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To present a case of idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome that was successfully managed with serial intravitreal aflibercept injections.Ophthalmic imaging and visual acuity were used to monitor disease state and track treatment methods to determine the most valuable combination of treatment medication and treatment interval.A 28-year-old woman with idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome status after panretinal photocoagulation of both eyes presented with bilateral cystoid macular edema. We demonstrate successful management of retinal cystoid macular edema associated with idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome using serial intravitreal aflibercept injections.Intravitreal aflibercept has a useful role in managing the potential retinal complications associated with idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome and provides further insights into treatment of the later stages of this rare disease.

Charcot-Marie-Tooth disease (CMT) is a common hereditary peripheral polyneuropathy encompassing distinct monogenetic disorders. Pathogenic mutations in mitofusin 2 (MFN2) are the most frequent cause of its axonal type, CMT type 2A, with diverse phenotypes. We herein report a Japanese patient with a novel heterozygous MFN2 pathogenic variant (c.740 G>C, p.R247P) and severe CMT phenotypes, including progressive muscle weakness, optic atrophy, urinary inconsistency, and restrictive pulmonary dysfunction with eventration of the diaphragm that developed over her 60-year disease course. Our case expands the clinico-genetic features of MFN2-related CMT and highlights the need to evaluate infrequent manifestations during long-term care of CMT patients.

BACKGROUND Optical coherence tomography angiography (OCTA) is a new noninvasive imaging modality that provides high resolution images of the optic nerve head and peripapillary retinal capillary vasculature which can be affected by optic nerve or retinal pathologies. High repeatability of peripapillary capillary density measurement using OCTA has been demonstrated in normal eyes and eyes with glaucoma. The purpose of our study was to quantify the repeatability of peripapillary capillary density measurement using OCTA in both normal eyes and eyes with optic atrophy, optic disc edema, and retinal vasculopathy. METHODS This prospective cross-sectional study enrolled 31 patients (59 eyes) including 16 eyes with optic nerve pathology (7 with disc edema from papilledema and 9 with optic atrophy), 35 eyes with retinal vascular disease, and 8 normal eyes. All eyes were imaged twice (30 minutes apart) with the Optovue AngioVue OCTA instrument to obtain 4.5 × 4.5 mm peripapillary scans. Scans were considered good quality if signal strength was 6 or greater. The OCTA parameters obtained include the radial peripapillary capillary (RPC) density of the whole disc, inside the disc, peripapillary region, and the 4 quadrants of the disc (superior, nasal, inferior, and temporal). A Student's t test was used to compare means. Intraclass correlation coefficient (ICC) was calculated to measure repeatability. RESULTS Repeatability of RPC density measurements for all regions analyzed demonstrated good to excellent repeatability for the whole cohort {ICC for the whole image was 0.915 (95% confidence interval [CI] = 0.855-0.951)}; ICC for the peripapillary region was 0.945 (95% CI = 0.905-0.969). In the subset of eyes with good image quality (i.e., signal strength ≥ 6), ICC was slightly higher for all regions, with excellent repeatability of the peripapillary region (ICC was 0.971 [95% CI = 0.943-0.986]). Conversely, for eyes with poor image quality scans (i.e., signal strength < 6), ICC was lower, corresponding to moderate to good repeatability for most parameters. For the subset of eyes with optic atrophy, disc edema from papilledema or retinal vasculopathy, all had good to excellent repeatability of the vessel density of the entire disc (ICC values were 0.954 [95% CI = 0.804-0.990], 0.921 [95% CI = 0.711-0.982], and 0.895 [95% CI = 0.788-0.951, respectively]) and of the peripapillary region (ICC values were 0.980 [95% CI = 0.904-0.996], 0.966 [95% CI = 0.854-0.993], and 0.916 [95% CI = 0.827-0.961], respectively). CONCLUSIONS The peripapillary capillary density measurement obtained using a commercial OCTA instrument is highly repeatable in eyes with optic nerve atrophy, disc edema from papilledema, or retinal vasculopathy.

We herein report a case of myoclonic epilepsy with ragged-red fibers (MERRF) harboring a novel variant in mitochondrial cysteine transfer RNA (MT-TC). A 68-year-old woman presented with progressive myoclonic epilepsy with optic atrophy and peripheral neuropathy. A skin biopsy revealed p62-positive intranuclear inclusions. No mutations were found in the causative genes for diseases known to be related to intranuclear inclusions; however, a novel variant in MT-TC was found. The association between intranuclear inclusions and this newly identified MERRF-associated variant is unclear; however, the rare complication of intranuclear inclusions in a patient with typical MERRF symptoms should be noted for future studies.

Autosomal dominant optic atrophy (DOA) is the most common inherited optic neuropathy in the United Kingdom. DOA has an insidious onset in early childhood, typically presenting with bilateral, central visual loss caused by the preferential loss of retinal ganglion cells. 60%–70% of genetically confirmed DOA cases are associated with variants in OPA1, a ubiquitously expressed GTPase that regulates mitochondrial homeostasis through coordination of inner membrane fusion, maintenance of cristae structure, and regulation of bioenergetic output. Whether genetic correction of OPA1 pathogenic variants can alleviate disease-associated phenotypes remains unknown. Here, we demonstrate generation of patient-derived OPA1 c.1334G>A: p.R445H mutant induced pluripotent stem cells (iPSCs), followed by correction of OPA1 through CRISPR-Cas9-guided homology-directed repair (HDR) and evaluate the effect of OPA1 correction on mitochondrial homeostasis. CRISPR-Cas9 gene editing demonstrated an efficient method of OPA1 correction, with successful gene correction in 57% of isolated iPSCs. Correction of OPA1 restored mitochondrial homeostasis, re-establishing the mitochondrial network and basal respiration and ATP production levels. In addition, correction of OPA1 re-established the levels of wild-type (WT) mitochondrial DNA (mtDNA) and reduced susceptibility to apoptotic stimuli. These data demonstrate that nuclear gene correction can restore mitochondrial homeostasis and improve mtDNA integrity in DOA patient-derived cells carrying an OPA1 variant., Graphical abstract, Cheetham and colleagues describe an efficient CRISPR-Cas9 gene editing strategy to correct a variant in the nuclear gene OPA1 in dominant optic atrophy patient-derived iPSCs. The correction rescued OPA1-associated defects in mitochondrial networks, bioenergetics, and mtDNA integrity, as well as improving resistance to apoptosis, highlighting the therapeutic potential.

