Neuro-Ophthalmic Phenotype of OPA3.

BACKGROUND: Type III 3-methylglutaconic aciduria (OPA 3) is a neuro-ophthalmologic syndrome consisting of early-onset bilateral optic atrophy. Since Costeff described the phenotype of 19 patients in 1989, several reports described approximately 50 patients, but most of them lack details about neuro-ophthalmic phenotype. Our aim was to characterize the clinical neuro-ophthalmic phenotype of this syndrome. METHODS: Nine patients underwent meticulous visual function history and medical documents' review. Results of best-corrected visual acuity (VA), color vision, visual field (VF), ocular motility, pupillary reaction, slit-lamp, and dilated fundus examinations were recorded. Optical coherence tomography (OCT) was performed whenever possible. RESULTS: The average VA was 1.4 ± 0.8 logarithm of the minimum angle of resolution. Poor vision was the presenting symptom in 5 patients. Six patients had decreased VA and variable degrees of optic atrophy. Humphrey VF testing of 7 patients revealed generalized depression in 5 and a cecocentral defect in 2. All patients demonstrated dysmetric saccades. Four patients had strabismus, 3 with exotropia, and one with esotropia. Seven patients had nystagmus. Ocular motility abnormality is possibly the result of cerebellar atrophy that was found in MRI studies of our patients. OCT of the retina was possible in 6 patients and revealed retinal nerve fiber layer (RNFL) thinning as well as average retinal thinning. Three patients, in whom ganglion cell layer-inner plexiform layer (IPL) measurement was possible, also showed diffused thinning. CONCLUSIONS: This study compiled data regarding neuro-ophthalmic manifestation of OPA 3 Type III patients. Contrary to established literature, poor vision was the presenting symptom in only 50% of our patients. This is the first report of OCT findings in 3MGA patients. The results demonstrated diffused thinning of the RNFL and ganglion cell complex-IPL with correlation to VA, which is in contrast to OPA1 patients in whom the most severe thinning is at the level of the papillomacular bundle. Average retinal thinning was identified at second and third decades of life, possibly resulting from early ganglion cell loss. These results may contribute to visual prognosis, and OCT may help monitor experimental therapies.

Characterization of SSBP1-related optic atrophy and foveopathy.

Dominant optic atrophy (DOA) is genetically heterogeneous and most commonly caused by mutations in OPA1. To distinguish between the classical OPA1-related and the recently identified SSBP1-related DOAs, the retina and fovea of 27 patients carrying the SSBP1 p.Arg38Gln variant were scrutinized using 20° × 20° macular cube and 30° and 55° field fundus autofluorescence photographs. Age of onset, visual acuity, retinal nerve fiber layer and macular thicknesses were recorded. Three SSBP1-patients were asymptomatic, 10 had isolated DOA, and 12 had a combined DOA plus foveopathy. The foveopathy, with a tiny defect of the ellipsoid and interdigitation lines, was similar in all patients, independent of age. There were no significant statistical differences in terms of visual acuity and SD-OCT measurements between patients with isolated DOA (mean visual acuity in decimals: 0.54 ± 0.41) and those with combined foveopathy (0.50 ± 0.23). Two patients over 50 years of age developed a progressive rod-cone dystrophy, leading to severe visual impairment. SSBP1-related DOA shares similarities with OPA1-related DOA with an incomplete penetrance and an early childhood visual impairment. Nevertheless, the presence of a congenital foveopathy with no impact on visual acuity is a major criterion to distinguish SSBP1 cases and orient the appropriate genetic analysis.

Neuroglobin effectively halts vision loss in Harlequin mice at an advanced stage of optic nerve degeneration.

