Search

Summary We conducted an updated epidemiological study of Leber hereditary optic neuropathy (LHON) in Australia by using registry data to establish the risk of vision loss among different LHON mutations, sex, age at onset, and mitochondrial haplogroup. We identified 96 genetically unrelated LHON pedigrees, including 56 unpublished pedigrees, and updated 40 previously known pedigrees, comprising 620 affected individuals and 4,948 asymptomatic carriers. The minimum prevalence of vision loss due to LHON in Australia in 2020 was one in 68,403 individuals. Although our data confirm some well-established features of LHON, the overall risk of vision loss among those with a LHON mutation was lower than reported previously—17.5% for males and 5.4% for females. Our findings confirm that women, older adults, and younger children are also at risk. Furthermore, we observed a higher incidence of vision loss in children of affected mothers as well as in children of unaffected women with at least one affected brother. Finally, we confirmed our previous report showing a generational fall in prevalence of vision loss among Australian men. Higher reported rates of vision loss in males with a LHON mutation are not supported by our work and other epidemiologic studies. Accurate knowledge of risk is essential for genetic counseling of individuals with LHON mutations. This knowledge could also inform the detection and validation of potential biomarkers and has implications for clinical trials of treatments aimed at preventing vision loss in LHON because an overestimated risk may lead to an underpowered study or a false claim of efficacy.

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.

PDXK encodes for a pyridoxal kinase, which converts inactive B6 vitamers to the active cofactor pyridoxal 5'-phosphate (PLP). Recently, biallelic pathogenic variants in PDXK were shown to cause axonal Charcot-Marie-Tooth disease with optic atrophy that responds to PLP supplementation. We present two affected siblings carrying a novel biallelic missense PDXK variant with a similar phenotype with earlier onset. After detection of a novel PDXK variant using Whole Exome Sequencing, we confirmed pathogenicity through in silico protein structure analysis, determination of pyridoxal kinase activity using liquid chromatography-tandem mass spectrometry, and measurement of plasma PLP concentrations using high performance liquid chromatography. Our in silico analysis shows a potential effect on PDXK dimer stability, as well as a putative effect on posttranslational ubiquitination that is predicted to lead to increased protein degradation. We demonstrate that the variant leads to almost complete loss of PDXK enzymatic activity and low PLP levels. Our patients' early diagnosis and prompt PLP replacement restored the PLP plasma levels, enabling long-term monitoring of clinical outcomes. We recommend that patients presenting with similar phenotype should be screened for PDXK mutations, as this is a rare opportunity for treatment.

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.

KDM5C encodes a demethylase of the histone H3 lysine 4 residue, involved in chromatin regulation and gene expression. Hemizygous KDM5C pathogenic variants cause X-linked intellectual disability of Claes-Jensen type. Because of its mode of inheritance and the low specificity of the clinical phenotype, interpretation of variants can be difficult, hence the need for functional studies and biomarkers specific to this disorder. We present the case of a male patient with intellectual disability, behavioral abnormalities and subtle dysmorphic features, in which genetic investigation identified a hemizygous novel missense KDM5C variant of uncertain significance (VUS), inherited from his asymptomatic mother and present in his paucisymptomatic sister. We assessed the global genomic DNA methylation status from a whole blood sample of the proband. Global DNA methylation profiling specifically identified the recently discovered epi-signature of Claes-Jensen syndrome. This result served as a biomarker which independently highlighted KDM5C as the cause of the disorder in this patient. Because of the X-linked mode of inheritance, variant reclassification had a high impact on genetic counseling in this family. This example highlights the value of global methylome profiling in situations of variants of uncertain significance in genes with a known specific epi-signature.

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.

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.

Introduction SYNE1 encodes nesprin-1, a scaffold protein which is involved in the binding between cytoskeleton, nuclear envelope and other subcellular compartments. In 2007, recessive truncating SYNE1 mutations have been linked to a genetic form of pure cerebellar ataxia with adult onset and mild phenotype. Subsequent reports described a number of patients with SYNE1-ataxia and widespread neurological involvement including features of motor neuron disease. Recently, heterozygote missense SYNE1 mutations have been associated with muscular disorders, such as Emery-Dreifuss muscular dystrophy, arthrogryposis multiplex congenita and dilated cardiomyopathy. Methods Herein we describe novel genotypic and phenotypic findings in an independent cohort of 5 patients with SYNE1-ataxia referring to the Department of Neurology of the Innsbruck Medical University and performed a review of the related literature. Results We report 3 novel mutations and describe for the first time myocardial involvement in a patient with a complicated spastic-ataxic phenotype and C-terminal mutation. In the literature, mutations associated with additional motor neuron signs spanned over the entire gene, but patients with a particularly severe phenotype and premature death bore C-terminal mutations. Conclusion Our findings support a genotype-phenotype correlation in SYNE1-ataxia and suggest the need for a systematic cardiologic evaluation in the setting of complicated spastic-ataxia phenotypes.

We report a child with hypotonia, optic atrophy, progressive encephalopathy and intractable infantile spasms who was diagnosed with PEHO syndrome. Extensive investigation was performed to diagnose an underlying etiology. Electron transport chain activities in muscle biopsies showed an isolated complex IV deficiency. Genetic examination focused on complex IV genes such as mtDNA and relevant nuclear DNA analysis was unremarkable. Whole exome sequencing with trio revealed a heterozygous de novo mutation at c.757G>A (p.E253K) in the KIF1A gene. The protein encoded by this gene functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. The relation between this genetic mutation and decreased activity of the mitochondrial respiratory chain complex is discussed in details. Our study further confirmed that the molecular basis of PEHO syndrome at least in a subset of patients is a dominant KIF1A variant affecting the motor domain of the protein. This is the first description of the decreased activity of mitochondrial respiratory chain complex in association with either PEHO syndrome or KIF1A mutation. This study emphasizes that the results of the mitochondrial enzymes should be interpreted with caution and clinicians should be actively looking for other underlying diagnoses with further comprehensive studies.

