CMT2A Harboring Mitofusin 2 Mutation with Optic Nerve Atrophy and Normal Visual Acuity.
Ontology highlight
ABSTRACT:
SUBMITTER: Guerriero S
PROVIDER: S-EPMC7039061 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
CMT2A Harboring Mitofusin 2 Mutation with Optic Nerve Atrophy and Normal Visual Acuity.
Guerriero Silvana S D'Oria Francesco F Rossetti Giacomo G Favale Rosa Anna RA Zoccolella Stefano S Alessio Giovanni G Petruzzella Vittoria V
International medical case reports journal 20200220
Charcot-Marie-Tooth (CMT) constitutes a group of heterogeneous hereditary motor and sensor neuropathies. Mutations in mitofusin-2 (<i>MFN2</i>) cause CMT type 2A by altering mitochondrial fusion and trafficking along with the axonal microtubule system. In literature patients presenting with CMT2A are reported as having a subacute onset of optic atrophy associated with central scotoma and color vision defects. We report on the clinical and genetic findings in a 40 years-old Caucasian woman presen ...[more]
Similar Datasets
Project description:We previously documented that idebenone treatment in OPA1-Dominant Optic Atrophy (OPA1-DOA) led to some degrees of visual improvement in seven patients. We here present the results of a cohort study, which investigated the effect of off-label idebenone administration in a larger OPA1-DOA group compared with untreated patients. Inclusion criteria were: OPA1-DOA clinical and molecular diagnosis, baseline visual acuity (VA) greater than/equal to counting fingers and treatment duration greater than 7 months. We found a significant difference between the last visit and baseline VA in favor of stabilization/recovery in idebenone-treated as compared to untreated patients. This effect was retained after controlling for confounders.
| S-EPMC7187718 | biostudies-literature
Project description:Charcot-Marie-Tooth disease type 2A (CMT2A) is an untreatable childhood peripheral neuropathy caused by mutations of the mitochondrial fusion protein, mitofusin (MFN) 2. Here, pharmacological activation of endogenous normal mitofusins overcame dominant inhibitory effects of CMT2A mutants in reprogrammed human patient motor neurons, reversing hallmark mitochondrial stasis and fragmentation independent of causal MFN2 mutation. In mice expressing human MFN2 T105M, intermittent mitofusin activation with a small molecule, MiM111, normalized CMT2A neuromuscular dysfunction, reversed pre-treatment axon and skeletal myocyte atrophy, and enhanced axon regrowth by increasing mitochondrial transport within peripheral axons and promoting in vivo mitochondrial localization to neuromuscular junctional synapses. MiM111-treated MFN2 T105M mouse neurons exhibited accelerated primary outgrowth and greater post-axotomy regrowth, linked to enhanced mitochondrial motility. MiM111 is the first pre-clinical candidate for CMT2A.
| S-EPMC7655101 | biostudies-literature
Project description:To evaluate mesopic functional visual acuity (FVA) with a newly developed system in normal subjects and to compare the results with photopic FVA, sixty-eight healthy volunteers (24.03 ± 4.42 [mean ± standard deviation] years) were enrolled in this study. A commercially available FVA measurement system (AS-28; Kowa, Aichi, Japan) was modified to measure FVA under mesopic conditions as well as photopic conditions. Measurements were performed monocularly in photopic conditions during 60 seconds. After dark adaptation for 15 minutes, the same measurements were repeated in mesopic conditions. Outcomes included starting visual acuity (VA), FVA (the average of VAs), visual maintenance ratio (VMR), maximum VA, minimum VA, and numbers of blinks during the 60-second measurement session, and were compared between mesopic and photopic conditions. Starting VA was -0.11 ± 0.08 and 0.39 ± 0.12 logarithm of the minimum angle of resolution (logMAR) in photopic and mesopic conditions, respectively. FVA was -0.06 ± 0.09 and 0.52 ± 0.14 logMAR, VMR was 0.98 ± 0.02 and 0.94 ± 0.04, maximum VA was -0.15 ± 0.06 and 0.33 ± 0.12 logMAR, the minimum VA was 0.05 ± 0.12 and 0.78 ± 0.20 logMAR, and the number of blinks was 8.23 ± 7.54 and 7.23 ± 6.20, respectively. All these parameters except the number of blinks were significantly different between the two conditions (P < 0.001). Besides, the difference between maximum and minimum VAs and standard deviation of VA were significantly larger in mesopic than in photopic conditions (P < 0.001). This study revealed that not only overall visual function decline but also instability of vision under mesopic conditions even in healthy subjects.
