6,028 results on '"Optic Atrophy"'
Search Results
2. Effects of a Supervised Rehabilitation Program on Disease Severity in Spastic Ataxias
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McGill University, Université de Sherbrooke, Université du Québec a Montréal, Laval University, University of Calgary, Corporation de recherche et d'action sur les maladies héréditaires (CORAMH), Cégep de Jonquière, Centre intégré universitaire de santé et de services sociaux du Saguenay-Lac-St-Jean, Muscular Dystrophy Canada, University of Alberta, Integrated University Health and Social Services Center of the Capitale-Nationale, and Elise Duchesne, Full Professor
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- 2024
3. Stem Cell Ophthalmology Treatment Study II (SCOTS2)
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- 2024
4. Genetic diversity of 1,845 rhesus macaques improves genetic variation interpretation and identifies disease models
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Wang, Jun, Wang, Meng, Moshiri, Ala, Harris, R Alan, Raveendran, Muthuswamy, Nguyen, Tracy, Kim, Soohyun, Young, Laura, Wang, Keqing, Wiseman, Roger, O’Connor, David H, Johnson, Zach, Martinez, Melween, Montague, Michael J, Sayers, Ken, Lyke, Martha, Vallender, Eric, Stout, Tim, Li, Yumei, Thomasy, Sara M, Rogers, Jeffrey, and Chen, Rui
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Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Human Genome ,Machine Learning and Artificial Intelligence ,Neurosciences ,Eye Disease and Disorders of Vision ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being ,Animals ,Macaca mulatta ,Humans ,Optic Atrophy ,Autosomal Dominant ,Disease Models ,Animal ,Gene Frequency ,Genotype ,Phenotype ,Mutation ,Missense ,Polymorphism ,Single Nucleotide ,Genetic Variation ,Machine Learning - Abstract
Understanding and treating human diseases require valid animal models. Leveraging the genetic diversity in rhesus macaque populations across eight primate centers in the United States, we conduct targeted-sequencing on 1845 individuals for 374 genes linked to inherited human retinal and neurodevelopmental diseases. We identify over 47,000 single nucleotide variants, a substantial proportion of which are shared with human populations. By combining rhesus and human allele frequencies with established variant prediction methods, we develop a machine learning-based score that outperforms established methods in predicting missense variant pathogenicity. Remarkably, we find a marked number of loss-of-function variants and putative deleterious variants, which may lead to the development of rhesus disease models. Through phenotyping of macaques carrying a pathogenic OPA1:p.A8S variant, we identify a genetic model of autosomal dominant optic atrophy. Finally, we present a public website housing variant and genotype data from over two thousand rhesus macaques.
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- 2024
5. A Clinical Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome
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National Institutes of Health (NIH) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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- 2024
6. Natural History Study of SLC25A46 Mutation-related Mitochondriopathy
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Hadley Jo Foundation and Taosheng Huang, Principal Investigator
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- 2024
7. Natural History Study of FDXR Mutation-related Mitochondriopathy
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The Callum McKeefery and Nikki Albano McKeefery Pediatric Division of Genetics Fund and Taosheng Huang, Principal Investigator
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- 2024
8. Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford (CoRDS)
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National Ataxia Foundation, International WAGR Syndrome Association, 4p- Support Group, ML4 Foundation, Cornelia de Lange Syndrome Foundation, Stickler Involved People, Kawasaki Disease Foundation, Klippel-Feil Syndrome Alliance, Klippel-Feil Syndrome Freedom, Hyperacusis Research Limited, Hypersomnia Foundation, Kabuki Syndrome Network, Kleine-Levin Syndrome Foundation, Leiomyosarcoma Direct Research Foundation, Marinesco-Sjogren Syndrome Support Group - NORD, Mucolipidosis Type IV (ML4) Foundation, People with Narcolepsy 4 People with Narcolepsy (PWN4PWN), Soft Bones Incorporated, American Multiple Endocrine Neoplasia Support, Atypical Hemolytic Uremic Syndrome Foundation, All Things Kabuki, Wiedemann-Steiner Syndrome Foundation, Breast Implant Victim Advocates, PROS Foundation, American Behcet's Disease Association, Alstrom United Kingdom, Athymia, Curing Retinal Blindness Foundation, HSAN1E Society, 1p36 Deletion Support and Awareness, The Alagille Syndrome Alliance, Autoinflammatory Alliance, Beyond Batten Disease Foundation, Bohring-Opitz Syndrome Foundation, INC, Cockayne Syndrome Network (Share and Care), CRMO Foundation, Cure VCP Disease,INC, FOD Support, Cystinosis Research Foundation, Global DARE Foundation, Hypnic Jerk-Sleep Myoclonus Support Group, Jansen's Foundation, KCNMA1 Channelopathy International Advocacy Foundation, Kawasaki Disease Foundation Australia, Life with LEMS Foundation, Lowe Syndrome Association, The Malan Syndrome Foundation, Maple Syrup Urine Disease Family Support Group, International Association for Muscle Glycogen Storage Disease (IamGSD), Myhre Syndrome Foundation, DNM1 Families, Nicolaides Baraitser Syndrome (NCBRS) Worldwide Foundation, The PBCers Organization, Pitt Hopkins Research Foundation, Recurrent Meningitis Association, Recurrent Respiratory Papillomatosis Foundation, Remember the Girls, Smith-Kingsmore Syndrome Foundation, SPG Research Foundation, Team Telomere, Transient Global Amnesia Project, The Charlotte & Gwenyth Gray Foundation, The Cute Syndrome Foundation, The Maddi Foundation, White Sutton Syndrome Foundation, Zmynd11 Gene Disorder, Cauda Equina Foundation, Inc, Tango2 Research Foundation, Noah's Hope - Hope4Bridget Foundation, Project Sebastian, SMC1A Epilepsy Foundation, International Foundation for Gastrointestinal Disorders, Endosalpingiosis Foundation, Inc, International Sacral Agenesis/Caudal Regression Association (ISACRA), Scheuermann's Disease Fund, Batten Disease Support and Research Association, Kennedy's Disease Association, Cure Mito Foundation, Warburg Micro Research Foundation, Cure Mucolipidosis, Riaan Research Initiative, CureARS A NJ Nonprofit Corporation, CACNA1H Alliance, IMBS Alliance, SHINE-Syndrome Foundaion, Non- Ketotic Hyperglycinemia (NKH) Crusaders, Hypertrophic Olivary Degeneration Association (HODA), National Organization for Disorders of the Corpus Callosum (NODCC), Team4Travis, Taylor's Tale Foundation, Lambert Eaton (LEMS) Family Association, BARE Inc, STAG1 Gene Foundation, Coffin Lowry Syndrome Foundation, BLFS Incorporate, Aniridia North America, Cure Blau Syndrome Foundation, ARG1D Foundation, CURE HSPB8 Myopathy, International Society of Mannosidosis and Related Disorders, TBX4Life, Cure DHDDS, MANDKind Foundation, Krishnan Family Foundation, and SPATA Foundation
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- 2024
9. Severe mitochondrial encephalomyopathy caused by de novo variants in OPA1 gene.
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Di Nottia, Michela, Rizza, Teresa, Baruffini, Enrico, Nesti, Claudia, Torraco, Alessandra, Diodato, Daria, Martinelli, Diego, Canto, Flavio Dal, Gilea, Alexandru Ionut, Zoccola, Martina, Siri, Barbara, Dionisi-Vici, Carlo, Bertini, Enrico, Santorelli, Filippo Maria, Goffrini, Paola, and Carrozzo, Rosalba
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MITOCHONDRIAL dynamics ,MITOCHONDRIAL DNA ,GENETIC variation ,GENETIC mutation ,FISSION (Asexual reproduction) - Abstract
Background: Mitochondria adjust their shape in response to the different energetic and metabolic requirements of the cell, through extremely dynamic fusion and fission events. Several highly conserved dynamin-like GTPases are involved in these processes and, among those, the OPA1 protein is a key player in the fusion of inner mitochondrial membranes. Hundreds of monoallelic or biallelic pathogenic gene variants have been described in OPA1, all associated with a plethora of clinical phenotypes without a straightforward genotypephenotype correlation. Methods: Here we report two patients harboring novel de novo variants in OPA1. DNA of two patients was analyzed using NGS technology and the pathogenicity has been evaluated through biochemical and morphological studies in patient's derived fibroblasts and in yeast model. Results: The two patients here reported manifest with neurological signs resembling Leigh syndrome, thus further expanding the clinical spectrum associated with variants in OPA1. In cultured skin fibroblasts we observed a reduced amount of mitochondrial DNA (mtDNA) and altered mitochondrial network characterized by more fragmented mitochondria. Modeling in yeast allowed to define the deleterious mechanism and the pathogenicity of the identified gene mutations. Conclusion: We have described two novel-single OPA1 mutations in two patients characterized by early-onset neurological signs, never documented, thus expanding the clinical spectrum of this complex syndrome. Moreover, both yeast model and patients derived fibroblasts showed mitochondrial defects, including decreased mtDNA maintenance, correlating with patients' clinical phenotypes. [ABSTRACT FROM AUTHOR]
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- 2024
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10. Overview of Neuro-Ophthalmic Findings in Leukodystrophies.
