The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands.

Hereditary optic neuropathies are caused by the degeneration of retinal ganglion cells whose axons form the optic nerves, with a consistent genetic heterogeneity. As part of our diagnostic activity, we retrospectively evaluated the combination of Leber hereditary optic neuropathy mutations testing with the exon sequencing of 87 nuclear genes on 2186 patients referred for suspected hereditary optic neuropathies. The positive diagnosis rate in individuals referred for Leber hereditary optic neuropathy testing was 18% (199/1126 index cases), with 92% (184/199) carrying one of the three main pathogenic variants of mitochondrial DNA (m.11778G>A, 66.5%; m.3460G>A, 15% and m.14484T>C, 11%). The positive diagnosis rate in individuals referred for autosomal dominant or recessive optic neuropathies was 27% (451/1680 index cases), with 10 genes accounting together for 96% of this cohort. This represents an overall positive diagnostic rate of 30%. The identified top 10 nuclear genes included OPA1, WFS1, ACO2, SPG7, MFN2, AFG3L2, RTN4IP1, TMEM126A, NR2F1 and FDXR. Eleven additional genes, each accounting for less than 1% of cases, were identified in 17 individuals. Our results show that 10 major genes account for more than 96% of the cases diagnosed with our nuclear gene panel.

[Metabolic disorders in hereditary optic neuropathies]. / Metabolicheskie narusheniya pri nasledstvennykh opticheskikh neiropatiyakh.

Folate metabolism disorders are known to have a potential involvement in the pathophysiology of mitochondrial diseases. Many researchers suggest that profound systemic folate deficiency may contribute to mitochondrial folate deficiency. Folic acid metabolism is closely related to vitamin B12 and homocysteine. Considering that hereditary optic neuropathies (HON) are mitochondrial diseases, it is important to study the folate status, the content of vitamin B12 and homocysteine in patients with this pathology. OBJECTIVE: To compare the content of folic acid, vitamin B12 and homocysteine in the blood serum of patients with Leber's hereditary optic neuropathy (LHON) and autosomal recessive optic neuropathy (ARON), optic neuropathy of other genesis, and the comparison group. MATERIAL AND METHODS: The study involved 58 patients with LHON and ARON, the control group of 49 patients with ischemic, inflammatory, traumatic and compressive optic neuropathies, and the comparison group of 20 healthy volunteers. RESULTS: A decrease in blood folic acid levels was revealed (4.0±1.6 ng/mL) in patients with HON compared to the control group (p=1.3·10-8) and the comparison group (p=1·10-17). The content of vitamin B12 in patients with HON was 380.8±168.1 pg/mL, which was significantly lower than in the comparison group (p=0.0001). The homocysteine content was 14.1±5.6 µmol/L in patients with HON, which was significantly higher than in the control group (p=0.0007) and the comparison group (p=0.000003). At the same time, an increase in homocysteine level of more than 10 µmol/L was revealed in 75% of patients with HON. Similar metabolic disorders were found in groups with various mutations in mitochondrial and nuclear DNA. CONCLUSION: Patients with HON showed marked decrease in the levels of folic acid and vitamin B12, as well as hyperhomocysteinemia. It is very important to identify the causes of metabolic disorders in order to determine the role of folate deficiency in the development of HON, as well as the possibility of its pharmacological treatment.

[Autosomal recessive optic neuropathies: genetic variants, clinical manifestations]. / Autosomno-retsessivnye opticheskie neiropatii: geneticheskie varianty, klinicheskie proyavleniya.

Hereditary optic neuropathies (HON) - a group of neurodegenerative diseases characterized by primary loss of structure and function of the retinal ganglion cells and subsequent death of their axons, development of partial optic nerve atrophy. Autosomal dominant optic neuropathy and Leber`s hereditary optic neuropathy until recently were considered the most common genetic hereditary optic neuropathies, while autosomal recessive optic neuropathies (ARON) were described as rare types of HON, usually accompanying severe syndromic pathologies. In the 2000s it has become clear that ARON occur significantly more often, are underestimated, and their clinical variability is poorly studied. Despite the fact that non-syndromic ARON are less common than syndromic optic neuropathies, their contribution to the development of isolated hereditary optic neuropathies should be considered. This article presents a literature review on non-syndromic ARON developing as a result of mutations in the ACO2, MCAT, WFS1, RTN4IP1, TMEM126A, NDUFS2, DNAJC30 genes.