| S-EPMC4517889 | biostudies-literature
Project description:Replicative and chronological lifespan are two different modes of cellular aging. Chronological lifespan is defined as the duration during which quiescent normal cells retain their capacity to re-enter the proliferative cycle. This study investigated whether changes in metabolism occur during aging of quiescent normal human fibroblasts (NHFs) and the mechanisms that regulate these changes. Bioenergetics measurements were taken in quiescent NHFs from younger (newborn, 3-day, 5-month, and 1-year) and older (58-, 61-, 63-, 68-, and 70-year) healthy donors as well as NHFs from the same individual at different ages (29, 36, and 46 years). Results show significant changes in cellular metabolism during aging of quiescent NHFs: Old NHFs exhibit a significant decrease in glycolytic flux and lactate levels, and increase in oxygen consumption rate (OCR) and ATP levels compared to young NHFs. Results from the Seahorse XF Cell Mito Stress Test show that old NHFs with a lower Bioenergetic Health Index (BHI) are more prone to oxidative stress compared to young NHFs with a higher BHI. The increase in OCR in old NHFs is associated with a shift in mitochondrial dynamics more toward fusion. Genetic knockdown of mitofusin 1 (MFN1) and optic atrophy 1 (OPA1) in old NHFs decreased OCR and shifted metabolism more toward glycolysis. Downregulation of MFN1 and OPA1 also suppressed the radiation-induced increase in doubling time of NHFs. In summary, results show that a metabolic shift from glycolysis in young to mitochondrial respiration in old NHFs occurs during chronological lifespan, and MFN1 and OPA1 regulate this process.
| S-EPMC5595680 | biostudies-literature
Project description:ObjectivesTo compare the optic nerve head (ONH) structure between compressive optic neuropathy (CON) and glaucomatous optic neuropathy (GON), and to determine whether selected ONH quantitative parameters effectively discriminate between GON and CON, especially CON cases presenting with a glaucoma-like disc.MethodsWe prospectively assessed 34 patients with CON, 34 age-matched patients with moderate or severe GON, and 34 age-matched healthy control subjects. The quantitative parameters of ONH structure were compared using the Heidelberg Retina Tomograph 2 (HRT2) and Spectralis optical coherence tomography with an enhanced depth imaging method.ResultsThe mean and maximum cup depths of CON were significantly smaller than those with GON (P < 0.001 and P < 0.001, respectively). The distance between Bruch's membrane opening and anterior surface of the lamina cribrosa (BMO-anterior LC) of CON was also significantly smaller than that of glaucoma but was similar to that of the healthy group (P < 0.001 and P = 0.47, respectively). Based on Moorfields regression analysis of the glaucoma classification of HRT2, 15 eyes with CON were classified with a glaucoma-like disc. The cup/disc area ratio did not differ between cases of CON with a glaucoma-like disc and cases of GON (P = 0.16), but the BMO-anterior LC and mean and maximum cup depths of CON cases with a glaucoma-like disc were smaller than those in GON (P = 0.005, P = 0.003, and P = 0.001, respectively).ConclusionsMeasurements of the cup depths and the LC depth had good ability to differentiate between CON with a glaucoma-like disc and glaucoma. There was no laminar remodeling detected by laminar surface position in the patients with CON compared to those with GON.