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Bettinger, Charlotte Maria, Dulz, Simon, Atiskova, Yevgeniya, Guerreiro, Helena, Schön, Gerhard, Guder, Philipp, Maier, Sarah Lena, Denecke, Jonas, and Bley, Annette E.
- Abstract
Background: Leukodystrophies are a group of rare genetic diseases that primarily affect the white matter of the central nervous system. The broad spectrum of metabolic and pathological causes leads to manifestations at any age, most often in childhood and adolescence, and a variety of symptoms. Leukodystrophies are usually progressive, resulting in severe disabilities and premature death. Progressive visual impairment is a common symptom. Currently, no overview of the manifold neuro-ophthalmologic manifestations and visual impact of leukodystrophies exists. Methods: Data from 217 patients in the Hamburg leukodystrophy cohort were analyzed retrospectively for neuro-ophthalmologic manifestations, age of disease onset, and magnetic resonance imaging, visual evoked potential, and optical coherence tomography findings and were compared with data from the literature. Results: In total, 68% of the patients suffered from neuro-ophthalmologic symptoms, such as optic atrophy, visual neglect, strabismus, and nystagmus. Depending on the type of leukodystrophy, neuro-ophthalmologic symptoms occurred early or late during the course of the disease. Magnetic resonance imaging scans revealed pathologic alterations in the visual tract that were temporally correlated with symptoms. Conclusions: The first optical coherence tomography findings in Krabbe disease and metachromatic leukodystrophy allow retinal assessments. Comprehensive literature research supports the results of this first overview of neuro-ophthalmologic findings in leukodystrophies. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Pediatric onset neuronal ceroid lipofuscinoses: Unraveling clinical and genetic specifications.
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Ahdi, Saher Gul, Alvi, Javeria Raza, Ashfaq, Azeem, and Sultan, Tipu
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NEURONAL ceroid-lipofuscinosis , *GENETIC testing , *GENETIC counseling , *PEDIATRIC neurology , *CHILDREN'S hospitals - Abstract
Objective: To unravel the clinical and genetic specifications of Neuronal ceroid lipofuscinosis (NCL). Methods: This is a retrospective cross-sectional study conducted in the Department of Pediatric Neurology Children Hospital and University of Child Health Sciences, Lahore, Pakistan from March 2017 to March 2022. The primary outcome was to measure genotype-phenotype correlation by segregation of phenotypes according to genotype. The secondary outcomes included a correlation between genotype and distribution of age(s) of onset. Results: One hundred fifty three patients clinically diagnosed with NCL underwent genetic testing and pathologic mutation was identified in 32.7% of patients. About 59.6% were male and 37.2% had an affected sibling. The median age was 5.46±1.95 years at the onset of the first symptom i.e., myoclonic seizures in 68%, and motor difficulty in 24%. Other features found were global developmental delay (56%), hypotonia (23%), visual impairment (80%), ataxia (22%), and disc pallor (56%). The most common type was CLN6 (Ceroid lipofuscinosis neuronal) (42%), CLN2 (16%) followed by CLN7 (12%). When 50 patients with recognized mutations were compared with 103 patients with no mutation, family history (p=0.049), early visual loss (p=0.016), hypotonia (p=0.001), white matter signals (p=0.026) and pan-atrophy(p=0.047) was statistically significant in the genetically confirmed NCL. Multiple pairwise comparisons indicated that the estimated age of onset for the CLN1 and CLN2 mutation group was significantly lower than other genotypes including CLN6 (p 0.012), CLN10 (p 0.007) and CLN12 (p 0.007). Conclusion: Following a detailed review of NCL symptomatology, a clinically-oriented approach should be used for a rapid diagnosis with confirmation by targeted molecular testing for future genetic counseling. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Phenotypic variability related to dominant UCHL1 mutations: about three families with optic atrophy and ataxia.
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Marelli, C., Ramond, F., Vignal, C., Blanchet, C., Frost, S., Hao, Q., Bocquet, B., Nadjar, Y., Leboucq, N., Taieb, G., Benkirane, M., Hersent, C., Koenig, M., and Meunier, I.
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SENSORY ataxia , *CEREBELLAR ataxia , *PHENOTYPIC plasticity , *GENETIC variation , *INTELLECTUAL development - Abstract
Introduction: Ubiquitin C-terminal hydrolase L1 (UCHL1) has been associated with a severe, complex autosomal recessive spastic paraplegia (HSP79) [1] [2] [3] [4]. More recently, UCHL1 loss of function (LoF) variants have been associated to an autosomal dominant disease characterized by late-onset spastic ataxia, neuropathy, and frequent optic atrophy [5]. Methods: Routine clinical care whole-genome (WGS) and exome (ES) sequencing. Results: We present three families with autosomal dominant UCHL1-related disorder. The clinical phenotype mainly associated optic atrophy, mixed cerebellar and sensory ataxia, and possible hearing loss. We delineated two major phenotypes, even within the same family: (1) juvenile severe optic atrophy followed by a later-onset ataxia, or (2) late-onset ataxia with asymptomatic or mild optic atrophy. The families harboured three novel heterozygous variants in UCHL1: two loss of function (p.Lys115AsnfsTer40; c.171_174 + 7del11), and one missense (p.Asp176Asn) involving the catalytic site of the protein and potentially altering the adjacent splice site. Discussion: We confirm the existence of dominantly inherited UCHL1 pathogenic variants. We describe a considerable intrafamilial phenotypic variability, with two main phenotypes. Optic atrophy was consistently present, but with varying degrees of severity. Neither delayed motor or intellectual development, nor dysmorphic features were part of the dominant phenotype in comparison with the autosomal recessive form. The molecular mechanism appears to be haploinsufficiency. UCHL1 monoallelic variants should therefore be considered in any case of early-onset optic atrophy or in late-onset complex ataxic syndrome with asymptomatic optic atrophy. [ABSTRACT FROM AUTHOR]
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- 2024
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13. Erythropoietin for the Treatment of Methanol Toxic Optic Neuropathy: Does It Really Work? A Case Series.
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Badeeb, Nooran O., Alharazi, Shaima, Mohammedsaleh, Asmaa, Hijazi, Hasan, M. Sadaga, Nihal, and Hadrawi, Manal
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ERYTHROPOIETIN , *NEUROPATHY , *ATROPHY , *METHANOL , *VISION - Abstract
Erythropoietin (EPO) has demonstrated neuroprotective properties and has been used in small case series to treat methanol optic neuropathy. This study aims to evaluate the effectiveness of EPO. This retrospective case series included data from patients diagnosed with methanol optic neuropathy between November 2022 and December 2023 from two centers in Jeddah, Saudi Arabia. Demographic information, time of consumption of methanol to EPO treatment, and other treatments administered were collected. Vision assessment was performed before and after EPO treatment. A total of 8 male patients were included, with an average age of 38.25 ± 7.15 years. The median duration of the follow-up was 66 days, ranging from 13 to 660 days. The means of vision in the logMAR of both eyes before EPO treatment was 1.98 ± 1.08, which changed to 1.87 ± 0.89 after EPO treatment. Patient’s presenting vision before EPO treatment is a significant positive predictor for the vision after treatment with coefficient = 0.782 and 95% CI = 0.349, 0.936. Time to EPO treatment was not statistically significant in defining end vision. Treating methanol optic neuropathy is challenging and time sensitive. In this case series, EPO and adjuvant steroids showed variable effects on visual improvement. Although the vision improved after the treatment, these differences were not statistically significant. Repeat EPO did not give better outcomes. Long-term follow-up is needed to determine the overall impact of EPO treatment. [ABSTRACT FROM AUTHOR]
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- 2024
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14. Wolfram Syndrome Type I Case Report and Review—Focus on Early Diagnosis and Genetic Variants.
