Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

An erroneous glycosaminoglycan metabolism leads to corneal opacification in macular corneal dystrophy


Macular corneal dystrophy (MCD) is a rare, potentially blinding disease whose fundamental genetic defect and exact pathogenesis are yet to be elucidated. It is, however, an especially interesting pathology, which highlights how an erroneous glycosaminoglycan or proteoglycan metabolism can induce physical symptoms in a specific connective tissue. Based on immunochemical data, MCD is a heterogeneous condition, and at least two types of the disease have been identified. The cornea, cartilage, and serum from MCD type I patients all contain an unsulphated form of keratan sulphate. In contrast, these tissues contain normally sulphated keratan sulphate in MCD type II patients. A normal population of keratan sulphate proteoglycans (and chondroitin/dermatan sulphate proteoglycans) in the cornea seems to be a requirement of corneal transparency. However, a clinical diagnosis of MCD is unable to distinguish between the keratan sulphate positive and negative types of MCD. The histopathology of MCD is fairly well established, and various corneal aberrations—such as fibrillogranular and glycosaminoglycan deposits, abnormal diameter collagen, and collagen-free lacunae—result in a breakdown of the regular corneal architecture that presumably contributes to the subsequent corneal opacification.

This is a preview of subscription content, log in to check access.


  1. 1.

    Groenouw A. Knötchenfömige Hornhauttrübungen.Arch Augenheilkd 1890:21; 281–9.

  2. 2.

    Fuchs E. Ueber knötchenfömige Hornhauttrübungen.v Graefs Arch Ophthalmol 1902:53; 428–38.

  3. 3.

    Klintworth GK. Research into the pathogenesis of macular corneal dystrophy.Trans Ophthalmol Soc UK 1980:100; 186–94.

  4. 4.

    Klintworth GK. Macular corneal dystrophy: a localized disorder of mucopolysaccharide metabolism?Proc Clin Biol Res 1982:82; 69–101.

  5. 5.

    Klintworth GK. Disorders of glycosaminoglycans (mucopolysaccharides) and proteoglycans. In: Klintworth GK, Garner A, eds.The Pathobiology of Ocular Disease: A Dynamic Approach. New York: Marcel Decker, 1994; 855–92.

  6. 6.

    Jonasson F, Johannsson JH, Garner A, Rice NSC. Macular corneal dystrophy in Iceland.Eye 1989:3; 446–54.

  7. 7.

    Faran MFA, Tabbara KF. Corneal dystrophies among patients undergoing keratoplasty in Saudi Arabia.Cornea 1991:10; 13–16.

  8. 8.

    Davson H.Physiology of the Eye, 5th edn. Oxford: Pergamon Press, 1990.

  9. 9.

    Pepose JS, Ubels JL. The cornea. In: Hart WM, ed.Adler's Physiology of the Eye. St. Louis: Mosby-Year Book, 1992; 29–70.

  10. 10.

    Maurice DM. The structure and transparency of the cornea.J Physiol 1957:136; 263–86.

  11. 11.

    Hart RW, Farrell RA. Light scattering in the cornea.J Opt Soc Am, 1969:59; 766–74.

  12. 12.

    Benedek GB. Theory of transparency of the eye.Appl Opt 1971:10; 459–73.

  13. 13.

    McCally RL, Farrell RA. Light scattering from cornea and corneal transparency. In: Masters BR, ed.Noninvasive Diagnostic Techniques in Ophthalmology. New York: Springer, 1990; 189–210.

  14. 14.

    Goldman JN, Benedek GB, Dohlman CH, Kravitt B. Structural alterations affecting transparency in swollen human corneas.Invest Ophthalmol 1968:7; 501–19.

  15. 15.

    Quantock AJ, Meek KM, Fullwood NJ, Zabel RW. Scheie's syndrome: the architecture of corneal collagen and distribution of corneal proteoglycans.Can J Opthalmool 1993:28; 266–72.

  16. 16.

