Documenta Ophthalmologica

, Volume 125, Issue 1, pp 51–62 | Cite as

Multimodal fundus imaging in fundus albipunctatus with RDH5 mutation: a newly identified compound heterozygous mutation and review of the literature

  • Nan-Kai Wang
  • Lan-Hsin Chuang
  • Chi-Chun Lai
  • Chai Lin Chou
  • Hsueh-Yen Chu
  • Ling Yeung
  • Yen-Po Chen
  • Kuan-Jen Chen
  • Wei-Chi Wu
  • Tun-Lu Chen
  • An-Ning Chao
  • Yih-Shiou Hwang
Original Research Article


The aim of this study was to describe multimodal retinal imaging of fundus albipunctatus (FA) with the newly identified compound heterozygous RDH5 mutation and to review the relevant literature. Five family members were examined, and the RDH5 gene was analyzed by direct sequencing. The clinical features and genetic study of FA are reviewed. The proband had a compound heterozygotic missense mutation of Cys59Ser (TGC → AGC) and a nonsense mutation of Trp95ter (TGG → TGA) in the RDH5 gene. Fundus examination revealed diffuse yellow flecks with foveal sparing. Infrared reflectance (IR) imaging showed multiple discrete round lesions, and fundus autofluorescence (FAF) imaging showed decreased autofluorescence. In spectral domain optical coherence tomography (SD-OCT), the lesions spanned across the retinal pigment epithelium complex and the photoreceptor inner segment ellipsoid band. The outer nuclear layer thickness is decreased compared to normal control. Electroretinography (ERG) showed improved dark-adapted responses after a prolonged 2.5-h dark adaptation. The fundi of the patient’s son and daughter both appeared unremarkable. The clinical findings, differential diagnosis, and genetic studies of these features are reviewed. This is the first time that IR imaging of this disease has been reported; IR imaging showed more detail than did FAF imaging. Although retinal imaging (fundus photographs, FAF, IR, SD-OCT) of FA showed characteristic findings, ERG and genetic study remain the most reliable tests for making the diagnosis.


Fundus albipunctatus Retinol dehydrogenase Visual cycle Infrared reflectance imaging 



We would like to thank the medical imaging division at Chang Gung Memorial Hospital for their excellent work. NKW is supported by the Taiwan National Science Council (grant number NSC-99-2314-B-182A-029-MY3) and the Chang Gung Memorial Hospital (grant numbers CMRPG 381561~381563 and 391801). The funding organization had no role in the design or conduct of this research.


