The challenge of CDG diagnosis

Francisco, Rita; Marques‐da‐Silva, Dorinda; Brasil, Sandra; Pascoal, Carlota; Ferreira, Vanessa; Morava, Éva; Jaeken, Jaak

doi:10.1016/j.ymgme.2018.11.003

Cited by 94 publications

(95 citation statements)

References 9 publications

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“…CDG (ORPHA:137) represents a large heterogeneous group of mostly autosomal recessive disorders with impaired synthesis and attachment of glycans to proteins and lipids [77], and defects in the synthesis of glycosylphosphatidylinositol anchors [77][78][79]. Presently, CDG counts over 130 genetic disorders [80], with PMM2-CDG (ORPHA:79318) being the most common N-glycosylation disease [81].…”

Section: Ai For Cdgmentioning

confidence: 99%

Artificial Intelligence (AI) in Rare Diseases: Is the Future Brighter?

Brasil

Pascoal

Francisco

et al. 2019

Genes

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The amount of data collected and managed in (bio)medicine is ever-increasing. Thus, there is a need to rapidly and efficiently collect, analyze, and characterize all this information. Artificial intelligence (AI), with an emphasis on deep learning, holds great promise in this area and is already being successfully applied to basic research, diagnosis, drug discovery, and clinical trials. Rare diseases (RDs), which are severely underrepresented in basic and clinical research, can particularly benefit from AI technologies. Of the more than 7000 RDs described worldwide, only 5% have a treatment. The ability of AI technologies to integrate and analyze data from different sources (e.g., multi-omics, patient registries, and so on) can be used to overcome RDs' challenges (e.g., low diagnostic rates, reduced number of patients, geographical dispersion, and so on). Ultimately, RDs' AI-mediated knowledge could significantly boost therapy development. Presently, there are AI approaches being used in RDs and this review aims to collect and summarize these advances. A section dedicated to congenital disorders of glycosylation (CDG), a particular group of orphan RDs that can serve as a potential study model for other common diseases and RDs, has also been included.

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Section: Ai For Cdgmentioning

confidence: 99%

Artificial Intelligence (AI) in Rare Diseases: Is the Future Brighter?

Brasil

Pascoal

Francisco

et al. 2019

Genes

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“…According to the current nomenclature, CDG can be classified into defects in protein N-glycosylation, Oglycosylation, glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation defects, and multiple glycosylation pathways defects. Since the description of phosphomannomutase two deficiency (PMM2-CDG), more than 130 other CDG subtypes, have been reported [2][3].…”

Section: Introductionmentioning

confidence: 99%

Clinical, biochemical and molecular phenotype of congenital disorders of glycosylation: long-term follow-up

Bogdańska

Lipiński

Szymańska-Rożek

et al. 2020

Preprint

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Background: Congenital disorders of glycosylation (CDG) result from defects in the synthesis of glycans and the attachment of glycans to proteins and lipids. Our study aimed to describe the clinical, biochemical and molecular findings of CDG patients, and to present the long-term follow-up. Material and methods: A single-centre study (1995-2019 years) of patients with congenital disorders of N-glycosylation and combined N- and O-hypoglycosylation, diagnosed based on the serum transferrin (Tf) and apolipoprotein C-III (apoC-III) isoforms analysis, and confirmed molecularly, was performed. Results: Among 32 patients included into the study, 24 had type I Tf isoform profile, in 12 of them deficient PMM2 activity was detected. Three patients were diagnosed with ALG13-CDG; serum Tf isoform profile was normal in one of them, in one other was indicative for type I. Four patients had type II Tf isoform profile. The phenotypic and genotypic spectrum of 32 patients with CDG during long-term (in some cases over 20 years) observation was characterised and several measurements of serum Tf isoforms taken. Statistical analysis revealed strong negative correlation between Asialo-Tf and Tetrasialo-Tf, as well as between Disialo-Tf and Tetrasialo-Tf. Positive correlation was shown between Tetrasialo-Tf and Penasialo-Tf. Within type I CDG, no difference in % Tf isoforms was revealed between PMM2-CDG and non-PMM2-CDG patients. However, these two groups differed significantly in the such diagnostic features as: cerebellar ataxia, failure to thrive, hypothyroidism, pericardial effusion, cardiomyopathy, inverted nipples, prolonged INR. The effect of treatment with mannose in 2 patients with MPI-CDG were assesed and we found that % of Asialo-Tf, Monosialo-Tf, and Disialo-Tf was significanty lowered, whereas Tetrasialo- Tf and Pentasialo-Tf rose, coming closer or falling into the reference range. Conclusions: The novel finding was an abnormal Tf IEF pattern in two ALG13-CDG patients and normal in one ALG1-CDG patient. Clinical manifestation of presented CDG patients was similar to that reported in the literature. Mannose supplementation in MPI-CDG patients, as well as galactose supplementation in PGM-CDG patient improved patients’ clinical picture and Tf isoform profiles.

