Ocular Manifestations of Mucopolysacchridosis

Ocular Manifestations of Mucopolysacchridosis Ocular manifestations of mucopolysacchridosis Praddep Sagar Arsikere, Pradeep Venkatesh, Yog Raj Sharma Mucopolysaccharidoses  (MPS)  are a group of disorders caused by  the  inherited deficiency of lysosomal enzymes involved in  the  metabolism of glycosaminoglycan  (GAG),  resulting in  the  widespread intracellular and extracellular accumulation of  GAG.  > Type Gene Deficient enzyme GAG deposited IInheritance  pattern Hurler syndrome (MPS I-H) IDUA (4p16.3) Alpha-L-iduronidase Dermatan sulfate, heparan sulfate AR Hurler-Scheie syndrome  (MPS I-H/S) IDUA (4p16.3) Alpha-L-iduronidase Dermatan sulfate, heparan sulfate AR Scheie syndrome (MPS I-S) IDUA (4p16.3) Alpha-L-iduronidase Dermatan sulfate, heparan sulfate AR Hunter syndrome, severe (MPS II-A) IDS (Xq28) Iduronate sulfatase Dermatan sulfate, heparan sulfate XR Hunter syndrome, mild (MPS II-B) IDS (Xq28) Iduronate  sulfatase Dermatan sulfate, heparan sulfate XR Sanfilippo syndrome A (MPS III-A) SGSH (17q25.3) Heparan  N-sulfatase Heparan sulfate AR Sanfilippo syndrome B (MPS III-B) NAGLU (17q21) Alpha-N-acetylglucosaminidase Heparan sulfate AR Sanfilippo syndrome C (MPS III-C) HGSNAT (8p11.1) Heparan-alpha-glucosaminide Nacetyltransferase Heparan sulfate AR Sanfilippo syndrome D (MPS III-D) GNS (12q14) N-acetyl alpha-glucosamine-6-sulfatase Heparan sulfate AR Morquio syndrome A (MPS IV-A) GALNS (16q24.3) N-acetylgalactosamine 6-sulfatase Keratan sulfate AR Morquio syndrome B (MPS IV-B) GLB1 (3p21.33) Beta-galactosidase Keratan sulfate AR Maroteaux-Lamy syndrome (MPS VI) ARSB (5q14.1) Arylsulfatase B Dermatan sulfate AR Sly syndrome (MPS VII) GUSB (7q21.11) Beta-glucuronidase Dermatan sulfate, heparan sulfate, Chondroitin sulfate AR Natowicz syndrome  (MPS IX) HYAL1 (3p21) Hyaluronidase AR Ocular manifestations 1. Ocular adnexa Eyelid thickening  occurs  due to  the  accumulation of  GAG. Hypertelorism has been reported in MPS types  III,  Ã‚  II and  Ã‚  VII. Pseudoproptosis due to shallow orbit has been reported in a patient with MPS VI  and MPS II. 2. Cornea The extracellular matrix of corneal stroma contains dermatan sulfate and keratan sulfate in equal proportion. Both dermatan sulfate and keratan sulfate are synthesized by stromal keratocytes. Dermatan sulfate proteoglycans are involved in  the  control of interfibrillar spacing and in  the  lamellar adhesion of corneal collagens. Keratan sulfate proteoglycans are involved in the regulation of collagen fibril diameter. Mainly,  epithelial cells synthesize heparan sulfate proteoglycans,  and they are minor components of cornea. Since dermatan sulfate and keratan sulfate are the major GAGs in  the  corneal stroma, corneal involvement is mainly seen in MPS types  I, IV, VI and VII. In corneas of patients with MPS,  the  excessive accumulation of dermatan sulfate or keratan sulfate in the form of vacuoles can be seen in epithelial cells, keratocytes, histiocytes and extracellular matrix. An increase in  the  mean fibril diameter of collagen and  an  increase in fibril spacing  are  noted in the corneal stroma of patients with MPS I. These structural alterations in collagen fibrils may contribute to light scattering. But the corneal clouding is mainly due to  the  accumulation of GAGs in all the layers of cornea with enlarged stromal keratocytes. Corneal involvement is typically not seen in type III, as the metabolism of heparan sulfate is impaired in type III and heparan sulfate is not synthesized by stromal keratocytes. Symptoms include gradually progressive painless diminution of visual acuity and light intolerance due to scattering of light. In early cases, fine grey punctuate opacities in anterior stroma are visible. In advanced cases,  there is diffuse corneal clouding. Corneal thickness is variable, and it may be increased or normal.  