Purpose Recent studies have suggested that OCT-based classification of parapapillary atrophy (PPA) may be helpful in distinguishing glaucomatous from myopic optic disc changes. However, the pathologic implications of PPA may be different in highly myopic eyes that exhibit optic disc deformations distinct from low-to-moderate myopia. Therefore, we conducted the current study to investigate factors associated with OCT-defined PPA zones measured in en face reconstructed swept-source OCT (SS OCT) images in highly myopic eyes. Design Retrospective, cross-sectional study. Participants Seventy-seven eyes of 55 subjects with high myopia (spherical equivalent refractive error ≤ −8 diopters or axial length ≥26.5 mm) were included. Forty-nine eyes of 33 subjects had open-angle glaucoma (MG group), and 28 eyes of 22 did not (M group). Methods The beta zone and the gamma zone PPA areas were measured in en face images reconstructed from 3-dimensional SS OCT volumetric scans. Relationships between the PPA areas and patient characteristics such as glaucoma, axial length, and age were evaluated using multivariate mixed-effects models. The diagnostic capability of each PPA zone area for detecting glaucoma was assessed with the receiver operating characteristic (ROC) curve analysis. Main outcome measures were areas of the beta zone and the gamma zone PPA measured in en face OCT images and factors associated with each PPA area. Results Average ± standard deviation area of the beta and the gamma zone was 1.1±1.1 and 1.1±1.1 mm2. The gamma zone was positively correlated with axial length (P = 0.006) and age (P = 0.04951) but not with glaucoma (P = 0.776). The beta zone was positively correlated with both axial length (P = 0.039) and glaucoma (P = 0.011). The areas under the ROC curve of the beta zone and the gamma zone areas were 0.686 and 0.560, respectively. Conclusions The OCT-defined beta zone was associated with glaucoma and axial length, whereas the gamma zone was correlated with axial length but not with glaucoma, in highly myopic eyes. The OCT-based classification showed poor diagnostic performance for glaucoma. Relationships between PPA areas and baseline clinical factors may be different between high myopia and non–high myopia.

Introduction Mitochondrial diseases are a group of disorders caused mainly by the impairment of the mitochondrial oxidative phosphorylation process, due to mutations either in the mitochondrial or nuclear genome. Among them, the mitochondrial neuro-gastrointestinal encephalo-myopathy (MNGIE) syndrome affects adolescents or young adults, and is mostly caused by TYMP mutations encoding a cytosolic thymidine phosphorylase (TP). Patients and methods The present study reports the molecular investigation by next-generation re-sequencing of 281 nuclear genes, encoding mitochondrial proteins, of consanguineous family including two individuals with MNGIE syndrome associated to optic atrophy. Bioinformatic analysis was also performed in addition to mtDNA deletion screening and mtDNA copy number quantification in blood of the two patients which were carried out by solf clipping program and qPCR respectively. Results Next-generation re-sequencing revealed a novel homozygous c.2391G > T POLG mutation (p.M797I) co-occurring with the hypomorphic c.1311A > G OPA1 variant (p.I437M). Analysis of the mitochondrial genome in the two patients disclosed mtDNA depletion in blood, but no deletion. Bio-informatics investigations supported the pathogenicity of the novel POLG mutation that is located in the C-terminal subdomain and might change POLG 3D structure, stability and function. Conclusion The novel homozygous p.M797I POLG mutation is responsible for MNGIE combined to optic atrophy and mtDNA depletion in the two patients.

Wolfram Syndrome (WS) is a rare progressive hereditary neurodegenerative disease with hallmark features of diabetes mellitus, optic atrophy, and hearing loss. Its other clinical manifestations may include diabetes insipidus, urological, neurological, and psychiatric abnormalities. We review systemic and ocular manifestations of WS as well as its pathophysiology, diagnostic approach, and treatment options. We then describe a case series of 5 patients (ages 15-38, 60% male) with WS. All had significant progressive visual loss. 3/5 patients had type 1 DM and 4/5 had hearing loss. Other neuro-ophthalmological findings included convergence impairment and end-gaze nystagmus. This case series highlights the variability in clinical presentations of patients with WS, reminding clinicians to maintain high suspicion for this diagnosis in order to allow for prompt diagnosis and genetic counselling for patients and their families.

To investigate the ophthalmic and neurological features of myelin oligodendrocyte glycoprotein antibody seropositive optic neuritis (MOG-ON) in pediatric patients.We analyzed the clinical data and orbital magnetic resonance images of patients aged below 15 years, diagnosed with MOG-ON at our institution (n = 40).The mean age at first ON onset was 7.7 ± 3.1 years, and 26 (65.0%) patients were girls. Twenty-three patients (57.5%) experienced bilateral ON, and ten (25.0%) had recurrent ON. Pain on eye movement was present in 30.6% of the eyes. In the acute stage, optic disk swelling and peripapillary hemorrhage was found in 82.6% and 15.2% of the eyes, respectively. In the chronic stage, optic atrophy was noted in 91.5% of the eyes. Although mean visual acuity (VA) at nadir was 1.72 ± 0.66 logMAR, all patients experienced visual improvement of ≥0.3 logMAR, and the mean final VA was 0.05 ± 0.14 logMAR. Twenty-one patients (52.5%) had other demyelinating diseases during the disease course (ON plus group), while 18 patients (45.0%) had experienced ON without other demyelinating disease (isolated ON group). Pain (19.4% vs. 38.5%, p = 0.098) and perineural enhancement (3.3% vs. 21.7%, p = 0.036) were less frequently observed in ON plus group.Pediatric MOG-ON has distinct clinical features, such as infrequent pain and perineural enhancement. Although optic atrophy is commonly observed, visual function is retained in most patients. A multidisciplinary approach and long-term follow-up are required for pediatric MOG-ON, since CNS involvement is more common than ON recurrence.