Mitochondrial diseases are among the most prevalent groups of inherited neurological disorders, affecting up to 1 in 5000 adults. Despite the progress achieved on the identification of gene mutations causing mitochondrial pathologies, they cannot be cured so far. Harlequin mice, a relevant model of mitochondrial pathology due to apoptosis inducing factor depletion, suffer from progressive disappearance of retinal ganglion cells leading to optic neuropathy. In our previous work, we showed that administering adeno-associated virus encompassing the coding sequences for neuroglobin, (a neuroprotective molecule belonging to the globin family) or apoptosis-inducing factor, before neurodegeneration onset, prevented retinal ganglion cell loss and preserved visual function. One of the challenges to develop an effective treatment for optic neuropathies is to consider that by the time patients become aware of their handicap, a large amount of nerve fibers has already disappeared. Gene therapy was performed in Harlequin mice aged between 4 and 5 months with either a neuroglobin or an apoptosis-inducing factor vector to determine whether the increased abundance of either one of these proteins in retinas could preserve visual function at this advanced stage of the disease. We demonstrated that gene therapy, by preserving the connectivity of transduced retinal ganglion cells and optic nerve bioenergetics, results in the enhancement of visual cortex activity, ultimately rescuing visual impairment. This study demonstrates that: (a) An increased abundance of neuroglobin functionally overcomes apoptosis-inducing factor absence in Harlequin mouse retinas at a late stage of neuronal degeneration; (b) The beneficial effect for visual function could be mediated by neuroglobin localization to the mitochondria, thus contributing to the maintenance of the organelle homeostasis.

Focal dystonia in a case of SYNE1 spastic-ataxia: Expanding the phenotypic spectrum.

Synaptic nuclear envelope protein-1 (SYNE1) related cerebellar ataxia also called ARCA1 or SCAR8, manifests as a relatively pure cerebellar ataxia or with additional neurological involvement. Dystonia is rarely seen in SYNE1 ataxia and to the best of our knowledge, there are only three reports of dystonia in patients with SYNE1 ataxia. This report describes a 22-year-old woman with chronic progressive spastic-ataxia of 3-year duration with additional focal dystonia of the right upper limb. Patient had cerebellar atrophy on MRI brain and a novel pathogenic homozygous variant in exon 74 of the SYNE1 gene (p.Gln4047Ter).

Clinical and genetic features of PEHO and PEHO-Like syndromes: A scoping review.

Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is a genetic neurological condition characterized by extreme cerebellar atrophy. PEHO-Like syndrome is comparable to PEHO syndrome, with the exception that there is no typical neuro-radiologic or neuro-ophthalmic findings. PEHO spectrum disorders are highly clinically and genetically heterogeneous, and this has challenged their diagnosis. This scoping review aims to summarize and discuss common clinical and genetic features of these syndromes to help future researches. This study was performed according to a six-stage methodology structure and PRISMA guideline. A systematic search of seven databases was performed to find eligible publications prior to June 2020. Articles screening and data extraction were independently performed by two reviewers and quantitative and qualitative analyses were conducted. Thirty-eight articles were identified that fulfill the inclusion criteria. Cerebellar atrophy was the main clinical difference between the two groups but data on optic atrophy and infantile spasms/hypsarrhythmia were not consistent with the previously essential diagnostic criteria. Genetic analysis was performed in several studies, leading to identification of pathogenic variants in different genes that caused these conditions due to different mechanisms. Genetic studies could revolutionize the diagnosis process and our understanding of the etiology of this challenging group of patients by providing targeted sequencing panels and exome- or genome-scale studies in the future.

Movement disorders rounds: Atypical cases in two Chinese families with novel variants in ATP1A3.

ATP1A3-related dystonia is a disorder with high heterogeneous spectrum of clinical manifestations caused by mutations in ATP1A3 gene. Here, 2 atypical cases carring 2 de-novo ATP1A3 variants with RDP-CAPOS overlapping phenotype or continuous hemi-dystonia are described.

Potentially blinding adverse drug reaction to peribulbar lignocaine anesthesia: A rare case report.