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Jurca, Alexandru Daniel, Galea-Holhos, Larisa Bianca, Jurca, Aurora Alexandra, Atasie, Diter, Petchesi, Codruta Diana, Severin, Emilia, and Jurca, Claudia Maria
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GENETIC disorder diagnosis ,GENETIC variation ,EARLY diagnosis ,CEREBRAL atrophy ,MISSENSE mutation ,DIABETES insipidus - Abstract
Background and Objectives: Wolfram syndrome type 1 (OMIM# 222300; ORPHAcode 3463) is an extremely rare autosomal recessive syndrome with a 25% recurrence risk in children. It is characterized by the presence of juvenile-onset diabetes mellitus (DM), progressive optic atrophy (OA), diabetes insipidus (DI), and sensorineural deafness (D), often referred to by the acronym DIDMOAD. It is a severe neurodegenerative disease with a life expectancy of 39 years, with death occurring due to cerebral atrophy. For a positive diagnosis, the presence of diabetes mellitus and optic nerve atrophy is sufficient. The disease occurs because of pathogenic variants in the WFS1 gene. The aim of this article is to present a case report of Wolfram Syndrome Type I, alongside a review of genetic variants, clinical manifestations, diagnosis, therapy, and long-term management. Emphasizing the importance of early diagnosis and a multidisciplinary approach, the study aims to enhance understanding and improve outcomes for patients with this complex syndrome. Materials and Methods: A case of a 28-year-old patient diagnosed with DM at the age of 6 and with progressive optic atrophy at 26 years old is presented. Molecular diagnosis revealed the presence of a heterozygous nonsense variant WFS1 c.1943G>A (p.Trp648*), and a heterozygous missense variant WFS1 c.1675G>C (p.Ala559Pro). Results: The molecular diagnosis of the patient confirmed the presence of a heterozygous nonsense variant and a heterozygous missense variant in the WFS1 gene, correlating with the clinical presentation of Wolfram syndrome type 1. Both allelic variants found in our patient have been previously described in other patients, whilst this combination has not been described before. Conclusions: This case report and review underscores the critical role of early recognition and diagnosis in Wolfram syndrome, facilitated by genetic testing. By identifying pathogenic variants in the WFS1 gene, genetic testing not only confirms diagnosis but also guides clinical management and informs genetic counseling for affected families. Timely intervention based on genetic insights can potentially reduce the progressive multisystem manifestations of the syndrome, thereby improving the quality of life and outcomes for patients. [ABSTRACT FROM AUTHOR]
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- 2024
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15. Mutation at the entrance of the quinone cavity severely disrupts quinone binding in respiratory complex I
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Yi, Jason Tae, Wang, Panyue, and Stuchebrukhov, Alexei A
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Macromolecular and Materials Chemistry ,Chemical Sciences ,Physical Sciences ,Genetics ,Humans ,Electron Transport Complex I ,DNA ,Mitochondrial ,Ubiquinone ,Mitochondria ,Mutation ,Optic Atrophy ,Hereditary ,Leber ,Water - Abstract
In all resolved structures of complex I, there exists a tunnel-like Q-chamber for ubiquinone binding and reduction. The entrance to the Q-chamber in ND1 subunit forms a narrow bottleneck, which is rather tight and requires thermal conformational changes for ubiquinone to get in and out of the binding chamber. The substitution of alanine with threonine at the bottleneck (AlaThr MUT), associated with 3460/ND1 mtDNA mutation in human complex I, is implicated in Leber's Hereditary Optic Neuropathy (LHON). Here, we show the AlaThr MUT further narrows the Q-chamber entrance cross-section area by almost 30%, increasing the activation free energy barrier of quinone passage by approximately 5 kJ mol-1. This severely disrupts quinone binding and reduction as quinone passage through the bottleneck is slowed down almost tenfold. Our estimate of the increase in free energy barrier is entirely due to the bottleneck narrowing, leading to a reduction of the transition state entropy between WT and MUT, and thus more difficult quinone passage. Additionally, we investigate details of possible water exchange between the Q-chamber and membrane. We find water exchange is dynamic in WT but may be severely slowed in MUT. We propose that LHON symptoms caused by 3460/ND1 mtDNA mutation are due to slowed quinone binding. This leads to an increased production of reactive oxidative species due to upstream electron backup at the FMN site of complex I, thus resulting in a mt bioenergetic defect.
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- 2023
16. Chromosome 16p11.2 microdeletion syndrome with microcephaly and Dandy-Walker malformation spectrum: expanding the known phenotype
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Liena Elbaghir Omer Elsayed, Norah Ayed AlHarbi, Ashwaq Mohammed Alqarni, Huda Hussein Elwasila Eltayeb, Noura Mostafa Mohamed Mostafa, Maha Mohammed Abdulrahim, Hadeel Ibrahim Bin Zaid, Latifah Mansour Alanzi, Sarah Abdullah Ababtain, Khawlah Aldulaijan, Sheka Yagub Aloyouni, Moneeb Abdullah Kassem Othman, Mohammad Abdullah Alkheilewi, Adel Mohammed Binduraihem, Hadeel Abdollah Alrukban, Hiba Yousif Ahmed, Faten Abdullah AlRadini, Hadil Mohammad Alahdal, Aziza Mufareh Mushiba, and Omaima Abdulazeem Alzaher
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de novo ,Recurrent proximal chromosome 16p11.2 microdeletion syndrome ,Saudi Arabia ,Global developmental delay ,Cognitive impairment ,Optic atrophy ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Chromosome 16p11.2 deletions and duplications were found to be the second most common copy number variation (CNV) reported in cases with clinical presentation suggestive of chromosomal syndromes. Chromosome 16p11.2 deletion syndrome shows remarkable phenotypic heterogeneity with a wide variability of presentation extending from normal development and cognition to severe phenotypes. The clinical spectrum ranges from neurocognitive and global developmental delay (GDD), intellectual disability, and language defects (dysarthria /apraxia) to neuropsychiatric and autism spectrum disorders. Other presentations include dysmorphic features, congenital malformations, insulin resistance, and a tendency for obesity. Our study aims to narrow the gap of knowledge in Saudi Arabia and the Middle Eastern and Northern African (MENA) region about genetic disorders, particularly CNV-associated disorders. Despite their rarity, genetic studies in the MENA region revealed high potential with remarkable genetic and phenotypic novelty. Results We identified a heterozygous de novo recurrent proximal chromosome 16p11.2 microdeletion by microarray (arr[GRCh38]16p11.2(29555974_30166595)x1) [(arr[GRCh37]16p11.2(29567295_30177916)x1)] and confirmed by whole exome sequencing (arr[GRCh37]16p11.2(29635211_30199850)x1). We report a Saudi girl with severe motor and cognitive disability, myoclonic epilepsy, deafness, and visual impairment carrying the above-described deletion. Our study broadens the known phenotypic spectrum associated with recurrent proximal 16p11.2 microdeletion syndrome to include developmental dysplasia of the hip, optic atrophy, and a flat retina. Notably, the patient exhibited a rare combination of microcephaly, features consistent with the Dandy-Walker spectrum, and a thin corpus callosum (TCC), which are extremely infrequent presentations in patients with the 16p11.2 microdeletion. Additionally, the patient displayed areas of skin and hair hypopigmentation, attributed to a homozygous hypomorphic allele in the TYR gene. Conclusion This report expands on the clinical phenotype associated with proximal 16p11.2 microdeletion syndrome, highlighting the potential of genetic research in Saudi Arabia and the MENA region. It underscores the importance of similar future studies.
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- 2024
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17. Coenzyme Q10 trapping in mitochondrial complex I underlies Lebers hereditary optic neuropathy.
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Sadun, Alfredo, Fuller, Jack, Sadun, Lorenzo, Ajmera, Pujan, Alexandrova, Anastassia, and Barnes, Steven
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Coenzyme Q10 ,blinding genetic disease ,mitochondria ,molecular dynamics simulation ,quantum electron tunneling ,Humans ,Optic Atrophy ,Hereditary ,Leber ,Reactive Oxygen Species ,Electron Transport Complex I ,Alanine - Abstract
How does a single amino acid mutation occurring in the blinding disease, Lebers hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria? We investigated changes induced by the m.3460 G>A mutation in mitochondrial protein ND1 using the tools of Molecular Dynamics and Free Energy Perturbation simulations, with the goal of determining the mechanism by which this mutation affects mitochondrial function. A recent analysis suggested that the mutations replacement of alanine A52 with a threonine perturbs the stability of a region where binding of the electron shuttling protein, Coenzyme Q10, occurs. We found two functionally opposing changes involving the role of Coenzyme Q10. The first showed that quantum electron transfer from the terminal Fe/S complex, N2, to the Coenzyme Q10 headgroup, docked in its binding pocket, is enhanced. However, this positive adjustment is overshadowed by our finding that the mobility of Coenzyme Q10 in its oxidized and reduced states, entering and exiting its binding pocket, is disrupted by the mutation in a manner that leads to conditions promoting the generation of reactive oxygen species. An increase in reactive oxygen species caused by the LHON mutation has been proposed to be responsible for this optic neuropathy.
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- 2023
18. Neuro-sarcoidosis with isolated optic neuropathy: unmasking the chameleon
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Shreyashi Jha, Santosh Kumar Pendyala, and Mona Tiwari
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Optic atrophy ,Optic neuritis ,Sarcoidosis ,Internal medicine ,RC31-1245 - Abstract
Abstract Isolated optic nerve involvement is rare in sarcoidosis. We report three cases describing atypical clinical and radiological features of isolated optic nerve involvement in sarcoidosis to expand the spectrum of neuro-ophthalmic sarcoidosis. Bilateral optic neuritis, sudden vision loss, primary optic atrophy, long segment optic neuritis, and isolated intrao-orbital sarcoidosis are described as atypical features of optic nerve involvement in this case series.
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- 2024
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19. Ophthalmic symptoms before and after surgery for tuberculum sellae meningioma
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K.S. Iegorova and V.V. Musulevska
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tuberculum sellae meningioma ,optic atrophy ,bitemporal heteronymous hemianopia ,Internal medicine ,RC31-1245 - Abstract
Purpose: To review the features of ophthalmic symptoms before and after surgery for tuberculum sellae meningioma (TSM). Material and Methods: We reviewed the results of diagnostic assessment and outcomes of 91 patients ((182 eyes; 70 (76.9%) women and 21 (23.1%) men; mean age, 48.4% ± 1.7 years) treated for TSM with or without diaphragm sellae involvement at the Romodanov institute during 2014 through 2023. Patients underwent clinical neurological and eye examination and neuroimaging procedures. The results were reviewed for analysis and generalization of visual functions to calculate visual abnormality scores as per the guidelines of the German Ophthalmological Society. Results: Asymmetric visual field defects were observed in 41 (45.1%) patients with a bilateral disease, and unilateral visual field defects, in 23 (25.3%) patients, which was caused by both tumor compression of the anterior chiasm and optic canal invasion. Of the 74 (81.3%) patients with optic atrophy, 45 had unilateral optic atrophy, and 29, bilateral optic atrophy. Postoperatively, visual function improved, worsened and did not change in 72.5%, 7.7%, and 19.8% of patients, respectively. Conclusion: The approach to TSM resection should be tailored to the degree of optic canal invasion, tumor size and tumor relationship with the surrounding neural and vascular structures. On this basis, transcranial resection was performed in 68.1%, and endoscopic endonasal resection of TSM, in 31.9% of patients. The mean visual acuity improved from 0.44 ± 0.07 at preoperative to 0.69 ± 0.04 at postoperative evaluation (p < 0.001), and the average mean defect (MD) improved from 15.34 ± 0.78 dB at preoperative to 9.14 ± 0.64 dB at postoperative evaluation (p < 0.001).
