BACKGROUND: Leber hereditary optic neuropathy (LHON) typically presents in young adults as bilateral painless subacute visual loss. Prevalence data are scarce. The aim of this study was to examine the validity of different ascertainment sources used in population-based rare diseases registries to detect cases, and to explore the impact of a capture-recapture method in the estimation of the prevalence of LHON in the Autonomous Community of Madrid (ACM) in 2022.
METHODS: Descriptive cross-sectional population-based study. Potential LHON cases were detected by automatic capture from the healthcare information sources usually explored for the Regional Registry for Rare Diseases (SIERMA). Ophthalmologists provided data from their clinical registry. Positive predictive values (PPV) and sensitivity with 95% confidence intervals (CI) were estimated. Global and by sex prevalences were calculated with confimed cases and with those estimated by the capture-recapture method.
RESULTS: A total of 102 potential LHON cases were captured from healthcare information sources, 25 of them (24.5%) finally were confirmed after revision, with an overall PPV of 24.5% (95%CI 17.2-33.7). By source, the electronic clinical records of primary care had the highest PPV (51.2, 95%CI 36.7-65.4). The ophthalmologists clinical registry provided 22 cases, 12 of them not detected in the automatic capture sources. The clinical registry reached a sensitivity of 59.5% (95%CI 43.5-73.6) and the combination of automatic capture sources reached a 67.6% (95%CI: 51.5-80.4). The total confirmed cases were 37, with a mean age of 48.9 years, and a men: women ratio of 2.4:1. Genetic information was recovered in 27 cases, with the m.3460 mutation being the most frequent (12 cases). The global prevalence was 0.55 cases/100,000 inhabitants (95%CI 0.40-0.75), and with the capture-recapture method reached 0.79 cases/100,000 (95%CI 0.60-1.03), a 43.6% higher, 1.15 cases/100,000 (95%CI 0.83-1.58) in men and 0.43 cases/100,000 (95%CI 0.26-0.70) in women.
CONCLUSIONS: The prevalence of LHON estimated in the ACM was lower than in other European countries. Population-based registries of rare diseases require the incorporation of confirmed cases provided by clinicians to asure the best completeness of data. The use of more specific coding for rare diseases in healthcare information systems would facilitate the detection of cases. Further epidemiologic studies are needed to assess potential factors that may influence the penetrance of LHON.

Mitochondrial dynamics were examined in human dermal fibroblasts biopsied from a confirmed Leber\'s Hereditary Optic Neuropathy (LHON) patient with a homoplasmic G11778A mutation of the mitochondrial genome. Expression of the G11778A mutation did not impart any discernible difference in mitochondrial network morphology using widefield fluorescence microscopy. However, at the ultrastructural level, cells expressing this mutation exhibited an impairment of mitochondrial morphological plasticity when forced to utilize oxidative phosphorylation (OXPHOS) by transition to glucose-free, galactose-containing media. LHON fibroblasts also displayed a transient increase in mitophagy upon transition to galactose media. These results provide new insights into the consequences of the G11778A mutation of LHON and the pathological mechanisms underlying this disease.

Leber\'s hereditary optic neuropathy (LHON), the most common mitochondrial optic neuropathy, causes visual loss, especially in young adults. Due to the absence of epidemiological data in Southeast Asia, we aimed to determine Thai LHON patients\' characteristics (demographic data, mutation types, and prognoses) as the first study in this region.
This retrospective chart review enrolled all Thai LHON patients confirmed by three mitochondrial DNA mutations (G11778A, T14484C, and G3460A) between January 1997 and December 2016. Patients with more than one year of follow-up were included in a visual progression analysis. The Mann-Whitney U-test was applied to compare groups, and prognosis-associated factors were analysed with the generalized estimating equation.
In all, 229 patients were enrolled, with only nineteen females. Most mutations were of the G11778A type (91%), with T14484C accounting for the remainder. The age at onset of G11778A (21.9 years; interquartile range [IQR] 14.9, 33.5) was younger than that of T14484C (33.0 years; IQR 19.4, 37.5). Of 45 patients, the T14484C group demonstrated good vision recovery, whereas the G11778A group did not improve (difference in logMAR -0.7 and IQR -1.5, -0.2 versus logMAR 0.0 and IQR -0.3, 0.2, respectively; P value .001). The G11778A mutation, male, and older age were related to poor prognoses.
The leading mutation in Thai LHON patients is the G11778A missense, followed by T14484C, while G3460A was not detected. The vast majority of patients were young adult males. The G11778A mutation, older age, and male gender are associated with poor vision outcomes. Key messageThe G11778A missense mutation is the most common among Thai LHON patients, followed by T14484C, while G3460A was not found. The G11778A mutation, older age, and male gender are associated with poor vision outcomes.

