Four Unique Genetic Variants in Three Genes Account for 62.7% of Early-Onset Severe Retinal Dystrophy in Chile: Diagnostic and Therapeutic Consequences.

Leber congenital amaurosis (LCA)/early-onset severe retinal dystrophy (EOSRD) stand as primary causes of incurable childhood blindness. This study investigates the clinical and molecular architecture of syndromic and non-syndromic LCA/EOSRD within a Chilean cohort (67 patients/60 families). Leveraging panel sequencing, 95.5% detection was achieved, revealing 17 genes and 126 variants (32 unique). CRB1, LCA5, and RDH12 dominated (71.9%), with CRB1 being the most prevalent (43.8%). Notably, four unique variants (LCA5 p.Glu415*, CRB1 p.Ser1049Aspfs*40 and p.Cys948Tyr, RDH12 p.Leu99Ile) constituted 62.7% of all disease alleles, indicating their importance for targeted analysis in Chilean patients. This study underscores a high degree of inbreeding in Chilean families affected by pediatric retinal blindness, resulting in a limited mutation repertoire. Furthermore, it complements and reinforces earlier reports, indicating the involvement of ADAM9 and RP1 as uncommon causes of LCA/EOSRD. These data hold significant value for patient and family counseling, pharmaceutical industry endeavors in personalized medicine, and future enrolment in gene therapy-based treatments, particularly with ongoing trials (LCA5) or advancing preclinical developments (CRB1 and RDH12).

Normal vision and development in mice with low functional expression of Kir7.1 in heterozygosis for a blindness-producing mutation inactivating the channel.

K+ channel Kir7.1 expressed at the apical membrane of the retinal pigment epithelium (RPE) plays an essential role in retinal function. An isoleucine-to-threonine mutation at position 120 of the protein is responsible for blindness-causing vitreo-retinal dystrophy. We have studied the molecular mechanism of action of Kir7.1-I120T in vitro by heterologous expression and in vivo in CRISPR-generated knockin mice. Full-size Kir7.1-I120T reaches the plasma membrane but lacks any activity. Analysis of Kir7.1 and the I120T mutant in mixed transfection experiments, and that of tandem tetrameric constructs made by combining wild type (WT) and mutant protomers, leads us to conclude that they do not form heterotetramers in vitro. Homozygous I120T/I120T mice show cleft palate and tracheomalacia and do not survive beyond P0, whereas heterozygous WT/I120T develop normally. Membrane conductance of RPE cells isolated from WT/WT and heterozygous WT/I120T mice is dominated by Kir7.1 current. Using Rb+ as a charge carrier, we demonstrate that the Kir7.1 current of WT/I120T RPE cells corresponds to approximately 50% of that in cells from WT/WT animals, in direct proportion to WT gene dosage. This suggests a lack of compensatory effects or interference from the mutated allele product, an interpretation consistent with results obtained using WT/- hemizygous mouse. Electroretinography and behavioral tests also show normal vision in WT/I120T animals. The hypomorphic ion channel phenotype of heterozygous Kir7.1-I120T mutants is therefore compatible with normal development and retinal function. The lack of detrimental effect of this degree of functional deficit might explain the recessive nature of Kir7.1 mutations causing human eye disease.NEW & NOTEWORTHY Human retinal pigment epithelium K+ channel Kir7.1 is affected by generally recessive mutations leading to blindness. We investigate one such mutation, isoleucine-to-threonine at position 120, both in vitro and in vivo in knockin mice. The mutated channel is inactive and in heterozygosis gives a hypomorphic phenotype with normal retinal function. Mutant channels do not interfere with wild-type Kir7.1 channels which are expressed concomitantly without hindrance, providing an explanation for the recessive nature of the disease.

Presentación atípica de síndrome antifosfolípido

El síndrome antifosfolípido es considerado un trastorno del colágeno asociado a presentaciones clínicas a edades intermedias con incidencias no mayores de 5 casos por cada 100.000 personas. Su espectro clínico oscila en la presencia de manifestaciones trombóticas multisistémicas de origen vascular. Sin embargo, las manifestaciones no vasculares tienen un espectro raro en su presentación habitual. Se presenta el caso de un varón de 64 años con manifestaciones oculares relacionadas a amaurosis fugaz asociado a alteraciones estructurales retinianas. Los hallazgos de tamizajes realizados fueron fuertemente sugestivos de trombofilias primarias. Se aplicó perfil para síndrome antifosfolípido el cual fue positivo, por lo que se instauró anticoagulación plena.