In 2003, a new syndrome was described in the Sephardi Jewish population, named progressive cerebello-cerebral atrophy (PCCA) based on the typical neuroradiological findings. Following the identification of the causal genes in 2010 and 2014, two types were defined: PCCA type 1 due to SEPSECS mutations and PCCA type 2 due to VPS53 mutations. Progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) was described in 1991 in Finland. The clinical and radiological phenotype resembles PCCA. The genetic background has been elusive for many years. Recently, mutations in multiple genes including SEPSECS have been described in patients with a PEHO-like syndrome. In 2007 two siblings of Moroccan-Jewish origin were diagnosed as having PEHO due to a severe developmental encephalopathy, limb and facial edema, intractable epilepsy, optic atrophy in one sibling and dysmorphic features. Six years ago an extensive workup, including whole exome sequencing, did not reveal the cause. Recently, a clinical reevaluation of the siblings suggested the possibility that they suffer from PCCA. A reanalysis of the exome data from 2014 revealed that the siblings indeed carried the two VPS53 mutations (exon 19 c.2084A>G p.(Gln695Arg) and c.1556 + 5G>A) and the parents were found to be carriers. The discovery that mutations in both VPS53 and SEPSECS can present with a PEHO-like phenotype, place PCCA and PEHO on the same clinical spectrum and suggest they may be allelic syndromes.

CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) is a rare neurological disorder, recently associated with the c.2452G > A hotspot mutation in the ATP1A3 gene, with sensorineural hearing loss as a prominent feature. We herein report on a girl who has experienced hearing loss for three years following an initial encephalitic episode when aged 15 months old. CAPOS was diagnosed only when she was six years old by targeted testing whilst she displayed optic atrophy, cerebellar signs and areflexia. CAPOS syndrome should be considered in the differential diagnosis of acquired childhood deafness, prompting clinicians to search for associated neurological features.

Short stature with optic atrophy and Pelger-Huët anomaly (SOPH) syndrome has been known to cause optic atrophy and achromatopsia resulting from stationary cone dysfunction. This report describes foveal hypoplasia in a brother and sister with SOPH syndrome, which is associated with defects in the neuroblastoma amplified sequence (NBAS) gene. As NBAS gene may play an important role in retinal homeostasis, patients with SOPH should be monitored carefully for ocular abnormalities.

Background CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) is a rare disease that has been reported in 22 patients so far. In all cases, the mutation c.2452G>A (p.Glu818Lys) in the ATP1A3 gene was identified. Patients typically present at an early age with an acute-onset fever-induced episode of ataxia frequently associated with encephalopathy and weakness. They usually present one to three episodes. The acute symptoms improve within days, but most patients show slow progression afterward. Methods We describe three new patients, a woman and her two sons diagnosed with CAPOS syndrome. A systematic review of literature on previously reported patients was performed. Results The first son presented with acute-onset ataxia, encephalopathy, and sensorineural hearing loss, induced by febrile illness. The second one developed generalized areflexia and mild instability without an acute episode. The mother had been previously diagnosed with sensorineural hearing loss and optic nerve atrophy. The c.2452G>A mutation in ATP1A3 was found in all three patients. Conclusion Only 25 Individuals with CAPOS syndrome have been reported, including our family. This is the first time a Spanish family has been described. The fact that both siblings were assessed before the first acute-onset episode contributes to the description of early symptoms and signs of the disease, which could aid early diagnosis and management before the onset of acute episodes.

Background Glutaric aciduria type 1 (GA-1) is an organic acidemia with potentially severe neurological sequelae. In Taiwan, newborn screening (NBS) for GA-1 began in 2001, but large-scale reporting is lacking. This study describes Taiwan's largest newborn screening population to date. Methods Between 2001 and 2015, 1,490,636 newborns were screened for GA-1. Confirmatory examinations included the carnitine loading test. Confirmed patients were treated with a low lysine diet, carnitine, and high-energy intake during illness. Clinical, laboratory, and neuroimaging data were analyzed. Results Fourteen newborns were diagnosed with GA-1 (incidence: 1/106,474). C5DC concentration was clearly increased after carnitine loading in the affected newborns, but not in false-positive newborns (p = 0.004), indicating that this test is useful as an adjuvant diagnostic method. Eleven patients followed in our hospital were enrolled, namely nine NBS patients and two patients diagnosed clinically. IVS10-2A>C was the most common mutation. Two novel mutations (T36fs and N291K) were identified. Pendular nystagmus was found in two pediatric GA-1 patients. The corresponding pathology was optic atrophy in one patient, but remained undetermined in the other patient. The frequency of encephalopathic crisis decreased substantially following NBS. Among patients diagnosed by NBS, cognitive functioning was better among patients with good compliance than patients with poor compliance (p = 0.03). Abnormalities were detected by brain MRI including diffusion-weighted imaging and apparent diffusion coefficient maps; these affected various brain regions at different stages of the disease. Basal ganglion injuries occurred after an encephalopathic crisis. White matter disease was prevalent among older patients, either with or without an encephalopathic crisis. Conclusion Early diagnosis by newborn screening followed by full compliance with treatment guidelines is important to a good outcome.

Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285∗), c.247_250del (p.Asn83Hisfs∗4), and splice site c.830+2_830+3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.

