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Review
. 2014 Jul;37(4):609-17.
doi: 10.1007/s10545-014-9720-9. Epub 2014 May 15.

Congenital disorders of glycosylation: new defects and still counting

Kyle Scott  1 , Therese Gadomski, Tamas Kozicz, Eva Morava
Affiliations
Review

Congenital disorders of glycosylation: new defects and still counting

Kyle Scott et al. J Inherit Metab Dis. 2014 Jul.

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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Figures

Fig. 1
Fig. 1
Recognizable clinical features in different N-linked glycosylation defects. a Abnormal fat distribution in phosphomannomutase 2 (PMM2)-CDG; CDG-Ia). b Liver cirrhosis in phosphomannose isomerase (MPI)-CDG (CDG-Ib). c Distal phalangeal aplasia in ALG6-CDG (CDG-Ic). d Ichthyosis and iridial and retinal coloboma are characteristic for SRD5A3-CDG. e Distal arthrogryposis in ALG8-CDG (CDG-Ih). f Myasthenic face and ptosis are common in DPAGT1-CDG (CDG-Ij). g Venous thrombosis leads to asymmetry in limb circumference in ALG1-CDG (CDG-Ik)
Fig. 2
Fig. 2
Recognizable clinical features in N-glycosylation defects affecting the Golgi system. a Cutis laxa and abnormal fat distribution in ATP6V0A2-CDG. b Adducted thumbs and c microcephaly in COG7-CDG. d Abnormal abdominal fat distribution, high forehead, deep-set eyes, and prominent eyebrows in MAN1B1-CDG
Fig. 3
Fig. 3
Immunohistochemistry of intercellular adhesion molecule 1 (ICAM-1) (green fluorescence) in a healthy control fibroblasts and in b phosphoglucomutase-1 (PGM1)-deficient patient fibroblasts. ICAM-1 antibodies bind to membrane-associated glycoproteins on the cell surface. Nucleus: 4′-6′-diamidino-2-phenylindole (DAPI) staining (blue). Patients with PGM1 congenital disorders of glycosylation (CDG) show little or no fluorescence label on fibroblast cell surface
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