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Show Journal of Neuro- Ophthalmology 16( 2): 120- 123, 1996. © 1996 Lippincott- Raven Publishers, Philadelphia Stargardt's Type Maculopathy in a Patient with 11778 Leber's Optic Neuropathy May- Yung Yen, M. D., Yau- Huei Wei, Ph. D., and Jorn- Hon Liu, M. D. A 13- year- old boy presented with a 2- month history of blurred vision. Visual acuity was 20/ 200 in both eyes. Ophthalmoscopic examination revealed normal discs and " beaten bronze atrophy" in the maculae. Subsequently, progressive vision loss with optic atrophy occurred over the next few years. Fluorescein angiographic findings were compatible with Stargardt's maculopathy. Because his cousin developed sequential vision loss diagnosed as Leber's hereditary optic neuropathy, molecular genetic analysis was performed on blood mitochondrial DNA ( mtDNA) from our patient, his cousin with vision loss, and another three asymptomatic cousins. The results showed that they all harbored homoplasmic G to A point mutations at nucleotide position 11778 of the ND4 gene in mtDNA. Key Words: Stargardt's maculopathy- Leber's hereditary optic neuropathy- Mitochondrial DNA mutation. Leber's hereditary optic neuropathy ( LHON) is a maternally inherited disease characterized by acute or subacute loss of central vision that occurs predominantly in healthy young men. Wallace et al. ( 1) reported in 1988 a G to A point mutation at nucleotide position 11778 of mtDNA from patients with LHON. Since that time, three other mtDNA mutations- 3460 ( 2), 14484 ( 3), 15257 ( 4)- have been reported to be associated with LHON. Because of molecular investigations, the original phe-notype of LHON has been modified, and many atypical cases are reported ( 5- 8). In 1993, Heher and Johns ( 9) reported three patients with Stargardt- like maculopathy associated with the 15257 mtDNA mutation, one presenting with acute bilateral vision loss due to acquired maculopathy, a second with a more typical clinical profile of Stargardt's disease, and the third with acute vision loss with maculopathy and later onset optic neuropathy. Here, we report the finding of maculopathy in a patient with the development of 11778 Leber's optic neuropathy. Manuscript received September 7, 1994; accepted September 30, 1995. From the Department of Ophthalmology ( M. Y. Y., J. H. L.), Taipei Veterans General Hospital, and the Department of Biochemistry ( Y. H. W.), National Yang- Ming University, Taipei, Taiwan, ROC. This work was supported by a grant to M- YY ( No. NSC 83- 0412- B- 075- 107) from the National Science Council. Address correspondence and reprint requests to Dr. May- Yung Yen, Department of Ophthalmology, Taipei Veterans General Hospital, National Yang- Ming University, Taipei, 11217 Taiwan, ROC CASE REPORT A 13- year- old boy presented with a 2- month history of blurred vision and headache on November 22, 1984. The best corrected visual acuity was 20/ 200 in each eye. He read 9 of 15 Ishihara color plates with the right eye and 12 of 15 with the left eye. Both fundi were normal. Farnsworth Dichot-omous test D- 15 of each eye was normal. Gold-mann visual fields and skull x- ray examinations were normal. Erythrocyte sedimentation rate ( ESR) was 20 mm/ h. The patient returned on April 1, 1985 complaining of a black spot in his central vision for 3 weeks. Visual acuity was still 20/ 200 in each eye. He read 7 of 15 Ishihara color plates with the right eye and 5 of 15 with the left eye. Ophthalmoscopic 220 STARGARDT'S MACULOPATHY IN LHON 121 examination revealed normal normal discs and retinal pigment epithelial degeneration in both maculae ( Fig. 1). Goldmann perimetry examination revealed a small central scotoma in each eye. Fluorescein angiography revealed retinal pigment epithelial window defects in both maculae in a bull's eye pattern and absence of normal background fluorescence ( a dark choroid) ( Fig. 2). On this basis, he was diagnosed as having Stargardt's maculopathy. Two months later, his visual acuity was unaltered, but color vision had deteriorated further. He now read 4 of 15 Ishihara color plates with the right eye and 5 of 15 with the left eye. Then, he was lost to follow- up for 20 months. During this period, he visited other hospitals and received examinations including fluorescein angiography and computed tomography ( CT) scan of the brain ( normal finding), with the same diagnosis of Stargardt's disease. On February 19, 1987, he returned for examination. His vision was limited to seeing hand motion in the right eye and finger counting in the left eye. Both discs were pale and the nerve fiber layer was not visible. The macular appearance was unaltered. The electroretinogram was normal. Electro-oculographic assessment was impossible because the patient was unable to make rhythmic conjugate eye movements of constant amplitude. He was lost from surveillance again. In October 1993, because his cousin, aged 16 years, developed sequential central vision loss and was diagnosed as having