Globally, the World Health Organization ranks major depressive disorder (MDD) as the leading cause of disability. However, MDD molecular etiology is still poorly understood.

To explore the possible association between mitochondrial ND6 T14502C mutation and MDD.

Clinical data were collected from two pedigrees, and detailed mitochondrial genomes were obtained for the two proband members. The assessment of the resulting variants included an evaluation of their evolutionary conservation, allelic frequencies, as well as their structural and functional consequences. Detailed mitochondrial whole genome analysis, phylogenetic, and haplotype analysis were performed on the probands.

Herein, we reported the clinical, genetic, and molecular profiling of two Chinese families afflicted with MDD. These Chinese families exhibited not only a range of onset and severity ages in their depression but also extremely low penetrances to MDD. Sequence analyses of mitochondrial genomes from these pedigrees have resulted in the identification of a homoplasmic T14502C (I58V) mutation. The polymorphism is located at a highly conserved isoleucine at position 58 of ND6 and distinct mitochondrial DNA (mtDNA) polymorphisms originating from haplogroups M10 and H2.

Identifying the T14502C mutation in two individuals with no genetic relation who exhibit symptoms of depression provides compelling evidence that this mutation may be implicated in MDD development. Nonetheless, the two Chinese pedigrees that carried the T14502C mutation did not exhibit any functionally significant mutations in their mtDNA. Therefore, the phenotypic expression of the T14502C mutation related to MDD may be influenced by the nuclear modifier gene(s) or environmental factors.

A 29-year-old female with no family history presented with bilateral progressive blurred vision. Her symptoms appeared at 12-years-old and her visual acuity had since deteriorated from 0.6 to 0.2 bilaterally with decreased critical flicker frequency and bilateral central scotomas. She did not have a relative afferent pupillary defect. Fundoscopy revealed no distinct disc hyperaemia, atrophy, or peripapillary telangiectatic vessels. The retinal nerve fibre layer appeared normal on optical coherence tomography in each eye; however, loss of the interdigitation zone and the disruption of the ellipsoid zone at the fovea were observed in both eyes. Multifocal electroretinography revealed decreased amplitudes at both macula regions. Mitochondrial deoxyribonucleic acid analysis identified an m.14502T>C mutation, one of the primary mutations causing Leber's hereditary optic neuropathy (LHON). Despite the presence of a marked LHON mutation, however, she was clinically diagnosed as having an occult macular dystrophy. There have only been five previous case reports, all of which were sporadic, which detail the clinical characteristics of the m.14502T>C mutation. The m.14502T>C phenotype is somewhat consistent with that of the other major mutations, including young onset, bilateral progressive visual impairment, and a typical LHON fundus. Nevertheless, m.14502T>C alone has an extremely low penetrance and its phenotype may be minimal or subclinical, as seen in our case. Since little is known about the clinical course of the m.14502T>C mutation it may be possible that the LHON phenotype may appear in later stages of life. Moreover, m.14502T>C may function as a modifier gene, which alters the phenotype of other coexisting major LHON mutations, including penetrance and the severity of the disease, through synergistic effects.

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.

The current research aims to investigate relationships between the optic nerve (ON) lesion length with visual function in the pre-chronic phase ( illness duration < 12 months) of LHON.

Orbital MRI was retrospectively analyzed for 45 patients with LHON in the pre-chronic phase. ON lesion length was measured by 2 trained independent readers and it was recorded as multiplication of the number of abnormal MRI slices and slice thickness on T2-STIR sequence in the coronal plane. Decimal visual acuity was converted to the logarithm of minimum angle of resolution. Intra-class correlation coefficients (ICCs) were used to assess intra- and inter-observer agreements. Pearson's correlation analysis and multivariate linear regression models were performed to analyze the correlations of the lesion length with best corrected visual acuity (BCVA) and visual field parameters.

81 afflicted eyes were selected. The ICCs for intra-observer and inter-observer analyses were 0.989 and 0.980 respectively. Both Pearson's correlation analysis and multivariate linear regression models indicated a significant positive correlation between the BCVA or mean deviation (MD) and ON lesion length (r_BCVA=0.368, P_BCVA=0.001; r_MD=-0.269, P_MD=0.045) with a coefficient of determination (R²) of 0.152 and 0.114 respectively adjusted for patients' sex, age of onset, onset of vision loss to performance of MRI, mitochondrial DNA mutations.

ON length with T2-STIR hyperintensities was positively associated with both BCVA and MD, and it was suspected to be a biomarker of visual disability in the pre-chronic phase of LHON.

Current research has not provided a consistent and qualitative description of MRI features in Leber hereditary optic neuropathy (LHON). Our study aims to investigate the MRI findings in the pregeniculate visual pathway and discuss their clinical significance in LHON.

Orbital MRI was retrospectively analyzed for 53 patients with LHON (101 afflicted eyes) admitted to the Department of Neurology, Beijing Tongren Hospital, Capital Medical University, from 2014 to 2019. We described the imaging abnormalities and discussed their associations with the time interval from the onset of vision loss to the performance of MRI (TIOVP), prevalence of m.11778G>A, and best-corrected visual acuity (BCVA).

T2 hyperintense signal (HS) was determined in 82 afflicted eyes, with 34 located in the intraorbital segment (IO) of the optic nerve (ON), 26 in the IO concurrent with intracanalicular segment (ICn), 14 in the IO and ICn concurrent with intracranial segment (ICr) of the ON, 4 in the IO, ICn, and ICr concurrent with optic chiasm (OCh), and 4 in the IO, ICn, ICr, and OCh concurrent with optic tract (OTr). MRI was normal in the remaining 19 afflicted eyes. Among the 6 groups, no statistical differences were found in the TIOVP (P = 0.071), prevalence of m.11778G>A (P = 0.234), and BCVA (P = 0.076). As T2 HS extended, the BCVA gradually decreased. Nineteen of the 54 afflicted eyes revealed contrast enhancement, with the TIOVP ranging from 0.25 to 6 months.

T2 HS was common in the pregeniculate visual pathway in LHON. It was not correlated with the prevalence of m.11778G>A and did not benefit in disease staging. As it extended, the BCVA gradually decreased. Contrast enhancement was relatively rare, always occurring in the subacute stage.

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.

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.

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.

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.