Prevalence of Leber hereditary optic neuropathy in the Community of Madrid (Spain), estimation with a capture-recapture method.

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.

Aproximaciones a la epidemiología de la neuropatía óptica hereditaria de Leber en la comunidad autónoma de Madrid a través de una encuesta a los neuroftalmólogos / Approaches to the epidemiology of NOHL in the region of Madrid: Survey of neuro-ophthalmologists

Objective To estimate the epidemiology of Leber's optic neuropathy (NOHL) in the Region of Madrid. Material and methodsThe neuro-ophthalmologists who work at public hospitals of the CAM were interviewed by telephone. They were asked about the number of patients with NOHL that they had diagnosed during the time that they had been responsible for the neuro-ophthalmology department of that public hospital. The time worked and the population attended by the hospital were used to calculate the number of patient-years in follow-up by each center during the corresponding period. The basic information of each case (date of birth, mutation, and date of visual loss) was registered to avoid duplications. Results Our work estimates a global incidence of 2.34 cases for 10,000,000 inhabitants-year and a prevalence estimated from incidence of one case for each 106,682 inhabitants. This prevalence was very similar in all the studied areas and considerably lower than that reported by other studies. Conclusion This work constitutes the first approach to the epidemiology of this disease in Spain. The prevalence of NOHL in the region of Madrid is probably lower than that reported in the literature in other regions. The prevalence and the incidence were homogeneously low in the 26 studied areas. (AU)

Objetivo Estimar la epidemiología (incidencia y prevalencia) de la neuropatía óptica de Leber (NOHL) en la comunidad autónoma de Madrid (CM). Material y métodosLos neuroftalmólogos que trabajan en los hospitales públicos de la CAM fueron entrevistados telefónicamente. Se les preguntó por el número de pacientes con NOHL que habían diagnosticados durante el tiempo que han sido responsables de la consulta de neuroftalmología de ese hospital público. El tiempo trabajado y la población atendida por el hospital se utilizaron para calcular el número de habitantes-años en seguimiento por cada centro durante el periodo correspondiente y estimar la incidencia en cada área. La prevalencia estimada a partir de la incidencia (PEI) se calculó considerando que un paciente con NOHL vive unos 40 años con la enfermedad. Se registró la información básica de cada caso cuando estaba disponible (sexo, fecha de nacimiento, mutación, fecha de la pérdida visual) para evitar duplicaciones. Resultados Nuestro trabajo estima una incidencia global de 2,34 casos por cada 10.000.000 habitantes-año y una PEI de 1 caso por cada 106.682 habitantes. Esta prevalencia es inferior a la referida por otros estudios. Conclusión Este trabajo constituye la primera aproximación a la epidemiología de esta enfermedad en España. La prevalencia estimada de la NOHL en la CM es probablemente inferior a la reportada en la literatura en otras regiones. La prevalencia y la incidencia fueron homogéneamente bajas en las 26 áreas estudiadas. (AU)

Autosomal recessive Leber's hereditary optic neuropathy caused by a homozygous variant in DNAJC30 gene.

Recently, Stenton et al. (2021) described a new, autosomal recessive inheritance pattern of Leber's hereditary optic neuropathy (LHON) caused by missense variants in the DNAJC30 gene. The DNAJC30 c.152A > G, p.(Tyr51Cys) variant was by far the most common variant reported in patients originating from Eastern Europe, therefore, it is believed to be a founder variant in these populations. We report the first two cases of DNAJC30-linked autosomal recessive LHON in a young male and a female originating from Estonia. The patients presented severe loss of central vision and clinical features indistinguishable from mitochondrial LHON. The whole exome sequencing carried out in the male patient and the next-generation sequencing panel in the young female patient identified the same homozygous missense variant in the DNAJC30 gene. Our cases further reinforce the pathogenicity of c.152A > G, p.(Tyr51Cys) DNAJC30 variant causing autosomal recessive LHON. According to the gnomAD database, the allele frequency of this variant in the Estonian population is 0.8%, translating into a prevalence of carriers of 1:60. It is the highest among different gnomAD populations. Applying the Hardy-Weinberg equation, an estimated 92 persons in the Estonian population carry the homozygous variant c.152A > G, p.(Tyr51Cys) in DNAJC30. In patients with LHON, we advise sequencing both the DNAJC30 gene and mitochondrial DNA simultaneously.

