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Congenital disorders of glycosylation: new defects and still counting

  • ICIEM Symposium 2013
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Almost 50 inborn errors of metabolism have been described due to congenital defects in N-linked glycosylation. These phenotypically diverse disorders typically present as clinical syndromes, affecting multiple systems including the central nervous system, muscle function, transport, regulation, immunity, endocrine system, and coagulation. An increasing number of disorders have been discovered using novel techniques that combine glycobiology with next-generation sequencing or use tandem mass spectrometry in combination with molecular gene-hunting techniques. The number of “classic” congenital disorders of glycosylation (CDGs) due to N-linked glycosylation defects is still rising. Eight novel CDGs affecting N-linked glycans were discovered in 2013 alone. Newly discovered genes teach us about the significance of glycosylation in cell–cell interaction, signaling, organ development, cell survival, and mosaicism, in addition to the consequences of abnormal glycosylation for muscle function. We have learned how important glycosylation is in posttranslational modification and how glycosylation defects can imitate recognizable, previously described phenotypes. In many CDG subtypes, patients unexpectedly presented with long-term survival, whereas some others presented with nonsyndromic intellectual disability. In this review, recently discovered N-linked CDGs are described, with a focus on clinical presentations and therapeutic ideas. A diagnostic approach in unsolved N-linked CDG cases with abnormal transferrin screening results is also suggested.

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Abbreviations

ApoC-III:

Apoprotein C-III

CDG:

Congenital disorders of glycosylation

CK:

Creatine kinase

CNS:

Central nervous system

CMS:

Congenital myasthenic syndromes

DPM:

Dolichol phosphomannose

ER:

Endoplasmic reticulum

GDP:

Guanosine diphosphate

GPI:

Glycophosphatidylinositol

ID:

Intellectual disability

MS:

Mass spectrometry

MS/MS:

Tandem mass spectrometry

NGS:

Next-generation sequencing

OST:

Oligosaccharyltransferase

PMI:

Phosphomannose isomerase

TIEF:

Transferrin isoelectric focusing

TRAP:

Translocon-associated protein

UDP:

Uridine diphosphate

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Acknowledgments

The authors are grateful for the support of the Hayward Trustees, the LaCATS grant (2014), and our patients.

Conflict of interest

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Authors and Affiliations

  1. Hayward Genetics Center, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, 70112, USA

    Kyle Scott, Therese Gadomski, Tamas Kozicz & Eva Morava

  2. Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, USA

    Eva Morava

  3. Department of Anatomy, Radboud University Medical Center, Nijmegen, Netherlands

    Tamas Kozicz

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  1. Kyle Scott
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  2. Therese Gadomski
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  3. Tamas Kozicz
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  4. Eva Morava
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Correspondence to Eva Morava.

Additional information

Communicated by: Jaak Jaeken

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Supplementary Table 1

(DOCX 136 kb)

Supplementary Fig. 1

Glycosylation pathway based on the figure by Wopereis et al. Dolichol-phosphate mannose activates mannose (green circle) and synthesizes dolichol (black parabola) to start the stepwise endoplasmic reticulum (ER)-associated glycan synthesis before the glycan chain is synthesized along the membrane and then translocated to the inner ER membrane. Glucose (blue circles) residues are added to signal oligosaccharyltransferase, and the glycan leaves dolichol and is transferred to the protein. Further steps are in the three Golgi apparatus compartments. Galactose (yellow circles) and sialic acid (pink parabolas) are transported to the Golgi apparatus and added in the final steps. Disorders are labeled in red. New diseases are highlighted in grey boxes. (GIF 265 kb)

High Resolution Image (TIFF 1521 kb)

Supplementary Fig. 2

Diagnostic flowchart in suspected N-linked glycosylation disorder. Screening starts with transferrin isoelectric focusing (TIEF) [or mass spectroscopy (MS)], revealing either a type 1 or 2 congenital disorders of glycosylation (CDG) pattern. In patients with a CDG-I, blood or fibroblast phosphomannose isomerase (PMI) and phosphomannomutase (PMM) enzyme activity measurements are indicated. In the case of negative results (blue arrow), lipid-linked oligosaccharide analysis in fibroblasts might reveal a specific biochemical diagnosis. In CDG-II, additional apoprotein C (ApoC)-III isofocusing or tandem MS (MS/MS) can narrow down the possible candidate genes. Direct sequencing can be performed in characteristic syndromal presentations. In unsolved cases (blue arrow), next-generation sequencing (NGS) might be the best diagnostic approach. (GIF 281 kb)

High Resolution Image (TIFF 1521 kb)

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Scott, K., Gadomski, T., Kozicz, T. et al. Congenital disorders of glycosylation: new defects and still counting. J Inherit Metab Dis 37, 609–617 (2014). https://doi.org/10.1007/s10545-014-9720-9

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  • DOI: https://doi.org/10.1007/s10545-014-9720-9

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