Glycobiology and the Paediatric Eye in Health and Disease

The Congenital Disorders of Glycosylation (CDG) are a clinically and genetically heterogeneous family of inherited diseases. Their clinical manifestations are truly multi-system. While the ophthalmological manifestations of CDG are not life threatening, they carry the potential for significant disease burden for the child and their family. In this brief review we highlight the ophthalmological manifestations in patients with CDG, and discuss the importance of ocular glycobiology in health and disease. *Corresponding author: A/Prof David Coman, Department of Metabolic Medicine, The Royal Children’s Hospital, Herston Road, Herston 4029, Brisbane, Australia, Tel: +61736368111; Fax: +61736365505; E-mail: [email protected] Received July 03, 2013; Accepted September 24, 2013; Published September 28, 2013 Citation: Coman D, Gole GA (2013) Glycobiology and the Paediatric Eye in Health and Disease. Pediatr Therapeut S3: 004. doi:10.4172/2161-0665.S3-004 Copyright: © 2012 Heywood W, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction Glycosylation is a ubiquitous post translational modification (PTM) of proteins and lipids [1]. PTM of proteins and lipids is essential for their proper folding, stability, cell signalling and interactions. The transfer of initial sugar(s) to glycoproteins or glycolipids occurs in the endoplasmic reticulum (ER) or on the ER membrane. The subsequent addition of the many different sugars that make up a mature glycan is accomplished in the Golgi apparatus. Golgi membranes are embedded with glycosidases, glycosyltransferases, and nucleotide sugar transporters from the cis-Golgi to the trans-Golgi network (TGN). N-glycosylation starts primarily in the ER while O-glycosylation occurs in the Golgi. In eukaryotes the linkage of glycans to proteins and lipids is carried out by eleven biosynthetic pathways [1], six of which are associated with human genetic disorders known as the congenital disorders of glycosylation (CDG). The last decade has seen an explosion in the identification of genetic glycosylation disorders, predominantly in the individual N-linked and O-linked protein glycosylation pathways (16 and 8 diseases respectively), while combined defects in both the Nand the O-glycosylation pathways, or other pathways e.g. O-Mannosylation have also been described (17 diseases). The clinical features observed in CDG are protean, those that incur the highest disease burden involve the central nervous system, gastrointestinal and cardiac disease systems [2]. In this brief review we discuss the ophthalmological manifestations in CDG and the role glycosylation has in normal ocular function. Clinical Ophthalmological Manifestations of Congenital Disorders of Glycosylation Gylcosylation is a ubiquitous cellular process; approximately 1% of the human genome is dedicated to glycosylation [1]. The CDG are an eclectic group of disorders with a multisystem phenotype. Common clinical features associated with CDG involve developmental delay and intellectual impairment, ataxia, seizures, hepatic dysfunction, coagulopathies, failure to thrive, cardiomyopathy and pericardial effusion, hydrops fetalis, endocrine abnormalities, renal dysfunction, skeletal defects, early lethality, dysmorphic features, and ophthalmological features [3]. Glycosylation is essential for normal development and function of the human eye and visual pathways from cornea to the occipital cortex, so purturbed glycosylation produces clinical phenotypes throughout the visual system (Table 1). PMM2-CDG (OMIM 212065) is the most common CDG with an estimated incidence of 1 in 20,000 live births, with the biochemical block being in the assembly of N-glycan structures [1,2]. The multisystem clinical presentation, while often involving ophthalmological features, is dominated by potential for severe end organ disease which is life limiting in 20% of affected infants [1]. Ophthalmological features are often present at diagnosis but can be over looked due to the emerging severity of end organ disease and the neurological and neurodevelopmental disease burden imparted by CDG. Common features include esotropia, reduced visual acuity, cone-rod dysfunction, and delayed visual maturation (Table 1). PMM2-CDG patients can develop photoreceptor degeneration which ultimately causes a pigmentary retinopathy with specific dysfunction in the “on-pathway” in the retina [4,5]. Electroretinography demonstrates characteristic attenuation of the b-wave with relative sparing of the a-wave, which localises the dysfunction to the Muller cells or ON-bipolar cells. In less common CDG, the ophthalmological manifestations can be a key component in making the diagnosis. Anterior chamber defects such as iris coloboma and glaucoma are a key diagnostic clue for the newly described defect in Dolichol metabolism SRD5A3-CDG (Table 1). In recent years specific CDG disease phenotypes have been associated with unique defective glycosyltransferases, in which the ophthalmological features are main components of the clinical presentation. Key examples include Peters Plus Syndrome (OMIM 261540) and the alpha-dystrogylcanopathy family. Peters Plus syndrome is an autosomal recessive disorder with the main clinical features involving anterior chamber defects, short stature, developmental delay and cleft lip/palate [6-8]. Reported ophthalmological manifestations include deficiency of the corneal endothelium and Descemet membrane (causing a corneal opacity), iridocorneal adhesions and congenital glaucoma [7,9,10]. It is caused by mutations in beta-1,3-galactosyltransferase-like gene (B3GALTL) which encodes a β1,3-glucosyltransferase [6], which adds glucose to an O-Linked fructose and hence is a CDG, B3GALTL-CDG. Citation: Coman D, Gole GA (2013) Glycobiology and the Paediatric Eye in Health and Disease. Pediatr Therapeut S3: 004. doi:10.4172/2161-0665. S3-004