Congenital disorders of glycosylation: new defects and still counting

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.

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

“…Most CDG are multisystem disorders, and many are associated with skeletal abnormalities, including short stature and microcephaly (166,167,168).…”

Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity

“…Hypomorphic Slc39a8 mice exhibited diminished tissue Zn and Fe levels, stunted growth, multiple-organ hypoplasia, anemia, and perinatal death (15). Patients carrying SLC39A8 mutations had severe Mn deficiency, neurological and skeletal defects, and biomarkers of type II congenital disorders of glycosylation (CDG) (16)(17)(18), a growing family of genetic diseases that affect multiple organs and systems (19). However, there is virtually nothing known about how ZIP8 regulates metal ion metabolism in vivo.…”

Classical Galactosaemia and CDG, the N-Glycosylation Interface. A Review

“…Over 100 disorders are now described with on-going characterization of new subsets (Rymen and Jaeken 2014;Scott et al 2014;Cartault et al 2015;Freeze et al 2015). While different CDG have well characterized defects in glycosylation, disorders such as galactosaemia, often termed secondary disorders of glycosylation, are less well defined (Morava et al 2015).…”