Wanicha Chuenkongkaew

The unique characteristics of Thai Leber hereditary optic neuropathy: analysis of 30 G11778A pedigrees

AbstractLeber hereditary optic neuropathy (LHON) is characterized by acute or subacute bilateral visual loss, and affects mostly young males. The most common mitochondrial DNA mutation responsible for LHON worldwide is G11778A. Despite different genetic backgrounds, which are believed to influence the disease expression, most features of LHON are quite common in different populations. However, there seem to be a few ethnic-specific differences. Analyses of our 30 G11778A LHON pedigrees in Thailand showed some characteristics different from those of Caucasians and Japanese. In particular, our pedigrees showed a lower male to female ratio of affected persons (2.6:1) and much higher prevalence of G11778A blood heteroplasmy (37% of the pedigrees contained at least one heteroplasmic G11778A individual). Heteroplasmicity seemed to influence disease manifestation in our patients but did not appear to alter the onset of the disease. The estimated overall penetrance of our G11778A LHON population was 37% for males and 13% for females. When each of our large pedigrees were considered separately, disease penetration varied from 9 to 45% between the pedigrees, and also varied between different branches of the same large pedigree. Survival analysis showed that the secondary LHON mutations G3316A and C3497T had a synergistic deleterious effect with the G11778A mutation, accelerating the onset of the disease in our patients.

Mitochondrial Haplogroup Background May Influence Southeast Asian G11778A Leber Hereditary Optic Neuropathy

PURPOSE To investigate the role of mitochondrial DNA (mt DNA) background on the expression of Leber hereditary optic neuropathy (LHON) in Southeast Asian carriers of the G11778A mutation. METHODS Complete mtDNA sequences were analyzed from 53 unrelated Southeast Asian G11778A LHON pedigrees in Thailand and 105 normal Thai controls, and mtDNA haplogroups were determined. Clinical phenotypes were tested for association with mtDNA haplogroup, with adjustment for potential confounders such as sex and age at onset. RESULTS mtDNA subhaplogroup B was significantly associated with LHON. Follow-up analysis narrowed the association down to subhaplogroup B5a1 (P = 0.008). Survival analyses with Coxs proportional hazards modeling on 469 samples (91 affected and 378 unaffected), adjusted for sex and heteroplasmy, revealed that haplogroup B5a1 tended to increase the risk of visual loss, but the trend was not statistically significant. Conversely, haplogroup F, the second most common haplogroup in the control population, was the least frequent haplogroup in LHON. This negative association was narrowed down to subhaplogroup F1 (P = 0.00043), suggesting that haplogroup F1 confers a protective effect. The distributions of sex, age at onset and heteroplasmy were not significantly different among haplogroups. CONCLUSIONS The specific mtDNA background B5a1 was significantly associated with Southeast Asian G11778A LHON and appeared to modify the risk of visual loss.

Mitochondrial DNA haplogroup distribution in pedigrees of Southeast Asian G11778A Leber hereditary optic neuropathy.

Abstract: To investigate the association of mitochondrial DNA (mtDNA) haplogroups and Leber hereditary optic neuropathy (LHON) in the Southeast Asian population, mtDNA haplogroup determination was performed by high-resolution restriction fragment length polymorphism in 42 patients with LHON who were carrying the G11778A mutation and in control subjects drawn from a Thai urban population unaffected by LHON. The patients with LHON were of Thai, Thai-Chinese, and Indian origin. Three mtDNA haplogroups, M, B*, and B, were found in LHON patients in a frequency similar to that in control subjects. mtDNA haplogroup F was found in none of the patients with LHON but was the second most common haplogroup in control subjects. The G11778A mutation must have arisen in our population independently from the mutation in Caucasians. In contrast to Caucasians, no specific mtDNA haplotype was associated with the patients with LHON in the Southeast Asian population. The mitochondrial polymorphisms that modify the expression of LHON in Southeast Asians could not be identified in this study. The lack of haplogroup F in our patients with LHON may indicate the protective effect of this haplogroup in the expression of this disorder.

Transmission of heteroplasmic G11778A in extensive pedigrees of Thai Leber hereditary optic neuropathy

AbstractLeber hereditary optic neuropathy (LHON) is characterized by the acute or subacute bilateral painless loss of central vision, predominantly in young males. G11778A is the most common mitochondrial DNA mutation responsible for the disease. Thirty-seven percent of our LHON pedigrees (which is a much higher prevalence than that generally found) carried heteroplasmic G11778A. Analyses of four large Thai LHON pedigrees spanning four to six generations strongly suggested that the transmission of the heteroplasmic G11778A mutation is under selective pressure in favour of the mutated allele and that heteroplasmy influences the disease expression.