Non-Pharmaceutical Interventions against COVID-19 Causing a Lower Trend in Age of LHON Onset.

Leber hereditary optic neuropathy (LHON) is a monogenic but multifactorial disease vulnerable to environmental triggers. Little is known about how LHON onset changed during the COVID-19 pandemic and how non-pharmaceutical interventions (NPHIs) against COVID-19 impact LHON onset. One hundred and forty-seven LHON patients with the m.11778G>A mutation complaining of vision loss were involved between January 2017 and July 2022. The onset time points, age of onset, and possible risk factors were evaluated. Analyses were conducted among 96 LHON patients in the Pre-COVID-19 group and 51 in the COVID-19 group. The median (IQR) age of onset decreased significantly from 16.65 (13.739, 23.02) in pre-COVID-19 to 14.17 (8.87, 20.29) during COVID-19. Compared with the Pre-COVID-19 group, the COVID-19 group exhibited bimodal distribution with an additional peak at six; the first quarter of 2020 also witnessed a relatively denser onset, with no subsequent second spike. NPHIs against COVID-19 significantly changed patients' lifestyles, including higher secondhand smoke exposure (p < 0.001), adherence to masks (p < 0.001), reduction in time spent outdoors for leisure (p = 0.001), and prolonged screen time (p = 0.007). Multivariate logistic regression revealed that secondhand smoke exposure and mask-wearing were independent risk factors of younger LHON onset. Lower age of onset of LHON appeared after the breakout of the COVID-19 pandemic, and novel risk factors were detected, including secondhand exposure and long mask-wearing. Carriers of LHON mtDNA mutations, especially teenagers or children, should be advised to avoid secondhand smoke exposure and there are possible adverse outcomes of longer mask-wearing.

Leber Hereditary Optic Neuropathy in Southwestern Ontario: A Growing List of Mutations.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is a rare but bilaterally blinding disease. Three characteristic disease-causing point mutations, and other less common mutations, are most often found on the mitochondrially encoded genes of NADH-ubiquinone oxidoreductase core subunits (MT-ND). The purpose of this study is to provide an overview of LHON mutations in Southwestern Ontario and to describe the associated demographic and clinical characteristics. METHODS: A retrospective genetic and clinical chart review was performed from January 2015 to 2020. Patients were identified within a mitochondrial mutation database and included if a mutation was detected on the MT-ND1, -ND4, or -ND6 genes. A clinical chart review was done on all available patients. RESULTS: Forty-five of 63 patients identified had classic disease-causing mutations (6.7% m.3460G>A, 44.4% m.11778G>A, and 48.9% m.14484T>C). Several of the remaining 18 patients had rare mutations previously documented in association with LHON. Of the 14 patients with clinical charts accessible for review, 12 had symptomatic disease, and all but one had bilateral optic neuropathies. Nine patients had classic LHON mutations and 3 had possible novel mutations; 7 were males; 9 had final visual acuity ≤ 20/200 in at least one eye; and 6 of those had ≤20/400 in both eyes. CONCLUSIONS: This study adds to the literature on LHON in Canada, and specifically Southwestern Ontario. The demographic and clinical data regarding LHON in this geographic location, as well as possible novel disease-causing mutations, provide important information to aid clinicians in recognizing cases of LHON that may otherwise be disregarded.

Childhood-Onset Leber Hereditary Optic Neuropathy-Clinical and Prognostic Insights.