  1. 1.
    Mooren A (1882) Fünf Lustren Ophthalmologische Wirksamkeit. Verlag Von J. F, BergmannGoogle Scholar
  2. 2.
    Lauber H (1910) Die sogenannte Retinitis punctata albescens. Klin Monatsbl Augenheilkd 48:133–148Google Scholar
  3. 3.
    Yamamoto H, Simon A, Eriksson U, Harris E, Berson EL, Dryja TP (1999) Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus. Nat Genet 22:188–191PubMedCrossRefGoogle Scholar
  4. 4.
    Krill AE, Folk MR (1962) Retinitis punctata albescens. A functional evaluation of an unusual case. Am J Ophthalmol 53:450–455PubMedGoogle Scholar
  5. 5.
    Krill AE (1977) Krill’s hereditary retinal and choroidal diseases, vol 1. Harper & Row Hagerstown, MDGoogle Scholar
  6. 6.
    Simon A, Hellman U, Wernstedt C, Eriksson U (1995) The retinal pigment epithelial-specific 11-cis retinol dehydrogenase belongs to the family of short chain alcohol dehydrogenases. J Biol Chem 270:1107–1112PubMedCrossRefGoogle Scholar
  7. 7.
    Driessen CA, Janssen BP, Winkens HJ, van Vugt AH, de Leeuw TL, Janssen JJ (1995) Cloning and expression of a cDNA encoding bovine retinal pigment epithelial 11-cis retinol dehydrogenase. Invest Ophthalmol Vis Sci 36:1988–1996PubMedGoogle Scholar
  8. 8.
    Schmitz-Valckenberg S, Holz FG, Bird AC, Spaide RF (2008) Fundus autofluorescence imaging: review and perspectives. Retina 28:385–409PubMedCrossRefGoogle Scholar
  9. 9.
    Wang NK, Fine HF, Chang S, Chou CL, Cella W, Tosi J, Lin CS, Nagasaki T, Tsang SH (2009) Cellular origin of fundus autofluorescence in patients and mice with a defective NR2E3 gene. Br J Ophthalmol 93:1234–1240PubMedCrossRefGoogle Scholar
  10. 10.
    Morimura H, Berson EL, Dryja TP (1999) Recessive mutations in the RLBP1 gene encoding cellular retinaldehyde-binding protein in a form of retinitis punctata albescens. Invest Ophthalmol Vis Sci 40:1000–1004PubMedGoogle Scholar
  11. 11.
    Hood DC, Zhang X, Ramachandran R, Talamini CL, Raza A, Greenberg JP, Sherman J, Tsang SH, Birch DG (2011) The inner segment/outer segment border seen on optical coherence tomography is less intense in patients with diminished cone function. Invest Ophthalmol Vis Sci 52:9703–9709PubMedCrossRefGoogle Scholar
  12. 12.
    Wang NK, Lai CC, Chu HY, Chen YP, Chen KJ, Wu WC, Yeh LK, Chuang LH, Chen TL (2012) Classification of early dry-type myopic maculopathy with macular choroidal thickness. Am J Ophthalmol 153:669–677, 677.e1–2Google Scholar
  13. 13.
    Marmor MF, Fulton AB, Holder GE, Miyake Y, Brigell M, Bach M (2009) ISCEV standard for full-field clinical electroretinography (2008 update). Doc Ophthalmol 118:69–77PubMedCrossRefGoogle Scholar
  14. 14.
    Sergouniotis PI, Sohn EH, Li Z, McBain VA, Wright GA, Moore AT, Robson AG, Holder GE, Webster AR (2011) Phenotypic variability in RDH5 retinopathy (fundus albipunctatus). Ophthalmology 118:1661–1670PubMedCrossRefGoogle Scholar
  15. 15.
    Nakamura M, Skalet J, Miyake Y (2003) RDH5 gene mutations and electroretinogram in fundus albipunctatus with or without macular dystrophy: RDH5 mutations and ERG in fundus albipunctatus. Doc Ophthalmol 107:3–11PubMedCrossRefGoogle Scholar
  16. 16.
    Nakamura M, Hotta Y, Tanikawa A, Terasaki H, Miyake Y (2000) A high association with cone dystrophy in Fundus albipunctatus caused by mutations of the RDH5 gene. Invest Ophthalmol Vis Sci 41:3925–3932PubMedGoogle Scholar
  17. 17.
    Miyake Y, Shiroyama N, Sugita S, Horiguchi M, Yagasaki K (1992) Fundus albipunctatus associated with cone dystrophy. Br J Ophthalmol 76(6):375–379PubMedCrossRefGoogle Scholar
  18. 18.
    Marmor MF (1977) Fundus albipunctatus: a clinical study of the fundus lesions, the physiologic deficit, and the vitamin A metabolism. Doc Ophthalmol 43:277–302PubMedCrossRefGoogle Scholar
  19. 19.
