Disease relevance of LHON

• The Tas2 and Vic2 Australian families are affected with a variant of Leber hereditary optic neuropathy (LHON) [1].
• The risk of developing the optic neuropathy shows strict maternal inheritance, and the ophthalmological changes in affected family members are characteristic of LHON [1].
• Mean complex I polymorphic frequencies in cytopathic (CPEO, MERRF, MELAS and LHON collectively) patients and in LHON patients differed significantly from controls (P < or = 0.05, t) [2].
• These results imply that biochemical studies on mitochondrial diseases should always be integrated with mtDNA analysis of the same tissue investigated and also suggest that the mtDNA analysis on the leukocyte fraction, as usually performed in LHON, does not necessarily reflect the mutant genotype level of other tissues [3].
• Taken together with the sex bias in symptom manifestation, the results indirectly suggest that an extramitochondrial factor, such as an X-chromosome-linked gene, possibly contributes to the development of optic atrophy in the Japanese LHON pedigrees tested [4].

Psychiatry related information on LHON

• However, six of the LHON patients had frequent alcohol consumption, while none of the asymptomatic carriers claimed frequent drinking habit [5].

High impact information on LHON

• Phenotypic variations and loss of retinal ganglion cells, as found in Leber hereditary optic neuropathy (LHON), have suggested possible mitochondrial impairment [6].
• Pre-excitation syndrome is common in families with Leber's hereditary optic neuropathy (LHON) [7].
• Mitochondrial DNA causal for LHON may contribute to pre-excitation syndrome [7].
• Overall, 5 of 51 LHON patients and 9 of 112 symptom-free maternal relatives had Wolff-Parkinson-White syndrome (9%) [7].
• Only seven pairs and three triplets of identical haplotypes were observed, attesting that the large majority of the LHON mutations were due to independent mutational events [8].

Chemical compound and disease context of LHON

• Leber's hereditary optic neuropathy (LHON) pathogenic mutations induce mitochondrial-dependent apoptotic death in transmitochondrial cells incubated with galactose medium [9].
• Changes in mitochondrial complex I activity and coenzyme Q binding site in Leber's hereditary optic neuropathy (LHON) [10].
• Wolfram (DIDMOAD) syndrome and Leber hereditary optic neuropathy (LHON) are associated with distinct mitochondrial DNA haplotypes [11].
• Given the clinical similarities of subnormal vitamin B12, LHON, and nutritional/tobacco amblyopia, deficiency of adenosine triphosphate might be a unifying etiology for several types of optic neuropathy [12].
• Partial mitochondrial complex I inhibition induces oxidative damage and perturbs glutamate transport in primary retinal cultures. Relevance to Leber Hereditary Optic Neuropathy (LHON) [13].

Biological context of LHON

• One possibility is that there is a primary LHON mutation within the mitochondrial genome but that it is at a site that was not included in the sequencing analyses [1].
• Biochemical and molecular genetic evidence is presented that in six independent pedigrees the development of Leber hereditary optic neuropathy (LHON) is due to the same primary mutation in the mitochondrial ND1 gene [14].
• Four different but related mitochondrial genotypes were identified in seven of the Dutch pedigrees with LHON, including six of those described by van Senus [15].
• These studies provide the first direct evidence that not all LHON lineages--even those associated with a biochemical defect in mitochondrial respiratory chain Complex I--carry a mutation in the ND4 gene [16].
• This is only the second instance in which both a biochemical abnormality and a mitochondrial gene mutation have been identified in an LHON pedigree [14].

Anatomical context of LHON

• Leber's hereditary optic neuropathy (LHON) is a common cause of bilateral optic nerve disease [17].
• In conclusion, LHON cybrid cells forced by the reduced rate of glycolytic flux to utilize oxidative metabolism are sensitized to an apoptotic death through a mechanism involving mitochondria [9].
• Moreover, we also document the mitochondrial involvement in the activation of the apoptotic cascade, as shown by the increased release of cytochrome c into the cytosol in LHON cybrid cells as compared with controls [9].
• No previous study has investigated the effects of LHON primary or primary plus secondary mutations on the respiratory competence of cell lines [18].
• Total lymphocyte DNA was analyzed for all common LHON mutations [19].

Associations of LHON with chemical compounds

• Similarly, the rate of muscle phosphocreatine resynthesis after exercise, a sensitive index of the rate of mitochondrial ATP production, was reduced by the same extent in both groups of LHON subjects [20].
• In conclusion, the caspase-independent death of LHON cybrids incubated in galactose medium is triggered by rapid ATP depletion and mediated by AIF and EndoG [21].
• The glutamate uptake maximal velocity was significantly reduced in all LHON cybrids compared with control cybrids [22].
• The new sequence variant of A9016G in the ATPase 6 gene changed highly conserved amino acid of isoleucine to valine, has not been found in the rest of 13 LHON patients and controls [23].
• We report that this amino acid substitution alters the affinity of complex I for the ubiquinone substrate and induces resistance towards its potent inhibitor rotenone in mitochondria of LHON patients [24].

Physical interactions of LHON

• The same gene was also reported to carry another mutation, at position 14459, associated with the LHON/dystonia phenotype that induces a reduction of complex I-specific activity and increases the sensitivity to the product decylubiquinol [25].
• METHODS: Assays for the activities of NADH-cytochrome c reductase (complex I+complex III), succinate-cytochrome c reductase (complex II+complex III), and cytochrome c oxidase (complex IV) on blood cell mitochondria of seven LHON patients and 15 normal controls [26].

Regulatory relationships of LHON

• 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 [27].
• Secondary LHON mutations were identified more frequently in control subjects than in the children with MS [28].

Other interactions of LHON

• We conclude that the 3733G-->A transition is a novel cause of LHON and, after those at positions 3460 and 4171, is the third ND1 mutation to be identified in multiple unrelated families [29].
• In contrast, in galactose, GSSG concentrations increased significantly in all cells, indicating severe oxidative stress, whereas GR and MnSOD activities further decreased in all LHON cybrids [30].
• The sequence analysis of the ND81 gene was extended to a further 11, unrelated LHON pedigrees that had been screened previously and found not to carry the mitochondrial ND4/R340H mutation [14].
• We report the effect on complex I function of the 14484 Leber's hereditary optic neuropathy (LHON) mutation affecting the ND6 subunit gene [25].
• Similarly, complex IV mutation COI/7444 was screened in Finnish LHON families, and it was found in one family carrying the ND1/3460 mutation [31].

Analytical, diagnostic and therapeutic context of LHON

• Mae III digested the 515-bp PCR product of mtDNAs from LHON patients who had lost the Sfa NI site [32].
• We have applied time-resolved fluorometry (TRF) to construct a DNA hybridization assay for the diagnosis of Leber hereditary optic neuroretinopathy (LHON) [33].
• We compared mtDNA variants identified in DIDMOAD patients with those found in LHON patients as well as in a control group consisting of 67 healthy German blood donors [11].
• The frequency of additional neurological features in LHON and the role of a number of past medical and environmental factors in the development of the disease were investigated using a case-control study [34].
• Twenty-eight patients from 25 maternal lineages with Leber's hereditary optic neuropathy (LHON) were investigated by restriction enzyme analysis for the presence or absence of the point mutation described by Wallace et al [35].

References