| S-EPMC4223062 | biostudies-literature
Project description:Optic neuritis (ON) has been considered to be an important factor in the diagnosis of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), making ON detection increasingly critical for early diagnosis. Furthermore, subclinical ONs presenting no distinct decrease in visual acuity can be missed. Low contrast visual acuity (LC-VA) is known to be able to capture visual loss not seen in conventional high-contrast visual acuity (HC-VA) in MS. Therefore, to increase the sensitivity of ON detection, we investigated the advantage of LC-VA over conventional HC-VA. One hundred and eight patients with demyelinating disease (35 MS, 73 NMOSD) with ON at least 3 months prior and 35 controls underwent neuro-ophthalmic evaluation, including best-corrected conventional high contrast visual acuity (HC-VA) and 2.5% and 1.25% low contrast visual acuity (LC-VA). Receiver operating characteristic (ROC) curve analysis and the area under the curve (AUC) of various visual functions were used to determine the most relevant visual function test for the detection of optic nerve involvement. Additionally, the optimal cutoff point was obtained from the Youden index (J-index) as the points with the best sensitivity-specificity balance. When distinguishing ON from non-ON, the area under the ROC curve (AUC) was highest for the 2.5% LC-VA (0.835, P < 0.001; sensitivity 71.5%, specificity 88.6%), while it was 0.710 (P < 0.001) for the HC-VA and 0.770 (P < 0.001) for the 1.25% LC-VA. In discriminating between controls and ON, the AUC was also highest for the 2.5% LC-VA 0.754 (P < 0.001; sensitivity 71.5%, specificity 78.5%), while it was 0.719 (P < 0.001) for HC-VA and 0.688 (P < 0.001) for 1.25% LC-VA. In eyes with a history of ON (n = 137), the HC-VA and 2.5% LC-VA were abnormal in 64.2 and 71.5%, respectively (P < 0.001), with their combination detecting abnormalities in approximately 85.4% (P < 0.001). The 2.5% LC-VA was superior to HC-VA in detecting ON when distinguishing ON from non-ON or control. The 2.5% LC-VA might be a useful, feasible, and rapid method to detect ON. Furthermore, combining 2.5% LC-VA with conventional HC-VA would be better for detecting optic nerve involvements.
| S-EPMC7783398 | biostudies-literature
Project description:ImportanceOptic neuritis (ON) in children is uncommon. There are limited prospective data for visual acuity (VA) outcomes, associated diseases, and neuroimaging findings. Prospective data from a large sample would be useful for counseling families on treatment decisions and prognosis.ObjectiveTo prospectively study children with a first episode of ON, describe VA after 6 months, and ascertain the network's (Pediatric Eye Disease Investigator Group and Neuro-Ophthalmology Research Disease Investigator Consortium) ability to enroll pediatric patients with ON prospectively.Design, setting, and participantsThis nonrandomized cohort study was conducted from September 20, 2016, to July 20, 2018, at 23 sites in the United States and Canada in pediatric ophthalmology or neuro-ophthalmology clinics. A total of 44 children (aged 3-15 years) presented with a first episode of ON (visual loss, pain on eye movements, or both) within 2 weeks of symptom onset and at least 1 of the following in the affected eye: a distance high-contrast VA (HCVA) deficit of at least 0.2 logMAR below age-based norms, diminished color vision, abnormal visual field, or optic disc swelling. Exclusion criteria included preexisting ocular abnormalities or a previous episode of ON.Main outcomes and measuresPrimary outcomes were monocular HCVA and low-contrast VA at 6 months. Secondary outcomes were neuroimaging, associated diagnoses, and antibodies for neuromyelitis optica and myelin oligodendrocyte glycoprotein.ResultsA total of 44 children (mean age [SD], 10.2 [3.5] years; 26 boys [59%]; 23 White individuals [52%]; 54 eyes) were enrolled in the study. Sixteen patients (36%) had bilateral ON. Magnetic resonance imaging revealed white matter lesions in 23 children (52%). Of these children, 8 had myelin oligodendrocyte glycoprotein-associated demyelination (18%), 7 had acute disseminated encephalomyelitis (16%), 5 had multiple sclerosis (11%), and 3 had neuromyelitis optica (7%). The baseline mean HCVA was 0.95 logMAR (20/200), which improved by a mean 0.76 logMAR (95% CI, 0.54-0.99; range, -0.70 to 1.80) to 0.12 logMAR (20/25) at 6 months. The baseline mean distance low-contrast VA was 1.49 logMAR (20/640) and improved by a mean 0.72 logMAR (95% CI, 0.54-0.89; range, -0.20 to 1.50) to 0.73 logMAR (20/100) at 6 months. Baseline HCVA was worse in younger participants (aged <10 years) with associated neurologic autoimmune diagnoses, white matter lesions, and in those of non-White race and non-Hispanic ethnicity. The data did not suggest a statistically significant association between baseline factors and improvement in HCVA.Conclusions and relevanceThe study network did not reach its targeted enrollment of 100 pediatric patients with ON over 2 years. This indicates that future treatment trials may need to use different inclusion criteria or plan a longer enrollment period to account for the rarity of the disease. Despite poor VA at presentation, most children had marked improvement by 6 months. Associated neurologic autoimmune diagnoses were common. These findings can be used to counsel families about the disease.
