[Pathogenetic basis of optic nerve atrophy in methanol poisoning]. / Patogeneticheskie osnovy razvitiya atrofii zritel'nogo nerva pri toksicheskom porazhenii metanolom.

Optic nerve atrophy is a pathomorphological consequence of diseases of the peripheral neuron of the visual pathway, manifested as atrophy of nerve fibers of varying severity. The toxic effect of methanol is mainly associated with formic acid and formaldehyde, which suppress the cytochrome system, inhibit oxidative phosphorylation, and thereby cause a deficiency of adenosine triphosphoric acid, to which brain and retinal tissues are especially susceptible. When formiate accumulates, tissue respiration is disrupted, leading to pronounced tissue hypoxia. As a result of such methanol metabolism, metabolic acidosis occurs. Tissue hypoxia develops in the first few hours as a result of the action of formic acid on the respiratory enzyme chain at the cytochrome oxidase level. Hypoxia and, as a consequence, a decrease in energy supply lead to a disruption of biological oxidation and the development of apoptosis in the optic nerve fibers. Understanding the process of optic nerve atrophy development at the pathogenetic level in methyl alcohol intoxication will help make a correct early diagnosis and prescribe timely treatment.

Comprehensive overview of disease models for Wolfram syndrome: toward effective treatments.

Wolfram syndrome (OMIM 222300) is a rare autosomal recessive disease with a devastating array of symptoms, including diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing loss, and neurological dysfunction. The discovery of the causative gene, WFS1, has propelled research on this disease. However, a comprehensive understanding of the function of WFS1 remains unknown, making the development of effective treatment a pressing challenge. To bridge these knowledge gaps, disease models for Wolfram syndrome are indispensable, and understanding the characteristics of each model is critical. This review will provide a summary of the current knowledge regarding WFS1 function and offer a comprehensive overview of established disease models for Wolfram syndrome, covering animal models such as mice, rats, flies, and zebrafish, along with induced pluripotent stem cell (iPSC)-derived human cellular models. These models replicate key aspects of Wolfram syndrome, contributing to a deeper understanding of its pathogenesis and providing a platform for discovering potential therapeutic approaches.

[Clinical features of CAPOS syndrome caused by maternal ATP1A3 gene variation: a case report].

CAPOS syndrome is an autosomal dominant neurological disorder caused by mutations in the ATP1A3 gene. Initial symptoms, often fever-induced, include recurrent acute ataxic encephalopathy in childhood, featuring cerebellar ataxia, optic atrophy, areflflexia, sensorineural hearing loss, and in some cases, pes cavus. This report details a case of CAPOS syndrome resulting from a maternal ATP1A3 gene mutation. Both the child and her mother exhibited symptoms post-febrile induction,including severe sensorineural hearing loss in both ears, ataxia, areflexia, and decreased vision. Additionally, the patient's mother presented with pes cavus. Genetic testing revealed a c. 2452G>A（Glu818Lys） heterozygous mutation in theATP1A3 gene in the patient . This article aims to enhance clinicians' understanding of CAPOS syndrome, emphasizing the case's clinical characteristics, diagnostic process, treatment, and its correlation with genotypeic findings.

Optic Nerve MRI T2-Hyperintensity: A Nonspecific Marker of Optic Nerve Damage.