PURPOSE: To investigate the clinical and molecular genetic features of childhood-onset Leber hereditary optic neuropathy (LHON) to gain a better understanding of the factors influencing the visual outcome in this atypical form of the disease. DESIGN: Retrospective cohort study. METHODS: We retrospectively included 2 cohorts of patients with LHON with onset of visual loss before the age of 12 years from Italy and the United Kingdom. Ophthalmologic evaluation, including best-corrected visual acuity, orthoptic evaluation, slit-lamp biomicroscopy, visual field testing, and optical coherence tomography, was considered. Patients were classified based on both the age of onset and the pattern of visual loss. RESULTS: A total of 68 patients were stratified based on the age of onset of visual loss: group 1 (<3 years): 14 patients (20.6%); group 2 (≥3 to <9 years): 27 patients (39.7%); and group 3 (≥9 to ≤12 years): 27 patients (39.7%). Patients in group 2 achieved a better visual outcome than those in group 3. Patients in groups 1 and 2 had better mean deviation on visual field testing than those in group 3. The mean ganglion cell layer thickness on optical coherence tomography in group 2 was higher than those in groups 1 and 3. Patients were also categorized based on the pattern of visual loss as follows: Subacute Bilateral: 54 patients (66.7%); Insidious Bilateral: 14 patients (17.3%); Unilateral: 9 patients (11.1%); and Subclinical Bilateral: 4 patients (4.9%). CONCLUSIONS: Children who lose vision from LHON before the age of 9 years have a better visual prognosis than those who become affected in later years, likely representing a "form frustre" of the disease.

Low disease risk and penetrance in Leber hereditary optic neuropathy.

The risk of Leber hereditary optic neuropathy (LHON) has largely been extrapolated from disease cohorts, which underestimate the population prevalence of pathogenic primary LHON variants as a result of incomplete disease penetrance. Understanding the true population prevalence of primary LHON variants, alongside the rate of clinical disease, provides a better understanding of disease risk and variant penetrance. We identified pathogenic primary LHON variants in whole-genome sequencing data of a well-characterized population-based control cohort and found that the prevalence is far greater than previously estimated, as it occurs in approximately 1 in 800 individuals. Accordingly, we were able to more accurately estimate population risk and disease penetrance in LHON variant carriers, validating our findings by using other large control datasets. These findings will inform accurate counseling in relation to the risk of vision loss in LHON variant carriers and disease manifestation in their family. This Matters Arising paper is in response to Lopez Sanchez et al. (2021), published in The American Journal of Human Genetics. See also the response by Mackey et al. (2022), published in this issue.

Incidence of Leber hereditary optic neuropathy in 2019 in Japan: a second nationwide questionnaire survey.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is an acute or subacute optic neuropathy that mainly affects young males. The first nationwide epidemiological survey of LHON was conducted in 2014 in Japan, and LHON was officially designated as a rare intractable disease by the Japanese government in 2015. We conducted a second survey of the annual incidence of LHON in 2019, and estimated the total number of patients with LHON in Japan. RESULTS: A questionnaire was sent to 997 facilities accredited by the Japanese Ophthalmological Society and/or affiliated with the councilors of the Japanese Neuro-Ophthalmology Society. Responses were received from 791 facilities, with a response rate of 79%. Fifty-five newly diagnosed cases (49 males and 6 females) of LHON were reported from 35 institutions in 2019, with a median age of 28.5 for males and 49.5 years for females. The total number of newly diagnosed cases was calculated as 69 (62 were males and 7 were females, 95% confidence interval 55-83), and the total number of patients was estimated to be 2491 (95% confidence interval: 1996-2986), suggesting a prevalence of LHON in Japan of 1:50,000. CONCLUSION: The incidence of LHON in 2019 was lower than the estimate in 2014, whereas its prevalence may be similar to that reported in other countries. The accurate estimation of the incidence and prevalence of patients with LHON requires prospective registration.

