Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy is a maternally inherited disease resulting in optic nerve degeneration and cardiac dysrhythmia. A mitochondrial DNA replacement mutation was identified that correlated with this disease in multiple families. This mutation converted a highly conserved arginine to a histidine at codon 340 in the NADH dehydrogenase subunit 4 gene and eliminated an Sfa NI site, thus providing a simple diagnostic test. This finding demonstrated that a nucleotide change in a mitochondrial DNA energy production gene can result in a neurological disease.

Virus antibody levels in serum and cerebrospinal fluid specimens from patients with optic neuritis.

Virus antibody levels in serum specimens from 77 patients with optic neuritis (ON) were compared with those in healthy controls which had been matched with regard to sex, age and place of residence. A group of 58 patients with various neurological diseases other than multiple sclerosis (MS) or infectious diseases of the central nervous system (CNS) served as a second control group. The ON patients had significantly higher measles antibody titers in serum than the two control groups in both measles HI and HLI tests. Tests of cerebrospinal fluid (CSF) specimens revealed similar differences between ON patients and controls. Tests for antibodies to other viruses showed no statistically significant differences between ON patients and controls. There were several ON patients with normal serum/CSF albumin ratios but low serum/CSF IgG and measles antibody ratios. An increase in measles antibody CSF titers was observed during the study time in two ON patients. The results support the hypothesis that local production of measles antibodies takes place in the CNS of some patients with ON as has been earlier suggested to occur in patients with MS.

mtDNA haplotype analysis in Finnish families with leber hereditary optic neuroretinopathy.

The mitochondrial DNA (mtDNA) sequence variation of 24 Finnish Leber hereditary optic neuroretinopathy (LHON) probands was characterized by sequencing and restriction endonuclease analyses. All LHON-associated substitutions and Caucasoid haplogroup-specific mutations were screened in the families. Analysis of the mtDNAs revealed that the Finnish LHON families have two unique features: an absence of the ND6/14484 mutation and a high number of families (10/24) without the primary mutations ND1/3460 and ND4/11778. Furthermore, the LHON families showed considerable mtDNA heterogeneity: among 24 families 22 haplotypes were detected. Overall, the haplogrouping of LHON families was similar to other European populations. However, the frequency of ND4/11778-positive families in haplogroup J was high, which may indicate that background mutations in this haplogroup together with the ND4/11778 primary mutation promote the penetrance of LHON.

Electron transfer properties of NADH:ubiquinone reductase in the ND1/3460 and the ND4/11778 mutations of the Leber hereditary optic neuroretinopathy (LHON).

We report the electron transfer properties of the NADH:ubiquinone oxidoreductase complex of the respiratory chain (Complex I) in mitochondria of cells derived from LHON patients with two different mutations in mitochondrial DNA (mtDNA). The mutations occur in the mtDNA genes coding for the ND1 and ND4 subunits of Complex I. The ND1/3460 mutation exhibits 80% reduction in rotenone-sensitive and ubiquinone-dependent electron transfer activity, whereas the proximal NADH dehydrogenase activity of the Complex is unaffected. This is in accordance with the proposal that the ND1 subunit interacts with rotenone and ubiquinone. In contrast, the ND4/11778 mutation had no effect on electron transfer activity of the Complex in inner mitochondrial membrane preparations; also Km for NADH and NADH dehydrogenase activity were unaffected. However, in isolated mitochondria with the ND4 mutation, the rate of oxidation of NAD-linked substrates, but not of succinate, was significantly decreased. This suggests that the ND4 subunit might be involved in specific aggregation of NADH-dependent dehydrogenases and Complex I, which may result in fast ('solid state') electron transfer from the former to the latter.

Mutations in subunit 6 of the F1F0-ATP synthase cause two entirely different diseases.

A lowered efficiency of oxidative phosphorylation was recently found in a Leber hereditary optic neuropathy (LHON) proband carrying a mutation in the mtDNA gene for subunit 6 of the membrane-bound F0 segment of the F1F0-ATP synthase [9]. This phenotype was transferred to cytoplasmic hybrid cells together with the mutation, proving its functional significance. Increasing the respiratory rate in the mitochondria from this mutant raised the ATP/2e- ratio back to normal values. A different mutation in the same mtDNA gene has been found in patients with the NARP syndrome [10]. Although the ATP/2e- ratio is also decreased in this mutant, in this case an increase in the respiratory rate could not compensate for it. Whilst both mutations affect subunit 6 of the proton-translocating F0 segment, the LHON mutation induces a proton leak whereas the NARP mutation blocks proton translocation. Hence, the latter will have much more destructive metabolic consequences in agreement with the large clinical differences between the two diseases.

Vigabatrin, a gabaergic antiepileptic drug, causes concentric visual field defects.

OBJECTIVE: To determine whether there is a causal link between vigabatrin treatment and concentric visual field defects and to evaluate the prevalence of these visual field constrictions. BACKGROUND: While the GABAergic antiepileptic drug (AED) vigabatrin was being clinically developed, only rare cases (less than 1:1000) of symptomatic visual field constriction and retinal disorders were reported. During 1997 to 1998, concentric visual field constrictions were described in case reports of mostly drug-resistant epilepsy patients receiving vigabatrin concurrently with other AEDs. METHODS: Ophthalmologic tests including Goldmann perimetry were performed on 32 adult patients on long-term successful vigabatrin monotherapy (treatment duration 29 to 119 months) and on 18 patients on carbamazepine monotherapy (treatment duration 32 to 108 months). Eighteen healthy adults served as controls. RESULTS: None of the patients complained about vision problems when asked to participate into the study. Thirteen out of the 32 (40%) epilepsy patients treated with vigabatrin monotherapy had concentrically constricted visual fields (9% severely, 31% mildly constricted), whereas none of the carbamazepine monotherapy patients or normal controls presented with a visual field defect (chi-square test, p = 0.0001). The extents of the visual fields were significantly constricted in vigabatrin group as compared with the visual fields of the patients in carbamazepine group or healthy controls (analysis of variance, Scheffe F-test, significant at 99%). CONCLUSIONS: The use of vigabatrin seems to increase the risk of a unique and specific pattern of bilateral, mainly asymptomatic visual field constriction. This risk should be considered when using vigabatrin. Visual field testing should also be performed before treatment and during routine follow-up for patients on vigabatrin.