BACKGROUND: MRI abnormalities are common in optic neuropathies, especially on dedicated orbital imaging. In acute optic neuritis, optic nerve T2-hyperintensity associated with optic nerve contrast enhancement is the typical imaging finding. In chronic optic neuropathies, optic nerve T2-hyperintensity and atrophy are regularly seen. Isolated optic nerve T2-hyperintensity is often erroneously presumed to reflect optic neuritis, frequently prompting unnecessary investigations and neuro-ophthalmology consultations. Our goal was to determine the significance of optic nerve/chiasm T2-hyperintensity and/or atrophy on MRI. METHODS: Retrospective study of consecutive patients who underwent brain/orbital MRI with/without contrast at our institution between July 1, 2019, and June 6, 2022. Patients with optic nerve/chiasm T2-hyperintensity and/or atrophy were included. Medical records were reviewed to determine the etiology of the T2-hyperintensity and/or atrophy. RESULTS: Four hundred seventy-seven patients (698 eyes) were included [mean age 52 years (SD ±18 years); 57% women]. Of the 364 of 698 eyes with optic nerve/chiasm T2-hyperintensity without atrophy, the causes were compressive (104), inflammatory (103), multifactorial (49), glaucoma (21), normal (19), and other (68); of the 219 of 698 eyes with optic nerve/chiasm T2-hyperintensity and atrophy, the causes were compressive (57), multifactorial (40), inflammatory (38), glaucoma (33), normal (7), and other (44); of the 115 of 698 eyes with optic nerve/chiasm atrophy without T2-hyperintensity, the causes were glaucoma (34), multifactorial (21), inflammatory (13), compressive (11), normal (10), and other (26). Thirty-six eyes with optic nerve/chiasm T2-hyperintensity or atrophy did not have evidence of optic neuropathy or retinopathy on ophthalmologic examination, and 17 eyes had clinical evidence of severe retinopathy without primary optic neuropathy. CONCLUSIONS: Optic nerve T2-hyperintensity or atrophy can be found with any cause of optic neuropathy and with severe chronic retinopathy. These MRI findings should not automatically prompt optic neuritis diagnosis, workup, and treatment, and caution is advised regarding their use in the diagnostic criteria for multiple sclerosis. Cases of incidentally found MRI optic nerve T2-hyperintensity and/or atrophy without a known underlying optic neuropathy or severe retinopathy are rare. Such patients should receive an ophthalmologic examination before further investigations.

Sensitivity, Specificity, and Cutoff Identifying Optic Atrophy by Macular Ganglion Cell Layer Volume in Syndromic Craniosynostosis.

PURPOSE: To determine the sensitivity, specificity, and cutoff of macular ganglion cell layer (GCL) volume consistent with optic atrophy in children with syndromic craniosynostosis and to investigate factors independently associated with reduction in GCL volume. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: Patients with syndromic craniosynostosis evaluated at Boston Children's Hospital (2010-2022) with reliable macular OCT scans. METHODS: The latest ophthalmic examination that included OCT macula scans was identified. Age at examination, sex, ethnicity, best-corrected logarithm of the minimum angle of resolution (logMAR) visual acuity, cycloplegic refraction, and funduscopic optic nerve appearance were recorded in addition to history of primary or recurrent elevation in intracranial pressure (ICP), Chiari malformation, and obstructive sleep apnea (OSA). Spectral-domain OCT software quantified segmentation of macula retinal layers and was checked manually. MAIN OUTCOME MEASURES: The primary outcome was determining sensitivity, specificity, and optimal cutoff of GCL volume consistent with optic atrophy. The secondary outcome was determining whether previously elevated ICP, OSA, Chiari malformation, craniosynostosis diagnosis, logMAR visual acuity, age, or sex were independently associated with lower GCL volume. RESULTS: Median age at examination was 11.9 years (interquartile range, 8.5-14.8 years). Fifty-eight of 61 patients (112 eyes) had reliable macula scans, 74% were female, and syndromes represented were Apert (n = 14), Crouzon (n = 17), Muenke (n = 6), Pfeiffer (n = 6), and Saethre-Chotzen (n = 15). Optimal cutoff identifying optic atrophy was a GCL volume < 1.02 mm3 with a sensitivity of 83% and specificity of 77%. Univariate analysis demonstrated that significantly lower macular GCL volume was associated with optic atrophy on fundus examination (P < 0.001), Apert syndrome (P < 0.001), history of elevated ICP (P = 0.015), Chiari malformation (P = 0.001), OSA (P < 0.001), male sex (P = 0.027), and worse logMAR visual acuity (P < 0.001). Multivariable median regression analysis confirmed that only OSA (P = 0.005), optic atrophy on fundus examination (P = 0.003), and worse logMAR visual acuity (P = 0.042) were independently associated with lower GCL volume. CONCLUSIONS: Surveillance for optic atrophy by GCL volume may be useful in a population where cognitive skills can limit acquisition of other key ophthalmic measures. It is noteworthy that OSA is also associated with lower GLC volume in this population. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Optic atrophy in prematurity: pathophysiology and clinical features.

Optic atrophy is an important cause of visual impairment in children, and the aetiological profile has changed over time. Technological advancements led by neuroimaging of the visual pathway and imaging of the optic nerve with optical coherence tomography have accelerated the understanding of this condition. In the new millennium, an increasing prevalence of prematurity as a cause of optic atrophy in children has been highlighted. This new shift has been linked with increasing rates of premature births and improved neonatal survival of preterm infants. The available literature is limited to hospital and registry-based cohorts with modest sample sizes, methodological heterogeneity and selection bias limitations. Larger studies that are better designed are required to better understand the contribution of prematurity to the disease burden. In addition to considering other life-threatening aetiologies, screening for premature birth should be covered as part of a comprehensive history when evaluating a child with paediatric optic atrophy.