Purpose To investigate factors associated with dropout of the parapapillary deep retinal layer microvasculature assessed by optical coherence tomography angiography (OCTA) in glaucomatous eyes. Design Cross-sectional study. Participants Seventy-one eyes from 71 primary open-angle glaucoma (POAG) patients with β-zone parapapillary atrophy (βPPA) enrolled in the Diagnostic Innovations in Glaucoma Study. Methods Parapapillary deep-layer microvasculature dropout was defined as a complete loss of the microvasculature located within the deep retinal layer of the βPPA from OCTA-derived optic nerve head vessel density maps by standardized qualitative assessment. Circumpapillary vessel density (cpVD) within the retinal nerve fiber layer (RNFL) also was calculated using OCTA. Choroidal thickness and presence of focal lamina cribrosa (LC) defects were determined using swept-source optical coherence tomography. Main Outcome Measures Presence of parapapillary deep-layer microvasculature dropout. Parameters including age, systolic and diastolic blood pressure, axial length, intraocular pressure, disc hemorrhage, cpVD, visual field (VF) mean deviation (MD), focal LC defects βPPA area, and choroidal thickness were analyzed. Results Parapapillary deep-layer microvasculature dropout was detected in 37 POAG eyes (52.1%). Eyes with microvasculature dropout had a higher prevalence of LC defects (70.3% vs. 32.4%), lower cpVD (52.7% vs. 58.8%), worse VF MD (−9.06 dB vs. −3.83 dB), thinner total choroidal thickness (126.5 μm vs. 169.1 μm), longer axial length (24.7 mm vs. 24.0 mm), larger βPPA (1.2 mm 2 vs. 0.76 mm 2 ), and lower diastolic blood pressure (74.7 mmHg vs. 81.7 mmHg) than those without dropout ( P P = 0.012), reduced cpVD (OR, 1.27; P = 0.002), worse VF MD (OR, 1.27; P = 0.001), thinner choroidal thickness (OR, 1.02; P = 0.014), and lower diastolic blood pressure (OR, 1.16; P = 0.003) were associated significantly with the dropout. Conclusions Systemic and ocular factors including focal LC defects more advanced glaucoma, reduced RNFL vessel density, thinner choroidal thickness, and lower diastolic blood pressure were factors associated with the parapapillary deep-layer microvasculature dropout in glaucomatous eyes. Longitudinal studies are required to elucidate the temporal relationship between parapapillary deep-layer microvasculature dropout and systemic and ocular factors.

Purpose To search for WFS1 mutations in patients with optic atrophy (OA) and assess visual impairment. Design Retrospective molecular genetic and clinical study. Participants Patients with OA followed at a national referral center specialized in genetic sensory diseases. Methods Mutation screening in WFS1 was performed by Sanger sequencing. WFS1 -positive patients were evaluated on visual acuity (VA) and retinal nerve fiber layer (RNFL) thickness using time-domain (TD) or spectral-domain (SD) optical coherence tomography (OCT). Statistical analysis was performed. Main Outcome Measures Mutation identification, VA values, and RNFL thickness in sectors. Results Biallelic WFS1 mutations were found in 3 of 24 unrelated patients (15%) with autosomal recessive nonsyndromic optic atrophy (arNSOA) and in 8 patients with autosomal recessive Wolfram syndrome (arWS) associated with diabetes mellitus and OA. Heterozygous mutations were found in 4 of 20 unrelated patients (20%) with autosomal dominant OA. The 4 WFS1 -mutated patients of this latter group with hearing loss were diagnosed with autosomal dominant Wolfram-like syndrome (adWLS). Most patients had VA decrease, with logarithm of the minimum angle of resolution (logMAR) values lower in arWS than in arNSOA (1.530 vs. 0.440; P = 0.026) or adWLS (0.240; P = 0.006) but not differing between arNSOA and adWLS ( P = 0.879). All patients had decreased RNFL thickness that was worse in arWS than in arNSOA (SD OCT, 35.50 vs. 53.80 μm; P = 0.018) or adWLS (TD-OCT, 45.84 vs. 59.33 μm; P = 0.049). The greatest difference was found in the inferior bundle. Visual acuity was negatively correlated with RNFL thickness ( r = −0.89; P = 0.003 in SD OCT and r = −0.75; P = 0.01 in TD-OCT). Conclusions WFS1 is a gene causing arNSOA. Patients with this condition had significantly less visual impairment than those with arWS. Thus systematic screening of WFS1 must be performed in isolated, sporadic, or familial optic atrophies.

SummaryA CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous or heterozygous CAPN1-null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knockout (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1-mediated cleavage of PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans.

International audience; Introduction: The Mitofusin 2 gene (MFN2), which encodes a mitochondrial membrane protein, is known to be the first cause of autosomal dominant Charcot Marie Tooth disease type 2 (CMT2) with early onset. This gene is involved in typical CMT2A and in more atypical phenotypes as optic atrophy or spastic paraplegia. CMT2 refers to inherited axonal polyneuropathy, which associates progressive peripheral motor and sensory neuropathy, a family history consistent mainly with autosomal dominant inheritance, and normal nerve conduction velocities. Subjects: Between 1999 and 2012, the genetic diagnosis of MFN2 mutation was made in 11 children who were treated in our department for different neurological symptoms. All data including family and personal history data, results of standardized clinical and electrophysiology testing, brain magnetic resonance imaging (MRI), neuro-ophthalmic evaluation, muscle biopsy histopathology and molecular diagnosis were retrospectively analyzed. Results: Five different mutations were found in 6 unrelated families. Three of them have previously been described; the two remaining are new mutations: one of them related a new phenotype. Clinical signs appeared before the age of 6 years in more than half of the patients (54%). The motor deficit was predominant in 8 patients (72%). Two children presented an acute onset of disease that stabilized afterwards; the other children showed a more progressive deterioration that was managed symptomatically. Conclusion: This large pediatric study describes a great interfamilial and intrafamilial phenotypic variability. We recommend screening this gene in pediatric patient with chronic neurologic symptoms such as motor deficit or optic atrophy but also in acute neurologic deficiencies such as subacute polyradiculoneuritis. (C) 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

To investigate the relationship between the microstructure of β-zone peripapillary atrophy (PPA) and the subsequent visual field (VF) progression in eyes with primary open-angle glaucoma (POAG), including highly myopic eyes.Retrospective cohort study.A total of 129 patients with POAG who had been followed up for a minimum of 2 years and had undergone at least 5 reliable standard automated perimetry tests after spectral-domain (SD) optical coherence tomography (OCT) examination.β-Zone PPA was evaluated from 3 SD OCT scans centered on the optic disc. Upper and lower scans were defined as scans at 30° above and below the horizontal scan, respectively. From 3 scans of each eye, β-zone PPA was classified as PPA(+BM) or PPA(-BM) on the basis of the presence or absence of Bruch's membrane (BM), respectively. Eyes were classified into 3 groups according to the horizontal scan images: group A (only PPA(+BM)), group B (both PPA(+BM) and PPA(-BM)), and group C (only PPA(-BM)). Factors associated with the subsequent mean deviation (MD) slope after OCT examination were analyzed, and the hemifield total deviation (TD) slope was assessed in eyes with unilateral hemifield VF defects in the corresponding direction.Subsequent MD slope after OCT examination.The VF progression in group A was faster than in group C (P = 0.004). A larger PPA(+BM) width was associated with a faster MD slope in all eyes (P0.001) and highly myopic eyes (P0.001) and with a faster TD slope in eyes with superior or inferior hemifield VF defects in the corresponding direction (P = 0.002 and P = 0.035, respectively). A larger PPA(-BM) was correlated with a slower MD slope in all eyes (P = 0.030 and P = 0.034) but not in highly myopic eyes.There were significant differences in VF progression according to the microstructure of the β-zone PPA in eyes with POAG. The PPA(+BM) width may be an important risk factor for VF progression in POAG, including high myopia, and the PPA(-BM) width may have a protective effect for VF progression in this subtype of POAG.