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- 2024
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20. Exploring the evidence for mitochondrial dysfunction and genetic abnormalities in the etiopathogenesis of tropical ataxic neuropathy.
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Sharma, Shivani, Mahadevan, Anita, Narayanappa, Gayathri, Debnath, Monojit, Govindaraj, Periyasamy, Shivaram, Sumanth, Seshagiri, Doniparthi V., Siram, Ramesh, Shroti, Akhilesh, Bindu, Parayil S., Chickabasaviah, Yasha T., Taly, Arun B., and Nagappa, Madhu
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MITOCHONDRIAL DNA , *MITOCHONDRIA , *NEUROPATHY , *AUDITORY pathways , *SENSORINEURAL hearing loss , *DELETION mutation - Abstract
Tropical ataxic neuropathy (TAN) is characterised by ataxic polyneuropathy, degeneration of the posterior columns and pyramidal tracts, optic atrophy, and sensorineural hearing loss. It has been attributed to nutritional/toxic etiologies, but evidence for the same has been equivocal. TAN shares common clinical features with inherited neuropathies and mitochondrial disorders, it may be hypothesised that genetic abnormalities may underlie the pathophysiology of TAN. This study aimed to establish evidence for mitochondrial dysfunction by adopting an integrated biochemical and multipronged genetic analysis. Patients (n = 65) with chronic progressive ataxic neuropathy with involvement of visual and/or auditory pathways underwent deep phenotyping, genetic studies including mitochondrial DNA (mtDNA) deletion analysis, mtDNA and clinical exome sequencing (CES), and respiratory chain complex (RCC) assay. The phenotypic characteristics included dysfunction of visual (n = 14), auditory (n = 12) and visual + auditory pathways (n = 29). Reduced RCC activity was present in 13 patients. Mitochondrial DNA deletions were noted in five patients. Sequencing of mtDNA (n = 45) identified a homoplasmic variant (MT-ND6) and a heteroplasmic variant (MT-COI) in one patient each. CES (n = 45) revealed 55 variants in nuclear genes that are associated with neuropathy (n = 27), deafness (n = 7), ataxia (n = 4), and mitochondrial phenotypes (n = 5) in 36 patients. This study provides preliminary evidence that TAN is associated with a spectrum of genetic abnormalities, including those associated with mitochondrial dysfunction, which is in contradistinction from the prevailing hypothesis that TAN is related to dietary toxins. Analysing the functional relevance of these genetic variants may improve the understanding of the pathogenesis of TAN. [ABSTRACT FROM AUTHOR]
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- 2024
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21. Childhood Cerebral Adrenoleukodystrophy: Case Report and Literature Review Advocating for Newborn Screening.
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Rajakumar, Hamrish Kumar, Sathyabal, Varsha Coimbatore, Nachiappan, Revathi, and Vijayaramanujam, Sivakumar Krishnaswamy
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GENETIC testing ,ADRENOLEUKODYSTROPHY ,NEWBORN screening ,STEM cell transplantation ,GENETIC disorders - Abstract
Background: X-linked adrenoleukodystrophy (ALD) is a rare genetic disorder caused by a pathogenic variant of the ABCD1 gene, leading to impaired peroxisomal function and the accumulation of very long-chain fatty acids (VLCFAs). ALD presents a wide range of neurological and adrenal symptoms, ranging from childhood cerebral adrenoleukodystrophy to adrenomyeloneuropathy and adrenal insufficiency. Newborn screening (NBS) for ALD is available in some regions but remains lacking in others, such as India. Case Presentation: We present a case of a 10-year-old boy with ALD who presented with seizures, progressive weakness, visual impairment, and adrenal insufficiency. Despite symptomatic management and dietary adjustments, the disease progressed rapidly, leading to respiratory failure and eventual demise. The diagnosis was confirmed through molecular analysis and elevated VLCFA levels. Neuroimaging revealed characteristic white matter changes consistent with ALD. Conclusion: ALD is a devastating disease with no cure, emphasizing the importance of early detection through newborn screening and genetic testing. Management strategies include adrenal hormone therapy, gene therapy, and allogenic stem cell transplantation, as well as investigational treatments such as VLCFA normalization. Our case advocates the need for worldwide NBS and pediatric neurologic follow-up to enable early intervention and improve patient outcomes. Additionally, the association between ALD, recurrent febrile seizures, and unexplained developmental delay warrants further investigation to better understand disease progression and potential therapeutic targets. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
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22. Establishing Optic Nerve Diameter Threshold Sensitive and Specific for Optic Atrophy Diagnosis.
- Author
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Prairie, Michael L., Gencturk, Mehmet, McClelland, Collin M., Marka, Nicholas A., Jiang, Ziou, Folkertsma, Mark, and Lee, Michael S.
- Abstract
Purpose: To determine a potential threshold optic nerve diameter (OND) that could reliably differentiate healthy nerves from those affected by optic atrophy (OA) and to determine correlations of OND in OA with retinal nerve fiber layer (RNFL) thickness, visual acuity (VA), and visual field mean deviation (VFMD). Methods: This was a retrospective case control study. Magnetic resonance (MR) images were reviewed from individuals with OA aged 18 years or older with vision loss for more than 6 months and an OA diagnosis established by a neuro-ophthalmologist. Individuals without OA who underwent MR imaging of the orbit for other purposes were also collected. OND was measured on coronal T2-weighted images in the midorbital section, 1cm posterior to the optic disc. Measurements of mean RNFL thickness, VA and VFMD were also collected. Results: In this study 47 OA subjects (63% women, 78 eyes) and 75 normal subjects (42.7% women, 127 eyes) were assessed. Healthy ONDs (mean 2.73 ± 0.24 mm) were significantly greater than OA nerve diameters (mean 1.94 ± 0.32 mm; P < 0.001). A threshold OND of ≤2.3 mm had a sensitivity of 0.92 and a specificity of 0.93 in predicting OA. Mean RNFL (r = 0.05, p = 0.68), VA (r = 0.17, p = 0.14), and VFMD (r = 0.18, p = 0.16) were not significantly associated with OND. Conclusion: ONDs are significantly reduced in patients with OA compared with healthy nerves. A threshold OND of ≤2.3 mm is highly sensitive and specific for a diagnosis of OA. OND was not significantly correlated with RNFL thickness, VA, or VFMD. [ABSTRACT FROM AUTHOR]
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- 2024
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23. Neuro-sarcoidosis with isolated optic neuropathy: unmasking the chameleon.
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Jha, Shreyashi, Pendyala, Santosh Kumar, and Tiwari, Mona
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OPTIC neuritis ,SARCOIDOSIS ,OPTIC nerve ,CHAMELEONS ,NEUROPATHY ,VISION disorders - Abstract
Isolated optic nerve involvement is rare in sarcoidosis. We report three cases describing atypical clinical and radiological features of isolated optic nerve involvement in sarcoidosis to expand the spectrum of neuro-ophthalmic sarcoidosis. Bilateral optic neuritis, sudden vision loss, primary optic atrophy, long segment optic neuritis, and isolated intrao-orbital sarcoidosis are described as atypical features of optic nerve involvement in this case series. [ABSTRACT FROM AUTHOR]
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- 2024
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24. Biallelic BORCS8 variants cause an infantile-onset neurodegenerative disorder with altered lysosome dynamics.
