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Show Journal of Neuro- Ophthalmology 15( 1): 15- 19, 1995. CO 1995 Raven Press, Ltd., New York Lack of Differences Among Mitochondrial DNA in Family Members with Leber's Hereditary Optic Neuropathy and Differing Visual Outcomes Yukihiko Mashima, M. D., Yoshiki Hiida, M. D., and Yoshihisa Oguchi, M. D. Investigation of a maternal family of three generations of Leber's hereditary optic neuropathy ( LHON) showed four affected and three unaffected individuals. Two of the four patients had recovered near- normal vision, one spontaneously, and one following treatment with ide-benone, a quinol compound. One patient whose visual impairment persisted was a heavy consumer of alcohol and tobacco. Molecular genetic analysis of 12 known primary or secondary mutations in mitochondrial DNA ( mtDNA) associated with LHON revealed only the 11778 mutation in a homoplasmic fashion with no secondary mutations. The variations in clinical outcome thus could not be explained by synergistically interacting secondary mutations in mtDNA. Environmental factors may play an etiologic role in the development of optic atrophy. Key Words: Leber's hereditary optic neuropathy- Visual recovery- 11778 mitochondrial mutation- Idebenone- Alcohol- Tobacco. From the Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan. Address correspondence and reprint requests to Dr. Yukihiko Mashima, Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku- ku, Tokyo 160, Japan. Leber's hereditary optic neuropathy ( LHON) is a maternally inherited eye disease with an acute or subacute loss of central vision that mainly affects young men. Visual loss is generally severe and persistent, although visual improvement has been reported in some patients ( 1). The pattern of inheritance in LHON consists with underlying mutations in mitochondrial DNA ( mtDNA). The most common mutation is the substitution of a guanine to an adenine at nucleotide position 11778 in the NADH dehydrogenase subunit 4 gene of mtDNA, being identified in 40- 90% of the LHON families ( 2- 7). The visual impairment in patients with the 11778 mutation has a particularly poor prognosis as compared with those having the 11778- negative mutations, the 3460 ( 8), the 14484 ( 9), or the 15257 mutations ( 10). Only about 4% of the patients with the 11778 mutation have had a documented recovery of vision ( 11). We previously reported in a letter ( 12) the treatment with idebebone, a novel quinol compound, for the case of a 10- year- old Japanese boy with the 11778 mutation and whose visual acuity recovered. This maternal family of three generations of LHON includes four affected and three unaffected members; two of the four showed recovery of visual acuity. We report here the visual function of this child after his vision had recovered. We surveyed six members of this family concerning 12 different mtDNA mutations associated with LHON to investigate the different visual outcomes in view of the possibility of synergistically interacting mtDNA mutations. PATIENTS AND METHODS Case Report The proband is a 10- year- old Japanese boy born in 1980. His mother noticed early in 1990 that he 15 16 Y. MASH1MA ET AL. seemed to have poor vision. He was brought to the local eye clinic in May 1990 because of deterioration of vision in both eyes, and was referred in July to our university hospital for the unexplained loss of vision. As he did not experience a progressive deterioration of vision, the actual onset of the visual loss could not be determined. Visual acuity was 15/ 200 in the right eye and 20/ 200 in the left eye with correction. Ophthalmoscopy revealed hy-peremic and slightly elevated optic discs with some mild temporal pallor. Small tortuous peripapillary vessels were apparent in both eyes. There was a family history of optic atrophy, and a diagnosis of LHON was suspected in his case ( Fig. 1). Molecular genetic analysis of mtDNA revealed a mutation at position 11778, confirming the diagnosis. He was administered idebenone ( Takeda Chemical Industries, Japan), given orally at a dose of 90 mg per day from August 1990 to July 1991 ( 12). Visual acuity in the right eye improved slightly to 20/ 90 one month after initiation of treatment and reached 25/ 20 four months later ( Fig. 2). Visual acuity in the left eye improved slightly to 20/ 90 two months after the initiation of treatment and reached 20/ 20 after 7 months, a slower response than observed with the right eye. In November 1992, IV2 years after he had recovered his vision, we used the standard Humphrey 30- 2 threshold test to measure the visual fields. Central