Leber's Hereditary Optic Neuropathy Patients Research Articles

Mitochondrial DNA analysis in the Turkish Leber's hereditary optic neuropathy population.

To define the prevalence of a panel of mitochondrial DNA (mtDNA) mutations associated with Leber's hereditary optic neuropathy (LHON) in the Turkish LHON population. LHON-associated mtDNA mutations have been found in LHON patients from around the world, but the Turkish LHON population has not been studied. Thirty-two Turkish patients were defined clinically as having LHON on the basis of painless, subacute, bilateral optic neuropathy and the exclusion of other causes of subacute optic neuropathy. mtDNA was extracted from blood of the 32 probands and assayed for a panel of primary and secondary LHON-associated mtDNA mutations by polymerase chain reaction (PCR)-based methods. We studied three well-known LHON-associated primary mutations (at nucleotide positions 11778, 3460 and 14484) and one common secondary mutation (at nucleotide 15257) in all 32 probands. In addition to these mutations, 18 of the 32 probands were tested for the Complex IV, COX III gene, LHON associated 9804 and 9438 mutations and secondary LHON mutations at nucleotide positions 3394, 4160, 4216, 4917, 5244, 7444, 7706, 13708, 13730 and 15812. Among the 32 probands tested for four common LHON mutations, 3 carried the 14484 mutation, 1 carried the 11778 mutation, 1 carried the 3460 mutation and 1 carried the 15257 mutation. Among the 18 LHON patients who tested for additional mutations, 1 proband harboured the 9804 mutation and 4 carried the secondary mutations at nucleotide positions 4216, 4917 and 13708. The results of mtDNA analysis of the Turkish LHON patients appear to be different from those of previous reports.

Clinical, genetic, and biochemical characterization of a Leber hereditary optic neuropathy family containing both the 11778 and 14484 primary mutations

Four mitochondrial DNA (mtDNA) mutations at nps 3460, 11778, 14484, and 14459 account for roughly 90% of cases of Leber hereditary optic neuropathy (LHON) and are designated as "primary" LHON mutations since they act as major predisposition factors for LHON. Although each primary mutation can arise independently on different mtDNA backgrounds during human evolution, they characteristically do not co-occur in LHON patients. We report here a family with the simultaneous occurrence of the 11778A and 14484C mutations. Neuro-ophthalmological examination of the proband, a nine-year-old Caucasian female, revealed the bilateral optic atrophy, central scotomas, and reduced visual acuity typical of LHON. Her mother had normal appearing optic discs and is today visually asymptomatic. Analysis of the proband blood mtDNA revealed that she harbored both the 11778A (heteroplasmic, 94% mutant) and the 14484C (homoplasmic mutant) mutation. This genotype was maintained in proband lymphoblasts and transmitochondrial cybrids. The mother also had both mutations, with the 14484C mutation homoplasmic in all cell types examined. However, only 31% of her blood mtDNAs carried the 11778 mutation, which segregated to essentially 100% wild-type in lymphoblast and cybrid mtDNA. Complex I-linked respiration and specific enzyme activity were consistently lowest in proband lymphoblast and cybrid mitochondria compared to those from the mother, 11778A patients, 14484C patients, or controls, thus demonstrating both a deleterious synergistic interaction between the 11778A and 14484C mutations and the magnitude of 11778A-associated complex I dysfunction. Remarkably, spontaneous vision recovery occurred in the proband, highlighting the complexities encountered when associating mtDNA genotype and complex I function with LHON expression.

Coenzyme Q10 treatment in Leber's hereditary optic neuropathy

The clinical manifestations and molecular genetic analysis of two patients with Leber's hereditary optic neuropathy (LHON) in a Taiwanese family are reported. A point mutation from G to A at the 11778th nucleotide position in the ND4 gene of mitochondrial DNA was found in the two probands.They were characterized by acute visual loss in the second or third decade of life.The clinical course was progressive in nature. Except for optic atrophy, there were no other neurological abnormalities. Intriguingly, a trial with coenzyme Q10 therapy for four months resulted in the rapid improvement of visual acuity in these two patients. To our knowledge, the prognosis of visual function is poor in LHON patients with the G11778A mutation. We conclude that, although spontaneous improvement may exist, coenzyme Q10 treatment may either be effective or speed up spontaneous improvement, particularly in the acute stage in the treatment of LHON patients.