We present a patient with progressive spastic ataxia, with dystonia and anarthria undiagnosed until detailed genetic analysis revealed an MPAN mutation. Highlighting the worldwide MPAN distribution, a 30 year history of absent diagnosis and the impact and cost saving of an early but detailed genetic analysis in complex progressive movement disorders, particularly the anarthric NBIA group.

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.

PEHO syndrome is characterized by Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy, which was first described in Finnish patients. A homozygous missense substitution p.Ser31Leu in ZNHIT3 was recently identified as the primary cause of PEHO syndrome in Finland. Variants in ZNHIT3 have not been identified in patients with PEHO or PEHO-like syndrome in other populations. It has therefore been suggested that PEHO syndrome caused by ZNHIT3 variants does not occur outside of the Finnish population. We describe the first patient outside Finland who carries compound heterozygous variants in ZNHIT3 gene causing PEHO syndrome. Trio genome sequencing was carried out and the identified variants were confirmed by Sanger sequencing. The patient filled all diagnostic clinical criteria of PEHO syndrome. We identified biallelic missense variants in ZNHIT3 gene: the c.92C > T p.(Ser31Leu) variant (NM_004773.3), which is described previously as causing PEHO syndrome and the second novel variant c.41G > T p.(Cys14Phe). There are only eight heterozygous carriers of c.41G > T variant in the gnomAD database and it is predicted damaging by multiple in silico algorithms. The ZNHIT3-associated PEHO syndrome exists outside of the Finnish population.

Ophthalmological abnormalities may occur in specific subtypes of hereditary spastic paraplegia (HSP) and in genetic diseases that present with spastic paraplegia mimicking HSP. These ophthalmological changes may precede the motor symptoms and include pigmentary retinal degeneration, ophthalmoplegia, optic atrophy, cataracts and nystagmus. Some ophthalmological abnormalities are more prevalent in specific forms of HSP. Considering that the diagnosis of HSP is usually difficult and complex, specific ophthalmological changes may guide the genetic testing. There are other genetic diseases such as autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), X-linked adrenoleukodystrophy and spastic paraplegia, optic atrophy and neuropathy (SPOAN) that may mimic HSP and also may present with specific ophthalmological changes. In this article, we review the main ophthalmological changes observed in patients with HSP and HSP-like disorders.

Introduction The combination of cerebellar ataxia and spasticity is common. However, autosomal dominant genetic diseases presenting with spastic-ataxia are a smaller group. Pyramidal signs have been frequently observed in several SCA subtypes, particularly in spinocerebellar ataxia type 1. Methods We prospectively evaluated the pyramidal signs and spasticity in SCA1 patients, and correlated the data with genetic and clinical features. Results In this study, we observed that spasticity may be an early and presenting feature of SCA1, since 3 patients had pyramidal signs and spasticity as the first neurological sign. SCA1 patients with spasticity were significantly younger. Conclusion SCA1 may rarely present with pure spastic paraplegia, resembling hereditary spastic paraplegia, before the appearance of cerebellar signs. This observation may confuse the neurologist when a genetic testing is requested for an autosomal dominant spastic paraplegia, directing research to hereditary spastic paraplegia group.

Purpose To report a case of Wolfram syndrome (WS) characterized by diabetes mellitus, diabetes insipidus, progressive optic atrophy, and deafness. Case report A 19-year-old female patient, a known case of diabetes mellitus type I from six years before, presented with progressive vision loss since four years earlier. On fundoscopic examination, she had bilateral optic atrophy without diabetic retinopathy. The patient also had diabetes insipidus, neurosensory deafness, and neurogenic bladder. Conclusion WS should be considered a differential diagnosis in patients with diabetes mellitus who present with optic atrophy, and it is necessary to perform a hearing test as well as collecting 24-h urine output.

Summary Purpose We measured the amount of hemoglobin at the optic nerve head of fibromyalgia (FM) patients using new colorimetric analysis software. We also investigated whether perfusion defects of the optic nerve head in patients with FM lead to tissue atrophy and corresponding retinal nerve fiber layer (RNFL) thinning measured by optical coherence tomography (OCT). Methods We recruited for this cross-sectional study 118 FM patients and 76 sex- and age-matched healthy controls. All subjects underwent a complete neuro-ophthalmologic examination, which also included visual field testing using the Spark strategy in an Easyfield perimeter, and OCT examinations using the Spectralis. One photograph of the optic disc was obtained using a Cirrus™ Photo 800 multi-modality imager. We analyzed fundus photographs using Laguna ONhE software, a new method that allows hemoglobin levels to be measured at the optic nerve head. We compared hemoglobin percentages in different sectors of the nerve head and RNFL thicknesses between the two groups. Results Mean hemoglobin percentages and hemoglobin content in all optic nerve head sectors calculated by the Laguna ONhE program were significantly lower in FM patients than in healthy controls, and the main differences were detected in the outer ring, which corresponds with the neuroretinal rim. However, only the differences in the superotemporal RNFL were statistically significant. Correlations between the RNFL thickness and the percentage of hemoglobin in the different sectors were weak. Conclusion Optic disc perfusion was decreased in patients with FM, especially within the neuroretinal rim, without clear involvement in the RNFL.