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Pace, Raffaella De, Maroofian, Reza, Paimboeuf, Adeline, Zamani, Mina, Zaki, Maha S, Sadeghian, Saeid, Azizimalamiri, Reza, Galehdari, Hamid, Zeighami, Jawaher, Williamson, Chad D, Fleming, Emily, Zhou, Dihong, Gannon, Jennifer L, Thiffault, Isabelle, Roze, Emmanuel, Suri, Mohnish, Zifarelli, Giovanni, Bauer, Peter, Houlden, Henry, and Severino, Mariasavina
- Subjects
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NEURODEGENERATION , *SPASTICITY , *GENETIC variation , *CENTRAL nervous system , *SIZE of brain , *FAMILIAL spastic paraplegia - Abstract
BLOC-one-related complex (BORC) is a multiprotein complex composed of eight subunits named BORCS1–8. BORC associates with the cytosolic face of lysosomes, where it sequentially recruits the small GTPase ARL8 and kinesin-1 and -3 microtubule motors to promote anterograde transport of lysosomes toward the peripheral cytoplasm in non-neuronal cells and the distal axon in neurons. The physiological and pathological importance of BORC in humans, however, remains to be determined. Here, we report the identification of compound heterozygous variants [missense c.85T>C (p.Ser29Pro) and frameshift c.71-75dupTGGCC (p.Asn26Trpfs*51)] and homozygous variants [missense c.196A>C (p.Thr66Pro) and c.124T>C (p.Ser42Pro)] in BORCS8 in five children with a severe early-infantile neurodegenerative disorder from three unrelated families. The children exhibit global developmental delay, severe-to-profound intellectual disability, hypotonia, limb spasticity, muscle wasting, dysmorphic facies, optic atrophy, leuko-axonopathy with hypomyelination, and neurodegenerative features with prevalent supratentorial involvement. Cellular studies using a heterologous transfection system show that the BORCS8 missense variants p.Ser29Pro, p.Ser42Pro and p.Thr66Pro are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution toward the cell periphery. The BORCS8 frameshift variant p.Asn26Trpfs*51, on the other hand, is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution toward the cell periphery. Therefore, all the BORCS8 variants are partial or total loss-of-function alleles and are thus likely pathogenic. Knockout of the orthologous borcs8 in zebrafish causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease. These findings thus identify BORCS8 as a novel genetic locus for an early-infantile neurodegenerative disorder and highlight the critical importance of BORC and lysosome dynamics for the development and function of the central nervous system. [ABSTRACT FROM AUTHOR]
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- 2024
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25. Mutations in NSUN3 , a Mitochondrial Methyl Transferase Gene, Cause Inherited Optic Neuropathy.
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de Muijnck, Cansu, Brink, Jacoline B. ten, de Haan, Hugoline G., Rodenburg, Richard J., Wolf, Nicole I., Bergen, Arthur A., Boon, Camiel J. F., and van Genderen, Maria M.
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CELL respiration , *CONSANGUINITY , *GENETIC testing , *GENETIC variation , *NEUROPATHY - Abstract
Inherited optic neuropathies (IONs) are rare genetic diseases characterized by progressive visual loss due the atrophy of optic nerves. The standard diagnostic workup involving next-generation sequencing panels has a diagnostic yield of about forty percent. In the other 60% of the patients with a clinical diagnosis of ION, the underlying genetic variants remain unknown. In this case study, we describe a potentially new disease-associated gene, NSUN3, for IONs. The proband was a young woman with consanguineous parents. She presented with bilateral optic atrophy and nystagmus at the age of seven years. Genetic testing revealed the homozygous variant c.349_352dup p.(Ala118Glufs*45) in NSUN3, with a segregation in the family compatible with autosomal recessive inheritance. Additional functional analysis showed decreased NSUN3 mRNA levels, slightly diminished mitochondrial complex IV levels, and decreased cell respiration rates in patient fibroblasts compared to healthy controls. In conclusion, pathogenic variants in NSUN3 can cause optic neuropathy. Trio whole-exome sequencing should be considered as a diagnostic strategy in ION cases where standard diagnostic analysis does not reveal disease-causing variants. [ABSTRACT FROM AUTHOR]
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- 2024
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26. Optic atrophy in prematurity: pathophysiology and clinical features.
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Scott, Daniel AR, Wang, Michael TM, Danesh-Meyer, Helen V, and Hull, Sarah
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ATROPHY , *OPTICAL coherence tomography , *PREMATURE infants , *PATHOLOGICAL physiology , *PREMATURE labor - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2024
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27. Ophthalmic manifestations of biotinidase deficiency: report of a case and review of literature.
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Abdi, Fatemeh, Parvin, Sadaf, Zare Hosseinabadi, Vahid, Kachuei, Maryam, Gordiz, Arzhang, Hemmati, Sara, and Karimzadeh, Parvaneh
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- *
LITERATURE reviews , *NEUROMYELITIS optica , *VISION disorders , *DEVELOPMENTAL delay , *OPTIC nerve , *VISUAL acuity , *NATALIZUMAB - Abstract
Biotinidase deficiency (BD) is an inherited autosomal recessive metabolic disorder. BD has been associated with optic nerve atrophy, eye infections, and retinopathy. The most prevalent ophthalmic manifestation of BD is optic atrophy, which might be misdiagnosed as multiple sclerosis or neuromyelitis optica, especially in late-onset BD cases. In this article, we report a 9-year-old boy with gradual vision loss. Ophthalmologic examination, Brain MRI, and several laboratory tests such as Aquaporin-4 IgG level and biotinidase level were done on the patient. Bilateral optic atrophy and impaired visual acuity were detected on examination. The patient had a biotin level of 1.25 U/min/ml (normal range 3-9 U/min/ml), favoring the BD. In this study, we report a 9-year-old boy with vision loss diagnosed with BD. We also reviewed the literature to highlight the ophthalmic manifestations of BD. Ophthalmologists must consider BD in children with unexplained ophthalmologic complaints, especially when other characteristic signs of BD (e.g., developmental delay, seizure) are present. Also, patients with BD should undergo regular annual ophthalmologic examinations to be checked for any signs of eye involvement. [ABSTRACT FROM AUTHOR]
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- 2024
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28. A novel stop-gain NF1 variant in neurofibromatosis type 1 and bilateral optic atrophy without optic gliomas.
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Fukunaga, Naoko, Hayashi, Takaaki, Yamada, Yuki, Mizobuchi, Kei, Ohta, Arihito, and Nakano, Tadashi
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OPTIC disc , *NEUROFIBROMATOSIS 1 , *ATROPHY , *PERIPHERAL nervous system , *GLIOMAS , *GENETIC variation , *LOW vision , *VISUAL acuity - Abstract
Neurofibromatosis type 1 (NF1) is a multisystem disorder that primarily affects the skin and peripheral nervous system and is caused by chromosomal abnormalities and mostly truncating variants in the NF1 gene. Ocular complications such as Lisch nodules and optic pathway gliomas (OPGs) can occur in NF1 patients. Herein, we report a novel NF1 variant in an NF1 patient with bilateral optic atrophy. Ophthalmological examinations and genetic analyses were performed using targeted next-generation sequencing (NGS). A 14-year-old girl diagnosed with NF1 visited our hospital with decreased visual acuity (VA). The patient had no family history of NF1 or visual impairment. Brain and orbital magnetic resonance imaging revealed no remarkable findings. Ophthalmoscopy revealed temporal pallor of the optic discs, which was confirmed by optical coherence tomography findings of significant thinning of the circumpapillary retinal nerve fiber layer in both eyes. At 23 years of age, the decimal-corrected VA had deteriorated to 0.2 in the right eye and 0.1 in the left eye. Additionally, the targeted NGS panel revealed a novel heterozygous stop-gain variant (p.Tyr628Ter) in the NF1 gene; however, no pathogenic variants in OPA1 or the mitochondrial DNA were identified. A patient with NF1 without OPGs developed bilateral optic atrophy and carried a novel de novo stop-gain variant of NF1. Although the relationship between NF1 variants and bilateral optic atrophy remains unclear, further investigations are required. [ABSTRACT FROM AUTHOR]
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- 2024
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29. Randomized trial of bilateral gene therapy injection for m.11778G>A MT-ND4 Leber optic neuropathy
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Newman, Nancy J, Yu-Wai-Man, Patrick, Subramanian, Prem S, Moster, Mark L, Wang, An-Guor, Donahue, Sean P, Leroy, Bart P, Carelli, Valerio, Biousse, Valerie, Vignal-Clermont, Catherine, Sergott, Robert C, Sadun, Alfredo A, Rebolleda Fernández, Gema, Chwalisz, Bart K, Banik, Rudrani, Bazin, Fabienne, Roux, Michel, Cox, Eric D, Taiel, Magali, Sahel, José-Alain, Giulia, Amore, Shweta, Anand, Rudrani, Banik, Piero, Barboni, Valérie, Biousse, Hayley, Boston, Asma, Burale, Michele, Carbonelli, Valerio, Carelli, Celia, Chen, Hui-Chen, Cheng, Steve, Cho, Manuela, Contin, Pietro, D’Agati, DeBusk, Adam A, Julie, De Zaeytijd, Jannah, Dobbs, Lindreth, DuBois, Simona, Esposti, Alcides, Fernandes Filho, Elizabeth, Fortin, Sapna, Gangaputra, Deborah, Gibbs, François, Girmens Jean, Rabih, Hage, Haller, Julia A, Gad, Heilweil, George Baker, Hubbard III, Jeong-Min, Hwang, Laia, Jaumendreu Urquijo, Neringa, Jurkute, Rustum, Karanjia, Wahiba, Khemliche, La Chiara, Morgia, Maria, Massini, Marc, Mathias, Memon, Muhammad A, Susan, Mohamed, Muñoz Negrete, Francisco J, Ghazala, O’Keefe, Shriji, Patel, Paula, Pecen, Peragallo, Jason H, Lise, Plaine, Mary, Preston, Gema, Rebolleda Fernández, Martina, Romagnoli, José-Alain, Sahel, Melissa, SantaMaria, Chuanbin, Sun, Katy, Tai, Heather, Tollis, Irena, Tsui, Tucker, William R, Catherine, Vignal-Clermont, An-Guor, Wang, Saige, Wilkins, and Patrick, Yu-Wai-Man
- Subjects
Biomedical and Clinical Sciences ,Ophthalmology and Optometry ,Clinical Research ,Genetics ,Neurosciences ,Clinical Trials and Supportive Activities ,Eye Disease and Disorders of Vision ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Eye ,Humans ,DNA ,Mitochondrial ,Genetic Therapy ,Inflammation ,Mutation ,Optic Atrophy ,Hereditary ,Leber ,LHON REFLECT Study Group ,NADH dehydrogenase 4 ,leber hereditary optic neuropathy ,lenadogene nolparvovec ,mitochondrial DNA ,recombinant adeno-associated virus vector 2 ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery ,Biomedical and clinical sciences ,Health sciences ,Psychology - Abstract
Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G>A mutation in the MT-ND4 gene being the most common disease-causing mtDNA variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G>A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary end point was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary end point). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (P < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (P < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G>A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.