Mitochondrial mutations of Leber's hereditary optic neuropathy: a risk factor for multiple sclerosis.

Multiple sclerosis (MS) and Leber's hereditary optic neuropathy (LHON) have been found to occur in combination. Based on an extensive literature search and on a clinical analysis of 55 LHON pedigrees (103 patients) and 40 patients with definite MS, this study concludes that the association of LHON and MS is more than a coincidence, and that carrying a primary LHON mutation is a risk factor for developing MS. All three primary LHON mutations occurring in the European and North American populations have been found to be associated with an MS-like syndrome. The neurological characteristics of MS associated with LHON are indistinguishable from those of MS in general, but the severe and bilateral visual symptoms and signs justify considering these patients as a clinical subgroup of MS and screening them for LHON mutations. However, screening LHON patients for MS appears to be more rewarding.

Genetic screening of Leber’s hereditary optic neuropathy by PCR with whole blood cell lysate

Leber’s hereditary optic neuropathy (LHON) is accompanied by a mitochondrial DNA (mtDNA) mutation. The G to A substitution at nucleotide position 11,778 (11,202) of mtDNA is most common in Japanese LHON patients. Whole blood cell lysate, not purified DNA, was used as a template of the polymerase chain reaction (PCR) for the analysis of the G11,778 (11,202)A point mutation. The amplified DNA fragment was concentrated and desalted with a centrifuge device, SUPREC TM -02, and digested by SfaNI and MaeIII. This method does not need purified DNA from blood and avoids the phenol/chloroform treatments for PCR products prior to the restriction enzyme digestion. Therefore, it is convenient and safe for the genetic screening of LHON.

Visual prognosis of Leber’s hereditary optic neuropathy with 14484/ND6 mutation in Koreans

The 14484 mutation in the ND6 gene of mitochondrial DNA (mtDNA)is one of the three primary mutations of Leber’s hereditary optic neuropathy (LHON). It shows a better visual prognosis than either the 11778 or the 3460 mutation. In order to determine if there is any difference in visual prognosis according to race,we evaluated 12 Korean LHON patients with this mutation who were negative for eight proposed secondary mutations. Two of the 12 patients had a family history of optic neuropathy. Four of the 12 patients (33%) showed an improvement in visual acuity of up to 20/50 or better in both eyes. Four of the remaining eight patients showed an improvement in visual acuity of up to 20/50 or better in one eye. The visual acuity of the remaining four patients, however, did not improve, even though they were were under 25 years of age and none of them were heavy alcohol drinkers or heavy tobacco users. These findings indicate that Korean patients with the 14484 mutation may have a visual prognosis similar to that of Caucasian or Japanese patients with the same mutation.

Exclusive Homoplasmic 11778 Mutation in Mitochondrial DNA of Chinese Patients With Leber’s Hereditary Optic Neuropathy

Purpose: To investigate the degree of heteroplasmy of the 11778 mtDNA mutation in Chinese patients with Leber’s hereditary optic neuropathy (LHON). Methods: Seventeen Chinese Leber’s pedigrees, including 24 patients, 17 unaffected maternal lineages, 4 internal controls, and 6 unrelated controls, were screened for the 11778 mtDNA mutation. This was carried out by analysis of the restriction fragment length polymorphism, single-strand conformation polymorphism, and DNA sequencing. Results: All patients and unaffected maternal lineages, regardless of their symptoms, had homoplastic 11778 mtDNA mutation, which was revealed by restriction fragment length polymorphism analysis and single-strand conformation polymorphism analysis. Conclusion: Exclusive homoplasmy of the 11778 mtDNA mutation in Chinese LHON patients was found in this study. Homoplasmy of the 11778 mtDNA mutation cannot account for the variation in the clinical phenotype of Chinese Leber’s patients.