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“…Congenital disorders of glycosylation (CDG) are a group of clinically complex metabolic disorders that frequently present with varying degrees of neurological impairments and, depending on the specific type, can have further organ system involvement . To date more than 130 unique disorders have been described covering nearly all known glycosylation pathways with most involving defects in the N‐linked glycosylation pathway …”

Section: Introductionmentioning

confidence: 99%

“…1,2 To date more than 130 unique disorders have been described covering nearly all known glycosylation pathways with most involving defects in the N-linked glycosylation pathway. 1,3,4 A useful and often reliable biomarker for detecting N-linked related CDG's is the abundant serum glycoprotein, transferrin. 5,6 Often referred to as carbohydrate-deficient transferrin (CDT), an abnormal transferrin profile is frequently designated as a type I or type II, which can indicate the specific portion of the affected pathway, but usually not the specific defective protein.…”

Section: Introductionmentioning

confidence: 99%

Mutations in the translocon‐associated protein complex subunit SSR3 cause a novel congenital disorder of glycosylation

Lourenço²,

Losfeld

et al. 2019

J of Inher Metab Disea

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The translocon‐associated protein (TRAP) complex facilitates the translocation of proteins across the endoplasmic reticulum membrane and associates with the oligosaccharyl transferase (OST) complex to maintain proper glycosylation of nascent polypeptides. Pathogenic variants in either complex cause a group of rare genetic disorders termed, congenital disorders of glycosylation (CDG). We report an individual who presented with severe intellectual and developmental disabilities and sensorineural deafness with an unsolved type I CDG, and sought to identify the underlying genetic basis. Exome sequencing identified a novel homozygous variant c.278_281delAGGA [p.Glu93Valfs*7] in the signal sequence receptor 3 (SSR3) subunit of the TRAP complex. Biochemical studies in patient fibroblasts showed the variant destabilized the TRAP complex with a complete loss of SSR3 protein and partial loss of SSR1 and SSR4. Importantly, all subunit levels were corrected by expression of wild‐type SSR3. Abnormal glycosylation status in fibroblasts was confirmed using two markers proteins, GP130 and ICAM1. Our findings confirm mutations in SSR3 cause a novel CDG. A novel frameshift variant in the translocon associated protein, SSR3, disrupts the stability of the TRAP complex and causes a novel Congenital Disorder of Glycosylation.

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The challenge of CDG diagnosis

Cited by 94 publications

References 9 publications

Artificial Intelligence (AI) in Rare Diseases: Is the Future Brighter?

Artificial Intelligence (AI) in Rare Diseases: Is the Future Brighter?

Clinical, biochemical and molecular phenotype of congenital disorders of glycosylation: long-term follow-up

Mutations in the translocon‐associated protein complex subunit SSR3 cause a novel congenital disorder of glycosylation

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