| S-EPMC7563662 | biostudies-literature
Project description:Mitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Mutations in MFN2 cause the neurodegenerative disease Charcot-Marie-Tooth type 2A (CMT2A). The molecular basis underlying the physiological and pathological relevance of MFN2 is unclear. Here, we present crystal structures of truncated human MFN2 in different nucleotide-loading states. Unlike other dynamin superfamily members including MFN1, MFN2 forms sustained dimers even after GTP hydrolysis via the GTPase domain (G) interface, which accounts for its high membrane-tethering efficiency. The biochemical discrepancy between human MFN2 and MFN1 largely derives from a primate-only single amino acid variance. MFN2 and MFN1 can form heterodimers via the G interface in a nucleotide-dependent manner. CMT2A-related mutations, mapping to different functional zones of MFN2, lead to changes in GTP hydrolysis and homo/hetero-association ability. Our study provides fundamental insight into how mitofusins mediate mitochondrial fusion and the ways their disruptions cause disease.
| S-EPMC6820788 | biostudies-literature
Project description:PurposeTo analyze topographic progression of geographic atrophy with different concentric circles centered on the fovea in correlation with decrease of visual acuity.MethodsWe retrospectively analyzed 36 eyes of 26 patients diagnosed with geographic atrophy and followed at least 1 year. One millimeter circular area at the foveal center were defined as zone 1, and doughnut shape areas from between 1 and 2 mm to between 5 and 6 mm were defined as zone 2 to 6. Then, changes of geographic atrophy area in each zone were measured with semi-automatic software. Correlation analysis and regression analysis were performed to determine the relationship between changes in visual acuity and atrophic area in each zone.ResultsMean age was 76.9 years and follow-up period were 3.38 years. The mean atrophic area increased from 8.09 to 16.34 mm2 and visual acuity decreased from 0.39 to 0.69 on logarithm of the minimal angle of resolution. Mean change of total geographic atrophy area was not significantly correlated with visual acuity decrease. While geographic atrophy progression within zone 1, 2, and 3 showed significant causal relationship with decrease of visual acuity (all, p < 0.05).ConclusionsIn contrast to the total geographic atrophy area, progression of geographic atrophy in parafoveal area was significantly correlated with decrease of visual acuity.
| S-EPMC8666263 | biostudies-literature
Project description:PurposeTo evaluate the age-related change in color visual acuity (CVA) in normal eyes.MethodsIn total, 162 normal eyes (162 subjects, women: 52, men: 110, age range: 15-68 years) with best-corrected visual acuity (BCVA) ≥20/13 were enrolled. Fifteen colors from the New Color Test (chroma 6) were applied to Landolt "C" rings, white point D65 was applied as background, and a luminance of 30 cd/m2 was set for both the rings and the background. These rings were used to measure the chromatic spatial discrimination acuity as the CVA value, while changing the stimulus size. Correlations of the CVA value of each color and age were evaluated. Mean CVA values of all 15 colors (logarithm of the minimum angle of resolution) were compared between age groups in 10-year increments.ResultsNine CVA values (red, yellow-red, red-yellow, green, blue-green, green-blue, purple, red-purple, and purple-red) were negatively correlated with age (all p<0.05); the remaining six (yellow, green-yellow, yellow-green, blue, purple-blue, and blue-purple), as well as BCVA were not. The age groups with the best to worst mean CVA values of 15 colors were as follows: 20-29 (mean ± standard deviation, 0.303 ± 0.113), 30-39 (0.324 ± 0.096), 10-19 (0.333 ± 0.022), 50-59 (0.335 ± 0.078), 40-49 (0.339 ± 0.096), and 60-69 (0.379 ± 0.125) years. There were statistically significant differences between mean CVA values of the following groups: 20-29 and 40-49 years; 20-29 and 60-69 years; 30-39 and 60-69 years (all p<0.01).ConclusionsThe CVA values related to the medium/long-wavelength-sensitive cones were more susceptible to aging than those related to the short-wavelength-sensitive cones. This differed from previous reports, and may be related to the difference in the range of foveal cone function evaluated with each examination.
| S-EPMC8629265 | biostudies-literature