Leber’s Hereditary Optic Neuropathy Mitochondrial DNA Mutations at Nucleotides 11778 and 3460 in Multiple Sclerosis

Objectives: Leber’s hereditary optic neuropathy (LHON) can be difficult to distinguish from optic neuritis seen in multiple sclerosis (MS). About half of the LHON patients harbor a mutation at nucleotide (nt) 11778 in the mitochondrial (mt) DNA. In addition, mutations at nt-3460 and nt-14484 have been associated with LHON. An association of LHON and MS has been suspected for decades, and, recently, the LHON nt-11778 and nt-3460 mtDNA mutations have been found in several patients with MS or MS-like disease. We attempted to determine which MS patients should be evaluated further for LHON mutations. Methods: We screened 103 clinically definite MS patients (age range from 18 to 72 years, 27 men and 76 women) for the LHON nt-11778 and nt-3460 mtDNA mutations. Results: Neither mutation was identified in the patients. Conclusions: Our findings confirm previous reports which found that both LHON mutations are rare in unselected MS patients. The reports to date suggest that MS patients with peripapillary teleangiectasia typical of LHON, with relatives harboring LHON or with early severe bilateral optic neuropathy, particularly if female, should be further evaluated for LHON mutations.

Secondary mutations of mitochondrial DNA in Japanese patients with Leber's hereditary optic neuropathy

Purpose: Based on studies on the pathogenesis of Leber's hereditary optic neuropathy (LHON), mitochondrial DNA (mtDNA) mutations have been divided into two types: primary and secondary. Primary mutations at nucleotide positions (nt) 11778, 3460, and 14484 can each cause LHON. Secondary mutations may be simultaneously found in LHON patients with a primary mutation, may occur at higher frequency in LHON patients than in normal controls, and may play an additional role in the pathogenesis of LHON. We examined the frequencies of secondary mutations of mtDNA at nt3394, 7444, 9438, 9804, 13708, and 15257 in 19 Japanese patients with LHON associated with primary mutations and 108 normal controls. Methods: Mutations were determined by restriction enzyme analysis or DNA sequencing using polymerase chain reaction (PCR) products. Results: One patient with an nt11778 mutation also had an nt13708 mutation. Another patient with an nt3460 mutation also had an nt7444 mutation. During DNA sequencing of the PCR fragment harboring nt3394, three novel mutations in the ND1 gene (nt3316, 3496, and 3497 mutations) were found in three patients with an nt11778 mutation. The frequency of these mutations in 108 control subjects was studied further: one (0.9%) had an nt3394 mutation, none (0%) had an nt9804 mutation, one (0.9%) had an nt13708 muation, two (1.9%) had nt3316 mutations, one (0.9%) had an nt3496 mutation, and two (1.9%) had nt3497 mutations. Conclusion: It is unlikely that the frequencies of secondary mutations in Japanese patients with LHON are higher than those in normal Japanese controls. It is possible that the mutations at nt3316, 3496, and 3497 are secondary mutations of LHON.

A Case of Leber's Hereditary Optic Nouropathy Showing 11778 Point Mutation of Mitochondrial DNA

Leber's hereditary optic neuropathy(LHON) is an optic nerve disease that causes blindness and is associated with maternally inherited mitochondrial DNA(mt DNA) mutations. The most common mitochondrial DNA mutation among LHON patients is a point mutation at the nucleotide 11778 in the subunit 4 of complex I. In one 45-year old male LHON patient with bilateral optic neuropathy. we investigated the presence of a point mutation of mitochondrial DNA and identified a single guanine to adenine transition mutation in the mitochondrial DNA at nucleotide point 11778.

Leber hereditary optic neuropathy: Potential opportunities/potential pitfalls for drug therapy of optic nerve degenerative disorders

Leber hereditary optic neuropathy (LHON) is an inherited form of bilateral optic atrophy in which the primary etiologic event is a mutation in the mitochondrial genome. The primary mitochondrial mutation is necessary—but not sufficient—for manifestation of the optic neuropathy, and secondary genetic and/or epigenetic risk factors are also involved. There is broad agreement that mutations at mtDNA nucleotides 3460, 11778, and 14484 are primary LHON mutations and that they account for 95% of the classic LHON cases in Caucasians of northern European descent. It appears that these three primary LHON mutations are associated with respiratory-chain dysfunction, but the derangement may be relatively subtle and/or vary among different tissues. The optic neuropathy involves a loss of central vision due to degeneration of the retinal ganglion cells and optic nerve axons that subserve central vision. The specific pattern of neurodegeneration in LHON may arise from a mitochondrial “chokepoint” in the region of the optic nerve that spans the nerve head and lamina cribosa. It is hypothesized that in the acute phase, a respiratory-chain dysfunction “crisis” leads to axoplasmic stasis and swelling, initially in the chokepoint, thereby blocking ganglion cell function and causing loss of vision. In some LHON patients, this loss of function is reversible in a subset of ganglion cells and a substantial recovery of vision occurs. However, in other patients, a cell death pathway (probably apoptotic) is activated, with subsequent extensive degeneration of the retinal ganglion cell layer and optic nerve with an irreversible loss of vision. The complex etiology of LHON may allow therapeutic intervention at any one of several steps, but there are also potential pitfalls. Drug Dev. Res. 46:34–43, 1999. © 1999 Wiley-Liss, Inc.

