Neurology of inherited glycosylation disorders

Abstract

Congenital disorders of glycosylation comprise most of the nearly 70 genetic disorders known to be caused by impaired synthesis of glycoconjugates. The effects are expressed in most organ systems, and most involve the nervous system. Typical manifestations include structural abnormalities (eg, rapidly progressive cerebellar atrophy), myopathies (including congenital muscular dystrophies and limb-girdle dystrophies), strokes and stroke-like episodes, epileptic seizures, developmental delay, and demyelinating neuropathy. Patients can also have neurological symptoms associated with coagulopathies, immune dysfunction with or without infections, and cardiac, renal, or hepatic failure, which are common features of glycosylation disorders. The diagnosis of congenital disorder of glycosylation should be considered for any patient with multisystem disease and in those with more specific phenotypic features. Measurement of concentrations of selected glycoconjugates can be used to screen for many of these disorders, and molecular diagnosis is becoming more widely available in clinical practice. Disease-modifying treatments are available for only a few disorders, but all affected individuals benefit from early diagnosis and aggressive management.

Figure 1. Pathways of glycosylation in the endoplasmic reticulum-Golgi network of mammalian cells

The main types of glycosylation are shown. Various representative sugar-chain structures are given as examples. The grey shaded areas denote common core regions. Most of the glycosylation disorders that affect the nervous system involve alterations in N-linked and O-mannosylated glycoproteins. Some glycophosphatidylinositol-anchor and glycosphingolipid disorders also involve these alterations, but most proteoglycan and O-GalNAc defects do not. Other types of glycosylation exist, such as cytoplasmic O-GlcNAc and C-mannosylation, but are not shown. Glc=glucose. Gal=galactose. Man=mannose. GlcNAc=N-acetylglucosamine. GalNAc=N-acetylgalactosamine. GlcA=glucuronic acid. IdoA=Iduronic acid. Fuc=fucose. Xyl=xylose. Sia=sialic acid. S=sulphation. P=phosphorylation. Ac=acetylation. S/T=serine or threonine. Adapted from Stanley and colleagues, by permission of the Consortium of Glycobiology Editors, La Jolla, CA, USA.

Figure 2. Clinical features of PMM2-CDG (CDG-1a)

Children frequently present with (A) facies and esotropia, (B) nipple inversion, and (C) supragluteal fat pads.

Figure 3. Cranial MRI in a patient with PMM2-CDG (CDG-1a)

Images were obtained from a girl aged 17 years. Notable atrophy of the cerebellar vermis and hemispheres can be seen in (A) sagittal T1, (B) axial T2, and (C) coronal fluid-attenuated inversion recovery images.