ライフサイエンスコーパス: LHON

1 LHON has no treatment, so identifying environmental trig

2 LHON leads to gradual, painless, and permanent vision lo

3 LHON optic nerves showed an orderly loss of axons, start

4 LHON preferentially involves small axons in the temporal

5 LHON tissues were further evaluated by determining regio

6 LHON-linked ND6 14484T > C (p.M64V) mutation affected st

7 ffected and 206 unaffected carriers from 125 LHON pedigrees known to harbour one of the three primary

8 imate that this lineage--including the 14484 LHON mutation--arose 900-1,800 years ago.

9 a haplogroup J mtDNA that carried the 14484 LHON mutation.

10 By studying 3,613 subjects from 159 LHON-affected pedigrees, we show that the risk of visual

11 tions in OPA1 we also screened a panel of 28 LHON patients who tested negatively for the three major

12 arry either the m.14484T>C or the m.11778G>A LHON variant.

13 enetically confirmed diagnosis of m.11778G>A LHON were eligible for this trial.

14 n exome sequencing approach, we identified a LHON susceptibility allele (c.572G>T, p.191Gly>Val) in Y

15 n these findings, asymptomatic carriers of a LHON mtDNA mutation should be strongly advised not to sm

16 dy, we investigated the pathophysiology of a LHON susceptibility allele (m.3394T>C, p.30Y>H) in the M

17 DNA sequences conservatively indicate that a LHON mutation has arisen at least 42 times in the Dutch

18 eported rates of vision loss in males with a LHON mutation are not supported by our work and other ep

19 erall risk of vision loss among those with a LHON mutation was lower than reported previously-17.5% f

20 mtDNA developed from a heteroplasmic A3460G LHON subject, confirming the association between the A34

21 However, in A3460G LHON fusion cybrids containing a different nuclear backg

22 Counseling about LHON should be offered to all maternal bloodline relativ

23 es were significantly increased in the acute LHON stage.

24 hronic patients compared to those with acute LHON (22 mum vs. 28 mum, p = 0.04).

25 At baseline, in all LHON eyes for each PERG and VEP parameter (amplitude and

26 It showed that women carrying an LHON mutation are at higher risk of losing vision than i

27 ikely to be pathogenic, that it can cause an LHON/MELAS overlap syndrome, and that it may be a more f

28 Control and LHON tissues were evaluated by measuring axonal dimensio

29 -zero-dependent, cybridization-dependent and LHON-dependent categories in these cells.

30 n any LHON patients, indicating that DOA and LHON are genetically distinct.

31 ry aim was to define MRI features of LMS and LHON, and to assess the proportions of individuals displ

32 No mutations were identified in any LHON patients, indicating that DOA and LHON are genetica

33 steosarcoma cybrids and lymphoblasts bearing LHON mutations.

34 Both the 11778G-->A and 14484T-->C LHON mutations are preferentially found on a specific mt

35 by improving cell survival in cells carrying LHON mutations that could be utilized as a potential the

36 significantly compromised in cells carrying LHON-specific mtDNA mutations, which results in reduced

37 creased levels of blood NSE may characterize LHON carriers as a biomarker of ongoing RGC stress.

38 stmortem from four molecularly characterized LHON patients with varying degrees of neurodegenerative

39 rom lymphoblastoid cell lines of one Chinese LHON family into mtDNA-less (rhoo) cells revealed decrea

40 : 5.2 +/- 5 months), while eight had chronic LHON.

41 the choroid is the common outcome in chronic LHON and in DOA.

42 choroidal thickness was decreased in chronic LHON and in DOA.

43 empts for treatments are proposed in chronic LHON.

44 Those with chronic LHON demonstrated significantly thinner GCL and RNFL.

45 In our untreated patients with chronic LHON, with different specific pathogenic mutations, RGCs

46 m those pedigrees that did not carry classic LHON mutations suggested candidate pathogenic mutations

47 ined, 56 of which carried one of the classic LHON mutations at nucleotide (nt) 3460, 11778, or 14484.