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- 2023
30. Celebration to Consequence: Case Report of Late Onset Ocular Effects of Firework Injuries
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Sudha Ranabhat, Saurya Pahadi, and Raghunandan Byanju
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Firework injury ,Glaucoma ,Ocular trauma ,Optic atrophy ,Traumatic cataract ,Medicine (General) ,R5-920 - Abstract
Firework-related injuries, particularly ocular trauma, pose a significant public health concern during cultural celebrations. We explore the case of a 20-year-old male who sustained firework-induced ocular trauma at the age of seven, subsequently developing traumatic cataract and glaucomatous optic atrophy. The patient presented with decreased vision and pain in the left eye (LE), 13 years post-injury. He underwent cataract surgery nine years after the incident, with subsequent development of glaucomatous optic atrophy. Examination revealed visual acuity impairment, exotropia, and pupil abnormalities in the LE, along with scleral thinning and corneal opacity. Posterior segment evaluation showed optic nerve cupping and hemorrhages. Gonioscopy indicated angle recession and synechiae in the LE. Optical coherence tomography revealed retinal nerve fiber layer defects. Elevated intraocular pressure in the LE was successfully managed with anti-glaucoma medication. Firework-related ocular trauma can lead to long-term complications, including traumatic cataract and glaucomatous optic atrophy. Timely cataract surgery and vigilant follow-up are essential for early detection and management of secondary glaucoma. Regulatory measures to mitigate firework-related injuries are imperative to prevent such incidents and preserve visual health.
- Published
- 2024
31. Introduction to Optic Nerve Disease
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Weiss, Jeffrey N. and Weiss, Jeffrey N.
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- 2024
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32. Tolerance and Efficacy Nicotinamide (Vitamin B3) in Dominant Optic Atrophy OPA1 (NICOPA1-TOL)
- Published
- 2023
33. PNPT1 Spectrum Disorders: An Underrecognized and Complex Group of Neurometabolic Disorders
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Paulo Sgobbi, Igor Braga Farias, Paulo de Lima Serrano, Bruno de Mattos Lombardi Badia, Hélvia Bertoldo de Oliveira, Alana Strucker Barbosa, Camila Alves Pereira, Vanessa de Freitas Moreira, Marco Antônio Troccoli Chieia, Adriel Rêgo Barbosa, Pedro Henrique Almeida Fraiman, Vinícius Lopes Braga, Roberta Ismael Lacerda Machado, Sophia Luiz Calegaretti, Isabela Danziato Fernandes, Roberta Correa Ribeiro, Marco Antonio Orsini Neves, Wladimir Bocca Vieira de Rezende Pinto, and Acary Souza Bulle Oliveira
- Subjects
inherited metabolic disorders ,spinocerebellar ataxia ,spastic ataxia ,optic atrophy ,mitochondrial disease ,PNPT1 ,Physiology ,QP1-981 ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
An 18-year-old man presented with slowly progressive infancy-onset spasticity of the lower limbs and cerebellar ataxia, associated with painless strabismus, intellectual disability, urinary incontinence, bilateral progressive visual loss, and cognitive decline since early adolescence. A neurological examination disclosed spastic dysarthria, left eye divergent strabismus, bilateral ophthalmoparesis, impaired smooth pursuit, severe spastic paraparesis of the lower limbs with global brisk tendon reflexes, bilateral extensor plantar responses, and bilateral ankle clonus reflex. Bilateral dysdiadochokinesia of the upper limbs, Stewart-Holmes rebound phenomenon, bilateral dysmetria, and a bilateral abnormal finger-to-nose test were observed. Markedly reduced bilateral visual acuity (right side 20/150, left side 20/400) and moderate to severe optic atrophy were detected. Neuroimaging studies showed cerebellar atrophy and bilateral optic nerves and optic tract atrophy as the main findings. As a complicated Hereditary Spastic Paraplegia, autosomal dominant Spinocerebellar Ataxia, or inherited neurometabolic disorders were suspected, a large next-generation sequencing-based gene panel testing disclosed the heterozygous pathogenic variant c.162-1G>A in intron 1 of the PNPT1 gene. A diagnosis of PNPT1-related spastic ataxia was established. Clinicians must be aware of the possibility of PNPT1 pathogenic variants in cases of spastic ataxia and spastic paraplegias that are associated with optic atrophy and marked cognitive decline, regardless of the established family history of neurological compromise.
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- 2024
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34. Wolfram Syndrome and WFS1-related Disorders International Registry and Clinical Study
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American Diabetes Association, National Institutes of Health (NIH), and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Published
- 2023
35. Solutions to a Radical Problem: Overview of Current and Future Treatment Strategies in Lebers Hereditary Opic Neuropathy.
- Author
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Spiegel, Samuel and Sadun, Alfredo
- Subjects
hereditary optic neuropathy ,idebenone ,leber’s hereditary optic neuropathy ,mitochondrial disorder ,mitochondrial optic neuropathy ,neuro-ophthalmology ,optic neuropathy ,Humans ,Optic Atrophy ,Hereditary ,Leber ,DNA ,Mitochondrial ,Retinal Ganglion Cells ,Mitochondria ,Forecasting - Abstract
Lebers Hereditary Optic Neuropathy (LHON) is the most common primary mitochondrial DNA disorder. It is characterized by bilateral severe central subacute vision loss due to specific loss of Retinal Ganglion Cells and their axons. Historically, treatment options have been quite limited, but ongoing clinical trials show promise, with significant advances being made in the testing of free radical scavengers and gene therapy. In this review, we summarize management strategies and rational of treatment based on current insights from molecular research. This includes preventative recommendations for unaffected genetic carriers, current medical and supportive treatments for those affected, and emerging evidence for future potential therapeutics.
- Published
- 2022
36. Bi-allelic variants in SNF8 cause a disease spectrum ranging from severe developmental and epileptic encephalopathy to syndromic optic atrophy.
- Author
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Brugger, Melanie, Lauri, Antonella, Zhen, Yan, Gramegna, Laura L., Zott, Benedikt, Sekulić, Nikolina, Fasano, Giulia, Kopajtich, Robert, Cordeddu, Viviana, Radio, Francesca Clementina, Mancini, Cecilia, Pizzi, Simone, Paradisi, Graziamaria, Zanni, Ginevra, Vasco, Gessica, Carrozzo, Rosalba, Palombo, Flavia, Tonon, Caterina, Lodi, Raffaele, and La Morgia, Chiara
- Subjects
- *
BRAIN diseases , *ATROPHY , *PEOPLE with epilepsy , *CORPUS callosum , *OPTIC nerve , *AGENESIS of corpus callosum , *EMBRYO transfer - Abstract
The endosomal sorting complex required for transport (ESCRT) machinery is essential for membrane remodeling and autophagy and it comprises three multi-subunit complexes (ESCRT I-III). We report nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative features caused by bi-allelic variants in SNF8 (GenBank: NM_007241.4), encoding the ESCRT-II subunit SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental arrest, and early death. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile). In patient-derived fibroblasts, bi-allelic SNF8 variants cause loss of ESCRT-II subunits. Snf8 loss of function in zebrafish results in global developmental delay and altered embryo morphology, impaired optic nerve development, and reduced forebrain size. In vivo experiments corroborated the pathogenicity of the tested SNF8 variants and their variable impact on embryo development, validating the observed clinical heterogeneity. Taken together, we conclude that loss of ESCRT-II due to bi-allelic SNF8 variants is associated with a spectrum of neurodevelopmental/neurodegenerative phenotypes mediated likely via impairment of the autophagic flux. We identified bi-allelic variants in SNF8 , encoding a subunit of the ESCRT-II complex, in individuals presenting with a disease spectrum ranging from epileptic encephalopathy to syndromic optic atrophy—findings also present in a zebrafish model. Functional experiments suggest impaired autophagic flux as the disease mechanism. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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37. Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.