Antiphospholipid syndrome is considered a collagen disorder associated with clinical presentations at intermediate ages with incidences of no more than 5 cases per 100,000 people. Its clinical spectrum ranges from the presence of multisystem thrombotic manifestations of vascular origin. However, non-vascular manifestations have a rare spectrum in their usual presentation. The case of a 64-year-old man with ocular manifestations related to amaurosis fugax associated with retinal structural alterations is presented. The findings of screening performed were strongly suggestive of primary thrombophilia. A profile for antiphospholipid syndrome was applied, which was positive and therefore, full anticoagulation was initiated.

Principais achados em um paciente com diagnóstico de Amaurose Congênita de Leber / Main findings in a patient diagnosed with Leber's Congenital Amaurosis

RESUMO A amaurose congênita de Leber, também conhecida como neuropatia óptica hereditária de Leber, é caracterizada por uma das formas mais graves de distrofia da retina com início na infância. Os achados clássicos são deficiência visual grave e precoce, nistagmo e eletrorretinograma (ERG) anormal ou não detectável. O objetivo deste estudo é relatar um caso de um paciente com amaurose congênita de Leber com comprometimento visual desde os 6 meses de vida e acentuado declínio visual a partir dos 15 anos de idade. A realização de exames específicos para confirmar o diagnóstico é importante para o manejo e o seguimento adequado do paciente e para proporcionar melhor qualidade de vida para o mesmo.

ABSTRACT Leber Congenital Amaurosis, also known as Leber hereditary optic neuropathy, is characterized by one of the most severe forms of childhood-onset retinal dystrophy. Classic findings are severe and early visual impairment, nystagmus, and abnormal or undetectable electroretinogram. The aim of this study is to report a case of a patient with Leber Congenital Amaurosis with visual impairment since the first six months of age and marked visual decline from fifteen years of age. Performing specific tests to confirm the diagnosis is important for the proper management and follow-up of the patient and to provide them with a better quality of life.

Multiple attacks of transient monocular visual loss in a previously healthy man: a possible complication after COVID-19 vaccination?

BACKGROUND: The present case aims to describe a previously healthy man who presented multiple attacks of transient monocular visual loss after Pfizer-BioNTech COVID-19 vaccination and to discuss the possible mechanisms related to occurrence of this condition. CASE PRESENTATION: We report a case of multiple attacks of transient monocular visual loss in a previously healthy middle-aged man two weeks after Pfizer-BioNTech COVID-19 vaccination. TVL attacks were described as sudden and painless complete visual loss, lasting about one minute, followed by a full recovery. He presented several non-simultaneous attacks in both eyes, 16 in the right eye, and 2 in the left eye on the same day, fifteen days after receiving the second dose of the Pfizer-BioNTech COVID-19 vaccine. The brain's magnetic resonance angiography, echocardiogram, and doppler ultrasound imaging of the carotid and vertebral arteries were non-revealing. The complete blood exam revealed a slightly elevated C-reactive protein test. We assessed fundus examination during the transient visual loss attack and revealed diffuse vascular narrowing for both arterial and venous branches, notably in the emergence of the optic disc in right eye. In addition, the circumpapillary optical coherence tomography angiography (OCTA) vessel density map was reduced. Oral verapamil hydrochloride 60 mg twice daily was initiated, and the attacks of transient visual loss improved after two days. CONCLUSIONS: To date, and the best of our knowledge, this is the first case report of multiple transient monocular visual loss attacks due to retinal vasospasm in a previously healthy middle-aged man documented by fundus retinography and OCTA. We discuss in this article the possible association of retinal vasospasm and Pfizer-BioNTech COVID-19 vaccination, probably related to vaccine-induced inflammation.

The first gene therapy for RPE65 biallelic dystrophy with voretigene neparvovec-rzyl in Brazil.