Spastic ataxia is characterized by the combination of cerebellar ataxia with spasticity and other pyramidal features. It is the hallmark of some hereditary ataxias, but it can also occur in some spastic paraplegias and acquired conditions. It often presents with heterogenous clinical features with other neurologic and non-neurological symptoms, resulting in complex phenotypes. In this review, the differential diagnosis of spastic ataxias are discussed and classified in accordance with inheritance. Establishing an organized classification method based on mode inheritance is fundamental for the approach to patients with these syndromes. For each differential, the clinical features, neuroimaging and genetic aspects are reviewed. A diagnostic approach for spastic ataxias is then proposed.

Pathogenic biallelic variants in POL3RA have been associated with different disorders characterized by progressive neurological deterioration. These include the 4H leukodystrophy syndrome (hypomyelination, hypogonadotropic hypogonadism, and hypodontia) and adolescent-onset progressive spastic ataxia, as well as Wiedemann-Rautenstrauch syndrome (WRS), a recognizable neonatal progeroid syndrome. The phenotypic differences between these disorders are thought to occur mainly due to different functional effects of underlying POLR3A variants. Here we present the detailed clinical course of a 37-year-old woman in whom we identified a homozygous synonymous POLR3A variant c.3336G>A resulting in leaky splicing r.[3336ins192, =, 3243_3336del94]. She presented at birth with intrauterine growth retardation, lipodystrophy, muscular hypotonia, and several WRS-like facial features, albeit without sparse hair and prominent scalp veins. She had no signs of developmental delay or intellectual disability. Over the years, above characteristic facial features, she showed severe postnatal growth retardation, global lipodystrophy, joint contractures, thoracic hypoplasia, scoliosis, anodontia, spastic quadriplegia, bilateral hearing loss, aphonia, hypogonadotropic hypogonadism, and cerebellar peduncles hyperintensities in brain imaging. These manifestations partially overlap the clinical features of the previously reported POLR3A-associated disorders, mostly mimicking the WRS. Thus, our study expands the POLR3A-mediated phenotypic spectrum and suggests existence of a phenotypic continuum underlying biallelic POLR3A variants.

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.

Wolfram Syndrome is a rare genetic disorder usually inherited in an autosomal recessive manner. The acronym DIDMOAD characterizes the classic constellation of findings: diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. However, other ocular and systemic manifestations may also be present. The aim of this report is to present a patient with Wolfram Syndrome presenting with vitelliform changes in the retina - an association that has not been previously reported.: Case Report.: Ophthalmologic examination and imaging studies showed bilateral optic neuropathy and scattered bilateral subretinal vitelliform deposits. Genetic testing was positive for Wolfram Syndrome.: This patient showed optic atrophy with associated vitelliform retinal changes. The previously unreported association of these findings present possible associations in the molecular pathophysiology underlying both Wolfram syndrome and the spectrum of retinal disorders associated with vitelliform changes.

Purpose: To report a rare case of primary pneumosinus dilatans (PSD) and to specify the cardinal imaging findings associated with this condition. Methods: A 20-year-old patient presented with bilateral profound visual loss as a result of primary PSD. A detailed review of clinical findings and presumed pathophysiological basis of vision loss was performed. Results: Other than undiagnosed primary hypothyroidism, no other abnormalities were found. With the diagnosis of PSD, the patient underwent optic nerve decompression through transnasal sphenoidotomy. However, after nine months of follow-up, no improvement in the patient's vision was attained. Conclusion: Unlike previous reports of favorable visual results after sphenoidotomy and bilateral decompression of the optic nerves, vision recovery was not achieved in this case.

BackgroundTo investigate the longitudinal change of localised retinal nerve fibre layer (RNFL) defects associated with change of ß-zone parapapillary atrophy (PPA) in primary open-angle glaucoma (POAG) eyes.MethodsPOAG patients with a localised RNFL defect and ß-zone PPA who had undergone disc/RNFL photography at 1-year intervals for 10 years or longer were enrolled. The topographic parameters of ß-zone PPA (area, maximal radial extent and angular extent around disc) were measured. Progression of RNFL defect was defined as widening of defect and/or appearance of new defect. The factors associated with progression of RNFL defect were assessed by OR using multivariable logistic regression.ResultsA total of 209 patients (209 eyes) with POAG were included (mean: 54 years old). Over the course of 11.5±2.3-year follow-up period, progression of RNFL defect was detected in 114 eyes (54.5%). Enlargement of PPA parameters (area and angular extent) was significantly more common in patients with RNFL defect progression than in eyes without progression (all pConclusionsProgression of RNFL defect is associated with increment of angular extent of PPA in POAG eyes.

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.

Background Wolfram syndrome (WFS) is characterized by deafness, diabetes mellitus, and diabetes insipidus along with optic atrophy. WFS has an autosomal recessive mode of inheritance and is due to variants in WFS1 and CISD2. Methods We evaluated the underlying molecular etiology of three affected members of a consanguineous family with hearing impairment, bicuspid aortic valve, diabetes mellitus and insipidus, clinodactyly, and gastrointestinal tract abnormalities via exome sequencing approach. We correlated clinical and imaging data with the genetic findings and their associated phenotypes. Results We identified a homozygous missense variant p.(Asn1097Lys) in CDK13, a gene previously associated with autosomal dominant congenital heart defects, dysmorphic facial features, clinodactyly, gastrointestinal tract abnormalities, intellectual developmental disorder, and seizures with variable phenotypic features. Conclusion We report a homozygous variant in CDK13 and suggest that this gene causes an autosomal recessive disorder with hearing impairment, bicuspid aortic valve, diabetes mellitus and insipidus, clinodactyly, and gastrointestinal tract abnormalities.