Quantification of peripapillary nerve fibre elevation and its association with axial length, optic disc tilt, and parapapillary atrophy area in young, healthy eyes.

BACKGROUND: Eyes with peripapillary nerve fibre elevation (pNFE) may have a gap between the optic nerve papillary margin on colour fundus photography and Bruch's membrane opening on cross-sectional optical coherence tomography (OCT). This study was conducted to evaluate the quantification of the height of pNFE in young healthy eyes and examine the relationship between pNFE height and axial length. METHODS: A prospective, observational, cross-sectional study was performed involving 117 right eyes. All participants (mean age 25.8 years) underwent comprehensive ophthalmologic examination involving axial length, fundus photography, and peripapillary and optic disc OCT. pNFE height was defined as the distance between the retinal surface plane and the upper edge of the pNFE in optic disc cross-sectional OCT images. Optic disc tilt was evaluated using a sine curve on retinal nerve fibre layer B-scan images. Parapapillary atrophy (PPA) area in colour fundus images was calculated using ImageJ and corrected using Bennett's formula. We evaluated relationships between pNFE height, axial length, optic disc papillary tilt, and PPA area using Spearman's correlation analysis. RESULTS: Sixty-five eyes had pNFE, with a mean pNFE height of 84.7 µm. pNFE height was significantly positively correlated with axial length (r = 0.32, p < 0.001), optic disc tilt (r = 0.25, p = 0.008), and PPA area (r = 0.27, p = 0.004). CONCLUSIONS: pNFE is not rare in young healthy eyes. Eyes with higher pNFE had a longer axial length and larger optic disc tilt and PPA area.

Risk factors associated with progression from papilloedema to optic atrophy: results from a cohort of 113 patients.

BACKGROUND: The aim of this study was to assess the risk factors for atrophic progression of patients with papilloedema secondary to intracranial hypertension, using optical coherence tomography parameters. METHODS: A retrospective study was conducted at Marseille University Hospitals' Ophthalmology departments between December 2015 and December 2021. All patients with papilloedema resulting from elevated intracranial hypertension at the initial presentation were included. Ophthalmological evaluations included analysing retinal nerve fibre layer (RNFL), ganglion cell layer (GCL) and total peripapillary retinal thickness (RT). RESULTS: The study included 222 eyes from 113 patients. The main aetiologies of intracranial hypertension were idiopathic intracranial hypertension (49/113), intracranial tumours (33/113) and cerebral venous thrombosis (15/113). The initial RNFL and RT showed significant correlations with optic atrophy. The mean RNFL was 199.63 µm in the 'no atrophy' group and 365.28 µm in the 'atrophy' group (p<0.001). Similarly, the mean RT was 483.72 µm in the 'non-atrophy' group and 796.69 µm in the 'atrophy' group (p<0.001). The presence of peripapillary haemorrhages showed a strong correlated with optic atrophy with an OR=19.12 (p<0.001). Impaired initial visual acuity was also associated with final optic atrophy with an OR=7.76 (p=0.020). Furthermore, impaired initial GCL was a major predictor of optic atrophy (OR=18.25 (p=0.021)). CONCLUSION: Our study highlights the risk factors for optic atrophy in papilloedema, aiming to facilitate the early detection of patients at a high risk of vision loss and enable more aggressive medical or surgical management.

Next generation sequencing identifies a pathogenic mutation of WFS1 gene in a Moroccan family with Wolfram syndrome: a case report.