OBJECTIVE: To investigate the foveal pit morphology changes in unaffected carriers and affected Leber\'s hereditary optic neuropathy (LHON) patients with the G11778A mutation from one family.
METHODS: This study was a prospective cross-sectional study. Both eyes from 16 family members (age from 9 to 47y) with the G11778A mutation were analyzed and compared with 1 eye from 20 normal control subjects. Eleven family members with the G11778A mutation but without optic neuropathy were classified as unaffected carriers (n=22 eyes). Five family members (n=10 eyes) expressed the LHON phenotype and were classified as affected patients. Retinal images of all the subjects were taken by optical coherence tomography (OCT), and an automatic algorithm was used to segment the retina to eight layers. Horizontal and vertical OCT images centered on the fovea were used to measure intra-retinal layer thicknesses and foveal morphometry.
RESULTS: Thicker foveal thickness, thinner foveal pit depth, and flatter foveal slopes were observed in unaffected carriers and affected LHON patients (all P<0.001). Further, the slopes of all four sectors in the LHON were flatter than those in the unaffected carriers (all P<0.001). Compared with the control group, affected LHON patients had a thinner retinal nerve fiber layer (RNFL), ganglion cell layer and inner plexiform layer (GCL+IPL), and total retina (all P<0.01). The retinal nerve fiber layer (RNFL) of affected patients was 38.0% thinner than that of controls while the GCL+IPL was 40.1% thinner.
CONCLUSIONS: The foveal pit morphology shows changes in both unaffected carriers and affects patients. RNFL and GCL+IPL are thinner in affected LHON patients but not in unaffected carriers.

OBJECTIVE: To analyze the influences of different genotypes (G11778A, T14484C and G3460A) of Leber hereditary optic neuropathy (LHON) on visual prognosis.
METHODS: After a systematic literature search, all relevant studies evaluating the association between the three primary mutations of LHON and visual prognosis were included. All statistical tests were calculated with Revman 5.2 and STATA 12.0.
RESULTS: Ten independent studies were included finally. A significant association between the three primary mutations and prognostic vision over 0.3 were found in G11778A versus T14484C [odds ratio (OR)=0.10, 95% confidence interval (CI)=0.05-0.17, P<0.001], G11778A versus G3460A (OR=0.18, 95%CI=0.09-0.37, P<0.001) and T14484C versus G3460A (OR=2.45, 95%CI=1.10-5.48, P<0.05). In addition, obtained by pairwise comparison, the vision during onset, age of onset and sex ratio of these three kinds of patients, have no statistical significance (P>0.05).
CONCLUSIONS: From pairwise comparison, we conclude that these three different genotypes of LHON are related to patients\' visual prognosis. The T14484C patients might have a best prognostic vision, G3460A second, and G11778A worst. And there is little relation between the three different genotypes and patients\' vision, age of onset and sex ratio.

BACKGROUND: Leber\'s hereditary optic neuropathy (LHON) is a mitochondrial disorder with optic nerve atrophy. Although there are no other associated neurological abnormalities in most cases of LHON, cases of \"LHON plus\" have been reported.
METHODS: The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations.
CONCLUSIONS: These results suggest that the combination of G11778A and T3394C mutations leads to an atypical LHON phenotype.