48 patient lymphoblasts bearing the most common LHON mutation (11778) and the most severe LHON mutation

49 activity, somewhat spared in the most common LHON mutation (G11778A), although adenosine triphosphate

50 rial cybrids harboring the three most common LHON mutations: 3460A, 11778A, and 14484C.

51 4, and m.3460 mutations were the most common LHON point mutations in both males and females, with a s

52 N who do not harbour one of the three common LHON mutations.

53 x I defect has been implicated in developing LHON phenotype such as retinal ganglion cell (RGC) death

54 lish the risk of vision loss among different LHON mutations, sex, age at onset, and mitochondrial hap

55 l characteristics of patients with differing LHON stages, with a specific emphasis on optical coheren

56 pedigree of m.11778G>A/ND4 mitochondrial DNA LHON mutation.

57 ic phase" of the disease, providing 42 eyes (LHON group) with different pathogenic mitochondrial DNA

58 le it was markedly lower [1.42% (5/353)] for LHON patients without primary mtDNA mutations.

59 e challenged the longstanding assumption for LHON to be exclusively maternally inherited and broadene

60 autosomal recessive mode of inheritance for LHON (arLHON), which to date has been a prime example of

61 d provides support for a polygenic model for LHON expression in some cases.

62 Using cybrid models for LHON, we show that autophagy is significantly compromise

63 Thus, male carriers are at higher risk for LHON-related neuronal stress.

64 ions 3460, 11778, and 14484 are specific for LHON and account for 90% of worldwide cases and are thus

65 indicating that this gene is a hot spot for LHON mutations.

66 ERbeta may become a therapeutic strategy for LHON specifically aimed at avoiding or delaying the onse

67 ilized as a potential therapeutic target for LHON treatment.

68 nts and research participants are tested for LHON mutations.

69 pt physicians to conduct genetic testing for LHON in all patients who meet the clinical criteria, reg

70 Allotopic gene therapy for LHON at low and medium doses seems to be safe and does n

71 bitors could have some therapeutic value for LHON.

72 less rho(o) cells with enucleated cells from LHON patients carrying both m.11778G > A and m.14502T >

73 tor influencing the risk of vision loss from LHON.

74 G11778A LHON gene therapy has a favorable safety profile.

75 nt of visual acuity in patients with G11778A LHON is not common and is partial and limited when it oc

76 tural history study of patients with G11778A LHON to plan a gene therapy clinical trial that will use

77 cipants included 44 individuals with G11778A LHON, recruited between September 2008 and March 2012, w

78 e-institution study of patients with G11778A LHON.

79 he eyes of 5 blind participants with G11778A LHON.

80 , and from previous studies of heteroplasmic LHON families, we conclude that there is no evidence for

81 ous study on 1516 probands with Leber's HON (LHON) who had mitochondrial DNA variants.

82 ells and their axons, the hallmarks of human LHON.

83 trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G>A mtDNA mutation treated

84 monstrated the involvement of the choroid in LHON pathology.

85 ure of identifying the date of conversion in LHON.

86 cating that increased Fas-dependent death in LHON cybrids was induced by the LHON pathogenic mutation

87 ant for the pathophysiology of cell death in LHON, and potential therapy.

88 the expression of the biochemical defect in LHON patients with the A3460G mutation.

89 ones ameliorate mitochondrial dysfunction in LHON through the estrogen receptors (ERs).

90 (P = .023), CONCLUSION: Asymptomatic eyes in LHON patients with unilateral visual loss may be beyond

91 vere irreversible loss of visual function in LHON support clinical testing with mutated G11778A mitoc

92 Serum NSE levels are higher in LHON carriers compared with affected and off-pedigree in

93 pathy, and sorbitol levels were increased in LHON cybrids.

94 Carlo simulation of the spread of injury in LHON axons to better understand the predilection for sma

95 reatments aimed at preventing vision loss in LHON because an overestimated risk may lead to an underp

96 seeks to predict the order of axonal loss in LHON optic nerves using the Nerve Fiber Layer Stress Ind

97 de insight into the nature of axonal loss in LHON.

