1/19. 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.- - - - - - - - - - ranking = 1keywords = family (Clic here for more details about this article) |
2/19. genetic counseling in Leber hereditary optic neuropathy (LHON).PURPOSE: To demonstrate the importance of mitochondrial dna (mtDNA) analysis in the diagnosis of Leber hereditary optic neuropathy (LHON) and illustrate the difficulties in genetic counseling of the disease. PARTICIPANTS AND methods: Ophthalmological and molecular genetic study of one affected and three unaffected members from a family with heteroplasmic ND1/3460 mtDNA mutation associated with LHON. RESULTS: The proband had variable amounts of mutant mtDNA in all his tissues studied, ranging from 58% in blood to 92% in subcutis. The mother had an extremely low amount of mutant mtDNA in her tissues, except for hair roots, which contained only normal mtDNA. No mutant mtDNA could be detected in the proband's unaffected sister and maternal aunt. CONCLUSIONS: Despite her minimal mutation load, the mother of the proband has still transmitted a considerable amount of mutant mtDNA to her son, who is severely affected. Although proband's unaffected sister and maternal aunt had no mutant mtDNA, a theoretical risk that they may transmit the disease to their offspring cannot be excluded.- - - - - - - - - - ranking = 0.20289964134668keywords = family, member (Clic here for more details about this article) |
3/19. phosphorus MR spectroscopy shows a tissue specific in vivo distribution of biochemical expression of the G3460A mutation in Leber's hereditary optic neuropathy.occipital lobe and calf muscle energy metabolism were studied in vivo by magnetic resonance spectroscopy (31P-MRS) in four members of a family harbouring the mitochondrial dna G3460A mutation causing Leber's hereditary optic neuropathy (LHON). Three siblings carried 100% mutated mitochondrial dna (homoplasmy), while their mother had coexistence of mutated and wild-type mitochondrial dna (heteroplasmy). Indices of brain energy metabolism on 31P-MRS were abnormal in all subjects examined, but the muscle oxidative phosphorylation rate was normal. These findings indicate a tissue specific distribution of the biochemical expression of the G3460A LHON mutation and suggest that extramitochondrial factors, such as nuclear genes, may influence expression of this mutation in vivo.- - - - - - - - - - ranking = 0.20289964134668keywords = family, member (Clic here for more details about this article) |
4/19. Novel de novo mutation in CRX gene in a Japanese patient with leber congenital amaurosis.PURPOSE: To report a novel de novo mutation in the cone-rod homeobox (CRX) gene in a Japanese patient with leber congenital amaurosis (LCA). methods: The CRX gene was analyzed by direct genomic sequencing in a patient with LCA and in his healthy parents. A complete ophthalmologic examination was performed on the family. RESULTS: A heterozygotic deletion of G at nucleotid 520 in CRX, predicting a frameshift in codon 174 and a premature termination of translation [Ala174(1-bp del)], was identified in the proband. The mutation was not present in his unaffected parents. CONCLUSION: A novel de novo mutation in CRX was found in a Japanese patient with LCA.- - - - - - - - - - ranking = 0.2keywords = family (Clic here for more details about this article) |
5/19. Confirmation of the 14568 mutation in the mitochondrial ND6 gene as causative in Leber's hereditary optic neuropathy.Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder characterized by a rapid bilateral loss of central vision. The majority of patients have one of three mutations in the mitochondrial dna. In order to identify the genetic cause of the disease in a family with two affected individuals without any of the three primary LHON mutations, we have sequenced the complete mitochondrial genome. sequence analysis revealed a point mutation at position 14568 in the mitochondrial ND6 gene that changes a conserved methionine residue to isoleucine. This mutation has been previously suggested to be of pathogenic significance and has not been detected in any controls. This case confirms the pathogenicity of this mutation. It is the seventh mutation in the ND6 gene leading to LHON. All seven identified mutations in the ND6 gene lie within the evolutionarily most conserved region of the ND6 gene in a hydrophobic pocket making it a hot spot for the disease. This clustering of mutations may help to understand the disease mechanism of LHON.- - - - - - - - - - ranking = 0.2keywords = family (Clic here for more details about this article) |