Objective Bi-allelic mutations in wolframin gene (WFS1) cause Wolfram syndrome 1 (WS1 or DIDMOAD) characterized with non-autoimmune diabetes mellitus (DM), optic atrophy (OA), diabetes insipidus (DI), sensorineural deafness (SND), urinary tract abnormalities, and neuropsychiatric disorders. We evaluated patients presented with an incomplete phenotype of WS1 using homozygosity mapping and subsequent whole-exome sequencing. Patients and methods Four unrelated consanguineous Turkish families (7 affected children), and their unaffected parents and siblings were evaluated. Homozygosity mapping (HZM) was performed, followed by whole-exome sequencing of WFS1. Mutations were classified according to results of "in silico" analyses, protein prediction, and functional consequences. Results Homozygosity mapping confirmed shared homozygous regions on chromosome 4 (chr4p16.1) between the affected individuals, and absent from their unaffected siblings. Exome sequencing identified three novel (c.1215T>A, c.554G>A, c.1525_1540dup) and one known (c. 1522_1523delTA) mutations in WFS1 gene. All mutations were predicted to cause stop codon leading to early termination of protein synthesis and complete loss-of-function. All patients were found to be homozygous for the change, with parents and other unaffected siblings being carriers. Conclusion Our study expands the mutation spectrum of WSF1 mutations with three novel mutations. Homozygosity mapping may provide enrichment for molecular genetic analysis and early diagnosis of WS1 patients with incomplete phenotype, particularly in consanguineous pedigrees.

Background To report a novel mutation and new clinical findings in a case with SPOAN syndrome (spastic paraplegia, optic atrophy, neuropathy). Case presentation Clinical examination, genetic testing and electroretinography were used to study a 2-year-old child who was referred to our clinic with no visual attention and documented SPOAN syndrome. Fundoscopy revealed optic atrophy, diffuse retinal pigment mottling, severe vascular attenuation, and completely non-vascularized peripheral retina in both eyes. Full-field electroretinogram (ERG) revealed flat responses. Conclusions Severe retinopathy and flat full-field ERG responses can occur in SPOAN syndrome.

Cerebral palsy (CP) is the most common cause of childhood physical disability globally. This study describes the spectrum of ocular morbidity and visual impairment in a community-based (recruited by key informants) sample of children with CP in Cross River State, Nigeria.MethodsA paediatric neurologist clinically confirmed CP and assessed systemic comorbidity. Ophthalmological assessment included developmental age appropriate acuity tests, objective refraction and objective and subjective tests of perceptual visual dysfunction (PVD).Results388 children aged 4–15 years with CP were identified. Visual problems were reported by carers in only 55 (14%) cases. Binocular visual acuity impairment was seen in 20/201 by Lea symbols test (10%) and 213/388 (55%) by the mirror test. Abnormal visual fields were seen in 58/388 (14.9%); strabismus in 183 (47%) abnormal contrast sensitivity in 178 (46%) and abnormal saccades in 84 (22%), spherical refractive errors in 223 (58%), significant astigmatism in 36 (12%), accommodative dysfunction in 41 (10.6%), optic atrophy in 198 (51%). Perceptual visual disorders were present in 22 (6%) subjectively and 177 (46%) objectively. The estimated frequency of cerebral visual impairment (CVI) in children ranged from 61 (16%) to 191 (49%) if children with optic atrophy were included.ConclusionChildren with CP have a wide spectrum of ocular morbidity and visual impairment, underestimated by carers. Children with CP require visual acuity assessments with a range of tests which account for associated comorbidities and oculomotor dysfunction. Functional vision assessments for PVD is important. CVI is common.

Micro and Martsolf syndromes are rare clinically and genetically overlapping disorders caused by mutations in RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20 genes. We describe 34 new patients, 27 with Micro and 7 with Martsolf. Patients presented with the characteristic clinical manifestations of the two syndromes including postnatal microcephaly, congenital cataracts, microphthalmia, optic atrophy, spasticity and intellectual disability. Brain imaging showed in the majority of cases polymicrogyria, thin corpus callosum, cortical atrophy, and white matter dysmyelination. Unusual additional findings were pectus excavatum (4 patients), pectus carinatum (3 patients), congenital heart disease (3 patients) and bilateral calcification in basal ganglia (1 patient). Mutational analysis of RAB3GAP1 and RAB3GAP2 revealed 21 mutations including 14 novel variants. RAB3GAP1 mutations were identified in 22 patients with Micro including a deletion of the entire gene in one patient. On the other hand, RAB3GAP2 mutations were identified in two patients with Micro and all Martsolf patients. Moreover, exome sequencing unraveled a TBC1D20 mutation in an additional family with Micro syndrome. Our results expand the phenotypic and mutational spectrum associated with Micro and Martsolf syndromes. Due to the overlapped severities and genetic basis of both syndromes, we suggest to be comprehended as one entity "Micro/Martsolf spectrum" or "RAB18 deficiency". This article is protected by copyright. All rights reserved.