scotomas were observed in both eyes, larger in the left eye ( Fig. 3). Visual acuity remained stable in both eyes until May 1993, when the visual acuity in the left eye decreased slightly to 20/ 25. We reinstituted the administration of idebenone in May 1993; visual acuity recovered to 20/ 20 one month later. Performance of the Humphrey 30- 2 threshold test in November 1993 showed no change in the central iff FIG. 1. Pedigree of a Japanese family with LHON. Numbered cases were investigated by molecular analysis in this study. Arrow indicates the 10- year- old proband. scotomas of both eyes. Both optic discs showed only temporal pallor. The patient, now aged 14 years, continues to receive idebenone. We measured the luminance visual evoked potential to evaluate the condition of the optic nerve in August 1990, and again at recovery in April 1991 ( 13). Figure 4 shows the luminance- amplitude curve and the luminance- latency curve at each clinical stage. The luminance- amplitude curve in the acute stage was highly depressed for all stimulus intensities, and became elevated, showing an increased amplitude after the patient's vision recovered ( Fig. 4A). At a higher intensity of the stimulus, both eyes showed a slight delay in latency time throughout his clinical course ( Fig. 4B). The visual evoked potential threshold in the left eye versus the right eye was persistently higher by 1 logarithm. This finding was consistent with the results of the Humphrey 30- 2 threshold test. However, latency time in the contrast visual evoked potential, evoked by checkerboard patterns, was delayed at the stage of visual recovery. Family history The proband's mother ( II- 2 in Fig. 1), 45 years old, and one of his uncles ( II- 4 in Fig. 1), 40 years old, were both asymptomatic and had normal visual acuity. Their optic discs appeared normal. The proband's brother ( III- 2 in Fig. 1), 11 years old, was asymptomatic and had normal visual acuity. However, he showed subtle signs of peripapillary microangiopathy in both eyes. The proband's 73- year- old grandmother ( 1- 1 in Fig. 1) had a visual acuity of 20/ 25 OD and 20/ 40 OS with correction. Her optic discs exhibited pallor. She said she had lost the vision in both eyes while in her early teens, but had recovered it spontaneously. She did not remember any relevant childhood details. The proband's other two uncles both had LHON. One ( II- 3 in Fig. 1), 42 years old, had lost his vision in his teens. No information was available on his eye condition currently. The other ( II- l in Fig. 1), 47 years old, lost his vision at the age of 37 years. He was a heavy consumer of alcohol and tobacco. Visual acuity in each eye was 20/ 200. Analysis of mtDNA Total DNA was extracted from 10 ml EDTA-blood using standard protenase K/ SDS procedures. The amplification of mtDNA by polymerase chain reaction ( PCR) was performed by using the appropriate pair of primers, including the different J Neuro- Ophthatmol, Vol. 15, No. 1, 1995 LEBER'S HEREDITARY OPTIC NEUROPATHY 17 Idebenone Idebenone 20/ 20 FIG. 2. Improvement of visual acuity in 10- year- old patient associated with administration of idebenone. Solid line indicates the right eye, and broken line, the left eye. u < rs C/) > 20/ 200- 2/ 200- 7 9 1990 1 1 12- point mutations associated with LHON; the nt3460, 4160, 11778, 14484, and 15257 mutation as primary mutations, and nt3394, 4216, 4917, 5244, 7444, 13708, and 15812 mutation as secondary mutations ( 7). After amplifying the mtDNA, the PCR products were digested by the respective restriction endonuclease ( 9,14), and electrophoresed in 3% or 4% agarose gels. Gain or loss of the restriction endonuclease site suggested a mutation of mtDNA. RESULTS The six members of this family carried only the 11778 mutations in more than 96% of blood specimens tested. Testing for another 11 mutations produced negative results in all six individuals. DISCUSSION LHON is genetically heterogenous with underlying mutations in mtDNA. At least 14 missence 1 3 5 1991 7 9 11 1 3 1992 5 7 9 1 3 5 1993 7 9 11 1 1994 mutations in mtDNA linked to LHON have been identified in all of the mitochondrial electron transport chain enzyme complexes I, III, and IV as a primary or secondary mutations ( 7,15,16). This suggests that LHON results from a nonspecific, generalized decrease in mitochondrial energy production rather than from a specific enzyme defect. None of the secondary mutations produced the risk of LHON when present in isolation from another ( 15). Some patients with LHON, however, exhibited symptoms related to the interaction of multiple secondary mutations ( 15,17). Secondary mutations