    Meek KM, Leonard DW. Ultrastructure of the corneal stroma: a comparative study.Biophys J 1993:64; 273–80.

  17. 17.

    Adachi E, Hayashi T.In vitro formation of hybrid fibrils of type V collagen and type I collagen. Limited growth of type I collagen into thick fibrils by type V collagen.Connect Tissue Res 1986:14; 257–66.

  18. 18.

    Birk DE, Fitch JM, Babiarz JP, Doane KJ, Linsenmayer TF. Collagen fibrillogenesisin vitro: interaction of types I and V regulates fibril diameter.J Cell Sci 1990:95; 649–57.

  19. 19.

    Harding JJ, Crabbe MJC, Panjwani NA. Corneal collagen: a review.Colloques Int Cent Natl Rech Sci 1980:287; 51–64.

  20. 20.

    Borcherding MS, Blacik LJ, Sittig RA, Bizzell JU, Breen M, Weinstein HG. Proteoglycans and collagen fibre organization in human corneoscleral tissue.Exp Eye Res 1975:21; 59–70.

  21. 21.

    Vogel KG, Paulsson M, Heinegard D. Specific inhibition of type I and type II collagen fibrillogenesis by the small proteoglycan of tendon.Biochem J 1984:223; 587–97.

  22. 22.

    Vogel KG, Trotter JA. The effect of proteoglycans on the morphology of collagen fibrils formedin vitro.Coll Relat Res 1987:7; 105–14.

  23. 23.

    Scott JE. Proteoglycan-fibrillar collagen interactions.Biochem J 1988:252; 313–23.

  24. 24.

    Rada JA, Cornuet PK, Hassell JR. Regulation of corneal collagen fibrillogenesis in vitro by corneal proteoglycan (lumican and decorin) core protein.Exp Eye Res 1993:56; 635–48.

  25. 25.

    Hassell JR, Cintron C, Kublin C, Newsome DA. Proteoglycan changes during restoration of transparency in corneal scars.Arch Biochem Biophys 1983:222; 362–9.

  26. 26.

    Hahn RA, Birk DE. β-D xyloside alters dermatan sulfate proteoglycan synthesis and the organization of the developing avian corneal stroma.Dev Biol 1992:115; 383–93.

  27. 27.

    Scott JE. Morphometry of Cupromeronic bluestained proteoglycan molecules in animal corneas, versus that of purified proteoglycans stainedin vitro, implies that tertiary structures contribute to corneal ultrastructure.J Anat 1992:180; 155–64.

  28. 28.

    Cho HI, Covington HI, Cintron C. Immunolocalization of type-VI collagen in developing and healing rabbit corneas.Invest Ophthalmol Vis Sci 1990:31; 1096–102.

  29. 29.

    Marshall GE, Konstas AG, Lee WR. Immunogold fine structural localisation of extracellular matrix components in aged human cornea II. Collagen types V and VI.Graefe's Arch Clin Exp Ophthalmol 1991:229; 164–71.

  30. 30.

    Underwood PA, Bennett FA, Mott MR, Strike P. Collagen-associated molecules in the cornea: localisation with monoclonal antibodies.Exp Eye Res 1994:58; 139–53.

  31. 31.

    Cintron C, Zahn Q, Burrows R. In situ hybridization of type XII collagen mRNA in healing rabbit corneas.Invest Ophthalmol Vis Sci (Suppl.) 1994:35; 1991.

  32. 32.

    Meek KM, Elliott GF, Nave C. A synchrotron X-ray diffraction study of bovine cornea stained with Cupromeronic blue.Coll Rel Res 1986:6; 203–18.

  33. 33.

    Scott JE, Haigh M. Small proteoglycan collagen interactions. Keratan sulphate proteoglycan associates with rabbit corneal collagen fibrils at the ‘a’ and ‘c’ bands.Biosci Rep 1985:5; 765–74.

  34. 34.

    Poole AR. Proteoglycans in health and disease: structures and functions.Biochem J 1986:236; 1–14.