PURPOSE: To report the first Brazilian patient with RPE65 deficiency-inherited retinal dystrophy (RPE65-IRD) treated with voretigene neparvovec-rzyl (VN). METHODS: An adult patient with Leber congenital amaurosis-2 with a homozygous mutation in the RPE65 gene (p.Phe83Leu) was treated bilaterally with VN. The clinical and surgical aspects are described. The baseline and 4-month postoperative ophthalmologic examinations included measurement of the best-corrected visual acuity (BCVA), full-field stimulus threshold (FST) test, Octopus 900 semiautomated kinetic visual fields (VFs), and microperimetry. RESULTS: No complications developed in this patient. The BCVA remained stable. The full-field stimulus threshold test (FST) and VFs showed clinically significant improvements bilaterally. The patient reported significant improvements in the ability to perform daily activities, mainly for those requiring the VFs and vision in a low-luminescence environment. CONCLUSIONS: The treatments were beneficial for this patient who was homozygous for RPE65 p.Phe83Leu. The first VN treatments in an adult Brazilian patient in clinical practice showed measurable improvements in visual outcomes that were meaningful for the patient's daily activities. TRANSLATIONAL RELEVANCE: This case reinforces the clinical trial results and proves that the procedure is feasible in countries such as Brazil.

Epidemiology of Mutations in the 65-kDa Retinal Pigment Epithelium (RPE65) Gene-Mediated Inherited Retinal Dystrophies: A Systematic Literature Review.

INTRODUCTION: Inherited retinal dystrophies (IRDs) represent a genetically diverse group of progressive, visually debilitating diseases. Adult and paediatric patients with vision loss due to IRD caused by biallelic mutations in the 65-kDa retinal pigment epithelium (RPE65) gene are often clinically diagnosed as retinitis pigmentosa (RP), and Leber congenital amaurosis (LCA). This study aimed to understand the epidemiological landscape of RPE65 gene-mediated IRD through a systematic review of the literature, as the current evidence base for its epidemiology is very limited. METHODS: Medline, Embase, and other databases were searched for articles on the epidemiology of RPE65 gene-mediated IRDs from inception until June 2021. Studies were included if they were original research articles reporting the epidemiology of RP and LCA and/or proportion of RPE65 gene mutations in these clinically diagnosed or molecularly confirmed IRDs patients. RESULTS: A total of 100 studies with relevant data were included in this systematic review. The range for prevalence of LCA and RP in the literature was 1.20-2.37 and 11.09-26.43 per 100,000, respectively. The proportion of RPE65 mutations in clinically diagnosed patients with LCA was found to be between ~ 2-16% within the US and major European countries (France, Germany, Italy, Spain, and the UK). This range was also comparable to our findings in the Asian region for RPE65-LCA (1.26-16.67%). Similarly, for these European countries, RPE65-RP was estimated between 0.23 and 1.94%, and RPE65-IRD range was 1.2-14%. Further, in the Americas region, mutations in RPE65 were reported to cause 1-3% of RP and 0.8-3.7% of IRD cases. Lastly, the RPE65-IRD range was 4.81-8% in the Middle East region. CONCLUSIONS: There are significant variations in reporting of RPE65 proportions within countries as well as regions. Generating robust epidemiological evidence on RPE65 gene-mediated IRDs would be fundamental to support rare disease awareness, timely therapeutic intervention, and public health decision-making.

Contractile peripapillary staphyloma: OCTA documentation of increased peripapillary vessel density during transient visual loss episodes.

PURPOSE: to describe a patient with a contractile peripapillary staphyloma and transient visual loss (TVL) that underwent repeated OCTA examination documenting disc contraction and increased peripapillary vessel density as the mechanism of TVL. OBSERVATIONS: a 28-year-old male presented multiple daily episodes of TVL for the last 5 years. Fundoscopic examination revealed a peripapillary staphyloma. The fundus photographs and SS-OCT demonstrated flattening of the posterior polo and crowding of the contracted optic disk, which became hyperemic with tortuous and dilated veins during visual loss episodes. OCTA showed temporary increased peripapillary vessel density, presumably from severe venous congestion leading to TVL during the contraction. CONCLUSION AND IMPORTANCE: increased peripapillary vessel density can be demonstrated by OCTA during TVL in contractile peripapillary staphyloma. These findings indicate that severe venous stasis during disc contraction is the cause of TVL.

Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients.

Leber congenital amaurosis (LCA) and early-onset retinal dystrophy (EORD) are severe inherited retinal dystrophy that can cause deep blindness childhood. They represent 5% of all retinal dystrophies in the world population and about 10% in Brazil. Clinical findings and molecular basis of syndromic and nonsyndromic LCA/EORD in a Brazilian sample (152 patients/137 families) were studied. In this population, 15 genes were found to be related to the phenotype, 38 new variants were detected and four new complex alleles were discovered. Among 123 variants found, the most common were CEP290: c.2991+1655A>G, CRB1: p.Cys948Tyr, and RPGRIP1: exon10-18 deletion.

Avaliação do Setor de Baixa Visão de pacientes gemelares com distrofia retiniana / Low vision center evaluation of twin patients with retinal dystrophy

Resumo É relatado o caso de duas pacientes gemelares idênticas do sexo feminino portadoras de distrofia retiniana em investigação. A principal hipótese diagnóstica é a amaurose congenita de leber. Foi realizada avaliação pelo setor de visão subnormal em centro oftalmológico, com orientação de uso de recursos ópticos e não ópticos para melhoria principalmente das relações socioeducativas das pacientes.

Abstract In this paper, we report a two identical female twin patients with retinal distrophy in investigation. The main diagnostic hypothesis is the leber congenital amaurosis. The patients were evaluated by the Low Vision Center at the Hospital Oftalmologico de Sorocaba, São Paulo-Brazil, using optical and non-optical resources for mainly patient's socio-educational relationship improvement.

Genetic testing for inherited ocular conditions in a developing country.

Background: Inherited ocular conditions are a frequent cause of blindness. Gene therapy has encouraged the development of genetic testing, currently able to detect up to 80% of mutations in contrast to the 5% sensitivity achieved a few decades ago.Materials and methods: One hundred sixty-three patients with suspected genetic ocular disorders who were referred to a single clinician between August 2014 and August 2019 underwent a thorough ophthalmologic examination. Those diagnosed with congenital cataract, retinoblastoma, anterior segment dysgenesis, autoimmune retinal disease, posterior microphthalmia, or cobalamin C deficiency were excluded, along with patients who opted against genetic testing. Included probands were classified into a diagnostic clinical category and offered genetic testing. Blood samples were sent to foreign accredited diagnostic laboratories, followed by clinical interpretation of the results.Results: Of the 163 patients referred, 104 were enrolled in the study. Median age at disease onset was 2 years (range, 0 to 43 years). A molecular diagnosis was established at a median age of 10 years (range, 0.4 to 50 years). Disease-causing genotypes were identified in 82 of the probands, indicating a mutation detection rate of 78.8%. Mutations were identified in 38 genes, ABCA4 being the most commonly affected (23% of mutations), followed by CRB1 (13% of mutations). Whole-exome sequencing was performed in 6 patients, resulting in a definite diagnosis in 3 (50%).Conclusions: Molecular testing for inherited ocular conditions is feasible in developing countries by sending samples to certified foreign laboratories, with a mutation detection rate comparable to published values in developed countries. Further studies to identify more disease-causing genes may improve the overall sensitivity.

Extensive genic and allelic heterogeneity underlying inherited retinal dystrophies in Mexican patients molecularly analyzed by next-generation sequencing.

BACKGROUND: Retinal dystrophies (RDs) are one of the most genetically heterogeneous monogenic disorders with ~270 associated loci identified by early 2019. The recent application of next-generation sequencing (NGS) has greatly improved the molecular diagnosis of RD patients. Genetic characterization of RD cohorts from different ethnic groups is justified, as it would improve the knowledge of molecular basis of the disease. Here, we present the results of genetic analysis in a large cohort of 143 unrelated Mexican subjects with a variety of RDs. METHODS: A targeted NGS approach covering 199 RD genes was employed for molecular screening of 143 unrelated patients. In addition to probands, 258 relatives were genotyped by Sanger sequencing for familial segregation of pathogenic variants. RESULTS: A solving rate of 66% (95/143) was achieved, with evidence of extensive loci (44 genes) and allelic (110 pathogenic variants) heterogeneity. Forty-eight percent of the identified pathogenic variants were novel while ABCA4, CRB1, USH2A, and RPE65 carried the greatest number of alterations. Novel deleterious variants in IDH3B and ARL6 were identified, supporting their involvement in RD. Familial segregation of causal variants allowed the recognition of 124 autosomal or X-linked carriers. CONCLUSION: Our results illustrate the utility of NGS for genetic diagnosis of RDs of different populations for a better knowledge of the mutational landscape associated with the disease.