Proportion of 11778 mutant mitochondrial DNA and clinical expression in a thai population with leber hereditary optic neuropathy.

The proportion of mutant mtDNA in blood has been found to correlate with the frequency of visual loss in cases with mtDNA mutations associated with Leber hereditary optic neuropathy (LHON), especially in men. We sought to determine this correlation in a Thai population of LHON. Methods: Densitometric quantification of blood mtDNA with the 11778 LHON mutation in 137 symptomatic cases and their asymptomatic maternal relatives in 30 Asian pedigree families was performed. Asymptomatic maternal relatives under the age of 16 years were excluded. The visual outcome in symptomatic cases with homoplasmy and heteroplasmy was compared. Results: Heteroplasmy was detected in eight (12.9%) symptomatic and 30 (40%) asymptomatic individuals. The quantification of blood mutant mtDNA in the eight symptomatic cases ranged from 44% to 93% (mean = 75%). The visual outcome of the cases with heteroplasmy was not different from that of cases with homoplasmy. There was a correlation between the proportion of mutant mtDNA and the likelihood of visual loss. Conclusions: The prevalence of heteroplasmy among pedigrees of the 11778 LHON mutation in Thailand was similar to that of other Asian populations and may be greater than in 11778 LHON pedigrees from white backgrounds. The proportion of mutated mtDNA correlated with visual loss, but the effect of heteroplasmy on clinical expression seemed not to relate to gender.

An unusual family with Leber's hereditary optic neuropathy and facioscapulohumeral muscular dystrophy

We performed an observational prospective analysis to study the clinical characteristics as well as a molecular genetic analysis of 17 members of a Thai family who had visual loss and/or muscle weakness. Their blood mitochondrial DNA were examined for the presence of the G11778A Lebers hereditary optic neuropathy (LHON) mutation. Facioscapulohumeral muscular dystrophy (FSHD) DNA analysis was performed in four members who had visual loss. Of 17 family members, the eight members who had the 11778 LHON mutation were all from branch ‘a’. Three of these eight members had FSHD with a 17–27‐kb deletion of a tandem repeat in the 4q35 subtelomere, and two had been clinically diagnosed as FSHD. Four of six examined members in branch ‘b’ showed muscular dystrophy clinically diagnosed as FSHD. No correlation of blood DNA analysis between LHON and FSHD in affected members was found. We describe the first family with FSHD and G11778A LHON in which a mutation in mitochondrial DNA at nucleotide position 11778 of branch ‘a’ was found to be the origin of the mutation.

Profiling the Mitochondrial Proteome of Leber’s Hereditary Optic Neuropathy (LHON) in Thailand: Down-Regulation of Bioenergetics and Mitochondrial Protein Quality Control Pathways in Fibroblasts with the 11778G>A Mutation

Leber’s Hereditary Optic Neuropathy (LHON) is one of the commonest mitochondrial diseases. It causes total blindness, and predominantly affects young males. For the disease to develop, it is necessary for an individual to carry one of the primary mtDNA mutations 11778G>A, 14484T>C or 3460G>A. However these mutations are not sufficient to cause disease, and they do not explain the characteristic features of LHON such as the higher prevalence in males, incomplete penetrance, and relatively later age of onset. In order to explore the roles of nuclear encoded mitochondrial proteins in development of LHON, we applied a proteomic approach to samples from affected and unaffected individuals from 3 pedigrees and from 5 unrelated controls. Two-dimensional electrophoresis followed by MS/MS analysis in the mitochondrial lysate identified 17 proteins which were differentially expressed between LHON cases and unrelated controls, and 24 proteins which were differentially expressed between unaffected relatives and unrelated controls. The proteomic data were successfully validated by western blot analysis of 3 selected proteins. All of the proteins identified in the study were mitochondrial proteins and most of them were down regulated in 11778G>A mutant fibroblasts. These proteins included: subunits of OXPHOS enzyme complexes, proteins involved in intermediary metabolic processes, nucleoid related proteins, chaperones, cristae remodelling proteins and an anti-oxidant enzyme. The protein profiles of both the affected and unaffected 11778G>A carriers shared many features which differed from those of unrelated control group, revealing similar proteomic responses to 11778G>A mutation in both affected and unaffected individuals. Differentially expressed proteins revealed two broad groups: a cluster of bioenergetic pathway proteins and a cluster involved in protein quality control system. Defects in these systems are likely to impede the function of retinal ganglion cells, and may lead to the development of LHON in synergy with the primary mtDNA mutation.