  35. 35.

    Evered D, Whelan J.Functions of the Proteoglycans (Ciba Foundation Symposium). Chichester: John Wiley & Sons, 1986.

  36. 36.

    Greiling H, Scott JE.Keratan Sulphate: Chemistry, Biology, Chemical Pathology. London: The Biochemical Society, 1989.

  37. 37.

    Cintron C. The function of proteoglycans in normal and healing corneas. In: Beuerman RW, Crosson CE, Kaufman HE, eds.Healing Process in the Cornea. Houston: Gulf Publishing, 1989; 99–110.

  38. 38.

    Hardingham TE, Fosang AJ. Proteoglycans: many forms and many functions.FASEB J 1992:6; 861–70.

  39. 39.

    Bettelheim F, Goetz D. Distribution of hexosamines in bovine cornea.Invest Opthalmol 1976:15; 301–4.

  40. 40.

    Scott JE. The chemical morphology of keratan sulphate proteoglycans. In: Greiling H, Scott JE. eds.Keratan Sulphate: Chemistry, Biology, Chemical Pathology. London: The Biochemical Society, 1989; 122–34.

  41. 41.

    Scott JE, Haigh M. Keratan sulphate and the ultrastructure of cornea and cartilage: a stand-in for chondroitin sulphate in conditions of oxygen lack?J Anat 1988:158; 95–108.

  42. 42.

    Baulduini C, DeLuca G, Passi A, Rindi S, Salvini R, Scott JE. Effect of oxygen tension and lactate concentration on keratan sulphate and chondroitin sulphate biosynthesis in bovine cornea.Biochim Biophys Acta 1992:1115; 187–91.

  43. 43.

    Castoro JA, Bettelheim AA, Bettelheim, FA. Water gradients across bovine cornea.Invest Ophthalmol Vis Sci 1988:29; 963–68.

  44. 44.

    Funderburgh JL, Conrad GW. Isoforms of corneal keratan sulfate proteoglycan.J Biol Chem 1990:265; 8297–303.

  45. 45.

    Jost CJ, Funderburgh JL, Mann M, Hassell JR, Conrad GW. Cell-free translation and characterization of corneal keratan sulfate proteoglycan core proteins.J Biol Chem 1991:266; 13336–41.

  46. 46.

    Blochberger TC, Vergnes J-P, Hempel J, Hassell JR. cDNA to chick lumican (corneal keratan sulfate proteoglycan) reveals homology to the small interstitial proteoglycan gene family and expression in muscle and intestine.J Biol Chem 1992:267; 347–52.

  47. 47.

    Gregory JD, Coster L, Damle SP. Proteoglycans of rabbit corneal stroma. Isolation and partial characterization.J Biol Chem 1982:257; 6965–70.

  48. 48.

    Midura RJ, Hascall VC. Analysis of the proteoglycans synthesized by corneal explants from embryonic chicken. II. Structural characterization of the keratan sulfate and dermatan sulfate proteoglycans from corneal stroma.J Biol Chem 1989:264; 1423–30.

  49. 49.

    Li W, Vergnes J-P, Cornuet PK, Hassell JR. cDNA clone to chick corneal chondroitin/dermatan sulfate proteoglycan reveals identity to decorin.Arch Biochem Biophys 1992:296; 190–7.

  50. 50.

    Axelsson I, Heinegard D. Fractionation of proteoglycans from bovine corneal stroma.Biochem J 1975:45; 491–500.

  51. 51.

    Cornuet PK, Blochberger TC, Hassell JR. Molecular polymorphism of lumican during corneal development.Invest Ophthalmol Vis Sci 1994:35; 870–7.

  52. 52.

    Scott PG, Winterbottom N, Dodd CM, Edwards E, Pearson CH. A role for disulphide bridges in the protein core in the interaction of proteodermatan sulphate and collagen.Biochem Biophys Res Comm 1986:138; 1348–54.

  53. 53.