Objective Recessive mutations in the CAPN1 gene have recently been identified in spastic paraplegia 76 (SPG76), a complex hereditary spastic paraplegia (HSP) that is combined with cerebellar ataxia, resulting in an ataxia‐spasticity disease spectrum. This study aims to assess the influence of CAPN1 variants on the occurrence of SPG76 and identify factors potentially contributing to phenotypic heterogeneity. Methods We screened a cohort of 240 unrelated HSP families for variants in CAPN1 using high‐throughput sequencing analysis. We described in detail the clinical and genetic features of the SPG76 patients in our cohort and summarized all reported cases. Results Six unreported CAPN1‐associated families containing eight patients with or without cerebellar ataxia were found in our cohort of HSP cases. These patients carried three previously reported homozygous truncating mutations (p.V64Gfs*103, c.759+1G>A, and p.R285*), and three additional novel compound heterozygous missense mutations (p.R481Q, p.P498L, and p.R618W). Lower limbs spasticity, hyperreflexia, and Babinski signs developed in about 94% of patients, with ataxia developing in 63% of cases. In total, 33 pathogenic mutations were distributed along the three reported functional domains of calpain‐1 protein, encoded by CAPN1, with no hotspot region. A comparison of gender distribution between the two groups indicated that female SPG76 patients were significantly more likely to present with complicated HSP than male patients (P = 0.015). Interpretation Our study supports the clinically heterogeneous inter‐ and intra‐family variability of SPG76 patients, and demonstrates that gender and calpain‐1 linker structure may contribute to clinical heterogeneity in SPG76 cases.

Neurological visual impairments in children have multiple causes, some of them reversible while others are not. Hydrocephalus is one of the most important and common ones as it can result in permanent impairment. There are multiple causes of hydrocephalus, intraventricular hemorrhage being the main one. This generally occurs when the germinal matrix bleeds and is very common in preterm newborns. We present the clinical case of a patient with cerebral palsy, intraventricular hemorrhage, and hydrocephalus as a result of a preterm multiple pregnancy who developed optic atrophy during childhood secondary to ventricle-peritoneal shunt dysfunction. During the rehabilitation and treatment period, she received neurorehabilitation sessions, which improved her visual acuity and capacity. We found similarities and differences with other cases and we confirmed the importance of the treatment chosen for the recovery of visual capacity.Las alteraciones visuales de origen neurológico en los niños tienen diversas causas, algunas reversibles y otras no. La hidrocefalia es una de las más comunes e importantes, ya que puede producir deficiencias permanentes. Las causas de la hidrocefalia son variadas; entre las principales está la hemorragia intraventricular, generalmente debida al sangrado de la matriz germinal, el cual es muy común en recién nacidos prematuros. Se presenta el caso clínico de una paciente prematura con parálisis cerebral infantil, hemorragia intraventricular e hidrocefalia, producto de un embarazo múltiple, que presentó atrofia óptica en la infancia secundaria a la disfunción del sistema de derivación ventrículo-peritoneal. Durante su rehabilitación y tratamiento, ha recibido sesiones de neurorrehabilitación que le han permitido mejorar su agudeza y capacidad visual. Se comparó el caso de la paciente con algunos similares para establecer las semejanzas y las diferencias entre los cuadros clínicos presentados y la importancia del tipo de tratamiento médico utilizado en el curso de recuperación de la capacidad visual.

Introduction The gene encoding myelin-associated glycoprotein (MAG) has been implicated in autosomal-recessive spastic paraplegia type 75. To date, only four families with biallelic missense variants in MAG have been reported. The genotypic and phenotypic spectrum of MAG-associated disease awaits further elucidation. Methods Four unrelated patients with complex neurologic conditions underwent whole-exome sequencing within research or diagnostic settings. Following determination of the underlying genetic defects, in-depth phenotyping and literature review were performed. Results In all case subjects, we detected ultra-rare homozygous or compound heterozygous variants in MAG. The observed nonsense (c.693C > A [p.Tyr231*], c.980G > A [p.Trp327*], c.1126C > T [p.Gln376*], and 1522C > T [p.Arg508*]) and frameshift (c.517_521dupAGCTG [p.Trp174*]) alleles were predicted to result in premature termination of protein translation. Affected patients presented with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms. Cerebellar signs, nystagmus, and pyramidal tract dysfunction emerged as unifying features in the majority of MAG-mutated individuals identified to date. Conclusions Our study is the first to describe biallelic null variants in MAG, confirming that loss of myelin-associated glycoprotein causes severe infancy-onset disease with central and peripheral nervous system involvement.

In autosomal dominant optic atrophy (ADOA), caused by mutations in the mitochondrial cristae biogenesis and fusion protein optic atrophy 1 (Opa1), retinal ganglion cell (RGC) dysfunction and visual loss occur by unknown mechanisms. Here, we show a role for autophagy in ADOA pathogenesis. In RGCs expressing mutated Opa1, active 5’ AMP-activated protein kinase (AMPK) and its autophagy effector ULK1 accumulate at axonal hillocks. This AMPK activation triggers localized hillock autophagosome accumulation and mitophagy, ultimately resulting in reduced axonal mitochondrial content that is restored by genetic inhibition of AMPK and autophagy. In C. elegans, deletion of AMPK or of key autophagy and mitophagy genes normalizes the axonal mitochondrial content that is reduced upon mitochondrial dysfunction. In conditional, RGC specific Opa1-deficient mice, depletion of the essential autophagy gene Atg7 normalizes the excess autophagy and corrects the visual defects caused by Opa1 ablation. Thus, our data identify AMPK and autophagy as targetable components of ADOA pathogenesis., K.P. was supported by a Bodossaki Foundation long-term fellowship, AXA Research Fund post-doctoral long-term fellowship and a grant from the Hellenic Foundation for Research and Innovation (HFRI) and the General Secretariat for Research and Technology (GSRT). S.H. was supported by a FP7-Cofund, an AIRC Postdoctoral Fellowship and a Fondazione Umberto Veronesi fellowship. K.I. is supported in part by the Japan Society for the Promotion of Science (S2603) and the Japan Foundation for Pediatric Research. This work was funded by Telethon Italy (TCR02016 and GGP15198), Italian Ministry of Health (GR 09.021), Italian Ministry of Research (FIRB RBAP11Z3YA_005), Fondation Leducq (TNE004015) to L.S.; by ERC (GA282280 to L.S.; GA695190 and GA737599 to N.T.); the Greek General Secretariat for Research and Technology to N.T.; the International Foundation for Optic Nerve Diseases (IFOND) to V.C. and A.A.S.

