[Past, present, and future in Leber's hereditary optic neuropathy].

Leber's disease is a disease of optic atrophy first reported by Theodor Leber in 1871. Since then, 130 years have passed. Recently, several new findings about the pathology, causes, and heredity of this disease have been made. In 1988 Wallace and others reported a new mutation of 11778 base pairs of mtDNA of patients with Leber's disease. Since then, the study of this disease has progressed remarkably. In this review clinical studies on Leber's disease which were carried out in our department from 1990 are summarized. 1. Genetic diagnosis and clinics Two hundred and twenty-four cases were examined, including patients at our hospital, for the 8 years between 1990 and 1998. Among them, 72 cases were diagnosed as Leber's disease. There were 3 cases (4%) of 3460 mutations, 63 cases(83%) of 11778 mutations, and 6 cases(8%) of 14484 mutations as primary mutations. The reasons for performing the genetic diagnosis were mostly the need for a definite diagnosis of Leber's disease and research on the genesis of optic nerve atrophy of unknown origin. Concerning the secondary mutations, it was confirmed that these mutations were polymorphic as seen in European and American patients. There is a problem of heteroplasmy about the mtDNA mutation. We developed a simple and exact method to evaluate heteroplasmy by using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). In a study of peripheral blood samples in one family, Leber's disease does not appear under conditions of less than 60% mtDNA mutation. As for the three kinds of mutation in Leber's disease, cases of recovery of a visual acuity of 0.3 and above were only 7% in 11778 mutations, but 38% in 3460 mutations and 50% in 14484 mutations. It is assumed that visual prognosis depends on the kind of mutation. 2. Characteristics of visual evoked potential(VEP) In pattern VEP in the acute stage, latency was not delayed very much, but the amplitude was low. On the other hand, in the acute stage of optic neuritis, the latency was very much delayed and the amplitude was diminished. Therefore, I deduced that not only demyelination of the optic nerve fibers but also papilla-macula bundle defects may play an important role. In flash VEP, only the amplitude was low, but latency was normal. 3. Image analysis of the optic nerve In high resolution T2-weighted fast spin-echo magnetic resonance imaging(MRI), the image of the optic nerve can be clearly demonstrated within a short operation time. In MRI in the acute stage of Leber's disease, the image of the optic nerve appeared almost normal. But in the course of time, patients with Leber's disease showed markedly high signals in the optic nerve on the T2-weighted fast spin-echo MRI, and in the atrophic stage the image of the optic nerve showed thinning. The results in this study support the hypothesis that a primary lesion in Leber's disease may be intraocular. 4. Possibility of therapy at the present time The effectiveness of using idebenone combined with vitamin B2, vitamin C, and isopropyl unoprostone(Rescula) for recovery of the circulation of the optic nerve head for patients in the acute stage was compared with untreated patients. In patients with visual acuity of 0.3 and more, there was no statistical difference between the two groups. The recovery interval up to 0.3 was significantly shorter in the treated group than in the untreated group. I suggest that this kind of treatment may aid spontaneous recovery. Among 15 cases of Leber's disease which occurred in the patients teens, at least one eye in 8 cases(53%) recovered to 0.3 or more. Among the 8 recovered cases, 5 cases were from the treated group. On the other hand, 6 cases were treated and 5 cases recovered visual acuity. It is said that the patients developing the disease at younger ages have a tendency toward visual recovery. Pharmacological treatment can aid recovery. 5. Visual function after the recovery of visual acuity The recovery of visual acuity in Leber's disease has the characteristics of fenestrated central scotoma. The visual acuity can be recovered by the appearance of a small part of sensitive area inside the absolute central scotoma. This phenomenon coincides with the results of VEP which does not recover in spite of recovery of vision. Good visual acuity or bad visual acuity depends not only on the recovery of the total area of the central part but on the existence of an area with good sensitivity. In the results of a Humphrey visual field analyzer(10-2) obtained from 8 recovering patients, the part nasal to the fovea was more sensitive than the temporal area. In the early stage of visual recovery, scanning laser ophthalmoscope(SLO) microperimetry can detect this sensitive area, and with the enlargement of this sensitive area, the Humphrey visual field analyzer(10-2) can also detect this recovery area. 6. Strategy for gene therapy We have succeeded in cloning a human retina-specific amine oxidase gene which was found specifically in retinal ganglion cells. By using this promoter, we are now developing a vector specific to the ganglion cells. The fact that there is spontaneous recovery shows the possibility that some papillamacular bundle may exist. In Leber's disease, retinal ganglion cells may die from the mechanism of apoptosis. Therefore it may be possible to treat this disease by transferring the apoptosis block gene to ganglion cells for protection, and to protect the cells from death by apoptosis.