Peribulbar lignocaine anesthesia is commonly used in ophthalmic surgeries. It rarely causes any severe allergic reaction. A 63-year-old male presented with complicated pseudophakia. He underwent successful vitrectomy under local anesthesia. He later presented with acute-onset proptosis, orbital swelling, and extraocular movement restriction. He was afebrile with normal blood workup and radiological investigations and gave a similar past history. The patient was treated successfully with intravenous medications but two months later developed optic atrophy. An adverse reaction to lignocaine appears to be the most probable cause. Early detection and prompt management of this condition may avert a potentially grave visual outcome. Literature review shows that this case is one of its kinds to report this potentially blinding complication of peribulbar lignocaine anesthesia.

Morphological Characteristics of the Optic Nerve Head and Choroidal Thickness in High Myopia.

Purpose: This study aimed to explore the morphological characteristics of Bruch's membrane opening distance (BMOD), border length (BL), border tissue angle (BTA), vertical tilt angle, and peripapillary atrophy (PPA), as well as their associations with choroidal thickness (ChT) in young healthy highly myopic eyes. Methods: A total of 167 patients with high myopia and 172 individuals without high myopia were enrolled. All of the subjects were divided by axial length. The PPA area was measured on fundus photographs. BMOD, BL, BTA, vertical tilt angle, macular ChT (mChT), and peripapillary ChT (pChT) were measured on swept-source optical coherence tomography scans. Results: The PPA area (P < 0.0001) and vertical tilt angle (P < 0.0001) were larger, BMOD (P < 0.0001) and BL (P < 0.0001) were longer, and BTA (P < 0.0001) was smaller in the high-myopia group compared with the group without high myopia. Every 1-µm increase in BMOD was associated with a 35.80-µm decrease in mChT; every 1° decrease in BTA was correlated with a 0.32-µm decrease in mChT and a 0.26-µm decrease in pChT; and no association was found between PPA area and ChT in the multivariate linear regression model. Conclusions: PPA area, BL, BMOD, and vertical tilt angle increased, but BTA decreased with axial elongation of the globe in young, healthy patients with myopia. Longer BMOD was positively correlated with lower mChT, and smaller BTA was positively correlated with lower mChT and pChT in this population.

A patient with pontocerebellar hypoplasia type 6: Novel RARS2 mutations, comparison to previously published patients and clinical distinction from PEHO syndrome.

Pontocerebellar hypoplasia type 6 (PCH6) is a rare infantile-onset progressive encephalopathy caused by biallelic mutations in RARS2 that encodes the mitochondrial arginine-tRNA synthetase enzyme (mtArgRS). The clinical presentation overlaps that of PEHO syndrome (Progressive Encephalopathy with edema, Hypsarrhythmia and Optic atrophy). The proband presented with severe intellectual disability, epilepsy with varying seizure types, optic atrophy, axial hypotonia, acquired microcephaly, dysmorphic features and progressive cerebral and cerebellar atrophy and delayed myelination on MRI. The presentation had resemblance to PEHO syndrome but sequencing of ZNHIT3 did not identify pathogenic variants. Subsequent whole genome sequencing revealed novel compound heterozygous variants in RARS2, a missense variant affecting a highly conserved amino acid and a frameshift variant with consequent degradation of the transcript resulting in decreased mtArgRS protein level confirming the diagnosis of PCH6. Features distinguishing the proband's phenotype from PEHO syndrome were later appearance of hypotonia and elevated lactate levels in blood and cerebrospinal fluid. On MRI the proband presented with more severe supratentorial atrophy and lesser degree of abnormal myelination than PEHO syndrome patients. The study highlights the challenges in clinical diagnosis of patients with neonatal and early infantile encephalopathies with overlapping clinical features and brain MRI findings.

Choline transporter-like 1 deficiency causes a new type of childhood-onset neurodegeneration.