To determine whether eyes with open-angle glaucoma (OAG) and a localized choroidal microvasculature dropout (MvD) are associated with a greater degree of generalized choroidal vascular insufficiency within the β-parapapillary atrophy (β-PPA) than OAG eyes without MvD.Retrospective cross-sectional study.This study included 100 OAG eyes with visual field (VF) loss confined to a single hemifield (50 with and 50 without MvD, matched for age [≤10 years ols], axial length [≤1 mm], and VF severity [≤1 dB]), as well as 50 healthy eyes. Using optical coherence tomography angiography, parapapillary choroidal vessel density (pCVD) was measured on en-face images of choroidal maps within the entire β-PPA after excluding the MvD area and hemi-sectors of the β-PPA. pCVDs were compared among the 3 groups. The relationships between pCVD outcomes and various clinical variables were assessed. Logistical regression analyses were performed to determine the clinical factors associated with the presence of MvD in eyes with OAG.pCVDs corresponding to the VF-intact hemi-sectors and the entire β-PPA, excluding the MvD area, were significantly lower in eyes with MvD than in matched sectors of eyes without MvD. Multivariate linear regression analysis showed that the presence of MvD and greater MvD angular extent were independently associated with lower global pCVD in OAG eyes (all P.05). Logistic regression analyses showed that lower pCVD was the only factor significantly associated with the presence of MvD.Localized MvD was a strong predictor of generalized pCVD loss within the β-PPA in OAG eyes.

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.

RTN4IP1 pathogenic variants (OPA10 syndrome) have been described in patients with early-onset recessive optic neuropathy and recently associated with a broader clinical spectrum, from isolated optic neuropathy to severe encephalopathies with epilepsy. Here we present a case of a patient with a complex clinical picture characterized by bilateral optic nerve atrophy, horizontal nystagmus, myopia, mild intellectual disability, generalized chorea, isolated small subependymal heterotopia, and asynchronous self-resolving midbrain MRI (magnetic resonance imaging) lesions. By using massive gene sequencing, we identified in this patient the c.308G > A (p.Arg103His) homozygous pathogenic variant in the RTN4IP1 gene. Complex movement disorders and relapsing-remitting neuroradiological lesions have not been previously reported in this condition. Our case expands the clinical spectrum of OPA10 syndrome and opens new opportunities for the molecular diagnosis.

Wolfram syndrome (WFS) is a rare, monogenic neurodegenerative syndrome characterised by insulin requiring non-autoimmune diabetes mellitus (DM) and optic atrophy which are usually the earliest and commonest manifestations. However, there are other features which are under-recognized, adding to morbidity and premature mortality in these patients. Five patients (three males, two females) with genetically confirmed WFS at a single tertiary care centre were prospectively followed up. Their symptomatology, clinical profile, genetic analysis and radiology were analyzed. Multidisciplinary approach was used for comprehensive clinical care of this cohort. Patients with primary gonadal failure were subjected to biopsy and immunohistochemistry (IHC) for wolframin was performed. DM was the earliest presenting manifestation at 6.2 ± 1.3 years followed by optic atrophy at 10.4 ± 2.3 years, diabetes insipidus at 12 ± 2.1 years and deafness at 12.8 ± 2.1 years. All patients were autoantibody negative with low C-peptide(

Objective Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed. Methods We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts. Results Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype-modifier variants. All the DOA-associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28-associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA-associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28-associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission-inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells. Interpretation This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 ANN NEUROL 2020;88:18-32.

We investigated the relationship between microstructure of β-parapapillary atrophy (β-PPA) and morphologic features of optic nerve head (ONH) and posterior pole in highly myopic eyes. Eighty-nine highly myopic eyes were included in this study. Bruch’s membrane opening (BMO) area, lamina cribrosa (LC) thickness, anterior laminar depth, peripapillary and subfoveal choroidal thickness (CT), macular Bruch’s membrane (BM) length, and width of β-PPA with and without Bruch’s membrane (PPA+BM and PPA−BM) were evaluated. The mean age and axial length of the included subjects were 26.88 ± 2.44 years and 27.03 ± 0.88 mm, respectively. The width of PPA−BM was larger with increasing BMO area (P = 0.001), whereas the BMO area was not associated with the width of PPA+BM. The large PPA+BM was significantly related to a thinner LC (P = 0.003), deeper anterior lamina surface (P P = 0.008), and thinner temporal peripapillary CT (P = 0.034). We found that the morphologic features of the ONH and posterior pole in highly myopic eyes were different based on the microstructure of β-PPA. Whether these features are linked to the development of glaucoma in myopic eyes should be investigated in future studies.

Background To investigate whether macular structure could be affected by axial elongation and to determine the association between macular intraretinal thickness and the microstructure of β-zone parapapillary atrophy (PPA) in myopic eyes. Methods The study recruited 113 healthy myopic subjects (113 eyes). Images of the macula, subfoveal choroid, and optic nerve head were acquired using spectral-domain optical coherence tomography (SD-OCT). An automatic segmentation algorithm was used to segment the macular images into 7 intraretinal layers. PPA widths with and without Bruch’s membrane (PPA+BM and PPA-BM, respectively) were evaluated. Linear regression analysis was performed to evaluate the association between macular intraretinal thickness and axial length and the microstructure of PPA. Results An increase in axial length was associated with a decrease in whole macular thickness of the peripheral region and an increase in whole macular thickness of the central region. Thickness alterations of the macular intraretinal layers were most apparent in the peripheral region. A significant correlation was found between PPA-BM width and macular intraretinal layer thickness, whereas no significant correlation was found between PPA+BM width and macular intraretinal layer thickness. Moreover, both PPA+BM and PPA-BM widths significantly correlated with subfoveal choroidal thickness. Conclusions Macular intraretinal layer thickness may be affected by PPA-BM width. These findings indicate that the microstructure of PPA should be considered when evaluating the macula in patient with myopia and glaucoma.