Multicenter study on the frequency of three primary mutations of mitochondrial DNA in Japanese pedigrees with Leber’s hereditary optic neuropathy: comparison with American and British counterparts

We retrospectively evaluated the incidence and clinical characteristics of three primary mutations in mitochondrial DNA at nucleotide positions (np) 3460, 11778, and 14484 in 142 Japanese patients (125 families) with Leber’s hereditary optic neuropathy (LHON). Data was collected on LHON patients at four institutions in Japan. Mutations were identified at np 3460 in 5/125 (4%) families, at np 11778 in 114/125 (91%) families, and at np 14484 in 6/125 (5%) families. Thus, Japanese patients with LHON exhibited a high incidence of the 11778 primary mutation. Except for a family history of optic atrophy, the clinical features of Japanese patients with these three mutations were similar to those reported for 114 patients (75 families) in the USA and 112 patients (79 families) in the UK, despite their different mtDNA backgrounds. The final visual outcome was better in the Japanese patients with the 3460 or 14484 mutation than the 11778 mutation. The proportion of Japanese patients with either the 3460 (20%) or the 14484 (33%) mutation and a family history of optic atrophy was lower than that reported in either American or British patients with LHON.

The influence of nuclear background on the biochemical expression of 3460 Leber's hereditary optic neuropathy.

The role of mitochondrial DNA (mtDNA) mutations in the pathogenesis of Leber's hereditary optic neuropathy (LHON) has yet to be characterized. Several clinical features of the disease imply that nuclear genes might also be involved in its expression. We have confirmed the presence of a severe NADH:coenzyme Q1 reductase (complex I) defect in association with the A3460G mtDNA LHON mutation in cultured fibroblasts compared with age-matched controls. This defect was not seen in clonal fibroblasts with 0% mutant mtDNA developed from a heteroplasmic A3460G LHON subject, confirming the association between the A3460G mutation and the complex I defect. Cybrids prepared from the fusion of enucleated fibroblasts homoplasmic for the A3460G mutation with 206 (osteosarcoma) cells lacking mtDNA (p0) also had a severe deficiency of complex I activity. However, in A3460G LHON fusion cybrids containing a different nuclear background, A549 p0 (lung derived), this biochemical defect was not apparent in all the clones studied. These results suggest that the nuclear environment can influence the expression of the biochemical defect in LHON patients with the A3460G mutation.

Leber hereditary optic neuropathy: respiratory chain dysfunction and degeneration of the optic nerve.

Leber hereditary optic neuropathy (LHON) is an inherited form of bilateral optic atrophy in which the primary etiological event is a mutation in the mitochondrial genome. The optic neuropathy involves a loss of central vision due to degeneration of the retinal ganglion cells and optic nerve axons that subserve central vision. The primary mitochondrial mutation is necessary, but not sufficient, for manifestation of the optic neuropathy and secondary genetic and/or epigenetic risk factors are also involved, although they are poorly defined at the present time. There is broad agreement that mutations at nucleotides 3460, 11,778 and 14,484 are primary LHON mutations, but there may also be other rare primary mutations. It appears that the three primary LHON mutations are associated with respiratory chain dysfunction, but the derangement may be relatively subtle. There is also debate on whether there are mitochondrial mutations that have a secondary etiological or pathogenic role in LHON. The specific pattern of neurodegeneration in LHON may arise from a 'chokepoint' in the optic nerve in the region of the nerve head and lamina cribosa and which may be more severe in those LHON family members who become visually affected. It is hypothesized that the respiratory chain dysfunction leads to axoplasmic stasis and swelling, thereby blocking ganglion cell function and causing loss of vision. In some LHON patients, this loss of function is reversible in a substantial number of ganglion cells, but in others, a cell death pathway (probably apoptotic) is activated with subsequent extensive degeneration of the retinal ganglion cell layer and optic nerve.