98 The PERG and VEP mean values observed in LHON eyes were compared (1-way analysis of variance [ANO

99 se reductase transcript was overexpressed in LHON cybrids and lymphoblasts.

100 complete penetrance and male predominance in LHON remains unclear.

101 lex I genes, ND5 mutations are quite rare in LHON.

102 ing the levels of reactive oxygen species in LHON cells.

103 the presymptomatic to the affected state in LHON.

104 efects and improves overall cell survival in LHON cell models.

105 revealed that the PMB is most susceptible in LHON, supporting clinical findings seen early in the cou

106 hat estrogen-like molecules may be useful in LHON prophylactic therapy.

107 s and thus are found in multiple independent LHON families.

108 a low likelihood that an optic neuropathy is LHON.

109 ntiation protocol yielded significantly less LHON cells than controls, by 30%, indicating either a de

110 ts who tested negatively for the three major LHON mutations.

111 arts, cybrids carrying the homoplasmic mouse LHON mutation demonstrated reduced respiration, reduced

112 defect in association with the A3460G mtDNA LHON mutation in cultured fibroblasts compared with age-

113 s after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated w

114 70% of Leber Hereditary Optic Neuropathies (LHON).

115 stic of Leber's hereditary optic neuropathy (LHON) 2 years before the first stroke-like episode.

116 Leber's hereditary optic neuropathy (LHON) and a multiple sclerosis (MS)-like illness appear

117 such as Leber's hereditary optic neuropathy (LHON) and Autosomal dominant optic atrophy (ADOA) are ca

118 riants in Leber hereditary optic neuropathy (LHON) and Leigh syndrome challenged the longstanding ass

119 ed with Leber's hereditary optic neuropathy (LHON) and their pathophysiology remains poorly understoo

120 cause of Leber hereditary optic neuropathy (LHON) and/or pediatric-onset dystonia in three unrelated

121 atment of Leber hereditary optic neuropathy (LHON) caused by a mutation in the nicotinamide adenine d

122 Leber's hereditary optic neuropathy (LHON) causes central vision loss from bilateral optic ne

123 lies with Leber hereditary optic neuropathy (LHON) closely fits a model in which a pathogenic mtDNA m

124 whether Leber's hereditary optic neuropathy (LHON) could be caused by mutations in OPA1 we also scree

125 ortion of Leber hereditary optic neuropathy (LHON) family members who carry a mitochondrial risk vari

126 esis of Leber's hereditary optic neuropathy (LHON) has yet to be characterized.

127 causing Leber's hereditary optic neuropathy (LHON) have demonstrated that some continent-specific mtD

128 study of Leber hereditary optic neuropathy (LHON) in Australia by using registry data to establish t

129 sible for Leber hereditary optic neuropathy (LHON) into the mouse germ line using fluorescence imagin

130 Leber's hereditary optic neuropathy (LHON) is a classical mitochondrial disease caused by mut

131 Leber's hereditary optic neuropathy (LHON) is a common cause of bilateral optic nerve disease

132 Leber hereditary optic neuropathy (LHON) is a degenerative disease of the optic nerve assoc

133 Leber hereditary optic neuropathy (LHON) is a disorder characterized by severe and rapidly

134 Leber's hereditary optic neuropathy (LHON) is a form of blindness caused by mitochondrial DNA

135 Leber hereditary optic neuropathy (LHON) is a genetic disorder primarily due to mutations o

136 Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease charact

137 Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease due to mitoc

138 Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease affecting retinal gangl

139 Leber's hereditary optic neuropathy (LHON) is a rare genetic mitochondrial disease and the pr

140 Leber hereditary optic neuropathy (LHON) is a syndrome of subacute loss of central vision a

141 Leber hereditary optic neuropathy (LHON) is a type of blindness caused by mtDNA mutations.

142 Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness

143 Leber hereditary optic neuropathy (LHON) is due primarily to one of three common point muta

144 f G11778A Leber hereditary optic neuropathy (LHON) is important to determine the optimal end points t

145 Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disease.