Mutation Screening of mtDNA Combined Targeted Exon Sequencing in a Cohort With Suspected Hereditary Optic Neuropathy.

Purpose: Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) are the two commonest forms of hereditary optic neuropathy. The aim of this study was to comprehensively investigate the incidence and spectrum of mutations in patients with suspected hereditary optic neuropathy by combining mitochondrial DNA (mtDNA) genome-wide and targeted exon sequencing. Methods: A cohort of 1101 subjects were recruited to participate in the study, comprising 177 families (177 probands and their family members, a total of 537 subjects, including 254 patients) and 164 sporadic cases with suspected hereditary optic neuropathy, and 400 unrelated control subjects for genetic analysis: all subjects (including control subjects) underwent a comprehensive ophthalmologic examination and were subjected to sequencing analysis of mtDNA genome-wide and targeted exon. Overall, targeted exon sequencing was used to screen 792 genes associated with common hereditary eye diseases, and the mtDNA genome-wide were screened by next-generation sequencing. Results: We found variants detected in 168 (40.2%, 168/418) of the 418 patients screened. Among these, 132 cases (78.6%, 132/168) were detected with known LHON disease-causing mtDNA variants; 40 cases (23.8%, 40/168) were detected with nuclear DNA (ntDNA) variants, which included 36 cases (21.4%, 36/168) with detected OPA1 mutations, 4 patients (2.4%, 4/168) with detected OPA3 mutations, and 2 patients (1.2%, 2/168) with detected TMEM126A homozygous mutation. Coexistence variation (mtDNA/mtDNA [n = 16], ntDNA/ntDNA [n = 4], mtDNA/ntDNA [n = 7]) was found in 27 patients (16.4%, 27/165), including mtDNA/ntDNA coexistence variation that was detected in seven patients. Among these ntDNA mutations, 38 distinct disease-causing variants, including autosomal recessive heterozygous mutations, were detected, which included 22 novel variants and two de novo variants. Total haplogroup distribution showed that 34.5% (29/84) and 28.6% (24/84) of the affected subjects with m.11778G>A belonged to haplogroup D and M, with a high frequency of subhaplogroups D4, D5, and M7. Conclusions: The LHON-mtDNA mutations are the commonest genetic defects in this Chinese cohort, followed by the OPA1 mutations. To our knowledge, this is the first comprehensive study of LHON, ADOA, and autosomal recessive optic atrophy combined with mtDNA genome-wide and targeted exon sequencing, as well as haplogroup analysis, in a large cohort of Chinese patients with suspected hereditary optic neuropathy. Our findings provide a powerful basis for genetic counseling in patients with suspected hereditary optic neuropathy. Translational Relevance: We applied mtDNA genome-wide sequencing combined with panel-based targeted exon sequencing to explore the pathogenic variation spectrum and genetic characteristics of patients with suspected hereditary optic neuropathy, providing a comprehensive research strategy for clinical assistant diagnosis, treatment, and genetic counseling.

Clinical approach to optic neuropathies.

Optic neuropathy is a frequent cause of vision loss encountered by ophthalmologist. The diagnosis is made on clinical grounds. The history often points to the possible etiology of the optic neuropathy. A rapid onset is typical of demyelinating, inflammatory, ischemic and traumatic causes. A gradual course points to compressive, toxic/nutritional and hereditary causes. The classic clinical signs of optic neuropathy are visual field defect, dyschromatopsia, and abnormal papillary response. There are ancillary investigations that can support the diagnosis of optic neuropathy. Visual field testing by either manual kinetic or automated static perimetry is critical in the diagnosis. Neuro-imaging of the brain and orbit is essential in many optic neuropathies including demyelinating and compressive. Newer technologies in the evaluation of optic neuropathies include multifocal visual evoked potentials and optic coherence tomography.