Background/aims: Optic atrophy is one of the leading causes of sight impairment in children. It frequently poses a diagnostic challenge, as it can be caused by many ocular and systemic conditions. We aimed to determine the current causes of optic atrophy at our centre and to describe the use of investigations, including molecular genetic testing. Methods: We reviewed the medical records of children with optic atrophy seen at Moorfields Eye Hospital between 2010 and 2015. We recorded demographic data, reason for referral, history, investigations and diagnosis. Results: We studied 143 cases aged below 16 years. A cause could be identified in all cases. Taking a full history was the most important part of the diagnostic workup, identifying a cause in 96 (67%) children. A developmental disorder of the brain and/or optic nerve, sometimes with retinal involvement, was the commonest cause (n = 33, 23%), followed by inheritable optic neuropathies (n = 27, 19%). Other causes included perinatal insults (n = 18, 13%), post-infectious or post-inflammatory conditions (n = 18, 13%), accidental or abusive trauma (n = 14, 10%) and inheritable retinal dystrophies (n = 13, 9%). Rare conditions included neurodegenerative disorders (n = 7, 5%), skeletal developmental disorders such as rickets (n = 4, 3%), tumours (n = 4, 3%), ischaemic events including large optic nerve head drusen (n = 4, 3%) and toxic events/metabolic conditions (n = 1, 0.7%). Conclusion: In this series, an underlying cause could be identified in all cases. Taking a comprehensive antenatal, perinatal, postnatal and family history will indicate a probable diagnosis in two-thirds of children, and targeted ancillary tests may identify the cause in most remaining cases.

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a recently described autosomal dominant disorder caused by mutations in the nuclear receptor subfamily 2 group F member 1 (NR2F1) gene. Its common features include optic atrophy and/or hypoplasia, developmental delay, intellectual disability, attention deficit disorder, autism spectrum disorder, seizures, hearing defects, spasticity, hypotonia, and thinning of the corpus callosum. Mitochondrial involvement has also been described with BBSOAS. Currently, 31 cases of BBSOAS have been described in the literature. Here we report a case of undiagnosed BBSOAS presenting as psychosis in a 32-year-old man with a history of bilateral optic nerve atrophy, intellectual disability, epilepsy, and mitochondrial complex I abnormality on muscle biopsy. Whole-genome sequencing identified a heterozygous de novo nonsense mutation in the NR2F1 gene [c.253 G>T (guanine to thymine mutation in coding position 253) in exon 1, p.E85X variant (GAG>TAG) (glutamic acid to stop codon mutation; protein truncated to 85 amino acids)]. A pathogenic nonsense mutation has not previously been reported in the literature in association with BBSOAS and represents an expansion of clinically relevant variants. Psychosis has also not been previously reported in this syndrome and may represent a phenotypic expansion of BBSOAS, a manifestation of prolonged disease, or a result of disease management.

BackgroundWolfram syndrome (WFS) is a rare disorder characterised by childhood-onset diabetes mellitus and progressive optic atrophy. Most patients have variants in theWFS1gene. We undertook functional studies ofWFS1variants and correlated these with WFS1 protein expression and phenotype.Methods9 patients with a clinical diagnosis of WFS were studied with quantitative PCR for markers of endoplasmic reticulum (ER) stress and immunoblotting of fibroblast protein extracts for WFS1 protein expression. Luciferase reporter assay was used to assess ATF-6 dependent unfolded protein response (UPR) activation.Results6 patients with compound heterozygous nonsense mutations inWFS1had no detectable WFS1 protein expression; 3 patients with missense variants had 4%, 45% and 48% WFS1 protein expression. One of these also had anOPA1mutation and was reclassified as autosomal dominant optic atrophy-plus syndrome. There were no correlations between ER stress marker mRNA and WFS1 protein expression. ERSE-luciferase reporter indicated activation of the ATF6 branch of UPR in two patients tested. Patients with partial WFS1 expression showed milder visual acuity impairment (asymptomatic or colour blind only), compared with those with absent expression (registered severe vision impaired) (p=0.04). These differences remained after adjusting for duration of optic atrophy.ConclusionsPatients with WFS who have partial WFS1 protein expression present with milder visual impairment. This suggests a protective effect of partial WFS1 protein expression on the severity and perhaps progression of vision impairment and that therapies to increase residual WFS1 protein expression may be beneficial.

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.

Pathogenic variants of the nuclear receptor subfamily 2 group F member 1 gene (NR2F1) are responsible for Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), an autosomal dominant disorder characterized by optic atrophy associated with developmental delay and intellectual disability, but with a clinical presentation which appears to be multifaceted. We created the first public locus-specific database (LSDB) dedicated to NR2F1. All variants and clinical cases reported in the literature, as well as new unpublished cases, were integrated into the database using standard nomenclature to describe both molecular and phenotypic anomalies. We subsequently pursued a comprehensive approach based on computed representation and analysis suggesting a refinement of the BBSOAS clinical description with respect to neurological features and the inclusion of additional signs of hypotonia and feeding difficulties. This database is fully accessible for both clinician and molecular biologists and should prove useful in further refining the clinical synopsis of NR2F1 as new data is recorded. This article is protected by copyright. All rights reserved.

Optic atrophy (OA) with autosomal inheritance is a form of optic neuropathy characterized by the progressive and irreversible loss of vision. In some cases, this is accompanied by additional, typically neurological, extra-ocular symptoms. Underlying the loss of vision is the specific degeneration of the retinal ganglion cells (RGCs) which form the optic nerve. Whilst autosomal OA is genetically heterogenous, all currently identified causative genes appear to be associated with mitochondrial organization and function. However, it is unclear why RGCs are particularly vulnerable to mitochondrial aberration. Despite the relatively high prevalence of this disorder, there are currently no approved treatments. Combined with the lack of knowledge concerning the mechanisms through which aberrant mitochondrial function leads to RGC death, there remains a clear need for further research to identify the underlying mechanisms and develop treatments for this condition. This review summarizes the genes known to be causative of autosomal OA and the mitochondrial dysfunction caused by pathogenic mutations. Furthermore, we discuss the suitability of available in vivo models for autosomal OA with regards to both treatment development and furthering the understanding of autosomal OA pathology.