Vitamin B12 in Leber hereditary optic neuropathy mutation carriers: a prospective cohort study.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder, frequently resulting in acute or subacute severe bilateral central vision loss. Vitamin B12 deficiency is also a known cause of optic neuropathy through mitochondrial dysfunction. Here we evaluated the prevalence and clinical significance of vitamin B12 deficiency in a large cohort of LHON patients and asymptomatic mutation carriers from a tertiary referral center. METHODS: From the Munich LHON prospective cohort study, participants included all LHON patients and asymptomatic LHON mutation carriers, who were recruited between February 2014 and March 2020 and consented to participate. Neurological, general, and ophthalmological examinations were regularly performed, as were laboratory tests. Vitamin B12 deficiency was diagnosed if serum vitamin B12 was below 201 pg/mL, or if 201-339 pg/mL plus low serum holotranscobalamin or elevated serum methylmalonic acid or elevated total plasma homocysteine. RESULTS: We analyzed 244 subjects, including 147 symptomatic LHON patients (74% males) and 97 asymptomatic mutation carriers (31% males). Median age at study baseline was 34 years (range 5-82 years). The prevalence of vitamin B12 deficiency was higher for LHON mutation carriers than for the general population in all age categories. This was statistically significant for the LHON mutation carriers under 65 years (21% vs. 5-7%, p = 0.002). While vitamin B12 deficiency prevalence was not statistically different between LHON patients and asymptomatic mutation carriers, its clinical correlates, e.g., macrocytosis and polyneuropathy, were more frequent in the subgroup of LHON patients. Excessive alcohol consumption was a significant predictor of vitamin B12 deficiency (p < 0.05). CONCLUSIONS: The high prevalence of vitamin B12 deficiency in LHON mutation carriers, both asymptomatic mutation carriers and LHON patients, highlights the need for regular vitamin B12 screening in this population, in order to ensure early treatment, aiming for better outcomes. Our study is not conclusive regarding vitamin B12 deficiency as determinant for disease conversion in LHON, and further research is warranted to disentangle the role of vitamin B12 in the pathophysiology and prognosis of LHON.

The epidemiology and mutation types of Leber's hereditary optic neuropathy in Thailand.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy.

BACKGROUND: Leber's hereditary optic neuropathy (LHON) has been considered a prototypical mitochondriopathy and a textbook example for maternal inheritance linked to certain disease-causing variants in the mitochondrial genome. Recently, an autosomal recessive form of LHON (arLHON) has been described, caused by disease-causing variants in the nuclear encoded gene DNAJC30. METHODS AND RESULTS: In this study, we screened the DNAJC30 gene in a large Central European cohort of patients with a clinical diagnosis of LHON or other autosomal inherited optic atrophies (OA). We identified likely pathogenic variants in 35/1202 patients, corresponding to a detection rate of 2.9%. The previously described missense variant c.152A>G;p.(Tyr51Cys) accounts for 90% of disease-associated alleles in our cohort and we confirmed a strong founder effect. Furthermore, we identified two novel pathogenic variants in DNAJC30: the nonsense variant c.610G>T;p.(Glu204*) and the in-frame deletion c.230_232del;p.(His77del). Clinical investigation of the patients with arLHON revealed a younger age of onset, a more frequent bilateral onset and an increased clinically relevant recovery compared with LHON associated with disease-causing variants in the mitochondrial DNA. CONCLUSION: This study expands previous findings on arLHON and emphasises the importance of DNAJC30 in the genetic diagnostics of LHON and OA in European patients.

Establishing risk of vision loss in Leber hereditary optic neuropathy.

We conducted an updated epidemiological study of Leber hereditary optic neuropathy (LHON) in Australia by using registry data to establish the risk of vision loss among different LHON mutations, sex, age at onset, and mitochondrial haplogroup. We identified 96 genetically unrelated LHON pedigrees, including 56 unpublished pedigrees, and updated 40 previously known pedigrees, comprising 620 affected individuals and 4,948 asymptomatic carriers. The minimum prevalence of vision loss due to LHON in Australia in 2020 was one in 68,403 individuals. Although our data confirm some well-established features of LHON, the overall risk of vision loss among those with a LHON mutation was lower than reported previously-17.5% for males and 5.4% for females. Our findings confirm that women, older adults, and younger children are also at risk. Furthermore, we observed a higher incidence of vision loss in children of affected mothers as well as in children of unaffected women with at least one affected brother. Finally, we confirmed our previous report showing a generational fall in prevalence of vision loss among Australian men. Higher reported rates of vision loss in males with a LHON mutation are not supported by our work and other epidemiologic studies. Accurate knowledge of risk is essential for genetic counseling of individuals with LHON mutations. This knowledge could also inform the detection and validation of potential biomarkers and has implications for clinical trials of treatments aimed at preventing vision loss in LHON because an overestimated risk may lead to an underpowered study or a false claim of efficacy.

Genetic Spectrum and Characteristics of Hereditary Optic Neuropathy in Taiwan.