Pathogenicity Reclasssification of RPE65 Missense Variants Related to Leber Congenital Amaurosis and Early-Onset Retinal Dystrophy.

A challenge in molecular diagnosis and genetic counseling is the interpretation of variants of uncertain significance. Proper pathogenicity classification of new variants is important for the conclusion of molecular diagnosis and the medical management of patient treatments. The purpose of this study was to reclassify two RPE65 missense variants, c.247T>C (p.Phe83Leu) and c.560G>A (p.Gly187Glu), found in Brazilian families. To achieve this aim, we reviewed the sequencing data of a 224-gene retinopathy panel from 556 patients (513 families) with inherited retinal dystrophies. Five patients with p.Phe83Leu and seven with p.Gly187Glu were selected and their families investigated. To comprehend the pathogenicity of these variants, we evaluated them based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) classification guidelines. Initially, these RPE65 variants met only three pathogenic criteria: (i) absence or low frequency in the population, (ii) several missense pathogenic RPE65 variants, and (iii) 15 out of 16 lines of computational evidence supporting them as damaging, which together allowed the variants to be classified as uncertain significance. Two other pieces of evidence were accepted after further analysis of these Brazilian families: (i) p.Phe83Leu and p.Gly187Glu segregate with childhood retinal dystrophy within families, and (ii) their prevalence in Leber congenital amaurosis (LCA)/early-onset retinal dystrophy (EORD) patients can be considered higher than in other inherited retinal dystrophy patients. Therefore, these variants can now be classified as likely pathogenic according to ACMG/AMP classification guidelines.

A novel Kir7.1 splice variant expressed in various mouse tissues shares organisational and functional properties with human Leber amaurosis-causing mutations of this K+ channel.

Kir7.1 is an inwardly rectifying K+ channel present in epithelia where it shares membrane localization with the Na+/K+-pump. In the present communication we report the presence of a novel splice variant of Kir7.1 in mouse tissues including kidney, lung, choroid plexus and retinal pigment epithelium (RPE). The variant named mKir7.1-SV2 lacks most of the C-terminus domain but is predicted to have the two transmembrane domains and permeation pathway unaffected. Similarly truncated predicted proteins, Kir7.1-R166X and Kir7.1-Q219X, would arise from mutations associated with Leber Congenital Amaurosis, a rare recessive hereditary retinal disease that results in vision loss at early age. We found that mKir7.1-SV2 and the pathological variants do not produce any channel activity when expressed alone in HEK-293 cells due to their scarce presence in the plasma membrane. Simultaneous expression with the full length Kir7.1 however leads to a reduction in activity of the wild-type channel that might be due to partial proteasome degradation of WT-mutant channel heteromers.

A high prevalence of biallelic RPE65 mutations in Costa Rican children with Leber congenital amaurosis and early-onset retinal dystrophy.