    Ehlers N, Bramsen T. Central thickness in corneal disorders.Acta Ophthalmol 1978:56; 412–16.

  54. 54.

    Donnenfeld ED, Cohen EJ, Ingraham HJ, et al. Corneal thinning in macular corneal dystrophy.Am J Ophthalmol 1986:101; 112–13.

  55. 55.

    Quantock AJ, Meek KM, Ridgway AEA, Bron AJ, Thonar EJ-MA. Macular corneal dystrophy: reduction in both corneal thickness and collagen interfibrillar spacing.Curr Eye Res 1990:9; 393–98.

  56. 56.

    Edward DP, Thonar EJ-MA, Srinivasan M, Yue BYTJ, Tso MOM. Macular dystrophy of the cornea. A systemic disorder of keratan sulfate metabolism.Ophthalmology 1990:97; 1194–1200.

  57. 57.

    Quantock AJ, Meek KM, Thonar EJ-MA, Assil KK. Synchrotron X-ray diffraction in atypical macular corneal dystrophy.Eye 1993:9; 779–84.

  58. 58.

    Klintworth GK, Vogel FS. Macular corneal dystrophy: an inherited acid mucopolysaccharide storage disease of the corneal fibroblast.Am J Pathol 1964:45; 565–86.

  59. 59.

    Morgan G. Macular dystrophy of the cornea.Br J Ophthalmol 1966:50; 57–67.

  60. 60.

    Lorenzetti DWC, Kaufman HE. Macular and lattice dystrophies and their recurrences after keratoplasty.Trans Am Acad Ophth Otol 1976:71; 112–18.

  61. 61.

    Robin AL, Green WR, Lapsa TP, Hoover RE, Kelley JS. Recurrence of macular corneal dystrophy after lamellar keratoplasty.Am J Ophthalmol 1977:84; 457–61.

  62. 62.

    Newsome DA, Hassell JR, Rodrigues MM, Rahe AE, Krachmer JH. Biochemical and histological analysis of ‘recurrent’ macular corneal dystrophy.Arch Ophthalmol 1982:100; 1125–31.

  63. 63.

    Klintworth GK, Reed J, Stainer GA, Binder PS. Recurrence of macular corneal dystrophy within grafts.Am J Ophthalmol 1983:95; 60–72.

  64. 64.

    Akova YA, Kirkness CM, McCartney ACE, Ficker LA, Rice NSC, Steele ADM. Recurrent macular corneal dystrophy following penetrating keratoplasty.Eye 1990:4; 698–705.

  65. 65.

    Jones ST, Zimmermann LE. Histopathologic differentiation of granular, macular and lattice dystrophies of the cornea.Am J Ophthalmol 1961:51; 394–410.

  66. 66.

    Teng CC. Macular dystrophy of the cornea.Am J Ophthalmol 1966:62; 436–54.

  67. 67.

    Garner A. Histochemistry of corneal macular dystrophy.Invest Ophthalmol 1969:8; 475–83.

  68. 68.

    Ghosh M, McCulloch C. Macular corneal dystrophy.Can J Ophthalmol 1973:8; 515–26.

  69. 69.

    François J, Hanssens M, Teuchy H, Sebruyns M. Ultrastructural findings in corneal macular dystrophy (Groenouw II type).Ophthalmic Res 1975:1; 80–98.

  70. 70.

    Klintworth GK, Smith CF. Macular corneal dystrophy: studies of sulfated glycosaminoglycans in corneal explant and confluent stromal cell cultures.Am J Pathol 1977:89; 167–82.

  71. 71.

    Klintworth GK, Smith CF. Abnormal product of corneal explants from patients with macular corneal dystrophy.Am J Pathol 1980:101; 143–57.

  72. 72.

    Hassell JR, Newsome DA, Krachmer JH, Rodrigues M. Macular corneal dystrophy: failure to synthesize a mature keratan sulfate proteoglycan.Proc Natl Acad Sci USA 1980:77; 3705–9.

  73. 73.