Leber's Hereditary Optic Neuropathy in Thailand

PURPOSE To study the clinical features of Lebers hereditary optic neuropathy (LHON) in Thai patients as compared with patients in the United States, Europe, and other Asian countries. METHODS The blood mitochondrial DNA of patients from 19 Thai pedigree families was studied for LHON mutation by restriction enzyme analysis. RESULTS Mitochondrial mutation at nucleotide position 11778 was detected in 37 affected patients and 21 unaffected maternal relatives. Ten of the 19 families were sporadic in transmission. The male preponderance in affected patients was 76%. The onset of visual loss ranged from 6 to 53 years of age (mean = 21.5 years). Of the 31 patients whose eyes were affected bilaterally, 48.4% developed visual loss simultaneously. Unilateral visual loss was found in 2 patients but 1 already had a blind eye resulting from trauma. Onset interval between eyes was up to 12 months (mean = 2.3 months). No associated heart disease or neurological disorder was detected in our pedigrees. Hyperemic disc, retinal telangiectasia, and tortuosity of vessels appeared on ophthalmoscopy in 29% of the patients. Final visual outcome was 0.1, or worse in 82.3%, with a mean follow-up period of 19.5 months. CONCLUSION The clinical features of LHON in Thai patients are similar to those found in patients harboring the 11778 mutation in the United States, Europe, and Japan. However, although there is a male predominance in all populations studied, this is not so marked in the European and Thai populations.

Isolated optic neuritis from an identified Gnathostoma spinigerum.

Purpose To describe a patient with isolated monocular optic neuritis caused by an identified Gnathostoma spinigerum infestation. Case report A 21-year-old man developed a swollen eyelid and painful monocular visual loss of his left eye which did not improve after treatment by intravenous steroid and albendazole. A remarkable eosinophilia in his peripheral blood count was demonstrated. The patient subsequently found a live parasite emerged from his lower eyelid and it was successfully removed by himself. Gross and histopathology examinations of the obtained parasite was undertaken. The parasite was identified as Gnathostoma spinigerum. His blood test for Gnathostoma antibody was positive. Discussion The etiology of isolated optic neuritis in this patient was Gnathostoma spinigerum which was confirmed by the histopathology of the obtained parasite and the positive serologic test. Conclusions We could identify the exact parasite that was proven to cause an isolated optic neuritis. The immediate removal of a causative parasite may not result in an improvement of the injured tissue but is beneficial in preventing further destruction as well as future complications. (Eur J Ophthalmol 2007; 17: 130–2)

An Unusual Cause of Persistent Bilateral Swollen Optic Discs

Besides systemic Rosai-Dorfman disease, Brenn et al. reported on purely cutaneous Rosai-Dorfman disease without lymph node involvement. In their report, patients with purely cutaneous Rosai-Dorfman disease were older at onset, from 15 to 68 years (median, 43.5 years). Although ocular lesions have been described in the eyelids and orbit, intraocular involvement is rare. As far as we know, only one case of bilateral uveitis and optic disc edema and five cases of uveitis associated with Rosai-Dorfman disease have been reported. Biopsy is required for diagnosis, and the results are characterized by proliferation of s-100 protein-positive histiocytes. Positivity for s-100 protein determined by immunohistochemistry is thought to be a clue for the diagnosis of Rosai-Dorfman disease. Although the correlation of uveitis with Rosai-Dorfman disease is not clear in our case, histopathologic examination of an enucleated eye, reported by Foucar et al. revealed histiocytic infiltration to the uveal tract. Pivetti-Pezzi et al. also suspected that uveitis was due to histiocytic infiltration in their case. We consider that the intraocular involvement with our patient may have been due to Rosai-Dorfman disease.This was an unusual case of Rosai-Dorfman disease with relapsing uveitis without nodal involvement. Ophthalmologists should check for intraocular lesions such as uveitis when examining patients with RosaiDorfman disease.