146 Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disorder.

147 Leber's hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was

148 Leber's hereditary optic neuropathy (LHON) is thought to be the most common disease resulting

149 Leber's hereditary optic neuropathy (LHON) is typically characterized by vascular alterations

150 e primary Leber hereditary optic neuropathy (LHON) mutation at nucleotide 3460 of the mitochondrial g

151 from five Leber hereditary optic neuropathy (LHON) pedigrees.

152 h primary Leber hereditary optic neuropathy (LHON) variants of the mitochondrial DNA, coding for CI s

153 model of Leber hereditary optic neuropathy (LHON) was produced by introducing the human optic atroph

154 rees with Leber hereditary optic neuropathy (LHON) were determined, 56 of which carried one of the cl

155 Leber's hereditary optic neuropathy (LHON), a mitochondrial disease, has clinical manifestati

156 causes Leber's Hereditary Optic Neuropathy (LHON), a specific degeneration of the optic nerve, resul

157 disease Leber's hereditary optic neuropathy (LHON), but has been less successful in clinical trials f

158 enesis of Leber hereditary optic neuropathy (LHON), caused by mutated complex I subunit genes.

159 isease, Leber's hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria?

160 curs in Leber's hereditary optic neuropathy (LHON), which has profound consequences in DeltaPsimt and

161 S), and Leber's hereditary optic neuropathy (LHON).

162 ly with Leber's hereditary optic neuropathy (LHON).

163 tion in Leber's hereditary optic neuropathy (LHON).

164 ophy in Leber's hereditary optic neuropathy (LHON).

165 ons and Leber's hereditary optic neuropathy (LHON).

166 ated in Leber's Hereditary Optic Neuropathy (LHON).

167 cted with Leber hereditary optic neuropathy (LHON).

168 ents with Leber hereditary optic neuropathy (LHON).

169 tory of Leber's hereditary optic neuropathy (LHON).

170 ons for Leber's hereditary optic neuropathy (LHON: G11778A; T14484C; and G3460A) were not present in

171 inical and genetic characterization of a new LHON mtDNA mutation.

172 Nine LHON-specific transcriptional alterations were shared am

173 This association of LHON and MS (LMS) raises an important question about whe

174 ND4 homologue responsible for most cases of LHON.

175 oping white matter lesions in the context of LHON.

176 ical analyses to compare the distribution of LHON patients on the Caucasian phylogenetic tree.

177 Here, we resolve the enigma of LHON in the absence of pathogenic mtDNA mutations.

178 posed to modify the phenotypic expression of LHON-associated mitochondrial DNA (mtDNA) mutations.

179 Peculiar features of LHON are incomplete penetrance and gender bias, with a m

180 viduals who develop the clinical features of LHON but who do not harbour one of these primary LHON mu

181 ta confirm some well-established features of LHON, the overall risk of vision loss among those with a

182 he optic neuropathy to the histopathology of LHON is powerful evidence supporting ROS as a key factor

183 The natural history of LHON is not a subacute process, as previously believed,

184 ROS have a role in the optic nerve injury of LHON, then increasing mitochondrial levels of ROS should

185 The majority of LHON patients harbour one of three point mutations of th

186 However, the mechanism of LHON pathogenesis is still not very clear and thus no ef

187 g ROS as a key factor in the pathogenesis of LHON.

188 m.14484T > C mutation in the pathogenesis of LHON.

189 ide new insights into the pathophysiology of LHON arising from the synergy between mitochondrial ND1

190 ded new insights into the pathophysiology of LHON that were manifested by interaction between mtDNA m

191 ded new insights into the pathophysiology of LHON that were manifested by interaction between primary

192 further insight into the pathophysiology of LHON.

193 defects contributed to higher penetrance of LHON in these families carrying both mtDNA mutations.