Spectrum of pathogenic mitochondrial DNA mutations and clinical features in Japanese families with Leber's hereditary optic neuropathy

Purpose. To investigate the incidence and clinical significance of primary or proposed secondary mitochondrial DNA (mtDNA) mutations in Japanese patients with Leber's hereditary optic neuropathy (LHON).Methods. Blood samples from the 80 unrelated Japanese patients with bilateral optic atrophy were screened for primary LHON mutations. Patients found to have a primary LHON mutation were then tested for 9 proposed secondary LHON mutations. We investigated the association between these mutations and clinical characteristics.Results. Primary mtDNA mutations were identified in 68 patients: at np 3460 in 3 (4%) of 68 patients, at np 11778 in 59 patients (87%), and at np 14484 in 6 patients (9%). We identified 5 secondary mtDNA mutations (at np 3394, 4216, 7444, 9438 or 13708) in 10 (15%) of 68 LHON patients and 3 mutations (at np 3394, 4216 or 3708) in 6 (7%) of 90 healthy Japanese individuals. No patient was positive for more than one secondary mutation. The frequency of secondary mutations was similar in the 68 LHON patients and 90 controls. The clinical features of the Japanese patients with any of the 3 primary LHON mutations were similar to those of Caucasian patients, despite different mtDNA backgrounds in these populations. The percentage of patients with familial LHON harboring the 3460 or 14484 mutations was lower in the Japanese population.Conclusions. Japanese patients with LHON exhibited a very high incidence (87%) of the 11778 primary mutation. Most of the proposed secondary LHON mutations were rare in the Japanese population and they, except the 7444 mutation, may not influence the clinical features of LHON. Curr. Eye Res. 17: 403–408, 1998.

Leber hereditary optic neuropathy: Mitochondrial mutations and degeneration of the optic nerve

The predominant manifestation of Leber hereditary optic neuropathy (LHON) is a sudden and usually severe bilateral loss of central vision, most often in the mid-20s, that is due to a degeneration of the ganglion cell layer and optic nerve. LHON is an inherited form of blindness in which a mutation in the mitochondrial genome (mtDNA) is the primary etiological event. More than 95% of the LHON pedigrees in peoples of Northern European descent harbor one of the three mitochondrial mutations at nucleotides 3460, 11,778 and 14,484, although there are other rare primary mutations. In addition, there may be mtDNA mutations that have a secondary etiological role. The penetrance of the optic neuropathy is incomplete in LHON families, and males are affected much more often then females. The incomplete penetrance indicates that secondary etiological factors are necessary for the development of the optic neuropathy, although they are poorly understood at the present time. Several types of studies suggest that optic nerve function in LHON patients is impaired in the presymptomatic phase, probably as a result of a mitochondrial respiratory chain abnormality, although visual acuity is not compromised. In some family members, the presence of secondary etiological factors triggers a wave of optic nerve dysfunction in which vision is lost (the acute phase). Depending upon the particular primary LHON mutation that the patient carries, a variable proportion of the dysfunctional ganglion cells and optic nerve axons die during the atrophic phase, probably through an apoptotic pathway. In 11,778 LHON patients, retinal ganglion cell degeneration occurs almost without exception, and recovery of vision is extremely rare. In contrast, activation of the cell death pathway is less frequent, or less extensive, in 14,484 LHON patients and there is often a substantial recovery of vision.

Genotypes of aldehyde dehydrogenase and alcohol dehydrogenase polymorphisms in patients with Leber's hereditary optic neuropathy.

To define whether alcohol drinking provides a risk for Leber's hereditary optic neuropathy (LHON), the genotypes of low K(m) aldehyde dehydrogenase (ALDH2) and alcohol dehydrogenase type 2 (ADH2), major enzymes involving the alcohol metabolism, were examined in 29 unrelated Japanese patients with LHON associated with mitochondrial DNA 11778 mutation, 24 unrelated asymptomatic carriers with the mutation and 57 normal controls without the mutation. PCR-restriction detection revealed three genotypes of ALDH2 and ADH2. The allele frequencies of either enzyme in LHON patients, asymptomatic carriers, or both, did not differ from those in normal controls. There is no association between LHON and genotypes of alcohol-metabolizing enzymes. However, six of the LHON patients had frequent alcohol consumption, while none of the asymptomatic carriers claimed frequent drinking habit. Thus, we could not make a denial of drinking effects on optic nerve damage in LHON.