6/19. lightning strikes twice: Leber hereditary optic neuropathy families with two pathogenic mtDNA mutations.OBJECTIVE: To report the clinical and mitochondrial genetic analyses of two families, each of which carries both the 11778 and 14484 Leber hereditary optic neuropathy (LHON) mutations in mitochondrial dna. methods: In addition to detailed clinical histories, the complete sequence of the mitochondrial dna (mtDNA) from each family was determined. RESULTS: A small Australian LHON family (Vic20) and a family from the united states carry the 11778 and 14484 LHON mutations. In addition to the optic neuropathy, one branch of the baltimore LHON pedigree had a high incidence of a fatal infantile encephalopathy. In both families, the 14484 LHON mutation was homoplasmic, whereas the 11778 LHON mutation was heteroplasmic. CONCLUSIONS: There are no additional mtDNA sequence changes that explain the encephalopathy in the baltimore LHON family, and a nuclear gene involvement is an alternative explanation that is supported by the available data. The ophthalmological characteristics and penetrance in the 11778 and 14484 "two-mutation" LHON families are not markedly more severe than those of classic LHON families who carry a single mtDNA mutation.- - - - - - - - - - ranking = 0.8keywords = family (Clic here for more details about this article) |
7/19. Ladies with Leber's hereditary optic neuropathy: an atypical disease.PURPOSE: Leber's Hereditary Optic Neuropathy (LHON) is considered to be a disease predominantly affecting young males. The risk of women becoming symptomatic if they are carriers of a primary mutation is 1/5 of that in males. The disease however appears to behave differently in women in some instances. We describe three cases of ladies with LHON and discuss the importance of making the diagnosis. case reports: A 28-year-old female presented with blurring of vision in her left eye with bilateral small hyperemic discs and telangiectatic vessels adjacent to them. dna analysis confirmed the 11778 mutation and the second eye remains unaffected 10 years later. The second case was 49 years old and presented with bilateral visual loss developing over 3 months. She had no family history of visual loss but had a past history of Wolf Parkinson White syndrome and 3460 mutation was confirmed. The last case was diagnosed with multiple sclerosis at age 24 and went on to develop visual loss with poor recovery. dna analysis demonstrated the 11778 mutation and confirmed LHON. CONCLUSIONS: All three cases, although not unique, posed considerable diagnostic difficulties over a long period of time. The authors have highlighted important associations of the disease and stress the importance of making the diagnosis in women. They are at increased risk of having affected children, unlike the affected males, especially if they are affected themselves and may wish to seek further genetic advice.- - - - - - - - - - ranking = 0.2keywords = family (Clic here for more details about this article) |
8/19. A very large Brazilian pedigree with 11778 Leber's hereditary optic neuropathy.PURPOSE: We conducted extensive epidemiological, neuro-ophthalmological, psychophysical, and blood examinations on a newly discovered, very large pedigree with molecular analysis showing mtDNA mutation for Leber's hereditary optic neuropathy (LHON). methods: Four patients representing four index cases from a remote area of brazil were sent to Sao Paulo, where complete ophthalmological examinations strongly suggested LHON. Molecular analysis of their blood demonstrated that they were LHON, homoplasmic 11778, J-haplogroup. They had an extensive family that all lived in one rural area in brazil. To investigate this family, we drew on a number of international experts to form a team that traveled to brazil. This field team also included several members of the Federal University of Sao Paulo, and together we evaluated 273 of the 295 family members that were still alive. We conducted epidemiological interviews emphasizing possible environmental risk factors, comprehensive neuro-ophthalmological examinations, psychophysical tests, Humphrey visual field studies, fundus photography, and blood testing for both mitochondrial genetic analysis and nuclear gene linkage analysis. RESULTS: The person representing the first-generation case immigrated from Verona, italy, to Colatina. Subsequent