Hereditary optic neuropathy (HON) is a group of genetically heterogeneous diseases that cause optic nerve atrophy and lead to substantial visual impairment. HON may present with optic nerve atrophy only or in association with various systemic abnormalities. Although a genetic survey is indispensable for diagnosing HON, conventional sequencing techniques could render its diagnosis challenging. In this study, we attempted to explore the genetic background of patients with HON in Taiwan through capture-based next-generation sequencing targeting 52 HON-related genes. In total, 57 patients from 48 families were recruited, with 6 patients diagnosed as having Leber hereditary optic neuropathy through initial screening for three common variants (m.3460G>A, m.11778G>A, m.14484T>C). Disease-causing genotypes were identified in 14 (33.3%) probands, and OPA1 variants were the most prevalent cause of autosomal HON. Exposure to medications such as ethambutol could trigger an attack of autosomal dominant optic atrophy. WFS1 variants were identified in three probands with variable clinical features in our cohort. Hearing impairment could occur in patients with OPA1 or WFS1 variants. This is the first comprehensive study investigating the genetic characteristics of HON in Taiwan, especially for autosomal HON. Our results could provide useful information for clinical diagnosis and genetic counseling in this field.

Molecular genetics of inherited retinal degenerations in Icelandic patients.

The study objective was to delineate the genetics of inherited retinal degenerations (IRDs) in Iceland, a small nation of 364.000 and a genetic isolate. Benefits include delineating novel pathogenic genetic variants and defining genetically homogenous patients as potential investigative molecular therapy candidates. The study sample comprised patients with IRD in Iceland ascertained through national centralized genetic and ophthalmological services at Landspitali, a national social support institute, and the Icelandic patient association. Information on patients' disease, syndrome, and genetic testing was collected in a clinical registry. Variants were reevaluated according to ACMG/AMP guidelines. Overall, 140 IRD patients were identified (point prevalence of 1/2.600), of which 70 patients had a genetic evaluation where two-thirds had an identified genetic cause. Thirteen disease genes were found in patients with retinitis pigmentosa, with the RLBP1 gene most common (n = 4). The c.1073 + 5G > A variant in the PRPF31 gene was homozygous in two RP patients. All tested patients with X-linked retinoschisis (XLRS) had the same possibly unique RS1 pathogenic variant, c.441G > A (p.Trp147X). Pathologic variants and genes for IRDs in Iceland did not resemble those described in ancestral North-Western European nations. Four variants were reclassified as likely pathogenic. One novel pathogenic variant defined a genetically homogenous XLRS patient group.

Smoking and alcohol, health-related quality of life and psychiatric comorbidities in Leber's Hereditary Optic Neuropathy mutation carriers: a prospective cohort study.

BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a rare mitochondrial disorder, characterized by acute or subacute bilateral vision loss, frequently leading to significant chronic disability, mainly in young people. The causal LHON mutations of the mitochondrial DNA have incomplete penetrance, with the highest risk of disease manifestation for male mutation carriers in the second and third decades of life. Here we evaluated smoking, alcohol drinking habits, health-related quality of life (QOL) and psychiatric comorbidities in a cohort of LHON patients and asymptomatic mutation carriers from a tertiary referral centre. METHODS: Cross-sectional analysis of the ongoing Munich LHON prospective cohort study. Participants included all LHON patients and asymptomatic LHON mutation carriers older than 16 years at baseline, who were recruited between February 2014 and June 2015 and consented to participate. General, neurological and ophthalmological investigations were performed, including validated questionnaires on smoking, alcohol drinking habits, depressive symptoms and health-related QOL. RESULTS: Seventy-one participants were included, 34 LHON patients (82% male) and 37 asymptomatic mutation carriers (19% male). Median age at baseline was 36 years (range 18-75 years). For LHON patients, median age at visual loss onset was 27 years (9 to 72 years). Smoking is more frequent in LHON patients than asymptomatic LHON mutation carriers, and significantly more frequent in both groups than in the general population. Sixty percent of LHON patients, who smoked at disease onset, stopped or significantly reduced smoking after visual loss onset, yet 40% of LHON patients continued to smoke at study baseline. Excessive alcohol consumption is more frequent in male LHON patients than in LHON asymptomatic and more frequent than in the male general population. Further, female asymptomatic LHON mutation carriers are at risk for depression and worse mental QOL scores. CONCLUSIONS: Given the high prevalence of smoking and excessive drinking in LHON mutation carriers, implementing effective measures to reduce these risk factors may have a significant impact in reducing LHON disease conversion risk. The underrecognized prevalence of mental health issues in this population of LHON mutation carriers highlights the need for awareness and more timely diagnosis, which may lead to improved outcomes.