often coexist with primary mutations as exacerbating genetic factors that can further inhibit the production of mitochondrial energy. However, no synergistic interaction of the secondary mtDNA mutations could be identified, even in a hetero-plasmic fashion in this family. The six family members carried only the 11778 mutation with ho-moplasmy. FIG. 3. Visual field after visual recovery. / Neuro- Ophthalmol, Vol. 15, No. 1, 1995 18 Y. MASHIMA ET Ah. B Stimulus Intensity 120- 100- E 80-- 60- 40 0 ( 0.3J) Stimulus Intensity FIG. 4. ( A) Luminance- amplitude curve and ( B) luminance- latency curve of visual evoked potential before ( circles) and after ( boxes) visual recovery. Latency time was calculated at the peak of the negative wave, which appeared at around 80 ms ( N80). Amplitude was calculated between N80 and P100 which appeared at around 100 ms with the positive wave. Closed circle indicates the right eye examined in 1990; open circle, the left eye in 1990; closed box, the right eye in 1991; open box, the left eye in 1991. Bar shows the range of mean amplitude ( A) or latency ( B) ± 2 standard deviation ( SD) among normal teenagers. These individuals showed a variable penetrance, age at onset, and/ or loss and recovery of vision. There was no evidence for an association between the intrafamilial variable clinical manifestations and the mtDNA mutations known to be associated with LHON in this study. Thus, the clinical variations could not be explained by an interaction of these mutations. In patient II- 1, the abuse of tobacco and alcohol at age 37, when his vision began to deteriorate, may point to involvement of environmental factors in the disease manifestations. Such factors may inhibit energy production ( 18) and lead to poor vision. Patients with LHON occasionally experience a spontaneous recovery of vision, but only 5 of the 136 patients ( 4%) with the 11778 mutation reported in the United States experienced spontaneous visual improvement within 6 years of their loss of vision ( 11). Four of the five patients recovered vision in one eye only. Jacobson and associates ( 19) described a 31- year- old man with the 11778 mutation who inexplicably lost vision in both eyes during his childhood. Vision in the right eye then recovered to 20/ 20 over a period of several years. Zhu and associates ( 20) reported a patient with LHON who regained 20/ 30 vision in the left eye and another who regained 20/ 25 vision in both eyes. Those male patients carried 90% and 62%, respectively, of mutant mtDNA at nucleotide position 11778. In Japan, Isashiki and Nakagawa ( 21) reported a male patient with the 11778 mutation who lost vision in both eyes at age 10 and regained 20/ 60 vision in the right eye and 20/ 25 in the left. Hotta and colleagues ( 22) reported a 32- year- old man with the 11778 mutation who regained 20/ 25 vision in the right eye. Of the 12 patients who showed visual improvement, 9 ( 75%), including our patient and his grandmother, lost their vision before age 15. Recovery seems more likely to occur when the vision deteriorates at an early age. Recovery of vision after the observation of its improvement required 1 hour to several months in the five patients described by Stone and coworkers ( 11), several months in the patient described by Hotta and coworkers ( 22), 4 months and 7 months in the right eye and the left, respectively, in our 10- year- old patient, and several years in the patient described by Jacobson and colleagues ( 19) and Isashiki and Nakagawa ( 21). In our patient, recovery began 1 month earlier in the right eye than the left. Evaluation of his visual function tested by visual acuity, visual field, and visual evoked potential after recovery revealed better results in the right eye than the left eye. Thus, recovery that begins faster after the initiation of visual improvement may indicate a better prognosis. There have been few reported patients with LHON having the homoplasmic 11778 mutation whose visual acuities spontaneously improved up to 20/ 20 in both eyes; most of the patients described recovered near- normal vision in at least one eye. Idebenone may perhaps have accelerated or promoted the spontaneous recovery in our patient. This agent stimulates net ATP formation in cerebral metabolism and inhibits lipid peroxidation in the mitochondrial membrane ( 23). Further genetic study of this interesting family is required to / Neuro- Ophthalmol, Vol. 15, No. 1, 1995 LEBER'S HEREDITARY OPTIC NEUROPATHY 19 verify the mechanism underlying the recovery of vision following pharmacologic intervention. 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