generations demonstrated penetrance rates of 71%, 60%, 34%, 15%, and 9%. The percentages of males were 60%, 50%, 64%, 100%, and 100%. Age at onset varied from 10 to 64 years, and current visual acuities varied from LP to 20/400. CONCLUSIONS: Almost 95% of a nearly 300-member pedigree with LHON 11778 were comprehensively studied. Analysis of environmental risk factors and a nuclear modifying factor from this group may help address the perplexing mystery of LHON: Why do only some of the genetically affected individuals manifest the disease? This fully described database may also provide an excellent opportunity for future clinical trials of any purported neuroprotective agent.- - - - - - - - - - ranking = 0.60869892404005keywords = family, member (Clic here for more details about this article) |
9/19. Leber's hereditary optic neuropathy triggered by antiretroviral therapy for human immunodeficiency virus.PURPOSE: To describe the clinical features of two cases of Leber's hereditary optic neuropathy (LHON) precipitated by antiretroviral treatment for human immunodeficiency virus (hiv) infection. methods: Two cases of LHON (from an expected four new cases a year throughout australia) were identified in men on treatment for hiv infection. RESULTS: Two hiv-infected men were receiving combination antiretroviral therapy that included nucleoside analogues. Both patients carried the 14 484 mitochondrial dna mutation and were distantly related (seventh cousins). Although both men presented with sequential visual loss typical of LHON and one had a known close relative affected by LHON, the correct diagnosis was delayed in both cases. The final visual outcome was profoundly reduced in both instances and cessation of antiretroviral therapy did not result in recovery of vision in one patient. CONCLUSION: patients with a family history of LHON who require antiretroviral treatment should be warned of the high risk of severe visual loss. The underlying mechanism of antiretroviral side effects may help characterize the other trigger factors for LHON.- - - - - - - - - - ranking = 0.2keywords = family (Clic here for more details about this article) |
10/19. Extensive investigation of a large Brazilian pedigree of 11778/haplogroup J Leber hereditary optic neuropathy.PURPOSE: To conduct systematic epidemiologic, neuro-ophthalmologic, psychophysical, and mitochondrial dna (mtDNA) genetic examinations on a newly identified pedigree with Leber hereditary optic neuropathy (LHON). DESIGN: Observational population cohort study. methods: A prospective investigation of an entire Brazilian LHON family. SETTING: A field investigation by an international team conducted in a remote part of brazil. STUDY population: We evaluated 265 (both eyes) of the 328 living family members of this LHON pedigree. Only members of this pedigree were studied. Those entering the pedigree as spouses were used as controls. observation PROCEDURES: We conducted epidemiologic interviews emphasizing possible environmental risk factors, comprehensive neuro-ophthalmologic examinations, psychophysical tests, Humphrey visual field studies, fundus photography, and blood testing for mitochondrial genetic analysis. RESULTS: We reconstructed a seven-generation maternal lineage descended from a common ancestor dating to the 1870s. All maternally related family members were invariably homoplasmic 11778 with a haplogroup J mtDNA, 33 being affected, of which 22 are still living. With each subsequent generation, there was a progressive decrease of penetrance, and only males were affected in the last two generations. A significant exposure (greater than 95% confidence intervals) to a variety of environmental risk factors characterized the affected individuals, with smoking as the most common (P <.01). Both affected and carriers (95% confidence intervals) presented with a significantly lower incidence of hypertension and high cholesterol compared with the control group (P <.05). CONCLUSIONS: Almost 95% of a 328-living-member pedigree with LHON 11778/J haplogroup was comprehensively studied. Our initial results indicate the strong influence of environmental risk factors. The remarkably reduced incidence of cardiovascular risk in the maternal lineage is discussed. Further genetic analysis may reveal a role for the nuclear genome.- - - - - - - - - - ranking = 0.61159856538673keywords = family, member (Clic here for more details about this article) |
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