Prevalence of primary mutations in Leber hereditary optic neuropathy: A five-year report from a tertiary eye care center in India.

PURPOSE: Genetic testing for primary mutations m.3460G>A, m.11778G>A, and m.14484T>C in ND1, ND4, and ND6 genes of mitochondrial DNA is the recommended assay for Leber hereditary optic neuropathy (LHON; OMIM 535000). This report discusses the outcome of molecular genetic screening for these three primary mutations in suspected LHON cases in India. METHODS: Two hundred and seventy-eight unrelated presumed LHON patients who were seen at the neuro-ophthalmology clinic of a tertiary eye care center from 2014-2018 were analyzed. They were genotyped for the three common variants by polymerase chain reaction-based direct sequencing, and their plasmy status was also determined by restriction enzyme digestion. RESULTS: Eighty two of 278 patients were positive for one of the 3 common mutations with m.11778G>A in ND4 gene more frequently distributed (N=72) in homoplasmic state (N=59/82). The mean onset age of visual loss was 21.1years (SD, 9.8 years; range, 5-58 years) in patients harboring the primary mutation. The most common clinical presentation was bilateral sequential painless vision loss with central and cecocentral scotomas in the visual field due to optic disc atrophy. CONCLUSIONS: The study subjects are a sample of a much larger number of suspected LHON cases tested for primary mutations in India. (N= 278) and 29.4% (82/278) of patients harbour one of the 3 common mutations. Screening the entire mitochondrial genome and the other nuclear genes encoding mitochondrial protein, would probably aid in identifying the other less common mtDNA mutations causing LHON in Indian population.

A hospital-based five-year prospective study on the prevalence of Leber's hereditary optic neuropathy with genetic confirmation.

Purpose: To estimate the prevalence of Leber hereditary optic neuropathy (LHON) along with genetic screening at a tertiary eye care center in southern India. Methods: Patients with LHON were identified at the Neuro-Ophthalmology Clinic, Aravind Eye Hospital (AEH; Madurai, India) from 2015 to 2019. Clinical data were collected along with blood samples. Genetic testing was performed for the confirmation of LHON using a multiplex PCR restriction fragment length polymorphism (RFLP) approach to detect the primary mutations 3460A, 11778A, and 14484C in mitochondrial DNA (mtDNA). Results: During the study period, 1,598,441 outpatients attended AEH of whom 40,527 were referred to the Neuro-Ophthalmology Clinic. Among them, 55 patients were diagnosed with LHON. The male to female ratio was 8.2:1.0, and the mean age at onset was 20.95 years (SD 8.940). The estimated prevalence was 1:737 or 13.57 per 10,000 (95% confidence intervals [CI] 10.23-17.66) at the Neuro-Ophthalmology Clinic. The frequency of primary mutations in the patients with LHON was determined as 43.6% (24/55), giving a prevalence of 1:1689 or 5.92 per 10,000 (95% CI 3.78-8.81). Conclusions: The high prevalence of LHON observed at a single hospital highlights the impact of the disease in southern India. As the epidemiology of LHON remains unexplored in this region, these findings will pave the way to evaluate the national prevalence. Further, screening the whole mitochondrial genome may help to increase the detection of mutations to estimate the accurate prevalence of the disease.

Mitochondrial genome variation in male LHON patients with the m.11778G > A mutation.

Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder with symptoms limited to a single tissue, optic nerve, resulting in vision loss. In the majority of cases it is caused by one of three point mutations in mitochondrial DNA (mtDNA) but their presence is not sufficient for disease development, since ~50% of men and ~10% women who carry them are affected. Thus additional modifying factors must exist. In this study, we use next generation sequencing to investigate the role of whole mtDNA variation in male Polish patients with LHON and m.11778G > A, the most frequent LHON mutation. We present a possible association between mtDNA haplogroup K and variants in its background, a combination of m.3480A > G, m.9055G > A, m.11299 T > C and m.14167C > T, and LHON mutation. These variants may have a negative effect on m.11778G > A increasing its penetrance and the risk of LHON in the Polish population. Surprisingly, we did not observe associations previously reported for m.11778G > A and LHON in European populations, particularly for haplogroup J as a risk factor, implying that mtDNA variation is much more complex. Our results indicate possible contribution of novel combination of mtDNA genetic factors to the LHON phenotype.