The association between combined methylmalonic acidemia and homocystinuria of cblC type (cobalamin C defect, cblC) and ocular disease is now well recognized, and is a significant component of morbidity and disability associated with the condition. In this review, through collation of historically reported cases of early- and late-onset cblC and previously unreported cases, we have attempted to characterize the epidemiology, clinical features, and pathomechanisms of individual ocular features of cblC. These data suggest that maculopathy and nystagmus with abnormal vision are extremely common and affect the majority of children with early-onset cblC, usually before school age; strabismus and optic atrophy are also seen at relatively high frequency. The timing of progression of macular disease may coincide with a critical period of postnatal foveal development. Maculopathy and retinal disease may be subclinical and show only partial correlation with the extent of visual deficits, and visual deterioration may be relentlessly progressive in spite of aggressive treatment of biochemical abnormalities. In later-onset forms of the disease, visual loss and ocular complications appear to be infrequent. Finally, we discuss investigational strategies in diagnosing and characterizing eye disease in individuals with cblC, explore possible therapeutic avenues that may attenuate progression and severity of eye disease, and propose a clinical surveillance guideline for monitoring progression of ocular disease in children and adults with cblC.

To investigate whether the rate of retinal nerve fiber layer (RNFL) thinning differs according to the microstructure of β-zone parapapillary atrophy (PPA) as evaluated by spectral-domain (SD) optical coherence tomography (OCT) in primary open-angle glaucoma (POAG).Prospective, observational, comparative study.A total of 195 eyes with POAG that had been evaluated by serial SD-OCT RNFL thickness measurements for ≥ 2 years.On the basis of the extent of Bruch's membrane (BM) within the β-zone PPA (area without retinal pigment epithelium [RPE]), as shown in the infrared fundus images, PPA was divided into PPA+BM (PPA with intact BM) and PPA-BM (PPA devoid of BM). Eyes were categorized into group A (having PPA+BM only, n=64), group B (having both PPA+BM and PPA-BM, n=58), group C (having PPA-BM only, n=32), and group D (without β-zone PPA, n=41). The rate of progressive OCT RNFL thinning was determined by linear regression and compared between groups. Factors influencing the rate of RNFL thinning were evaluated, including age, sex, follow-up duration, history of filtering surgery, baseline RNFL thickness, baseline intraocular pressure (IOP), mean IOP and IOP fluctuation during follow-up, PPA types, baseline PPA width, PPA width increase, axial length (AXL), central corneal thickness, and visual field mean deviation (MD).Rate of thinning of OCT RNFL thicknesses over time.Patients in groups B and C were significantly younger and more myopic, and had a greater AXL, than those in groups A and D (all P0.001). The rate of global RNFL thinning was significantly faster in group A (-1.66 ± 2.94 μm/year) than in the other groups (group B, -0.87 ± 1.28 μm/year; group C, 0.20 ± 1.86 μm/year; group D, -0.28 ± 1.74 μm/year; P = 0.001). Multivariate regression showed a significant association of shorter follow-up period (P = 0.016), greater baseline global RNFL thickness (P = 0.035), type of β-zone PPA (group A, P = 0.023), and greater baseline PPA+BM width (P = 0.034) with a faster rate of RNFL thinning.The rate of RNFL thinning differed according to the microstructure of β-zone PPA. It was faster for eyes with β-zone PPA with intact BM than for eyes without β-zone PPA or with β-zone PPA devoid of BM.

Neuroglobin (NGB) is considered as an endogenous neuroprotective molecule against stroke, since the protein alleviates the adverse effects of hypoxic and ischemic insults. We previously demonstrated the functional link between NGB and mitochondria since it is required for respiratory chain function. Thus, here, we evaluated the relevance of this effect in the Harlequin (Hq) mouse strain, which exhibits retinal ganglion cell (RGC) loss and optic atrophy due to a respiratory chain complex I (CI) defect. A twofold decrease of NGB amounts was observed in Hq retinas. We constructed a recombinant adeno-associated virus which combines to the mouse NGB open reading frame, its 5′ and 3′UTR, for guarantying mRNA stability and translation capacity. The vector was administrated intravitreally to Hq mice and NGB expression was stable for up to 7 months without negative effect on retinal architecture or function. On the contrary, RGCs and their axons were substantially preserved from degeneration; consequently, CI activity in optic nerves was protected conferring improvements in vision. Hence, we established that NGB prevents respiratory chain impairment, therefore, protecting visual function otherwise compromised by mitochondrial energetic failure.

Objective To describe the long-term ophthalmologic outcomes of patients with methylmalonic aciduria and homocystinuria, cobalamin C type (cblC). Design Retrospective case series. Participants All patients with cblC referred to the Department of Ophthalmology of the Centre Hospitalier Universitaire Sainte-Justine from 1984 through 2012 were studied. Twelve such patients were identified. Methods Clinical ophthalmic examinations, neuroimaging, electroretinography, and the results of MMACHC mutation analysis were reviewed retrospectively. Main Outcome Measures We examined visual acuity, ocular alignment, presence of maculopathy and peripheral retinopathy, optic atrophy, and nystagmus. Photopic and scotopic electroretinograms were reviewed. We examined and compared mutations in the MMACHC gene. Neuroimaging abnormalities were compiled when available. Results Twelve cblC patients were followed up from 2 to 23 years (average, 10 years). Eleven of 12 patients were diagnosed before the age of 1 year (range, birth−2 years). An initial ophthalmic examination was performed within the first year of age in 9 of 12 patients. Visual acuity at the time of presentation was variable, ranging from light perception to 20/20. Visual acuity was worse than 20/100 in 75% (9/12) of patients at last follow-up. Eight patients (67%) had obvious maculopathy on fundus examination. Other findings included peripheral retinopathy (8/12 [67%]), nystagmus (8/12 [67%]), strabismus (5/12 [42%]), and optic atrophy (6/12 [50%]). Funduscopic deterioration was documented in 1 patient, whereas electrophysiologic changes occurred in 4 patients. Neuroimaging results were available in 7 of the patients, revealing corpus callosum atrophy (7/7 [100%]) and periventricular white matter loss (6/7 [85%]). Conclusions Most children in our series had early-onset disease with neurologic manifestations and abnormal ophthalmologic examination results. Despite early treatment, many early-onset cblC patients have poor visual function.

