A Population-Based Study on Congenital Disorders of Protein N- and Combined with O-Glycosylation Experience in Clinical and Genetic Diagnosis

Pérez‐Cerdá, Celia; Girós, M.; Serrano, Mercedes; Ecay, María Jesús; Gort, Laura; Dueñas, Belén Pérez; Medrano, Celia; García‐Alix, Alfredo; Artuch, Rafael; Briones, Paz; Pérez, Belén

doi:10.1016/j.jpeds.2016.12.060

Cited by 29 publications

(34 citation statements)

References 48 publications

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“…PMM2-CDG was the most common (40%) CDG identified in our study, similarly to the literature [16][17]. Among the N-hypoglycosylation disorders, ALG6-CDG is reported as the second, while ALG1-CDG as the third most frequent type [18].…”

Section: Discussionsupporting

confidence: 87%

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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Section: Discussionsupporting

confidence: 87%

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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“…Due to the broad mutation spectrum, no genotype-phenotype correlations were evidenced (►Table 1). 13 Concerning the other used scales, NPCRS is a good tool for global evaluation of the patient. 11 However, it has poor specificity for cerebellar symptoms.…”

Section: Discussionmentioning

confidence: 99%

Clinical Assessment of Dysarthria in Children with Cerebellar Syndrome Associated with PMM2-CDG

et al. 2018

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Phosphomannomutase deficiency (PMM2-CDG) causes a cerebellar syndrome that has been evaluated using the International Cooperative Ataxia Rating Scale (ICARS). However, no particular dysarthria tests have been used. Speech ICARS subscore subjectively assesses fluency and clarity of speech with two items. Repetition of syllables, traditionally used for characterization of ataxic speech, was validated in early-onset ataxia conditions. We assess the validity of the PATA test (SCA Functional Index [SCAFI]) in PMM2-CDG patients.PATA rates from 20 patients were compared with a control population were and correlated with ICARS and neuroimaging.There was a difference between the PATA rate in patients and controls. PATA rate increased with age in controls. In patients, the improvement of PATA rate with age was not significant. In patients, the PATA rate was negatively correlated with the total ICARS score and the Speech ICARS subscore. Regarding neuroimaging, midsaggital vermis relative diameter was positively correlated with PATA results. These last differences were also significant when the results are corrected by age.PATA rate provides an easy measure for a quantitative assessment of dysarthria that may help clinicians to monitor patients' evolution in a regular consultation. It could also be used in PMM2-CDG clinical trials implementing ICARS speech subscore information.

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“…Homozygosity for a protein truncating mutation in B4GALT1 (1032insC) reported in two related patients is known to cause CDG type 2 (CDGII) 20,21 . Both patients have marked abnormal carbohydrate structures on glycosylated proteins and severe clinical phenotypes manifesting in early childhood with developmental delay, hypotonia, coagulopathy, and elevated transaminases 20,21,30 . Knock-out of b4galt1 in mice results in semi-lethality after birth and several other sever developmental abnormalities 31,32 .…”

Section: Discussionmentioning

confidence: 99%

Genetic and functional evidence relates a missense variant inB4GALT1to lower LDL-C and fibrinogen

Montasser

Hout

McFarland

et al. 2019

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Increased LDL-cholesterol (LDL-C) and fibrinogen are independent risk factors for cardiovascular disease (CVD). We identified novel associations between an Amishenriched missense variant (p.Asn352Ser) in a functional domain of beta-1,4galactosyltransferase 1 (B4GALT1) and 13.5 mg/dl lower LDL-C (p=1.6E-15), and 26 mg/dl lower plasma fibrinogen (p= 9.8E-05). N-linked glycan profiling found p.Asn352Ser to be associated (p-values from 1.4E-06 to 1.0E-17) with decreased glycosylation of glycoproteins including: fibrinogen, ApoB100, immunoglobulin G (IgG), and transferrin. In vitro assays found that the mutant (352Ser) protein had 50% lower galactosyltransferase activity compared to wild type (352Asn) protein. Knockdown of b4galt1 in zebrafish embryos resulted in significantly lower LDL-C compared to control, which was fully rescued by co-expression of 352Asn human B4GALT1 mRNA but only partially rescued by co-expression of 352Ser human B4GALT1 mRNA. Our findings establish B4GALT1 as a novel gene associated with lower LDL-C and fibrinogen and suggest that targeted modulation of protein glycosylation may represent a therapeutic approach to decrease CVD risk.

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A Population-Based Study on Congenital Disorders of Protein N- and Combined with O-Glycosylation Experience in Clinical and Genetic Diagnosis

Cited by 29 publications

References 48 publications

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

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

Clinical Assessment of Dysarthria in Children with Cerebellar Syndrome Associated with PMM2-CDG

Genetic and functional evidence relates a missense variant inB4GALT1to lower LDL-C and fibrinogen

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