Regular Article
Phenotypic and genotypic spectrum of congenital disorders of glycosylation type I and type II

https://doi.org/10.1016/j.ymgme.2016.12.014Get rights and content

Highlights

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    Nine new patients with PMM2-CDG

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    Six new patients with CDG-I and CDG-II subtypes ALG3-ALG9-, ALG11-, MPDU1-, ATP6V0A2-CDG

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    Five novel likely pathogenic variants in various CDG genes

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    Modified TIEF method using HPLC as screening test

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    Normal TIEF should not exclude CDG-I and CDG-II.

Abstract

Background

Congenital disorders of glycosylation (CDG) are inborn defects of glycan metabolism. They are multisystem disorders. Analysis of transferrin isoforms is applied as a screening test for CDG type I (CDG-I) and type II (CDG-II). We performed a retrospective cohort study to determine spectrum of phenotype and genotype and prevalence of the different subtypes of CDG-I and CDG-II.

Material and methods

All patients with CDG-I and CDG-II evaluated in our institution's Metabolic Genetics Clinics were included. Electronic and paper patient charts were reviewed. We set-up a high performance liquid chromatography transferrin isoelectric focusing (TIEF) method to measure transferrin isoforms in our Institution. We reviewed the literature for the rare CDG-I and CDG-II subtypes seen in our Institution.

Results

Fifteen patients were included: 9 with PMM2-CDG and 6 with non-PMM2-CDG (one ALG3-CDG, one ALG9-CDG, two ALG11-CDG, one MPDU1-CDG and one ATP6V0A2-CDG). All patients with PMM2-CDG and 5 patients with non-PMM2-CDG showed abnormal TIEF suggestive of CDG-I or CDG-II pattern. In all patients, molecular diagnosis was confirmed either by single gene testing, targeted next generation sequencing for CDG genes, or by whole exome sequencing.

Conclusion

We report 15 new patients with CDG-I and CDG-II. Whole exome sequencing will likely identify more patients with normal TIEF and expand the phenotypic spectrum of CDG-I and CDG-II.

Introduction

Congenital disorders of glycosylation (CDG) are a heterogeneous group of inherited metabolic disorders characterized by defective N- and O-glycosylation of proteins and lipids [15], [16], [37]. They are caused by inborn defects of glycan metabolism resulting in hypoglycosylation of proteins and lipids. N-glycosylation attaches N-glycans to the amino group of asparagine of proteins and occurs in the endoplasmic reticulum and Golgi. The steps necessary for the glycosylation involve assembly and processing components. N-glycosylation defects involving the assembly of protein glycosylation in the cytoplasm and endoplasmic reticulum are called CDG type I defects (CDG-I). Processing defects of protein glycosylation in the endoplasmic reticulum and Golgi are called CDG type II defects (CDG-II) [15], [34]. O-glycosylation attaches O-glycans to the hydroxyl group of threonine or serine of proteins and their defects are only assembly defects. Combined N- and O-glycosylation defects are usually classified in the group of CDG-II [15], [34], [42], [45].

The first CDG-I defect, PMM2-CDG, caused by phosphomannomutase 2 deficiency (EC 5.4.2.8) (OMIM#212065), was reported by Jaeken in 1984 [16]. So far about 50 different protein N-glycosylation defects have been identified [34]. Patients with CDG-I N-glycosylation defects present with multisystem involvement including neurological, hematological, gastrointestinal, renal, cardiovascular, ophthalmological and skeletal systems and skin and connective tissue. The phenotype ranges from prenatal onset hydrops foetalis with intrauterine growth retardation or dilated cardiomyopathy, to mild global developmental delay, cognitive dysfunction and ataxia [15], [35], [36]. Patients with combined N- and O-glycosylation defects have additional clinical features such as episodic hyperthermia in COG7-CDG and cutis laxa syndrome in ATP6V0A2-CDG [19].

Analysis of transferrin isoelectric focusing (TIEF) using capillary zone electrophoresis [6], high performance liquid chromatography (HPLC) [13] or mass spectrometry [2] is applied as a screening test for N-glycosylation CDG-I and CDG-II defects. The normal transferrin isoform pattern shows tetrasialotransferrin. In CDG-I, there is an increase in asilo- and disialotransferrin and a decrease in tetrasialotransferrin, whereas in CDG-II there is an increase in trisialo- and monosialotransferrin while tetrasialotransferrin can be normal or decreased [35], [36]. Normal transferrin isoform pattern has been reported in various CDG subtypes [47]. The diagnosis for specific subtypes is confirmed by targeted single gene testing or targeted next generation sequencing for CDG genes, or whole exome sequencing. The majority of CDG-I and CDG–II subtypes are treated symptomatically [32].

To evaluate the outcome of patients with CDG-I and CDG-II, we performed a retrospective cohort study. We determined phenotypic spectrum, the genotype and prevalence of the different subtypes of CDG-I and CDG-II. In 2012, our biochemical genetics laboratory developed an HPLC TIEF method for the investigations of CDG, which has been used as a clinical screening test since January 2013. We also briefly describe our method in this study. Additionally, we summarized patients with rare CDG-I and CDG-II subtypes, seen in our institution, as a literature review.

Section snippets

Patients

Institutional Research Ethics Board approved this retrospective cohort study (Approval# 1000050441). All patients with CDG-I and CDG-II seen in the Metabolic Genetics Clinics were included. Electronic and paper patient charts were reviewed for clinical features, biochemical investigations, molecular genetic testing, brain magnetic resonance imaging (MRI) and outcome by two independent research team members. All information was entered into an Excel database. Molecular genetic testing using

Results

Fifteen patients (5 males and 10 females) from 14 unrelated families were included in this retrospective cohort study. The clinical features were first noted at average age of 4months (range birth to 11 months). The current average age was 8.4 years (range 1 to 18 years). One patient was transferred to the adult metabolic clinic after 18 years of age: his follow-up was reported until the age of 18 years and his chronological age was not taken into account. Fourteen patients had CDG-I including 9

Discussion

We report the phenotypic and genotypic spectrum of 15 patients with CDG-I and CDG-II as a retrospective cohort study and a single center experience. PMM2-CDG was the most common CDG subtype (60% of the patients) in our study. TIEF raised the suspicion of CDG-I and CDG-II in 93% of the patients leading to genetic confirmatory diagnosis of CDG-I or CDG-II subtypes. Only one patient with ALG11-CDG had normal TIEF and the diagnosis was confirmed by whole exome sequencing. The majority of the

Conflicts of interest

The authors declare no conflict of interests.

Acknowledgements

We would like to thank all the patients and their families. We would like to thank Stacy Hewson for arranging genetic investigations and providing genetic counselling to families. We would like to thank Ashley Wilson for her help managing the Research Ethics Board approvals.

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