BACKGROUND: Wolfram syndrome is a rare autosomal recessive neurodegenerative disorder that affects 1/200,000 to 1/1,000,000 children. It is characterized by juvenile onset diabetes, optic nerve atrophy and other systemic manifestations. Symptoms of the disease arise mostly in early childhood with a high mortality rate due to severe neurological complications. Two causative genes have been identifed in this syndrome; the classical form is caused by autosomal recessive mutations of the WFS1 gene, and a smaller portion of patients has mutations in the CIDS2 gene, which are responsible for autosomal recessive Wolfram syndrome 2. CASE PRESENTATION: We report the case of a 28-year-old Moroccan boy born from consanguineous parents referred to the department of medical genetics at the National Institute of Health in Rabat. The diagnosis of Wolfram syndrome was made based on insulin-dependent diabetes, optic nerve atrophy, sensorineural deafness, urological abnormalities and psychiatric illness. To establish the diagnosis at a molecular level, we performed next-generation sequencing in the index patient, which revealed compound heterozygous WFS1 mutations: c.1113G > A (p.Trp371Ter) and c.1223_1224insGGAACCACCTGGAGCCCTATGCCCATTT (p.Phe408fs). This second variant has never been described in patients with Wolfram syndrome. CONCLUSION: The identification of the genetic substrate in our patient confirmed the clinical diagnosis of Wolfram syndrome and allowed us to provide him an appropriate management and genetic counseling to his family.

Delineating Wolfram-like syndrome: A systematic review and discussion of the WFS1-associated disease spectrum.

Wolfram-like syndrome (WFLS) is a recently described autosomal dominant disorder with phenotypic similarities to autosomal recessive Wolfram syndrome (WS), including optic atrophy, hearing impairment, and diabetes mellitus. We summarize current literature, define the clinical characteristics, and investigate potential genotype phenotype correlations. A systematic literature search was conducted in electronic databases Pubmed/MEDLINE, EMBACE, and Cochrane Library. We included studies reporting patients with a clinical picture consisting at least 2 typical clinical manifestations of WSF1 disorders and heterozygous mutations in WFS1. In total, 86 patients from 35 studies were included. The most common phenotype consisted of the combination of optic atrophy (87%) and hearing impairment (94%). Diabetes mellitus was seen in 44% of the patients. Nineteen percent developed cataract. Patients with missense mutations in WFS1 had a lower number of clinical manifestations, less chance of developing diabetes insipidus, but a younger age at onset of hearing impairment compared to patients with nonsense mutations or deletions causing frameshift. There were no studies reporting decreased life expectancy. This review shows that, within the spectrum of WFS1-associated disorders or "wolframinopathies," autosomal dominantly inherited WFLS has a relatively mild phenotype compared to autosomal recessive WS. The clinical manifestations and their age at onset are associated with the specific underlying mutations in the WFS1 gene.

Expanding SPG7 dominant optic atrophy phenotype: Infantile nystagmus and optic atrophy without spastic paraplegia.

Spastic paraplegia is a neurodegenerative disorder characterized by progressive leg weakness and spasticity due to degeneration of corticospinal axons. SPG7 encodes paraplegin, and pathogenic variants in the gene cause hereditary spastic paraplegia as an autosomal recessive trait. Various ophthalmological findings including optic atrophy, ophthalmoplegia, or nystagmus have been reported in patients with spastic paraplegia type 7. We report a 15-year-old male patient with a novel heterozygous variant, c.1224T>G:p.(Asp408Glu) in SPG7 (NM_003119.3) causing early onset isolated optic atrophy and infantile nystagmus prior to the onset of neurological symptoms. Therefore, SPG7 should be considered a cause of infantile nystagmus with optic atrophy.

Hereditary motor and sensory neuropathy type VIA with optic nerve pallor in two sisters with pathologic myopia: a case series and review.

PURPOSE: Hereditary Motor Sensory Neuropathy Type VIA with Optic Atrophy (HMSN6A) is a rare variant subtype of mitofusin 2 (MFN2) associated Charcot-Marie-Tooth disease, with ophthalmic manifestations largely limited to optic atrophy. We report a case series of two sisters with HMSN6A corresponding to known variants in the MFN2 gene. The proband's mother, maternal aunt, and maternal grandfather were also reportedly affected with the condition, although not examined at our institution. The clinical presentations of the proband and her sister are reviewed in detail. In addition, a comprehensive review of ophthalmic findings from prior reported cases of HMSN6A is provided. OBSERVATIONS: HMSN6A is a neurologic disorder characterized by a motor sensory axonal neuropathy and optic atrophy. A range of additional ophthalmic manifestations have been reported in the literature. We highlight the proband and her sister who demonstrate this phenotype but also manifested other ocular abnormalities from an early age. In addition to optic nerve pallor, both sisters had additional ophthalmic features of bilateral pathologic myopia, limited vision, nystagmus, and strabismus. CONCLUSIONS AND IMPORTANCE: This case series and review describe the ophthalmologic findings of HMSN6A and provides incentive to further investigate the correlation between molecular findings and the phenotype.