    Genead MA, Fishman GA, Lindeman M (2010) Spectral-domain optical coherence tomography and fundus autofluorescence characteristics in patients with fundus albipunctatus and retinitis punctata albescens. Ophthalmic Genet 31:66–72PubMedCrossRefGoogle Scholar
  20. 20.
    Querques G, Carrillo P, Querques L, Bux AV, Del Curatolo MV, Delle Noci N (2009) High-definition optical coherence tomographic visualization of photoreceptor layer and retinal flecks in fundus albipunctatus associated with cone dystrophy. Arch Ophthalmol 127:703–706PubMedCrossRefGoogle Scholar
  21. 21.
    Schatz P, Preising M, Lorenz B, Sander B, Larsen M, Rosenberg T (2011) Fundus albipunctatus associated with compound heterozygous mutations in RPE65. Ophthalmology 118:888–894PubMedCrossRefGoogle Scholar
  22. 22.
    Schatz P, Preising M, Lorenz B, Sander B, Larsen M, Eckstein C, Rosenberg T (2010) Lack of autofluorescence in fundus albipunctatus associated with mutations in RDH5. Retina 30:1704–1713PubMedCrossRefGoogle Scholar
  23. 23.
    Franceschetti A, Dieterle P, Ammann F, Marty F (1963) A new form of fundus albipunctatus with hemeralopia. Ophthalmologica 145:403–410PubMedCrossRefGoogle Scholar
  24. 24.
    Margolis S, Siegel IM, Ripps H (1987) Variable expressivity in fundus albipunctatus. Ophthalmology 94:1416–1422PubMedGoogle Scholar
  25. 25.
    Hajali M, Fishman GA, Dryja TP, Sweeney MO, Lindeman M (2009) Diagnosis in a patient with fundus albipunctatus and atypical fundus changes. Doc Ophthalmol 118:233–238PubMedCrossRefGoogle Scholar
  26. 26.
    Fishman GA, Roberts MF, Derlacki DJ, Grimsby JL, Yamamoto H, Sharon D, Nishiguchi KM, Dryja TP (2004) Novel mutations in the cellular retinaldehyde-binding protein gene (RLBP1) associated with retinitis punctata albescens: evidence of interfamilial genetic heterogeneity and fundus changes in heterozygotes. Arch Ophthalmol 122:70–75PubMedCrossRefGoogle Scholar
  27. 27.
    Granse L, Abrahamson M, Ponjavic V, Andreasson S (2001) Electrophysiological findings in two young patients with Bothnia dystrophy and a mutation in the RLBP1 gene. Ophthalmic Genet 22:97–105PubMedCrossRefGoogle Scholar
  28. 28.
    Katsanis N, Shroyer NF, Lewis RA, Cavender JC, Al-Rajhi AA, Jabak M, Lupski JR (2001) Fundus albipunctatus and retinitis punctata albescens in a pedigree with an R150Q mutation in RLBP1. Clin Genet 59:424–429PubMedCrossRefGoogle Scholar
  29. 29.
    Simon A, Romert A, Gustafson AL, McCaffery JM, Eriksson U (1999) Intracellular localization and membrane topology of 11-cis retinol dehydrogenase in the retinal pigment epithelium suggest a compartmentalized synthesis of 11-cis retinaldehyde. J Cell Sci 112:549–558PubMedGoogle Scholar
  30. 30.
    Krill AE, Klien BA (1965) Flecked retina syndrome. Arch Ophthalmol 74:496–508PubMedCrossRefGoogle Scholar
  31. 31.
    Michels RG (1977) Flecked retina syndrome. Int Ophthalmol Clin 17:35–74PubMedCrossRefGoogle Scholar
  32. 32.
    Uyemura M (1928) Ueber eine merkwurdige Augenhintergrundveranderung bei zwei Fallen yon idiopathischer Hemeralopie. Klin Monatsbl Augenheilkd 81:471–473Google Scholar
  33. 33.
    Hing TK (1965) Further contributions to the fundus xerophthalmicus. Ophthalmologica 150:219–238PubMedCrossRefGoogle Scholar
  34. 34.
    Levy NS, Toskes PP (1974) Fundus albipunctatus and vitamin A deficiency. Am J Ophthalmol 78:926–929PubMedGoogle Scholar
  35. 35.
    Isaacs TW, McAllister IL, Wade MS (1996) Benign fleck retina. Br J Ophthalmol 80:267–268PubMedCrossRefGoogle Scholar
  36. 36.
    Airiani S, Cella W, Chou CL, Tosi J, Tsang SH (2008) Benign panretinal uniform radial linear-shaped flecks. Clin Exp Ophthalmol 36:891–894CrossRefGoogle Scholar
  37. 37.
    Carr RE, Margolis S, Siegel IM (1976) Fluorescein angiography and vitamin A and oxalate levels in fundus albipunctatus. Am J Ophthalmol 82:549–558PubMedGoogle Scholar