LHON, molecular genetic analysis was performed on blood mtDNA FIG. 1. Ophthalmoscopic appearance of the right ( A) and epithelial degeneration over the macula. from the patient, his cousin with LHON, and three asymptomatic cousins. Figure 3 shows the pedigree of this family. The molecular analyses showed that the five family members carried the mtDNA 11778 point mutation homoplasmically in their blood cells. The patient's vision at this time was bare light perception in each eye. Both discs were pale, but macular appearance was unaltered. He refused to undergo fundus photography and other examination. Ophthalmoscopic examination of his cousins and fluorescein angiography of the cousin with LHON showed normal maculae. COMMENT For decades the diagnosis of LHON depended largely on the ophthalmoscopic findings of circum-papillary telangiectatic microangiopathy, swelling of the peripapillary nerve fiber layer, and absence of fluorescein leakage from the disc ( 10). Although these signs are still considered pathognomonic for LHON, molecular genetic analysis showed that LHON can present with normal fundoscopic examination including normal- appearing optic discs ( 11). Three cases of maculopathy associated with 15257 mtDNA mutation are reported by Heher and Johns ( 9). In the first case, the patient presented with acute bilateral vision loss, normal- appearing optic discs, and acquired maculopathy, and was initially diagnosed as having Stargardt's disease. Five years later, because his sister had developed left ( B) eyes revealed normal discs and retinal pigment J Neuro- Ophthalmol, Vol. 16, No. 2, 1996 M.- Y YEN ET AL FIG. 2. Fluorescein angiography revealed hyperfluorescence in the perimacular region and the fovea in both eyes. A, right eye. B, left eye. LHON, the patient had subsequent molecular genetic analysis that revealed the presence of the 15257 mutation in mtDNA. In the second case, the patient presented with a more typical clinical profile of Stargardt's disease. Because of the mtDNA finding of the first case, he was tested and found to be positive for the 15257 mutation. The patient in the third case presented with acute bilateral vision loss, normal optic discs, and maculopathy. A few months later, because additional visual field defects indicated a neuropathy, molecular genetic analysis was performed, which identified the 15257 mutation Stargardt's disease usually develops in individuals between the ages of 6 and 20 years with bilateral gradual diminution of vision ( 12). Early ophthalmoscopy may show no distinct foveal alteration. As the disease progresses, a horizontal oval of atrophic pigment epithelial alteration appears in the macular area. This typically measures two disc diameters in width and 1.5 disc diameters in height. Discs and vessels generally appear normal. Most patients show a " dark choroid" effect on fluorescein angiography ( 13- 14) that is shown to be due to an accumulation of intracellular " lipofus-cin- like" material in the retinal pigment epithelium ( 15). The dark choroid effect is occasionally noted even before other ophthalmoscopic signs are present. Vision generally stabilizes at the 20/ 200 level ( 16- 17). The mode of inheritance is autosomal recessive. In the early phase of his disease, our patient presented with visual impairment without disc or macula abnormalities. Then, retinal pigment epithelial alterations developed in the macular area with a bull's eye pattern. The differential diagnosis maculopathy includes Stargardt's disease, central retinitis pigmentosa, central areolar choroidal dystrophy, chloroquine ingestion, or a cone dystrophy. Fluorescein angiography of our patient revealed bull's eye retinal pigment epithelial window defects in both maculae and a dark choroid compatible with Stargardt's disease. Finally, optic atrophy was noted and visual acuity was bare light perception. Acute vision loss is not a feature of typical Stargardt's disease and Stargardt's disease never results in optic atrophy and nearly total blindness. Ill IV FIG. 3. The pedigree of the family. O and • represent normal female and male; • represents the patient with visual loss; O* and • * indicate family members who had their eyes and mtDNA examined. proband / Neuro- Ophthalmol, Vol. 16, No. 2, 1996 STARGARDT'S MACULOPATHY IN LHON 123 It is not uncommon for patients with LHON to have normal- appearing optic discs. The disc appearance may remain normal for months before atrophy appears. In the Newman et al. study ( 11) of phenotypic characteristics of pedigrees of LHON positive for the mtDNA mutation at position 11778, 22 of 52 patients had normal optic nerves ( no peripapillary telangiectasia). In nine of those patients examination took place at the time of acute vision loss. We believe that LHON is the most plausible cause of our patient's optic atrophy. We believe further that even his initial vision loss was caused by LHON. It is atypical, however, for patients with LHON to present with severe progressive vision loss over a 