Corneal hysteresis is increased. Corneal  oedema  occurs in cases with  increased intra-ocular  pressure  (IOP). 3.  Optic nerve GAGs  are the major components of  the  extracellular matrix of  the  optic nerve head.  Proteoglycans containing chondritin sulfate and dermatan sulfate are located in lamina cribrosa, supporting tissues of the optic nerve head like septae, pia. Proteoglycans containing heparan sulfate are located in margins of laminar plates of lamina cribrosa.  The  optic nerve involvement can be due to accumulation of  Ã‚  GAG  in  the  extracellular matrix of  the  optic nerve, narrowing of pores in lamina cribrosa, thickening of dura  and  narrowing of bony optic canal  Ã‚  that  leads  to disc  oedema  (pseudopapilloedema). It can also be due to raised intracranial pressure manifesting as true papilloedema.  Long-standing axonal compression or papilloedema  can lead to secondary optic atrophy.  The  accumulation of GAG in ganglion cells of retina can lead to axonal degeneration and optic atrophy. Optic nerve involvement is more commonly seen in types  I, II, VI  and  VII,  as the major  Ã‚  GAGs  in optic nerve and lamina cribrosa are dermatan sulfate and chondritin sulfate. Optic nerve involvement is less with type III,  as heparan sulfate is located in the margins of lamina cribrosa,  and in type IV,  as keratan sulfate is not present in the optic nerve head in human.   4.  Glaucoma The human trabecular meshwork contains chondroitin sulfate, keratan sulfate, heparan sulfate  and  dermatan sulfate.  The  accumulation of  Ã‚  GAG  in the anterior segment structures can lead to  the  narrowing of angle resulting in acute angle closure and chronic angle closure glaucoma. Anterior segment  optical coherence tomography  (OCT)  imaging in mucopolysacchridosis suggests crowded anterior segment and increased corneal thickness in type VI than  in  type I.  The  accumulation of GAG in trabecular cells can lead to features similar to open-angle glaucoma.  The  measurement of IOP by Goldmann applanation tonometer may be falsely high due to increased corneal thickness and corneal hysteresis.  The  visualization of angle by gonioscopy may be compromised due to corneal clouding,  thus posing difficulty in differentiating open angle from closed angle.  The  monitoring of progression and severity of glaucomatous optic neuropathy may be compromised by corneal clouding and disc  oedema. Anterior segment OCT is a valuable tool in  the  assessment of angle, particularly in patients with corneal clouding. Ocular response  Ã‚  analyser  can be used  for the  accurate measurement of IOP in these cases. 5. Retina Heparan sulfate, dermatan sulfate, chondroitin sulfate and hyaluronan are present throughout the retina and choroid. Heparan sulfate is particularly located in  the  basement membrane containing structures, the RNFL and RPE. Keratan sulfate is absent in  the  retina and choroid.  Ã‚  GAGs  are integral components of  the  basement membrane of retinal microvasculature,  and heparan sulfate is the predominant variety. Tapetoretinal degeneration has been reported in MPS types  I,  Ã‚  II,  Ã‚  III and  Ã‚  IV. 6.  Sclera Scleral thickening may lead to  the  uveal effusion syndrome. Suggested Reading 1.  Villas-Boas FS, Fernandes Filho DJ, Acosta AX.  Ocular findings in patients with mucopolysaccharidosis.  Arq Bras Oftalmol  2011;74(6):430–434. 2.  Viestenz A, Shin YS, Viestenz A, Naumann GO.  Ocular  manifestation of  mucopolysaccharidosis I-S (Scheies  syndrome).  Klin Monbl Augenheilkd  2002;219(10):745–748.