Neurological aspects of human glycosylation disorders - PubMed (original) (raw)

Review

Neurological aspects of human glycosylation disorders

Hudson H Freeze et al. Annu Rev Neurosci. 2015.

Abstract

This review presents principles of glycosylation, describes the relevant glycosylation pathways and their related disorders, and highlights some of the neurological aspects and issues that continue to challenge researchers. More than 100 rare human genetic disorders that result from deficiencies in the different glycosylation pathways are known today. Most of these disorders impact the central and/or peripheral nervous systems. Patients typically have developmental delays/intellectual disabilities, hypotonia, seizures, neuropathy, and metabolic abnormalities in multiple organ systems. Among these disorders there is great clinical diversity because all cell types differentially glycosylate proteins and lipids. The patients have hundreds of misglycosylated products, which afflict a myriad of processes, including cell signaling, cell-cell interaction, and cell migration. This vast complexity in glycan composition and function, along with the limited availability of analytic tools, has impeded the identification of key glycosylated molecules that cause pathologies. To date, few critical target proteins have been pinpointed.

Keywords: CDG; congenital disorders; epilepsy; glycans; glycoprotein; seizures.

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Conflict of interest statement

CONFLICTS OF INTEREST

Marc C. Patterson: Consulting: Actelion, Agios, Amicus, Cydan, Stem Cells, Shire HGT. Editorial: Journal of Child Neurology, Child Neurology Open (Editor-in-Chief); Journal of Inherited Metabolic Disease (Editor); Up-To-Date (Section Editor); Hudson H. Freeze: Consulting: Agios.

Figures

Figure 1

Figure 1. Protein complexes in the early steps of lipid linked oligosaccharide (LLO) synthesis

Initial steps in the synthesis of LLO glycan require UDP-GlcNAc generated from fructose-6-P. ALG7 (DPAGT1) adds the first GlcNAc-1-P to dolichol-P and a complex of ALG13 and ALG14 add the next GlcNAc. ALG7 and ALG13/14 exist as a complex and some myasthenia patients have mutations in these genes. The first five Man units are added by a complex of ALG1, ALG2 and ALG11 and other myasthenia patients have mutations in ALG2. In addition to the severity of gene mutations, the integrity, localization and distribution of these complexes may determine whether patients exhibit severe CDG or milder myasthenic condition.

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