2- year period as our patient did. In Newman et al.' s work, the progression of visual loss within each eye in 87 eyes ranged from sudden and complete to 24 months. The mean time to stabilization was 3.7 months ( 11). Pigmentary retinopathy is associated with several mitochondriopathies including chronic progressive external ophthalmoplegia ( 18) and Kearns- Sayre syndrome ( 19) ( caused by large deletions of mtDNA), mitochondrial encephalopathy, lactic acidosis, and stroke- like episodes ( MELAS syndrome) ( 20), the mitochondrial en-cephalomyopathy overlap syndrome ( 21) ( caused by a point mutation at nucletide position 3243), and 8993 mtDNA mutation ( 22). The pigmentary retinopathy of these diseases is characterized histologically by enlarged mitochondria in the retina, choroid ( 18), and retinal pigment epithelium ( 19), and by widespread loss or atrophy of retinal pigment epithelial cells with overlying outer retinal atrophy ( 23). Both photoreceptors and retinal pigment epithelial cells contain many mitochondria consistent with their great energy demand. When the mitochondrial function is defective, the retinal pigment epithelial cells and overlying retina may be subjected to destruction. Our case with the 11778 mutation and the cases of Heher and Johns with 15257 mutation demonstrate that a superimposed pigment epithelial mac-ulopathy of the Stargardt variety can develop in the course of Leber's optic neuropathy. Presumably these mitochondrial abnormalities can affect more than one cellular layer of the retina. REFERENCES 1. Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 1988; 242: 1427- 30. 2. Huoponen K, Vilkki J, Aula P, Nikoskelainen EK, Savon-taus ML. A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. Am J Hum Genet 1991; 48: 1147- 53. 3. Johns DR, Neufeld MJ, Park RD. An ND- 6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochem Biophys Res Commun 1992; 187: 1551- 7. 4. Johns DR, Neufeld MJ. Cytochrome b mutations in Leber hereditary optic neuropathy. Biochem Biophys Res Commun 1991; 181: 1358- 64. 5. Borruat FX, Green WT, Graham EM, Sweeney MG, Morgan- Hughes JA, Sanders MD. Late onset Leber's optic neuropathy: A case confused with ischemic optic neuropathy. Br j Ophthalmol 1992; 76: 571- 3. 6. Hotta Y, Hayakawa M, Fujiki K, et al. An atypical Leber's hereditary optic neuropathy with 11778 mutation. Br ] Ophthalmol 1993; 77: 748- 50. 7. Weiner NC, Newman NJ, Lessell S, Johns DR, Lott MT, Wallace DC. Atypical Leber's hereditary optic neuropathy with molecular confirmation. Arch Neurol 1993; 50: 470- 3. 8. Cullom ME, Heher KL, Miller NR, Savino PJ, Johns DR. Leber's hereditary optic neuropathy masquerading as tobacco- alcohol amblyopia. Arch Ophthalmol 1993; 111: 1482- 5. 9. Heher K, Johns DR. A maculopathy associated with the 15257 mitochondrial DNA mutation. Arch Ophthalmol 1993; 111: 1495- 9. 10. Smith JL, Hoyt WF, Susac JO. Ocular fundus in acute Leber optic neuropathy. Arch Ophthalmol 1973; 90: 349- 54. 11. Newman NJ, Lott MT, Wallace DC. The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 11778 mutation. Am } Ophthalmol 1991; 111: 750- 62. 12. Deutman AF. Macular dystrophies. In: Ryan SJ, ed. Retina, Vol. 2. St. Louis: CV Mosby, 1989: 257- 62. 13. Anmarkrud N. Fundus fluorescein angiography in fundus flavimaculatus and Stargardts disease. Acta Ophthalmologica 1979; 57: 172- 82. 14. Fish G, Grey R, Sehmi KS, Bird AC. The dark choroid in posterior retinal dystrophies. Br } Ophthalmol 1981; 65: 359- 63. 15. Eagle RC, Lucier AC, Bernardino VB, Yanoff M. Retinal pigment epithelial abnormalities in fundus flavimaculatus. A light and electron microscopic study. Ophthalmology 1980; 87: 1189- 200. 16. Fishman GA, Farber M, Patel BS, Derlacki DJ. Visual acuity loss in patients with Stargardt's macular dystrophy. Ophthalmology 1987; 94: 809- 14. 17. Mansour AM. Long- term follow- up of dominant macular dystrophy with flecks( Stargardt). Ophthalmologica 1992; 205: 138- 43. 18. Mullie MA, Harding AE, Petty RKH, Ikeda H, Hughes- Morgan JA, Sanders MD. The retinal manifestations of mitochondrial myopathy. A study of 22 cases. Arch Ophthalmol 1985; 103: 1825- 30. 19. McKechnie NM, King M, Lee WR. Retinal pathology in the Kearns- Sayre syndrome. Br ] Ophthalmol 1985; 69: 63- 75. 20. Rummelt V, Folberg R, Ionasescu V, Yi H, Moore KC. Ocular pathology of MELAS syndrome with mitochondrial DNA nucleotide 3243 point mutation. Ophthalmology 1993; 100: 1757- 66. 21. Chang TS, Johns DR, Walker D, de la Cruz Z, Maumenee IH, Green R. Ocular clinicopathologic study of the mitochondrial encephalomyopathy overlap syndromes. Arch Ophthalmol 1993; 111: 1254- 62. 22. Ortiz RG, Newman NJ, Shoffner JM, Kaufman AE, Koontz DA, Wallace DC. Variable retinal and neurologic manifestations in patients harboring the mitochondrial DNA 8993 mutation. Arch Ophthalmol 1993; 111: 1525- 30. 23. Eagle RC, Hedges TR, Yanoff M. The atypical pigmentary retinopathy of Kearns- Sayre syndrome. Ophthalmology 1982; 89: 1433^ 0. / Neuro- Ophthalmol, Vol. 16, No. 2, 19% |