194 T>C mutation, exhibited higher penetrance of LHON than those in families carrying single mtDNA mutati

195 explain the marked incomplete penetrance of LHON, but previous small studies have failed to confirm

196 r worse, suggesting a very low penetrance of LHON.

197 Extremely low penetrances of LHON were observed in 26 pedigrees carrying only m.3394T

198 generation of RGCs during the acute phase of LHON have not been very effective.

199 in asymptomatic, acute and chronic stages of LHON.

200 This was the largest study of LHON demographics to date.

201 culates on a pathogenic role for a subset of LHON secondary mutations and their interaction with prim

202 e prone to manifest the clinical symptoms of LHON than others.

203 pproach for genetic screening and testing of LHON mutations.

204 stigated as drug therapy in the treatment of LHON, although evidence for the efficacy of idebenone is

205 we tested the effects of ERbeta targeting on LHON mitochondrial defective metabolism by treating LHON

206 pproximately 75% of worldwide 14484-positive LHON patients occur in association with haplogroup J.

207 ng of six probands with LSS carrying primary LHON variants, and report digenic co-occurrence of the m

208 ion, segregation, or transmission of primary LHON mutations to white blood cells and platelets.

209 dulated the phenotypic expression of primary LHON-associated m.11778G > A mutation.

210 modify the phenotypic expression of primary LHON-associated mitochondrial DNA (mtDNA) mutations.

211 phorylation defects among all of the primary LHON mtDNA mutations, thus permitting insight into the u

212 ype and phylogenetic analysis of the primary LHON mutations in North American Caucasian patients and

213 e penetrance and expressivity of the primary LHON-associated G11778A mutation in this Chinese family.

214 but who do not harbour one of these primary LHON mutations.

215 e and quantitative analysis of three primary LHON mtDNA mutations, offering a promising approach for

216 e cases and are thus designated as "primary" LHON mutations.

217 and Italian families with genetically proven LHON has excluded the presence of such a VLSL over 169 c

218 The autosomal recessive LHON patients demonstrate an earlier age of disease onse

219 S due to biallelic variants in the recessive LHON-associated disease gene DNAJC30 in combination with

220 The remaining LHON mutations are rare.

221 Fifteen other "secondary" LHON mtDNA mutations have been identified, but their pat

222 ata indicate that the most common and severe LHON pathogenic mutations 11778 and 3460 predispose cell

223 on LHON mutation (11778) and the most severe LHON mutation (3460).

224 We observed that LHON cybrids were sensitized to Fas-dependent death.

225 We propose that LHON symptoms caused by 3460/ND1 mtDNA mutation are due

226 However, our data suggest that LHON is a disease that affects both females and males of

227 The LHON-specific increase in transcript level was confirmed

228 ase in reactive oxygen species caused by the LHON mutation has been proposed to be responsible for th

229 ochondrial superoxide which is caused by the LHON mutations, possibly mediated through neuron-specifi

230 ent death in LHON cybrids was induced by the LHON pathogenic mutations.

231 y the cybridization process, and finally the LHON mutations.

232 s of PERG and VEP parameters detected in the LHON group were significantly (P < 0.01) different with

233 In the LHON group, at 6 and 12 months of follow-up, the majorit

234 gnificant increases in ROS production in the LHON-NT2 neurons versus controls, which is abolished by

235 e in choroidal thickness is a feature of the LHON acute stage, which follows the thickening of RNFL.

236 euron-specific degenerative phenotype of the LHON genotype, we have created cybrids using a neuronal

237 e, safety of the test article, rescue of the LHON mouse model, and the severe irreversible loss of vi

238 ive potential or increased cell death of the LHON-NT2 cells.