To develop a classification of parapapillary atrophy (PPA) based on its relationship with the location of Bruch's membrane (BM) termination in primary open-angle glaucoma (POAG) patients.Cross-sectional observational study.This study analyzed 161 eyes from 161 POAG patients who had temporal β-zone PPA, the width of which was more than 200 μm on at least 1 horizontal scan image obtained by spectral-domain optical coherence tomography within the mid horizontal one third of the optic nerve.Based on the extent of BM within the PPA area, eyes were categorized as group A (intact BM; 76 eyes), group B (discontinuous BM; 65 eyes), and group C (lacking BM; 20 eyes). Differences in the demographic, clinical, and ocular characteristics were compared using analysis of variance and chi-square tests among the 3 groups. The distance from the temporal optic disc margin to the temporal margin of the β-zone PPA (PPA width) and to the edge of the BM (width of PPA without BM [PPA-BM]) were measured on 3 horizontal scans within the mid horizontal one third of the optic nerve, and the averages of the measured values were analyzed. The configuration of the border tissue of Elschnig at the temporal disc margin was assessed.Factors and configuration of the border tissue of Elschnig associated with each PPA type.The mean age of group A was significantly higher than that of groups of B and C (P0.001). The mean axial length was greatest in group C (group Cgroup Bgroup A; P0.001). In group A, the border tissue mainly had a nonoblique configuration (49/76 eyes; 64.5%), whereas most of the eyes in group B (59/65 eyes; 90.8%) and all eyes in group C (20 eyes) it had an externally oblique configuration (P0.001). A longer axial length was correlated significantly with a larger PPA-BM width (r = 0.478; P0.001).A morphologic classification of PPA, which may reflect differing pathogenesis among the groups, is proposed. Parapapillary atrophy with intact BM may be an age-related atrophic change, whereas PPA lacking BM may result from scleral stretching associated with elongation of the globe.Proprietary or commercial disclosure may be found after the references.

Objective To examine whether auditory evoked fields (AEFs) can be used to objectively evaluate hearing in patients with absent auditory brainstem responses (ABRs) due to auditory neuropathy. Methods Subjects were 3 patients with auditory neuropathy, 1 male aged 29 years and 2 females aged 18 and 27 years, with absence of click evoked ABRs for bilateral ear stimuli at a level of 105 dB nHL. All patients also had optic atrophy. AEFs were measured with a helmet-shaped magnetoencephalography system for 2.0 kHz tone bursts of 60 ms duration to the unilateral ear. Results Bihemispherical AEF responses were clearly recorded in all three patients for either left or right ear stimulus. Although the latencies of N100m were severely prolonged and amplitudes were considerably decreased compared to the normal range of N100m responses in our facilities, N100m latency of AEF was shorter in the contralateral hemisphere to the stimulated ear, as usually found in normal subjects, despite the abnormal delay in N100m latency in all conditions. Conclusions Presence and abnormality of auditory cortical responses can be evaluated by AEFs in patients with auditory neuropathy even under null responses in ABRs. Significance AEFs are useful to evaluate residual hearing in patients with auditory neuropathy.

Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) disorder in the general population. It is an important cause of severe, usually irreversible, visual loss among young adults with a peak age of onset in the second and third decades of life. Management is currently mostly supportive but recent developments in LHON research are pointing the way towards more effective treatments for this blinding mitochondrial disorder.

Purpose To determine if visual field (VF) progression occurs most rapidly in the region of largest β-zone parapapillary atrophy (PPA). Design Retrospective cohort. Participants One hundred twenty-five patients from the New York Glaucoma Progression Study with both β-zone PPA and VF progression. Methods Treated open-angle glaucoma patients with 8 or more Swedish Interactive Threshold Algorithm Standard 24-2 VFs (Humphrey Field Analyzer II; Carl Zeiss Meditec, Inc., Dublin, CA) in either eye were identified. Eyes with optic disc photographs, β-zone PPA, less than 6 diopters myopia, and VF progression were studied. Visual field progression was defined using trend analysis as the presence of at least 2 adjacent progressing points in the same hemifield using standard pointwise linear regression (PLR) criteria. Main Outcome Measures The correlation between β-zone PPA and location of most rapid future VF progression. Results One hundred twenty-five eyes (125 patients; mean age, 71.9±12.3 years; 58% women; 75% European descent) with β-zone PPA and VF progression were enrolled. The mean follow-up was 6.8±1.7 years and the mean number of VFs was 12.5±3.6. Ninety-three patients (74%) had more β-zone PPA inferiorly and 32 patients (26%) had more β-zone PPA superiorly. The fastest VF progression occurred in the superior hemifield in 77 patients (62%) and in the inferior hemifield in 48 (38%) patients. Patients with superior VF progression had a superior localized mean rate of progression of −1.57±1.7 dB/year, and patients with inferior VF progression had an inferior localized mean rate of −0.94±1.4 dB/year ( P = 0.012). The mean number of points reaching the predefined PLR end points was 5.6±7.5 for the superior VF hemifield and 3.0±4.9 for the inferior hemifield ( P = 0.006). The hemifield with more points reaching PLR progression end points, with fastest average velocity of progression, or both was spatially consistent with the location of largest β-zone PPA in 89 (71%) patients ( P = 0.0001, Fisher exact test; κ = 0.35; 95% confidence interval, 0.17–0.53). Conclusions In treated glaucoma patients with β-zone PPA and VF progression, the location of largest β-zone PPA typically correlates spatially with the region of the most rapid future VF progression. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Introduction Pathogenic mutations in the OPA1 gene are the most common identifiable cause of autosomal dominant optic atrophy (DOA), which is characterized by selective retinal ganglion cell loss, a distinctive pattern of temporal pallor of the optic nerve and a typical color vision deficit, with variable effects on visual acuity. Haploinsufficiency has been suggested as the major pathogenic mechanism for DOA. Here we present two siblings with severe ataxia, hypotonia, gastrointestinal dysmotility, dysphagia, and severe, early-onset optic atrophy who were found to be compound heterozygotes for two pathogenic OPA1 mutations. This example expands the clinical phenotype of OPA1-associated disorders and provides additional evidence for semi-dominant inheritance. Methods and results Molecular analysis of the OPA1 gene in this family by Sanger sequencing revealed compound heterozygosity for two mutations in trans configuration, a p.I382M missense mutation and a p.V903GfsX3 frameshift deletion in both affected siblings. Electron microscopy of a skeletal muscle biopsy of the older sibling revealed dense osmiophilic bodies within the mitochondria. Mitochondrial DNA (mtDNA) content was within normal limits, and electron transport chain analysis showed no deficiencies of the mitochondrial respiratory chain enzymes. Multiple mtDNA deletions were not found. Conclusion Compound heterozygosity of pathogenic OPA1 mutations may cause severe neuromuscular phenotypes in addition to early-onset optic atrophy. While a role for OPA1 in mtDNA maintenance has been discussed, compound biallelic pathogenic OPA1 mutations in our patients did not result in altered mtDNA copy number, mtDNA deletions, or deficiencies of the electron transport chain, despite the severe clinical phenotype.