Cerebral choline metabolism is crucial for normal brain function, and its homoeostasis depends on carrier-mediated transport. Here, we report on four individuals from three families with neurodegenerative disease and homozygous frameshift mutations (Asp517Metfs*19, Ser126Metfs*8, and Lys90Metfs*18) in the SLC44A1 gene encoding choline transporter-like protein 1. Clinical features included progressive ataxia, tremor, cognitive decline, dysphagia, optic atrophy, dysarthria, as well as urinary and bowel incontinence. Brain MRI demonstrated cerebellar atrophy and leukoencephalopathy. Moreover, low signal intensity in globus pallidus with hyperintensive streaking and low signal intensity in substantia nigra were seen in two individuals. The Asp517Metfs*19 and Ser126Metfs*8 fibroblasts were structurally and functionally indistinguishable. The most prominent ultrastructural changes of the mutant fibroblasts were reduced presence of free ribosomes, the appearance of elongated endoplasmic reticulum and strikingly increased number of mitochondria and small vesicles. When chronically treated with choline, those characteristics disappeared and mutant ultrastructure resembled healthy control cells. Functional analysis revealed diminished choline transport yet the membrane phosphatidylcholine content remained unchanged. As part of the mechanism to preserve choline and phosphatidylcholine, choline transporter deficiency was implicated in impaired membrane homeostasis of other phospholipids. Choline treatments could restore the membrane lipids, repair cellular organelles and protect mutant cells from acute iron overload. In conclusion, we describe a novel childhood-onset neurometabolic disease caused by choline transporter deficiency with autosomal recessive inheritance.

Clinical and neurocognitive issues associated with Bosch-Boonstra-Schaaf optic atrophy syndrome: A case study.

Nuclear receptor subfamily 2 group F member 1 (NR2F1) is an orphan receptor and transcriptional regulator that is involved in neurogenesis, visual processing and development, and cortical patterning. Alterations in NR2F1 cause Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), a recently described autosomal dominant disorder characterized by intellectual and developmental disabilities and optic atrophy. This study describes the clinical and neurocognitive features of an individual with a de novo nonsense variant in NR2F1 (NM_005654.5:c.82C > T, p.Gln28*), identified by whole exome sequencing. The patient was diagnosed with autism spectrum disorder (ASD) and unlike most previously reported cases, he had no developmental delay, superior verbal abilities (verbal IQ = 141), and high educational attainment despite reduced nonverbal abilities (nonverbal IQ = 63). He had optic nerve hypoplasia with minimal visual impairment as well as mild dysmorphic features. Compared to both age-matched individuals with ASD and healthy controls, the patient showed reductions in manual motor speed, accuracy of saccadic eye movements, and rates of successful behavioral response inhibition. Although the majority of previously reported cases of BBSOAS have been associated with more global intellectual dysfunction, we report on a patient with selective disruption of nonverbal abilities and superior verbal abilities.

The Clinical Journey of Patients with Riboflavin Transporter Deficiency Type 2.

PURPOSE: To identify symptoms and health care interactions with patients with riboflavin transporter deficiency (RTD) type 2 prior to diagnosis. METHODS: Parents of children with riboflavin transporter deficiency type 2 (n = 10) were interviewed to collect data on the patient's clinical journey. RESULTS: The average diagnostic delay was 27.6 months. Neurologists were the most commonly visited clinician (90%). Common symptoms during the first year of the patient's clinical journey included abnormal gait and/or ataxia (70%), nystagmus (50%), and upper body muscle weakness (40%). Prior to diagnosis, optic atrophy, sleep apnea, breath-holding spells, and dysphagia were commonly observed. Hearing loss was only reported in 40% of subjects prior to diagnosis. Riboflavin responsive megaloblastic anemia is reported for the first time. Mitochondrial disease was the most common suspected diagnosis (30%). CONCLUSION: Despite clinical variability, common early symptoms of riboflavin transporter deficiency type 2 exist that can better allow clinicians to more rapidly identify riboflavin transporter deficiency type 2.