    Hassell JR, Newsome DA, Nakazawa K, Rodrigues M, Krachmer JH. Defective conversion of a glycoprotein precursor to keratan sulfate proteoglycan in macular corneal dystrophy. In: Hacks S, Wang J, eds.Extracellular Matrix. New York: Academic Press, 1982; 397–406.

  74. 74.

    Klintworth GK, Smith CF. Abnormalities of proteoglycans synthesized by corneal organ cultures derived from patients with macular corneal dystrophy.Lab Invest 1983:48; 603–12.

  75. 75.

    Nakazawa K, Hassell JR, Hascall VC, et al. Defective processing of keratan sulfate in macular corneal dystrophy.J Biol Chem 1984:259; 13751–7.

  76. 76.

    Hassell JR, Hascall VC, Ledbetter S, et al. Corneal proteoglycan biosynthesis and macular corneal dystrophy. In: Sheffield JB, Hilfer SR, eds.Cell and Developmental Biology of the Eye. Heredity and Visual Development. New York: Springer, 1984; 101.

  77. 77.

    Thonar EJ-MA, Lenz ME, Klintworth GK, et al. Quantification of keratan sulfate in blood as a marker of cartilage catabolism.Arthritis Rheum 1985:28; 1367–76.

  78. 78.

    Thonar EJ-MA, Meyer RF, Dennis RF, et al. Absence of normal keratan sulfate in the blood of patients with macular corneal dystrophys.Am J Ophthalmol 1986:102; 561–69.

  79. 79.

    Klintworth GK, Meyer R, Dennis R, et al. Macular corneal dystrophy: Lack of keratan sulfate in the serum and cornea.Ophthalmic Paediatr Gen 1986:7; 139–43.

  80. 80.

    Yang CJ, SundarRaj N, Thonar EJ-MA, Klintworth GK. Immunohistochemical evidence of heterogeneity in macular corneal dystrophy.Am J Ophthalmol 1988:106; 65–71.

  81. 81.

    Edward DP, Yue BYJT, Sugar J, et al. Heterogeneity in macular corneal dystrophy.Arch Ophthalmol 1988:106; 1579–83.

  82. 82.

    Funderburgh JL, Funderburgh ML, Rodrigues MM, Krachmer JH, Conrad GW. Altered antigenicity of keratan sulfate proteoglycan in selected corneal diseases.Invest Ophthalmol Vis Sci 1990:31; 419–28.

  83. 83.

    Meek KM, Quantock AJ, Elliott GF, et al. Macular corneal dystrophy: the macromolecular structure of the stroma observed using electron microscopy and synchrotron X-ray diffraction.Exp Eye Res 1989:49; 941–58.

  84. 84.

    Klintworth GK, McCracken JS. Corneal diseases. In: Johannessen JV, ed.Electron Microscopy in Human Medicine. Vol. 6. New York: McGraw-Hill, 1979; 237–66.

  85. 85.

    Snip RC, Kenyon KR, Green WR. Macular corneal dystrophy: ultrastructural pathology of corneal endothelium and Descemet's membrane.Invest Ophthalmol 1973:12; 88–97.

  86. 86.

    Quantock AJ, Meek KM, Thonar EJ-MA. Analysis of high-angle X-ray diffraction patterns obtained from macular dystrophy corneas.Cornea 1992:11; 185–90.

  87. 87.

    Quantock AJ, Klintworth GK, Thonar EJ-MA. (1994) The unique 4.6 Å ultrastructure in macular dystrophy corneas may reside in hybrid proteoglycan macromolecules: synchrotron X-ray diffraction evidence.Exp Eye Res 1994, in press.

Download references

Author information

Correspondence to Andrew J. Quantock.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Quantock, A.J. An erroneous glycosaminoglycan metabolism leads to corneal opacification in macular corneal dystrophy. Glycosylation & Disease 1, 143–151 (1994).

Download citation


  • cornea
  • glycosaminoglycans
  • proteoglycans