We describe two familial and three nonfamilial cases from Argentina, examined between February 1, 1990-July 31, 2008, who met the diagnostic criteria of progressive encephalopathy, peripheral edema, hypsarrhythmia, and optic atrophy syndrome. All five children were products of normal gestation, although one was premature. Birth was uneventful in all patients. Two patients were twin brothers. During their first neurologic examination, between ages 2-6 months, patients presented with facial dysmorphia, poor visual contact, and generalized hypotonia with poor head control. Microcephaly and swelling of the dorsum of the hands and feet were evident. Hypsarrhythmia was observed in all patients (associated with epileptic spasms in four). Optic atrophy was evident in four cases. Magnetic resonance imaging indicated progressive cerebellum and brainstem atrophy in all cases. Toxoplasmosis, others, rubella, cytomegalovirus, herpes (TORCH), neurometabolic investigations, and karyotype studies produced normal results in all patients. Progressive encephalopathy, peripheral edema, hypsarrhythmia, and optic atrophy syndrome should be considered in infants with neonatal hypotonia, early onset of seizures (especially epileptic spasms), hypsarrhythmia, early loss of visual fixation, profound psychomotor retardation, typical dysmorphy, and progressive cerebellar and brainstem atrophy without a clear etiology. Autosomal recessive inheritance is suspected. Early diagnosis is important for adequate genetic counseling.

Purpose Autosomal-dominant optic atrophy (DOA) is one of the most common inherited optic neuropathies, and it is genetically heterogeneous, with mutations in both OPA1 and OPA3 known to cause disease. Approximately 60% of cases harbor OPA1 mutations, whereas OPA3 mutations have been reported in only 2 pedigrees with DOA and premature cataracts. The aim of this study was to determine the yield of OPA1 and OPA3 screening in a cohort of presumed DOA cases referred to a tertiary diagnostic laboratory. Design Retrospective case series. Participants One hundred eighty-eight probands with bilateral optic atrophy referred for molecular genetic investigations at a tertiary diagnostic facility: 38 patients with an autosomal-dominant pattern of inheritance and 150 sporadic cases. Methods OPA1 and OPA3 genetic testing was initially performed using polymerase chain reaction-based sequencing methods. The presence of large-scale OPA1 and OPA3 genomic rearrangements was assessed further with a targeted comparative genomic hybridization microarray platform. The 3 primary Leber hereditary optic neuropathy (LHON) mutations, m.3460G→>A, m.11778G→A, and m.14484T→C, also were screened in all patients. Main Outcome Measures The proportion of patients with OPA1 and OPA3 pathogenic mutations. The clinical profile observed in molecularly confirmed DOA cases. Results Twenty-one different OPA1 mutations were found in 27 (14.4%) of the 188 probands screened. The mutations included 6 novel pathogenic variants and the first reported OPA1 initiation codon mutation at c.1A→T. An OPA1 missense mutation, c.239A→G (p.Y80C), was identified in an 11-year-old black girl with optic atrophy and peripheral sensorimotor neuropathy in her lower limbs. The OPA1 detection rate was significantly higher among individuals with a positive family history of visual failure (50.0%) compared with sporadic cases (5.3%). The primary LHON screen was negative in the patient cohort, and additional molecular investigations did not reveal any large-scale OPA1 rearrangements or OPA3 genetic defects. The mean baseline visual acuity for the OPA1 -positive group was 0.48 logarithm of the minimum angle of resolution (units mean Snellen equivalent, 20/61; range, 20/20–20/400; 95% confidence interval, 20/52–20/71), and visual deterioration occurred in 54.2% of patients during follow-up. Conclusions OPA1 mutations are the most common genetic defects identified in patients with suspected DOA, whereas OPA3 mutations are very rare in isolated optic atrophy cases. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Dominant optic atrophy (DOA) is the most common inherited optic neuropathy affecting one in every 12,000 people. It presents with bilateral visual loss, central visual fields defects, colour vision disturbance and optic disc pallor. OPA1 has been identified as the responsible gene and its locus mapped to chromosome 3q28-q29. Mutations in this gene are responsible for the clinical phenotype in over 70% of patients with DOA. Histopathological studies in tissues from patients reveal loss of retinal ganglion cells but the paucity of viable human tissue has raised the importance of an animal model to study the pathophysiology of the disease. In the last decade considerable work has gone into the generation of animal, most notably mouse, models of Opa1 DOA. Two murine models of DOA have been published, designated B6;C3-Opa1Q285STOP and B6;C3-Opa1329-355del and they provide valuable insights with respect to neurological and visual phenotyping, mitochondrial dysfunction, optic nerve and axonal changes, retinal ganglion cell depletion and dendritic atrophy. Here we summarise the current state of knowledge of the mechanisms of disease based on data from these models of Opa1 DOA.