POLR3A-related spastic ataxia: new mutations and a look into the phenotype.

Adolescent-onset spastic ataxia is a proposed novel phenotype in compound heterozygous carriers of an intronic mutation (c.1909 + 22G > A) in the POLR3A gene. Here, we present ten new cases of POLR3A-related spastic ataxia and discuss the genetic, clinical and imaging findings. Patients belonged to six pedigrees with hereditary spastic paraplegia or cerebellar ataxia of unknown origin. All affected subjects presented with compound heterozygous variants, comprising c.1909 + 22G > A in combination in each pedigree with one of the following novel mutations (Thr596Met, Tyr665LeufsTer11, Glu198Ter, c.646-687_1185 + 844del). The new mutations segregated with the phenotype in all families. The phenotype combined variable cerebellar ataxia, gait and lower limb spasticity, involvement of central sensory tracts and in some cases also intention tremor. The reportedly characteristic hyperintensity along the superior cerebellar peduncle on MRI was observed in ~ 80% of the cases. Our study extends the clinical and molecular phenotype further supporting the pathogenic role of the c.1909 + 22G4A intronic mutation and identifying four novel causative mutations in POLR3A-related spastic ataxia. Certain characteristic MRI features may be useful to guide genetic diagnosis.

Function of hTim8a in complex IV assembly in neuronal cells provides insight into pathomechanism underlying Mohr-Tranebjærg syndrome.

Human Tim8a and Tim8b are members of an intermembrane space chaperone network, known as the small TIM family. Mutations in TIMM8A cause a neurodegenerative disease, Mohr-Tranebjærg syndrome (MTS), which is characterised by sensorineural hearing loss, dystonia and blindness. Nothing is known about the function of hTim8a in neuronal cells or how mutation of this protein leads to a neurodegenerative disease. We show that hTim8a is required for the assembly of Complex IV in neurons, which is mediated through a transient interaction with Complex IV assembly factors, in particular the copper chaperone COX17. Complex IV assembly defects resulting from loss of hTim8a leads to oxidative stress and changes to key apoptotic regulators, including cytochrome c, which primes cells for death. Alleviation of oxidative stress with Vitamin E treatment rescues cells from apoptotic vulnerability. We hypothesise that enhanced sensitivity of neuronal cells to apoptosis is the underlying mechanism of MTS.

Peripapillary Choroidal Vascularity Index and Microstructure of Parapapillary Atrophy.

Purpose: To investigate the association between the microstructure of ß-zone parapapillary atrophy (ßPPA) and choroidal vascularity index (CVI) determined by spectral-domain optical coherence tomography (SD-OCT) in glaucomatous eyes. Methods: A total of 160 eyes of 160 primary open-angle glaucoma patients with ßPPA were included. Total choroidal area (TCA), luminal area (LA), and CVI were measured at a 3.5-mm distance from the Bruch's membrane (BM) opening center by image binarization of SD-OCT B-scans. The widths of ßPPA with BM (ßPPA+BM) and without BM (ßPPA-BM), and juxtapapillary choroidal thickness (JPCT) were measured on six radial SD-OCT images. OCT angiography-derived parapapillary deep-layer microvasculature dropout (MvD_P) was also derived. Results: In the multivariate regression analysis, larger ßPPA+BM was significantly associated with smaller TCA and smaller LA (P < 0.05, respectively), but not with CVI and JPCT (P > 0.05, respectively). Meanwhile, ßPPA-BM was not significantly associated with TCA, LA, CVI, or JPCT in the multivariate regression analysis (P > 0.05). Conclusions: Despite significant relationship between the choroidal thinning and larger ßPPA+BM, choroidal vascularity was not associated with the ßPPA+BM width. These findings suggest that the presumed common pathogenic mechanism between RPE atrophy and peripapillary choroidal thinning may not be mediated by the impaired choroidal perfusion in glaucomatous eyes. Future studies on the mechanisms in explaining the relationship between the atrophy of retinal pigment epithelium (RPE) and choroid in glaucoma are needed.