  38. 38.
    Marmor MF (1990) Long-term follow-up of the physiologic abnormalities and fundus changes in fundus albipunctatus. Ophthalmology 97:380–384PubMedGoogle Scholar
  39. 39.
    Lorenz B, Wabbels B, Wegscheider E, Hamel CP, Drexler W, Preising MN (2004) Lack of fundus autofluorescence to 488 nanometers from childhood on in patients with early-onset severe retinal dystrophy associated with mutations in RPE65. Ophthalmology 111:1585–1594PubMedCrossRefGoogle Scholar
  40. 40.
    Braunstein A, Trief D, Wang NK, Chang S, Tsang SH (2010) Vitamin A deficiency in New York City. Lancet 376:267PubMedCrossRefGoogle Scholar
  41. 41.
    Elsner AE, Burns SA, Weiter JJ, Delori FC (1996) Infrared imaging of sub-retinal structures in the human ocular fundus. Vis Res 36:191–205PubMedCrossRefGoogle Scholar
  42. 42.
    Anastasakis A, Fishman GA, Lindeman M, Genead MA, Zhou W (2011) Infrared scanning laser ophthalmoscope imaging of the macula and its correlation with functional loss and structural changes in patients with Stargardt disease. Retina 31:949–958PubMedCrossRefGoogle Scholar
  43. 43.
    Sparrow JR, Wu Y, Kim CY, Zhou J (2010) Phospholipid meets all-trans-retinal: the making of RPE bisretinoids. J Lipid Res 51:247–261PubMedCrossRefGoogle Scholar
  44. 44.
    Zweifel SA, Spaide RF, Yannuzzi LA (2011) Acquired vitelliform detachment in patients with subretinal drusenoid deposits (reticular pseudodrusen). Retina 31:229–234PubMedCrossRefGoogle Scholar
  45. 45.
    Niwa Y, Kondo M, Ueno S, Nakamura M, Terasaki H, Miyake Y (2005) Cone and rod dysfunction in fundus albipunctatus with RDH5 mutation: an electrophysiological study. Invest Ophthalmol Vis Sci 46:1480–1485PubMedCrossRefGoogle Scholar
  46. 46.
    Driessen CA, Janssen BP, Winkens HJ, Kuhlmann LD, Van Vugt AH, Pinckers AJ, Deutman AF, Janssen JJ (2001) Null mutation in the human 11-cis retinol dehydrogenase gene associated with fundus albipunctatus. Ophthalmology 108:1479–1484PubMedCrossRefGoogle Scholar
  47. 47.
    Liden M, Romert A, Tryggvason K, Persson B, Eriksson U (2001) Biochemical defects in 11-cis-retinol dehydrogenase mutants associated with fundus albipunctatus. J Biol Chem 276:49251–49257PubMedCrossRefGoogle Scholar
  48. 48.
    Driessen CA, Winkens HJ, Hoffmann K, Kuhlmann LD, Janssen BP, Van Vugt AH, Van Hooser JP, Wieringa BE, Deutman AF, Palczewski K, Ruether K, Janssen JJ (2000) Disruption of the 11-cis-retinol dehydrogenase gene leads to accumulation of cis-retinols and cis-retinyl esters. Mol Cell Biol 20:4275–4287PubMedCrossRefGoogle Scholar
  49. 49.
    Nakamura M, Miyake Y (2002) Macular dystrophy in a 9-year-old boy with fundus albipunctatus. Am J Ophthalmol 133:278–280PubMedCrossRefGoogle Scholar
  50. 50.
    Nakamura M, Lin J, Miyake Y (2004) Young monozygotic twin sisters with fundus albipunctatus and cone dystrophy. Arch Ophthalmol 122:1203–1207PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Nan-Kai Wang
    • 1
    • 3
  • Lan-Hsin Chuang
    • 2
    • 3
  • Chi-Chun Lai
    • 1
    • 3
  • Chai Lin Chou
    • 4
  • Hsueh-Yen Chu
    • 1
    • 3
  • Ling Yeung
    • 2
    • 3
  • Yen-Po Chen
    • 1
    • 3
  • Kuan-Jen Chen
    • 1
    • 3
  • Wei-Chi Wu
    • 1
    • 3
  • Tun-Lu Chen
    • 1
    • 3
  • An-Ning Chao
    • 1
    • 3
  • Yih-Shiou Hwang
    • 1
    • 3
  1. 1.Department of OphthalmologyChang Gung Memorial Hospital, Linkuo Medical CenterKuei Shan, TaoyuanTaiwan
  2. 2.Department of OphthalmologyChang Gung Memorial HospitalKeelungTaiwan
  3. 3.College of MedicineChang Gung UniversityTaoyuanTaiwan
  4. 4.Faculty of MedicineThe University of British ColumbiaVancouverCanada

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