239 Pooling the LHON pedigree analyses yields a control-region divergenc

240 the reduced NT2 yield; and suggest that the LHON degenerative phenotype may be the result of an incr

241 We infer that the LHON genotype requires a differentiated neuronal environ

242 e have investigated the possibility that the LHON mutation confers a pro-apoptotic stimulus and have

243 In this study, we demonstrated that the LHON susceptibility allele (m.14502T > C, p.

244 neurodegenerative disease, as opposed to the LHON phenotype of isolated optic neuropathy, remains an

245 used a similar approach were pooled with the LHON pedigree studies, totaling >2,600 transmission even

246 Three LHON mtDNA mutations at nucleotide positions 3460, 11778

247 cost and easy to handle advantages for three LHON mtDNA mutations are rarely reported.

248 alitative and quantitative analyses of three LHON mtDNA mutations.

249 RMS) PCR for qualitative genotyping of three LHON mtDNA mutations.

250 Thus, LHON pathophysiology may result from oxidative stress.

251 The minimum prevalence of vision loss due to LHON in Australia in 2020 was one in 68,403 individuals.

252 ll participants carried a mutation linked to LHON.

253 is the missing link from oxidative stress to LHON pathogenesis.

254 tochondrial defective metabolism by treating LHON cybrid cells carrying the m.11778G>A mutation with

255 We describe two LHON pedigrees that harbour the same novel point mutatio

256 or lifelong disease prevention in unaffected LHON mutation carriers.

257 The undifferentiated LHON-NT2 mutant cells were not significantly different f

258 We identified 96 genetically unrelated LHON pedigrees, including 56 unpublished pedigrees, and

259 lated HON (nHON) and 353 cases with unsolved LHON.

260 ophy at examination (78.79%); the rarest was LHON-like optic atrophy (3.64%); and optic atrophy with

261 When LHON was suspected, blood samples were obtained to test

262 Of these, all patients with LMS and 25% with LHON were found to have an MRI appearance typical of MS.

263 that 10% of individuals become affected with LHON after 50 years of age.

264 The mutation associated with LHON, G391S, had little effect on these functions.

265 tDNA) mutations are strongly associated with LHON, only three account for roughly 90% of cases and th

266 d families with dystonia in association with LHON and mtDNA complex I gene mutations.

267 y, a total of 17 participants (34 eyes) with LHON treated with idebenone therapy within 1 year after

268 l for genetic counseling of individuals with LHON mutations.

269 This analysis included 22 individuals with LHON.

270 yr51Cys founder variant, 24 manifesting with LHON, two manifesting with Leigh syndrome, and two remai

271 Twenty-two patients with LHON (mean age, 36.3+/-9.3 years) in the "chronic phase"

272 RIs of 30 patients with MS, 31 patients with LHON and 11 patients with LMS was conducted by three ind

273 Female patients with LHON had a significantly greater risk of having white ma

274 l patients with LMS and 26% of patients with LHON had white matter lesions.

275 ie, 2-year) visual outcomes in patients with LHON treated with idebenone therapy in the first year af

276 onverted to affected status, 6 patients with LHON were identified.

277 Twelve patients with LHON were included in this study.

278 ene should be sequenced in all patients with LHON who do not harbour one of the three common LHON mut

279 Four unaffected eyes of 4 patients with LHON with the first eye affected were followed across co

280 We enrolled 49 patients with LHON, 19 with Dominant Optic Atrophy (DOA) and 22 health

281 nerves examined at autopsy of patients with LHON.

282 and optic nerve histology from patients with LHON.

283 and 12 months of follow-up in patients with LHON.

284 clinical development of MS in patients with LHON.

285 from 74 members of a Brazilian pedigree with LHON carrying the homoplasmic 11778/ND4 mitochondrial DN

286 nder sequence for these Dutch pedigrees with LHON matches the control-region sequence that Macmillan

287 tch and French Canadian 14484 pedigrees with LHON share a common ancestor, that the single origin of

288 ntified in seven of the Dutch pedigrees with LHON, including six of those described by van Senus.

289 nder mtDNA of French Canadian pedigrees with LHON.

290 DNA sequences of two Canadian pedigrees with LHON.

291 was 2.7% in the cohort of 1741 probands with LHON.