Six-month results of suprachoroidal adipose tissue-derived mesenchymal stem cell implantation in patients with optic atrophy: a phase 1/2 study.

PURPOSE: This prospective clinical case series aimed to investigate the safety and efficacy of suprachoroidal adipose tissue-derived mesenchymal stem cell (ADMSC) implantation in patients with optic nerve diseases. METHODS: This prospective, single-center, phase 1/2 study enrolled 4 eyes of 4 patients with optic atrophy of various reasons who underwent suprachoroidal implantation of ADMSCs. The best-corrected visual acuity (BCVA) in the study was HM at 1 m. The worse eye of the patient was operated. Patients were evaluated on the first day, first week, first month, third and sixth months postoperatively. BCVA, anterior segment and fundus examination, color photography, optical coherence tomography (OCT) and visual field examination were carried out at each visit. Fundus fluorescein angiography and multifocal electroretinography (mfERG) recordings were performed at the end of the first, third and sixth months and anytime if necessary during the follow-up. RESULTS: All 4 patients completed the six-month follow-up. None of them had any systemic or ocular complications. All of the patients experienced visual acuity improvement, visual field improvement and improvement in the mfERG recordings. We found choroidal thickening in OCT of the 4 patients. CONCLUSION: Even though the sample size is small, the improvements were still encouraging. Stem cell treatment with suprachoroidal implantation of ADMSCs seems to be safe and effective in the treatment for optic nerve diseases that currently have no curative treatment options.

A Sporadic Case of Charcot-Marie-Tooth Disease Type 2 with Left Vocal Fold Palsy due to Mitofusin 2 Mutation.

A 33-year-old Japanese woman was referred for hoarseness. She had been diagnosed with Charcot-Marie-Tooth disease at age 3 and bilateral optic atrophy at age 15. Laryngoscopy revealed left vocal fold palsy. These findings suggested Charcot-Marie-Tooth disease type 2; the diagnosis was confirmed by a mitofusin 2 mutation analysis. Her symptoms remained stable for almost 10 years. Although vocal fold palsy and optic atrophy have been previously reported in patients with mitofusin 2 mutations, detailed clinical information and clinical course have never been documented. These data might contribute to the elucidation of the pathological conditions associated with mitofusin 2 mutations.

Chronological dynamic changes in cortico-subcortical imbalance of cerebral blood flow in a boy with CAPOS syndrome.

BACKGROUND: Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss (CAPOS) syndrome is a known ATP1A3-related disorder, but little has been elucidated regarding its pathophysiology. We now report two new patients, a Japanese boy and his mother with a pathogenic mutation (c.2452G>A) in ATP1A3, who were diagnosed with CAPOS syndrome. METHODS: After febrile illnesses at 7 months of age, and again at 22 months of age, the boy had a reduced level of consciousness, truncal ataxia and eye movement-disorders. The patient's 32-year-old mother may have experienced an episode of acute encephalopathy in her childhood and sustained sensorineural hearing loss. In the present study, we demonstrated chronological dynamic changes in cerebral blood flow (CBF) in the son, using serial single-photon emission computed tomography (SPECT). RESULTS: The serial CBF-SPECT findings using statistical methods showed progressive hyperperfusion in the frontal lobes, basal ganglia and thalamus, and hypoperfusion in the occipital and temporal lobes during the acute and subacute phases. Thereafter, the dynamic changes of CBF improved in the chronic but hypoperfusion in thalamus appeared to the chronic phase. CONCLUSION: The abnormal cortico-subcortical CBF may contribute to an acute encephalopathy-like condition in the acute stage of CAPOS syndrome. CAPOS syndrome is not often reported, and is possibly an under-recognized syndrome in clinically mild cases.