Interferon-alpha and interferon-gamma production capacity of idiopathic isolated optic neuritis patients.

Interferon-alpha and interferon-gamma production by idiopathic isolated optic neuritis (ON) patients was studied. The production capacity was compared with that in two control groups: patients with iritis and healthy control subjects. A sensitive and reliable interferon bioassay was applied for interferon level measurements. Statistically significant differences were not found between patients and control groups in either interferon-alpha production or interferon-gamma production.

Ophthalmoscopic findings in Leber's hereditary optic neuropathy. II. The fundus findings in the affected family members.

Eighteen men and four women had Leber's disease. Fundus photographs obtained in three cases showed the following: Peripapillary microangiopathy, present from the beginning, slowly increased during the presymptomatic stage. At the end of the presymptomatic stage, the nerve fiber layer became swollen. During the acute stage, retinal vessels on and around the disc were dilated, tortuous, and telangiectatic. Nerve fiber layer hemorrhages occurred in two eyes. As atrophy appeared first in the papillomacular bundle and then in the remaining retina, the vascular bed involuted, leaving a capillary-poor retina with attenuated arterioles and a pale optic disc. The final degree of atrophy varied. Fifteen of the affected persons were blind with severe optic atrophy, but in seven optic atrophy was only partial, causing less visual handicap. Our results suggest that Leber's disease is primarily an intraocular, not a retrobulbar, optic neuropathy. It should be redesignated as Leber's hereditary neuroretinopathy.

Ophthalmoscopic findings in Leber's hereditary optic neuropathy. I. Fundus findings in asymptomatic family members.

A neuro-ophthalmological examination was performed on 47 asymptomatic offspring in the female line and 13 offspring in the male line in families with Leber's hereditary optic neuropathy. Fourteen (61%) of the 23 asymptomatic males and nine (38%) of the 24 asymptomatic females in the female line had telangiectatic microangiopathy of the peripapillary arterioles and capillaries. Increased tortuosity of capillaries, medium-sized arterioles, and venules were also seen in the fundi of several asymptomatic family members. The 13 offsprings in the male line did not have microangiopathy. Nerve fiber abnormalities were not seen in asymptomatic persons. The photographically verified findings are described, classified, and discussed. It is suspected that Leber's disease is primarily a microvascular disorder. The vascular abnormalities detected in the asymptomatic family members probably indicate increased risk of Leber's disease developing. During the prospective follow-up of three years, three asymptomatic boys with microangiopathy have experienced Leber's disease.

Fundus findings in Leber's hereditary optic neuroretinopathy. III. Fluorescein angiographic studies.

Fluorescein angiography was performed in nine members of families with Leber's disease. Serial studies were obtained in four men observed from asymptomatic to atrophic stages. Peripapillary microangiopathy was observed in six of nine asymptomatic eyes. Arteriovenous shunting occurred in the telangiectatic vascular bed. These changes remained stable in some eyes and progressed in others. In the acute stage, arteries and telangiectatic vessels were maximally dilated and flow was rapid. Angiography showed florid shunting in lower and upper vascular arcades and reduced filling of papillomacular capillaries. Vessels of the shunting vascular bed gradually narrowed irregularly. In the atrophic stage, disc vascularity diminished and arteriovenous circulation time increased markedly. Arterioles narrowed and peripapillary microangiopathy disappeared. These findings support our contention that Leber's disease is a hereditary vascular neuroretinopathy.

Leber's hereditary optic neuroretinopathy, a maternally inherited disease. A genealogic study in four pedigrees.

Previous genealogic studies of Leber's disease have focused on affected individuals with optic atrophy. Despite its diagnostic importance, peripapillary microangiopathy has not been widely recognized. In our study, the genealogic evaluation includes asymptomatic subjects with microangiopathy. Another new aspect is a genealogic analysis of the cardiovascular abnormalities found in members of families with Leber's disease. Our results suggest that every daughter and son of a female carrier inherits the trait, thus satisfying the criteria for a maternally inherited disease. Microangiopathy, without optic nerve dysfunction, probably represents the mildest stage of the disease. The high frequency of electrocardiographic abnormalities in the off-spring of the female carriers suggests an important link with Leber's disease.

The early phase in Leber hereditary optic atrophy.

Clinical, ophthalmoscopic, perimetric, and color vision tests and visual evoked responses were recorded in symptomatic and asymptomatic eyes in five members of a family with Leber hereditary optic atrophy. The presymptomatic eyes showed abnormalities in the retinal nerve fiber layer. Optic nerve dysfunction was found before central vision failed. The appearance of degenerating retinal nerve fibers, particularly in the papillomacular bundle, was documented photographically in the weeks after the onset of visual symptoms. Treatment with prednisone and hydroxocobalamin did not reverse or halt serious impairment of vision.