Parapapillary atrophy is one of the parameters of the optic nerve head area which are assessed during the ophthalmoscopic examination particularly useful to characterize glaucomatous optic neuropathy. Optical coherence tomography evaluation provides high-resolution images of the optic nerve head and surrounding area, and can be used to study parapapillary atrophy. Different parapapillary atrophy zones were described depending on their histological features and research has been conducted to investigate the possible association between the presence and/ or size of parapapillary atrophy zones and several optic nerve disorders. In this review we discuss the histology and the clinical findings related to parapapillary atrophy in patients with glaucomatous optic neuropathy, non-glaucomatous optic neuropathies (e.g. arteritic and non-arteritic anterior ischemic optic neuropathies; suprasellar and parasellar tumors), and other ocular conditions (e.g. high myopia; age-related macular degeneration). Two different histologic classifications were identified. Parapapillary atrophy was demonstrated in glaucoma and glaucoma-like neuropathies, but not in other types of optic nerve disorders.

Wolfram Syndrome (WS) is a rare neurodegenerative disease with autosomal recessive inheritance and characterized by juvenile onset, non-autoimmune diabetes mellitus and later followed by optic atrophy leading to blindness, diabetes insipidus, hearing loss, and other neurological and endocrine dysfunctions. A wide spectrum of neurodegenerative abnormalities affecting the central nervous system has been described. Among these complications, neurogenic bladder and urodynamic abnormalities also deserve attention. Urinary tract dysfunctions (UTD) up to end stage renal disease are a life-threatening complication of WS patients. Notably, end stage renal disease is reported as one of the most common causes of death among WS patients. UTD have been also reported in affected adolescents. Involvement of the urinary tract occurs in about 90% of affected patients, at a median age of 20 years and with peaks at 13, 21 and 33 years. The aim of our narrative review was to provide an overview of the most important papers regarding urological impairment in Wolfram Syndrome. A comprehensive search on PubMed including Wolfram Syndrome and one or more of the following terms: chronic renal failure, bladder dysfunction, urological aspects, and urinary tract dysfunction, was done. The exclusion criteria were studies not written in English and not including urinary tract dysfunction deep evaluation and description. Studies mentioning general urologic abnormalities without deep description and/or follow-up were not considered. Due to the rarity of the condition, we considered not only papers including pediatric patients, but also papers with pediatric and adult case reports

Increasing evidence suggests that neurodevelopmental alterations might contribute to increase the susceptibility to develop neurodegenerative diseases. We investigate the occurrence of developmental abnormalities in dopaminergic neurons in a model of Parkinson’s disease (PD). We monitor the differentiation of human patient-specific neuroepithelial stem cells (NESCs) into dopaminergic neurons. Using high-throughput image analyses and single-cell RNA sequencing, we observe that the PD-associated LRRK2-G2019S mutation alters the initial phase of neuronal differentiation by accelerating cell-cycle exit with a concomitant increase in cell death. We identify the NESC-specific core regulatory circuit and a molecular mechanism underlying the observed phenotypes. The expression of NR2F1, a key transcription factor involved in neurogenesis, decreases in LRRK2-G2019S NESCs, neurons, and midbrain organoids compared to controls. We also observe accelerated dopaminergic differentiation in vivo in NR2F1-deficient mouse embryos. This suggests a pathogenic mechanism involving the LRRK2-G2019S mutation, where the dynamics of dopaminergic differentiation are modified via NR2F1. publishedVersion

Funder: Fight for Sight UK; doi: http://dx.doi.org/10.13039/501100000615, Funder: Wellcome Trust; doi: http://dx.doi.org/10.13039/100004440, Wolfram syndrome (WS) is an ultra-rare progressive neurodegenerative disorder defined by early-onset diabetes mellitus and optic atrophy. The majority of patients harbour recessive mutations in the WFS1 gene, which encodes for Wolframin, a transmembrane endoplasmic reticulum protein. There is limited availability of human ocular and brain tissues, and there are few animal models for WS that replicate the neuropathology and clinical phenotype seen in this disorder. We, therefore, characterised two wfs1 zebrafish knockout models harbouring nonsense wfs1a and wfs1b mutations. Both homozygous mutant wfs1a−/− and wfs1b−/− embryos showed significant morphological abnormalities in early development. The wfs1b−/− zebrafish exhibited a more pronounced neurodegenerative phenotype with delayed neuronal development, progressive loss of retinal ganglion cells and clear evidence of visual dysfunction on functional testing. At 12 months of age, wfs1b−/− zebrafish had a significantly lower RGC density per 100 μm2 (mean ± standard deviation; 19 ± 1.7) compared with wild-type (WT) zebrafish (25 ± 2.3, p < 0.001). The optokinetic response for wfs1b−/− zebrafish was significantly reduced at 8 and 16 rpm testing speeds at both 4 and 12 months of age compared with WT zebrafish. An upregulation of the unfolded protein response was observed in mutant zebrafish indicative of increased endoplasmic reticulum stress. Mutant wfs1b−/− zebrafish exhibit some of the key features seen in patients with WS, providing a versatile and cost-effective in vivo model that can be used to further investigate the underlying pathophysiology of WS and potential therapeutic interventions.