Case Report: Optic Nerve Atrophy Secondary to Sjögren Syndrome.

SIGNIFICANCE: Optic neuropathy associated with Sjögren syndrome is rare and usually has an acute onset. PURPOSE: This study aimed to report a case of asymmetric optic nerve atrophy attributed to Sjögren syndrome. CASE REPORT: A 37-year-old woman was referred to neuro-ophthalmology service because of right optic nerve atrophy of unknown etiology. The patient was asymptomatic. Best-corrected visual acuity was 20/200 Snellen equivalent in the right eye and 20/20 Snellen equivalent in the left eye. The right eye had a relative afferent pupillary defect. Visual field demonstrated dense temporal loss, superior arcuate involvement, and an inferior paracentral defect in the right eye. Slit-lamp examination showed mild fluorescein staining of the cornea, moderate lissamine green staining of the conjunctiva, and abnormal tear breakup time in both eyes. Fundus examination revealed diffuse pallor of the right optic disc and a normal left optic disc. Optical coherence tomography showed inferior and superior retinal nerve fiber layer atrophy in the right eye and inferior retinal nerve fiber layer atrophy in the left eye. A diagnosis of right optic nerve atrophy was made. Immunologic studies were significant for positive anti-Ro and anti-La antibodies. MRI of the brain and orbit ruled out any intracranial or white-matter pathology. A diagnosis of optic nerve atrophy secondary to Sjögren syndrome was suspected, so corticosteroid treatment was started. CONCLUSIONS: Optic nerve atrophy may be the initial manifestation of Sjögren syndrome. Therefore, optic neuropathy associated with Sjögren syndrome remains a diagnostic challenge. In these cases, specific antibodies such as anti-Ro and anti-La facilitate early diagnosis and can prevent vision-threatening complications.

Novel NR2F1 variant identified by whole-exome sequencing in a patient with Bosch-Boonstra-Schaaf optic atrophy syndrome.

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an extremely rare autosomal dominant disorder characterized by intellectual disability, developmental delay, seizures, hypotonia, hearing loss, and optic nerve atrophy. This syndrome is caused by loss-of-function variants in the nuclear receptor subfamily 2 group F member 1 (NR2F1) gene. To date, approximately 80 patients have been reported with BBSOAS. Here, we describe a 3-year-old infant with delayed development, intellectual disability, strabismus, nystagmus, and optic atrophy with well-characterized features associated with BBSOAS. Whole-exome sequencing revealed a novel heterozygous missense mutation (NM_005654.6:c.437G>A, p.Cys146Tyr) in the NR2F1 gene. This missense variant is predicted to be deleterious by the protein prediction tools (SIFT, PolyPhen-2, and MutationTaster). To the best of our knowledge, this is the first patient with BBSOAS reported from Turkey.

Demographics and etiologic characteristics of non-glaucomatous optic atrophy: a single-center cross-sectional study from Turkey.

BACKGROUND: Optic atrophy is an end-stage pathology of optic nerve diseases that is characterized by optic nerve pallor and vision loss. Because of its sight-threatening effects, understanding its epidemiology and etiology is crucial. In this study, we aimed to determine the epidemiologic features of optic nerve pathologies which lead to optic atrophy. METHODS: This is a cross-sectional study in which, medical records of optic atrophy patients who were followed up in our clinic between 1999 and 2020 were evaluated. Three hundred and sixty eyes of 226 patients were included in the study. Demographic data were received from the patients' files. Patients with glaucomatous optic atrophy, consecutive optic atrophy and patients with less than a year follow-up were excluded from the study. RESULTS: The most frequent reason of optic atrophy was central nervous system diseases (27.43%) followed by secondary non-arteritic ischemic optic neuropathy (26.99%). The most frequent etiology of optic atrophy was non-arteritic ischemic optic neuropathy in males and central nerve system-related pathologies in females. The highest presentation age (mean 63.6 ± 17.85 years) was observed in arteritic ischemic optic neuropathy and central nerve system-related optic atrophy had the lowest presentation age (median 14 years, IQR [34]). CONCLUSION: Central nerve system diseases and non-arteritic ischemic optic neuropathies were the most common causes of non-glaucomatous and non-consecutive optic atrophy in Turkey. Better understanding of underlying etiologies of optic atrophy may lead us to take precautions timely for irreversible optic nerve dysfunction which is an important reason of blindness.