- Author
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Franchino, Camilla Aurora, Brughera, Martina, Baderna, Valentina, Ritis, Daniele De, Rocco, Alessandra, Seneca, Sara, Regal, Luc, Podini, Paola, D'Antonio, Maurizio, Toro, Camilo, Quattrini, Angelo, Scalais, Emmanuel, and Maltecca, Francesca
- Subjects
- *
SPINOCEREBELLAR ataxia , *ATAXIA , *CEREBELLAR ataxia , *EPILEPSY , *CELL survival , *MITOCHONDRIAL membranes , *MITOCHONDRIAL proteins , *PROTEIN kinases - Abstract
AFG3L2 is a mitochondrial protease exerting protein quality control in the inner mitochondrial membrane. Heterozygous AFG3L2 mutations cause spinocerebellar ataxia type 28 (SCA28) or dominant optic atrophy type 12 (DOA12), while biallelic AFG3L2 mutations result in the rare and severe spastic ataxia type 5 (SPAX5). The clinical spectrum of SPAX5 includes childhood-onset cerebellar ataxia, spasticity, dystonia and myoclonic epilepsy. We previously reported that the absence or mutation of AFG3L2 leads to the accumulation of mitochondria-encoded proteins, causing the overactivation of the stress-sensitive protease OMA1, which over-processes OPA1, leading to mitochondrial fragmentation. Recently, OMA1 has been identified as the pivotal player communicating mitochondrial stress to the cytosol via a pathway involving the inner mitochondrial membrane protein DELE1 and the cytosolic kinase HRI, thus eliciting the integrated stress response. In general, the integrated stress response reduces global protein synthesis and drives the expression of cytoprotective genes that allow cells to endure proteotoxic stress. However, the relevance of the OMA1-DELE1-HRI axis in vivo , and especially in a human CNS disease context, has been poorly documented thus far. In this work, we demonstrated that mitochondrial proteotoxicity in the absence/mutation of AFG3L2 activates the OMA1-DELE1-HRI pathway eliciting the integrated stress response. We found enhanced OMA1-dependent processing of DELE1 upon depletion of AFG3L2. Also, in both skin fibroblasts from SPAX5 patients (including a novel case) and in the cerebellum of Afg3l2 −/− mice we detected increased phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (eIF2α), increased levels of ATF4 and strong upregulation of its downstream targets (Chop , Chac1 , Ppp1r15a and Ffg21). Silencing of DELE1 or HRI in SPAX5 fibroblasts (where OMA1 is overactivated at basal state) reduces eIF2α phosphorylation and affects cell growth. In agreement, pharmacological potentiation of integrated stress response via Sephin-1, a drug that selectively inhibits the stress-induced eIF2alpha phosphatase GADD34 (encoded by Ppp1r15a), improved cell growth of SPAX5 fibroblasts and cell survival and dendritic arborization ex vivo in primary Afg3l2 −/− Purkinje neurons. Notably, Sephin-1 treatment in vivo extended the lifespan of Afg3l2 −/− mice, improved Purkinje neuron morphology, mitochondrial ultrastructure and respiratory capacity. These data indicate that activation of the OMA1-DELE1-HRI pathway is protective in the context of SPAX5. Pharmacological tuning of the integrated stress response may represent a future therapeutic strategy for SPAX5 and other cerebellar ataxias caused by impaired mitochondrial proteostasis. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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38. Sensitivity, Specificity, and Cutoff Identifying Optic Atrophy by Macular Ganglion Cell Layer Volume in Syndromic Craniosynostosis.
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Chang, Yoon-Hee, Staffa, Steven J., Yavuz Saricay, Leyla, Zurakowski, David, Gise, Ryan, and Dagi, Linda R.
- Subjects
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CELL size , *ATROPHY , *ARNOLD-Chiari deformity , *INTRACRANIAL pressure , *CRANIOSYNOSTOSES - Abstract
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. Retrospective cross-sectional study. Patients with syndromic craniosynostosis evaluated at Boston Children's Hospital (2010–2022) with reliable macular OCT scans. 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. 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. 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. 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. The author(s) have no proprietary or commercial interest in any materials discussed in this article. [ABSTRACT FROM AUTHOR]
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- 2024
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39. Cerebral venous thrombosis and the eye: the neuro-ophthalmology of cerebral venous blood clot.
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Mishra, Ashutosh Kumar, Shukla, Ruchi, Verma, Archana, and Chaurasia, Rameswar Nath
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THROMBOSIS , *VENOUS thrombosis , *CEREBRAL embolism & thrombosis , *NEUROOPHTHALMOLOGY , *SYMPTOMS , *SINUS thrombosis - Abstract
Introduction:Cerebral venous thrombosis (CVT) is a form of venous thromboembolism which has varied clinical presentation. Ocular clinical features are quite common in CVT and may be the sole presenting feature and often tend to get misdiagnosed. This study was conducted to analyse clinical features especially neuro ophthalmological manifestations in CVT patients. Materials and Methods: In this prospective study 60 patients were enrolled in a study period of 3 years at tertiary care hospital. Follow up visits were performed at 1 month, 3 months, 6 months and 12 months after the initial diagnosis. We analysed the clinical features as well as aetiology of CVT, special focus was on the ocular symptoms and signs. Results: Headache was the most common clinical symptom with 93.33% patients. Among ocular symptoms 43.33 % patients presented with complaint of blurring of vision. Among ophthalmological signs papilledema was reported in 40.0 % patients, cranial nerve involvement in 10.0 % patients, diplopia was seen in 6.66 % patients. In patients with papilledema the intensity reduced as time progressed. Vision loss was seen in 2 patients who had secondary optic atrophy. Conclusion: To avoid misdiagnosis and for the prevention of vision deterioration the ophthalmologist must pay attention to CVT symptoms and signs when patients present with ocular symptoms as the initial manifestation. [ABSTRACT FROM AUTHOR]
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- 2024
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40. Ophthalmic symptoms before and after surgery for tuberculum sellae meningioma.
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Iegorova, K. S. and Musulevska, V. V.
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MENINGIOMA ,EYE examination ,BRAIN imaging ,VISION disorders ,ENDOSCOPIC surgery - Abstract
Purpose: To review the features of ophthalmic symptoms before and after surgery for tuberculum sellae meningioma (TSM). Material and Methods: We reviewed the results of diagnostic assessment and outcomes of 91 patients ((182 eyes; 70 (76.9%) women and 21 (23.1%) men; mean age, 48.4% ± 1.7 years) treated for TSM with or without diaphragm sellae involvement at the Romodanov institute during 2014 through 2023. Patients underwent clinical neurological and eye examination and neuroimaging procedures. The results were reviewed for analysis and generalization of visual functions to calculate visual abnormality scores as per the guidelines of the German Ophthalmological Society. Results: Asymmetric visual field defects were observed in 41 (45.1%) patients with a bilateral disease, and unilateral visual field defects, in 23 (25.3%) patients, which was caused by both tumor compression of the anterior chiasm and optic canal invasion. Of the 74 (81.3%) patients with optic atrophy, 45 had unilateral optic atrophy, and 29, bilateral optic atrophy. Postoperatively, visual function improved, worsened and did not change in 72.5%, 7.7%, and 19.8% of patients, respectively. Conclusion: The approach to TSM resection should be tailored to the degree of optic canal invasion, tumor size and tumor relationship with the surrounding neural and vascular structures. On this basis, transcranial resection was performed in 68.1%, and endoscopic endonasal resection of TSM, in 31.9% of patients. The mean visual acuity improved from 0.44 ± 0.07 at preoperative to 0.69 ± 0.04 at postoperative evaluation (p < 0.001), and the average mean defect (MD) improved from 15.34 ± 0.78 dB at preoperative to 9.14 ± 0.64 dB at postoperative evaluation (p < 0.001). [ABSTRACT FROM AUTHOR]
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- 2024
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41. Recurrent "outsider" intronic variation in the SLC5A6 gene causes severe mixed axonal and demyelinating neuropathy, cyclic vomiting and optic atrophy in 3 families from Maghreb.
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Mansour-Hendili, Lamisse, Gitiaux, Cyril, Harion, Madeleine, Latouche, Céline, Heron, Bénédicte, Stojkovic, Tanya, Rama, Mélanie, Smol, Thomas, Jourdain, Anne Sophie, Mention, Karine, Nadjar, Yann, Schiff, Manuel, Lemale, Julie, Ghoumid, Jamal, Gottrand, Frédéric, Talbotec, Cécile, Rötig, Agnès, Funalot, Benoît, and Desguerre, Isabelle
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ATROPHY ,LIPOIC acid ,MOTOR neuron diseases ,GENETIC counseling ,CONSANGUINITY ,BLOOD coagulation factor XIII - Abstract
Sodium dependent multivitamin transporter (SMVT) deficiency is a very rare autosomal recessive disorder characterized by multisystemic clinical manifestations due to combined biotin, panthotenic acid and lipoic acid deficiency. About 10 families have been described so far. Accurate diagnosis is crucial because of the possibility of a supplementation treatment with proven efficacy. Here we describe 4 new patients (3 additional families) originating from the same world region (Algeria, Maghreb). All patients, born form consanguineous parents, were homozygous carriers of the same intronic variation, outside of canonical sites, in the SLC5A6 gene encoding SMVT. RNA study in one family allowed confirming the pathogenic effect of the variation and re-classifying this variant of uncertain significance as pathogenic, opening the possibility of genetic counseling and treatment. The identification of the same variation in three distinct and apparently unrelated families is suggestive of a founder effect. The phenotype of all patients was very similar, with systematic optic atrophy (initially considered as a very rare sign), severe cyclic vomiting, and rapidly progressive mixed axonal and demyelinating sensory motor neuropathy. [ABSTRACT FROM AUTHOR]
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- 2024
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42. Leber's hereditary optic neuropathy like disease in MT-ATP6 variant m.8969G>A
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Cansu de Muijnck, Mary J. van Schooneveld, Astrid S. Plomp, Richard J. Rodenburg, Maria M. van Genderen, and Camiel J.F. Boon
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MT-ATP6 ,Leber's hereditary optic neuropathy ,Optic atrophy ,Ophthalmology ,RE1-994 - Abstract
Purpose: To describe a case with Leber's hereditary optic neuropathy (LHON) like optic atrophy in the presence of MT-ATP6 gene variant m.8969G > A. Observations: A 20-year-old patient with a history of mild developmental delay, mild cognitive impairment, and positional tremor presented with subacute painless visual loss over a few weeks. Mitochondrial genome sequencing revealed a variant in MT-ATP6, m.8969G > A (p.Ser148Asn). This variant was previously reported in association with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) and with nephropathy, followed by brain atrophy, muscle weakness and arrhythmias, but not with optic atrophy. Conclusions and importance: Rare variants in MT-ATP6 can also cause LHON like optic atrophy. It is important to perform further genetic analysis of mitochondrial DNA in genetically unsolved cases suspected of Leber's hereditary optic neuropathy to confirm the clinical diagnosis.