Pathogenic variants of the aconitase 2 gene (ACO2) are responsible for a broad clinical spectrum involving optic nerve degeneration, ranging from isolated optic neuropathy with recessive or dominant inheritance, to complex neurodegenerative syndromes with recessive transmission. We created the first public locus-specific database (LSDB) dedicated to ACO2 within the “Global Variome shared LOVD” using exclusively the Human Phenotype Ontology (HPO), a standard vocabulary for describing phenotypic abnormalities. All the variants and clinical cases listed in the literature were incorporated into the database, from which we produced a dataset. We followed a rational and comprehensive approach based on the HPO thesaurus, demonstrating that ACO2 patients should not be classified separately between isolated and syndromic cases. Our data highlight that certain syndromic patients do not have optic neuropathy and provide support for the classification of the recurrent pathogenic variants c.220C>G and c.336C>G as likely pathogenic. Overall, our data records demonstrate that the clinical spectrum of ACO2 should be considered as a continuum of symptoms and refines the classification of some common variants., Measurement(s) sequence_variant • Phenotypic variability Technology Type(s) DNA sequencing • Ophthalmologist Factor Type(s) sequence variant • phenotype Sample Characteristic - Organism Homo sapiens Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.13574528

To characterize visual outcomes in children screened for retinopathy of prematurity (ROP).Retrospective, interventional case series.Patients who received ROP screening examinations at UCLA Medical Centers and were followed with outpatient eye examinations at Stein Eye Institute and/or Doheny Eye Institute (Los Angeles, California) were included. Data were collected on birth characteristics, worst type of ROP, and ROP treatment. Adverse visual outcomes included myopia, strabismus, amblyopia, macular dragging, and optic atrophy. Snellen visual acuity was reported for children 4 years and older.A total of 175 infants (350 eyes) were included for analysis (mean gestational age = 28.2 weeks and birth weight = 1059 g) from a screening population of 539 infants (1078 eyes, 32.4% follow-up) over a 9-year period. Fifteen eyes received primary anti-vascular endothelial growth factor (anti-VEGF) therapy, whereas 59 eyes received primary laser therapy. Primary anti-VEGF therapy, as compared with primary laser treatment, was associated with a decreased incidence of amblyopia (adjusted odds ratio [aOR] = 0.6-0.86, P.0001) after controlling for gestational age and birth weight. The rates of optic atrophy (P = .79), strabismus (P = .98), and myopia (P = .93) were not different between anti-VEGF and laser treatment groups. Infants receiving anti-VEGF therapy had more posterior disease than laser-treated infants (P = .041). Infants receiving laser therapy were more likely to have severe myopia (aOR = 1.02-1.3, P = .023), amblyopia (aOR = 1.12-1.61, P = .002), and optic atrophy (aOR = 1.01-1.32, P = .045) than infants not treated.These findings add to the advantages of anti-VEGF treatment compared with primary laser treatment, particularly in posterior ROP.

Spastic paraplegia type 7 (SPG7) is one of the most common hereditary spastic paraplegias. SPG7 mutations most often lead to spastic paraparesis (HSP) and/or hereditary cerebellar ataxia (HCA), frequently with mixed phenotypes. We sought to clinically and genetically characterize a Spanish cohort of SPG7 patients. Patients were recruited from our HCA and HSP cohorts. We identified twenty-one patients with biallelic pathogenic SPG7 mutations. Mean age at onset was 37.4 years (SD ± 14.3). The most frequent phenotype was spastic ataxia (57%), followed by pure spastic paraplegia (19%) and complex phenotypes (19%). Isolated patients presented with focal or multifocal dystonia, subclinical myopathy or ophthalmoplegia. p.Ala510Val was the most frequent pathogenic variant encountered. Compound heterozygous for p.Ala510Val displayed younger onset (p 0.05) and more complex phenotypes (p 0.05) than p.Ala510Val homozygotes. Two novel variants were found: p.Lys559Argfs*33 and p.Ala312Glu. In conclusion, spastic ataxia is the most common phenotype found in Spanish patients. Nonetheless, SPG7 analysis should also be considered in patients with less frequent clinical findings such as dystonia or ophthalmoplegia especially when these symptoms are associated with mild spastic ataxia.

FASTQ files of proband's WES (whole exome sequencing)

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.

Wolfram syndrome (WFS) is a rare neurodegenerative disorder characterized by young-onset diabetes mellitus, central diabetes insipidus, optic nerve atrophy, and hearing loss. The ophthalmic association of this order has been limited to optic nerve atrophy. We report here a case of WFS and its disease course with childhood glaucoma as a rare ophthalmic manifestation which has been reported just once earlier. The patient had young-onset diabetes mellitus (insulin dependent), diabetes insipidus, and optic-disc pallor suggestive of partial optic atrophy. However, hearing assessment was normal at the time of presentation and in due course of disease. Glaucoma is one of the rare possible ocular manifestations of WFS which should be highly considered while evaluating patient with this disorder.

PURPOSE: To describe and distinguish clinical phenotypes with the overlapping feature of optic atrophy caused by distinct mutations in the same gene, OPA3. We report 3 affected siblings in a consanguineous family harboring a novel OPA3 mutation causing 3-methylglutaconic aciduria type III with optic atrophy. METHODS: Retrospective case series. RESULTS: Three siblings (2 male, 1 female) among 6 children in a consanguineous Afghani family developed decreased vision from early childhood. Both parents and all extended family members were unaffected. All 3 affected siblings suffered from severe visual impairment ranging from visual acuities of 20/150 to counting fingers. All had spastic lower extremity weakness and ataxia. Two of the three affected siblings also had a history of seizures, and the female sibling had limited cognition with diffuse atrophic changes on brain MRI. Two of the three individuals also had migraine-like headaches. Urine organic acid analysis revealed mildly elevated 3-methylglutaconic acid for the male siblings. Whole exome sequencing and subsequent PCR confirmation revealed a novel variant in OPA3 (intron1, c.142+2_142+3dupTG), affecting the consensus sequence of the splice site, for which all 3 clinically affected siblings were homozygous. DISCUSSION: Mutations in OPA3 can cause optic atrophy in a dominant pattern of inheritance associated with cataract or in a recessive pattern associated with spastic paresis and ataxia. The novel recessive variant and clinical presentations described herein further support how different mutation types affecting OPA3 can produce distinct clinical phenotypes and underscore the critical and susceptible role of mitochondrial health in optic nerve function.

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.

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.