Usefulness of Neuromuscular Co-morbidity, Left Bundle Branch Block, and Atrial Fibrillation to Predict the Long-Term Prognosis of Left Ventricular Hypertrabeculation/Noncompaction.

The prognosis of patients with left ventricular hypertrabeculation/noncompaction (LVHT) is assessed controversially. LVHT is associated with other cardiac abnormalities and with neuromuscular disorders (NMD). Aim of the study was to assess cardiac and neurological findings as predictors of mortality rate in adult LVHT-patients. Included were patients with LVHT diagnosed between 1995 and 2019 in 1 echocardiographic laboratory. Patients underwent a baseline cardiologic examination and were invited for a neurological investigation. In January 2020, their survival status was assessed. End points were death or heart transplantation. LVHT was diagnosed by echocardiography in 310 patients (93 female, aged 53 ± 18 years) with a prevalence of 0.4%/year. A neurologic investigation was performed in 205 patients (67%). A specific NMD was found in 33 (16%), NMD of unknown etiology in 123 (60%) and the neurological investigation was normal in 49 (24%) patients. During follow-up of 84 ± 71 months, 59 patients received electronic devices, 105 patients died, and 6 underwent heart transplantation. The mortality was 4.7%/year, the rate of heart transplantation/death 5%/year. By multivariate analysis, the following parameters were identified to elevate the risk of mortality/heart transplantation: increased age (p = 0.005), inpatient (p = 0.001), presence of a specific NMD (p = 0.0312) or NMD of unknown etiology (p = 0.0365), atrial fibrillation (p = 0.0000), ventricular premature complexes (p = 0.0053), exertional dyspnea (p = 0.0023), left bundle branch block (p = 0.0201), and LVHT of the posterior wall (p = 0.0158). In conclusion, LVHT patients should be systematically investigated neurologically since neurological co-morbidity has a prognostic impact.

Genotypic and phenotypic characteristics of Korean children with childhood-onset Leber's hereditary optic neuropathy.

PURPOSE: We sought to identify the phenotypic and genotypic characteristics of Korean children with genetically confirmed Leber's hereditary optic neuropathy (LHON). METHODS: The medical records of 64 genetically confirmed LHON patients were reviewed. Seventeen patients aged 13 years or younger with optic atrophy with positive mitochondrial DNA (mtDNA) mutations were considered to demonstrate childhood-onset LHON. The non-childhood-onset group included 47 patients with genetically confirmed LHON who experienced disease onset later than 13 years of age. The type of mtDNA mutation, visual acuity (VA), color vision, fundus photography, retinal nerve fiber layer (RNFL) thickness, and visual field were investigated. RESULTS: Sequence analysis of the mitochondrial genome revealed five different kinds of LHON-associated mtDNA mutations among our childhood-onset patients, including m.11778G>A (58.8%), m.3496G>T (11.8%), m.3497C>T (5.9%), m.11696G>A (5.9%), and m.14502T>C (5.9%). The mean final best-corrected VA in the childhood-onset group was better than that in the non-childhood-onset group with the value of logMAR 0.29 (0.09-0.75) vs. 0.55 (0.27-1.29) (expressed as median (interquartile range); p = 0.05). Spontaneous visual recovery was observed in 35.3% of the childhood-onset group but in only 12.8% of the non-childhood-onset group (p = 0.04). Eight patients (47.1%) showed interocular asymmetry of the disease, with two presenting true unilateral involvement of the optic nerve and the other six patients demonstrating unilateral subclinical manifestations with bilateral optic atrophy. CONCLUSION: Involvement of secondary mitochondrial mutations was confirmed in patients with childhood-onset LHON. Characteristic clinical features of childhood-onset LHON included a higher proportion of subacute or insidious onset of symptoms, better VA, higher spontaneous recovery, and asymmetrical ocular involvement.