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- 2024
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43. Wolfram syndrome: A rare genetic disorder affecting multiple organ systems
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Annamneedi, Sree Bhagya Lekha, Sorra, Abhiram, Mugada, Vinod Kumar, and Yarguntla, Srinivasa Rao
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- 2023
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44. Compressive optic neuropathy in the setting of tumors of the chiasmal and sellar region: a review
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K.S. Iegorova
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compressive optic neuropathy ,optic nerve/chiasm complex ,optic atrophy ,tumors of the chiasmal and sellar region ,Internal medicine ,RC31-1245 - Abstract
This is a review on compressive optic neuropathy (CON) in the setting of tumors of the chiasmal and sellar region. CON is a difficult to manage neuro-ophthalmological condition that occurs when the optic nerve is damaged due to compression of the anterior visual pathway, commonly by scull-base tumors of the middle and anterior fossae. Compression of the optic nerve/chiasm complex is accompanied by reduced vision, visual field defects and descending optic atrophy, which, if not treated properly, can lead to permanent vision loss and blindness. The literature data on the prevalence and features of visual disturbances in chiasmal-sellar tumors which differ in histology have been reviewed.
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- 2023
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45. An Italian case series' description of thiamine responsive megaloblastic anemia syndrome: importance of early diagnosis and treatment
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Francesca Di Candia, Valentina Di Iorio, Nadia Tinto, Riccardo Bonfanti, Claudio Iovino, Francesco Maria Rosanio, Ludovica Fedi, Fernanda Iafusco, Francesca Arrigoni, Rita Malesci, Francesca Simonelli, Andrea Rigamonti, Adriana Franzese, and Enza Mozzillo
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Nonautoimmune diabetes ,Optic atrophy ,Sensorineural deafness ,Thiamine-responsive megaloblastic anemia syndrome ,Case series ,Pediatrics ,RJ1-570 - Abstract
Abstract Background Individuals with thiamine-responsive megaloblastic anemia (TRMA) mainly manifest macrocytic anemia, sensorineural deafness, ocular complications, and nonautoimmune diabetes. Macrocytic anemia and diabetes may be responsive to high-dosage thiamine treatment, in contrast to sensorineural deafness. Little is known about the efficacy of thiamine treatment on ocular manifestations. Cases presentation Our objective is to report data from four Italian TRMA patients: in Cases 1, 2 and 3, the diagnosis of TRMA was made at 9, 14 and 27 months. In 3 out of 4 subjects, thiamine therapy allowed both normalization of hyperglycemia, with consequent insulin suspension, and macrocytic anemia. In all Cases, thiamine therapy did not resolve the clinical manifestation of deafness. In Cases 2 and 3, follow-up showed no blindness, unlike Case 4, in which treatment was started for megaloblastic anemia at age 7 but was increased to high doses only at age 25, when the genetic diagnosis of TRMA was performed. Conclusions Early institution of high-dose thiamine supplementation seems to prevent the development of retinal changes and optic atrophy in TRMA patients. The spectrum of clinical manifestations is broad, and it is important to describe known Cases to gain a better understanding of this rare disease.
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- 2023
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46. Insight into adult-onset metachromatic leukodystrophy with optic atrophy: A comprehensive case report
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Shailendra Katwal, MD, Sundar Suwal, MD, Suman Lamichhane, MD, Amrit Bhusal, MBBS, and Aastha Ghimire, MBBS
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Adult onset ,Metachromatic leukodystrophy (MLD) ,Optic atrophy ,Motor weakness ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
This abstract provides an overview of metachromatic leukodystrophy (MLD), an autosomal recessive disorder stemming from arylsulfatase A deficiency. MLD leads to cerebroside sulfate accumulation, causing central and peripheral demyelination. Clinical manifestations vary by age group: late-infantile (rapid progression), juvenile (slower progression), and adult-onset (psychiatric symptoms). A case study details a 23-year-old with progressive vision impairment, motor weakness, and cognitive changes. Examination and MRI findings led to suspicion of MLD, later confirmed by enzyme testing. Optic nerve involvement is emphasized, along with diagnostic criteria involving enzyme assays, imaging, and urinary sulfatide excretion tests. While no cure exists, symptomatic and supportive care, including hematopoietic stem cell transplantation, remains key in MLD management.
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- 2023
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47. Optic Atrophy
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Pant, AB
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- 2024
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48. Natural history of patients with Leber hereditary optic neuropathy-results from the REALITY study.
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Yu-Wai-Man, Patrick, Newman, Nancy, Carelli, Valerio, La Morgia, Chiara, Biousse, Valérie, Bandello, Francesco, Clermont, Catherine, Campillo, Lorena, Leruez, Stephanie, Moster, Mark, Cestari, Dean, Foroozan, Rod, Sadun, Alfredo, Karanjia, Rustum, Jurkute, Neringa, Blouin, Laure, Taiel, Magali, and Sahel, José-Alain
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Adolescent ,Adult ,DNA ,Mitochondrial ,Europe ,Humans ,Mutation ,Optic Atrophy ,Hereditary ,Leber ,Retrospective Studies - Abstract
BACKGROUND/OBJECTIVES: REALITY is an international observational retrospective registry of LHON patients evaluating the visual course and outcome in Leber hereditary optic neuropathy (LHON). SUBJECTS/METHODS: Demographics and visual function data were collected from medical charts of LHON patients with visual loss. The study was conducted in 11 study centres in the United States of America and Europe. The collection period extended from the presymptomatic stage to at least more than one year after onset of vision loss (chronic stage). A Locally Weighted Scatterplot Smoothing (LOWESS) local regression model was used to analyse the evolution of best-corrected visual acuity (BCVA) over time. RESULTS: 44 LHON patients were included; 27 (61%) carried the m.11778G>A ND4 mutation, 8 (18%) carried the m.3460G>A ND1 mutation, and 9 (20%) carried the m.14484T>C ND6 mutation. Fourteen (32%) patients were under 18 years old at onset of vision loss and 5 (11%) were below the age of 12. The average duration of follow-up was 32.5 months after onset of symptoms. At the last observed measure, mean BCVA was 1.46 LogMAR in ND4 patients, 1.52 LogMAR in ND1 patients, and 0.97 LogMAR in ND6 patients. The worst visual outcomes were reported in ND4 patients aged at least 15 years old at onset, with a mean BCVA of 1.55 LogMAR and no tendency for spontaneous recovery. The LOESS modelling curve depicted a severe and permanent deterioration of BCVA. CONCLUSIONS: Amongst LHON patients with the three primary mtDNA mutations, adult patients with the m.11778G>A ND4 mutation had the worst visual outcomes, consistent with prior reports.
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- 2022
49. Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for Eye Diseases
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- 2022
50. Presumed Onchocerciasis Chorioretinitis Spilling over into North America, Europe and Middle East.
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Mansour, Ahmad, Rodriguez, Linnet, Mansour, Hana, Yehia, Madeleine, and Battaglia Parodi, Maurizio
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ONCHOCERCIASIS , *RETINAL diseases , *TROPICAL medicine , *DISEASE progression , *OPTIC neuritis , *IVERMECTIN - Abstract
Background: Newer generation ophthalmologists practicing in the developed world are not very familiar with some tropical ocular diseases due to the absence of reports in the ophthalmic literature over the past thirty years. Because of world globalization or due to influx of immigrants from sub-Saharan Africa, exotic retinal diseases are being encountered more often in ophthalmology clinics. Methods: A multicenter case series of chorioretinitis or optic neuritis with obscure etiology that used serial multimodal imaging. Results: Four cases qualified with the diagnosis of presumed ocular onchocerciasis based on their residence near fast rivers in endemic areas, multimodal imaging, long term follow-up showing progressive disease and negative workup for other diseases. Characteristic findings include peripapillary choroiditis with optic neuritis or atrophy, subretinal tracts of the microfilaria, progressive RPE atrophy around heavily pigmented multifocal chorioretinal lesions of varying shapes, subretinal white or crystalline dots, and response to ivermectin. Typical skin findings are often absent in such patients with chorioretinitis rendering the diagnosis more challenging. Conclusions: Familiarity with the myriad ocular findings of onchocerciasis, and a high-degree of suspicion in subjects residing in endemic areas can help in the correct diagnosis and implementation of appropriate therapy. Onchocercal chorioretinitis is a slow, insidious, progressive, and prolonged polymorphous disease. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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