Lund); Epilepsy Center
• publishing date: 2024
• type: Contribution to journal
• publication status: published
• subject: Medical Genetics
• keywords: CDG, Congenital disorders of glycosylation, Natural history, NPCRS, Adolescent, Adult, Child, Child, Preschool, Cohort Studies, Congenital Disorders of Glycosylation, Cross-Sectional Studies, Female, Glycosylation, Humans, Infant, Male, Prospective Studies, Retrospective Studies, Young Adult, carbohydrate deficient transferrin, dolichol, glycosylphosphatidylinositol, adolescent, adult, aged, Article, ataxia, autosomal recessive inheritance, biochemistry, cell transport, child, clinical feature, cohort analysis, congenital disorder of glycosylation, controlled study, cross-sectional study, delayed diagnosis, developmental delay, diagnosis time, disability, disease severity, feeding difficulty, female, gastrointestinal symptom, genetic variability, Golgi complex, homeostasis, human, major clinical study, male, metabolic disorder, middle aged, missense mutation, molecular diagnosis, mortality, muscle hypotonia, nonsense mutation, pathogenicity, patient-reported outcome, preschool child, prospective study, protein glycosylation, rating scale, retrospective study, school child, vesicle trafficking, clinical trial, genetics, glycosylation, infant, multicenter study, pathology, young adult
• in: Molecular Genetics and Metabolism
• volume: 142
• issue: 4
• article number: 108509
• publisher: Elsevier
• external identifiers: scopus:85197073996; pmid:38959600
• ISSN: 1096-7192
• DOI: 10.1016/j.ymgme.2024.108509
• language: English
• LU publication?: yes
• id: 0063afbb-d1ae-4b26-9405-c8cac370d11e
• date added to LUP: 2024-09-12 14:05:16
• date last changed: 2024-09-13 03:00:08