Leber hereditary optic neuropathy: how do mitochondrial DNA mutations cause degeneration of the optic nerve?

Leber hereditary optic neuropathy (LHON) is an inherited form of bilateral optic atrophy in which the primary etiological event is a mutation in the mitochondrial genome. The optic neuropathy involves a loss of central vision due to degeneration of the retinal ganglion cells and optic nerve axons that subserve central vision. The primary mitochondrial mutation is necessary--but not sufficient--for development of the optic neuropathy, and secondary genetic and/or epigenetic risk factors must also be present although they are poorly defined at the present time. There is broad agreement that mutations at nucleotides 3460, 11778, and 14484 are primary LHON mutations, but there may also be other rare primary mutations. It appears that the three primary LHON mutations are associated with respiratory chain dysfunction, but the derangements may be relatively subtle. There is also debate on whether there are mitochondrial mutations that have a secondary etiological or pathogenic role in LHON. The specific pattern of the optic neuropathy may arise from a "chokepoint" in the optic nerve in the region of the nerve head and lamina cribosa, and which may be more severe in those LHON family members who become visually affected. It is hypothesized that the respiratory chain dysfunction leads to axoplasmic stasis and swelling, thereby blocking ganglion cell function and causing loss of vision. In some LHON patients, this loss of function is reversible in a substantial number of ganglion cells, but in others, a cell death pathway (probably apoptotic) is activated with subsequent extensive degeneration of the retinal ganglion cell layer and optic nerve.

Clinical course of a cohort in the Cuban epidemic optic and peripheral neuropathy.

Nearly 51,000 Cubans were afflicted during an outbreak of an optic neuropathy (ON) and peripheral neuropathy (PN) between 1991 and 1993. We re-examined 14 of 20 affected individuals 16 months after an initial evaluation. The optic features were painless symmetric vision loss with poor visual acuity, color vision loss, central or cecocentral scotoma, optic disc pallor, and nerve fiber layer drop-out. The neurologic symptoms included stocking-glove sensory changes, hearing loss, leg cramps, sensory ataxia, hyperactive or absent reflexes, and complaints of memory loss. Two of 11 ON probands tested harbored Leber's hereditary optic neuropathy (LHON)-associated mitochondrial DNA mutations. All patients had received multivitamin therapy. We performed comparisons using the paired two-tailed t test. On re-examination, 12 of 14 patients demonstrated improvement. One patient remained unchanged. One woman with the nt-3460 mtDNA mutation showed a decline in vision. In patients not harboring mtDNA mutations, overall visual acuity, color vision, and peripheral neuropathy manifestations improved significantly (p < 0.001 for each manifestation). Most of the patients with Cuban ON and PN improved on multivitamin therapy. The significance of the mtDNA mutations is unclear. In the 2 LHON patients, manifestation of the disease may have been precipitated by nutritional deficiency. Patients with poor recovery or further deterioration should be evaluated for other factors, including poor vitamin therapy compliance and alternative diagnoses.

Screening of mtDNA mutations in Italian LHON pedigrees.

Leber's hereditary optic neuropathy (LHON) is characterized by acute or subacute bilateral loss of central vision and by maternal inheritance. Numerous primary or secondary mtDNA mutations have been described in association with LHON. The mutation at nucleotide position 11778 is the most frequent among primary mtDNA mutations, accounting for 35% to 90% of LHON patients depending on ethnic group (Brown and Wallace 1994). Nevertheless, the penetrance of LHON is variable and the aetiology of the disease remains not completely clear. To identify possible synergistic interactions between mtDNA mutations associated with LHON and their role in the variable penetrance of the disease within families, 4 affected and 19 unaffected members along the maternal lineage of three Italian LHON pedigrees have been analysed for the presence of 12 primary (at nt 11778, 3460, 4160, 14484, 15257) and secondary (nt 4136, 4216, 4917, 5244, 7444, 13708, 15812) mtDNA mutations.