BACKGROUND: Leber congenital amaurosis (LCA) and early-onset retinal dystrophy (EORD), are primary causes of inherited childhood blindness. Both are autosomal recessive diseases, with mutations in more than 25 genes explaining approximately ~70% of cases. However, the genetic cause for many cases remains unclear. Sequencing studies from genetically isolated populations with increased prevalence of a disorder has proven useful for rare variant studies, making Costa Rica an ideal place to study LCA/EORD genetics. MATERIALS AND METHODS: Twenty-eight affected children (25 LCA, three EORD) and their immediate family members, totaling 52 individuals (30 affected) from 22 families, were sequenced. Whole exome sequencing was performed on all affected individuals. Available parents were analyzed either by whole exome sequencing (WES) or Sanger sequencing to determine transmission. RESULTS: All affected individuals demonstrated compound heterozygous or homozygous mutations in known Inherited Retinal Disease (IRD) associated genes. Twelve variants were identified in at least one individual in three genes, RDH12, RPE65, and USH2A. Four recurrent RPE65 mutations were observed in 97% of individuals and 95% of families. All patients with LCA and two of the three individuals with EORD had biallelic mutations in RPE65; one child with EORD had a homozygous RDH12 mutation. CONCLUSIONS: These data suggest that the majority of LCA/EORD in Costa Rica is due to four founder mutations in RPE65 which have been maintained in this genetically isolated population. This finding is of great clinical significance due to the availability of gene therapy recently approved in the US and European Union for patients with biallelic RPE65 defects.

Amaurosis and contralateral cranial nerve pairs III and VI paralysis after peribulbar block - Case report / Amaurose e paralisia do III e do VI pares cranianos contralaterais após bloqueio peribulbar - relato de caso

Abstract Background and objectives: Peribulbar anesthesia has emerged as a safer option compared with intraconal retrobulbar block. Still, peribulbar anesthesia may not be considered without risk. Numerous complications have been described when performing this technique. This report aims to describe a rare case of amaurosis and contralateral paralysis while attempting to perform a peribulbar anesthesia. Case report: Male patient, 75-year old, physical status ASA II, undergoing cataract surgery by phacoemulsification with intraocular lens implantation. Sedated with fentanyl and midazolam and subjected to peribulbar anesthesia. There were no complications during surgery. After finishing the procedure, the patient reported lack of vision in the contralateral eye. Akinesia of the muscles innervated by the cranial nerve pairs III and VI, ptosis, and medium-sized pupils unresponsive to light stimulus were observed. Four hours after anesthesia, complete recovery of vision and eyelid and eyeball movements was seen in the non-operated eye. Conclusions: During peribulbar anesthesia, structures located in the intraconal space can be accidentally hit leading to complications such as described in the above report. Following the technical guidelines and using appropriate size needles may reduce the risk of such complication, but not completely.

Resumo Justificativa e objetivos: A anestesia peribulbar surgiu como uma opção mais segura quando comparada com o bloqueio retrobulbar intraconal. Ainda assim, a anestesia peribulbar não pode ser considerada isenta de riscos. Inúmeras complicações foram descritas quando da aplicação dessa técnica. O presente relato tem como objetivo descrever um caso raro caracterizado por amaurose e paralisia contralaterais quando da tentativa de se fazer a anestesia peribulbar. Relato de caso: Paciente masculino, 75 anos, estado físico ASA II, submetido à facectomia por facoemulsificação com implante de lente intraocular. Sedado com fentanil e midazolam e submetido a APB. Não houve intercorrências durante a cirurgia. Após o término do procedimento o paciente relatou ausência de visão no olho contralateral. Foram observadas acinesia da musculatura inervada pelo III e VI pares cranianos, ptose palpebral e pupilas de tamanho médio, não responsivas ao estímulo luminoso. Após quatro horas da anestesia, houve recuperação completa da visão, da movimentação das pálpebras e do globo ocular não operado. Conclusões: Durante a APB, estruturas localizadas no espaço intraconal podem ser atingidas acidentalmente levando a complicações como a descrita no relato acima. O respeito às diretrizes técnicas e o uso de agulhas com o tamanho adequado podem reduzir o risco de tal complicação, mas não de forma completa.

[Amaurosis and contralateral cranial nerve pairs III and VI paralysis after peribulbar block - case report]. / Amaurose e paralisia do III e do VI pares cranianos contralaterais após bloqueio peribulbar ­ relato de caso.

BACKGROUND AND OBJECTIVES: Peribulbar anesthesia has emerged as a safer option compared with intraconal retrobulbar block. Still, peribulbar anesthesia may not be considered without risk. Numerous complications have been described when performing this technique. This report aims to describe a rare case of amaurosis and contralateral paralysis while attempting to perform a peribulbar anesthesia. CASE REPORT: Male patient, 75-year old, physical status ASA II, undergoing cataract surgery by phacoemulsification with intraocular lens implantation. Sedated with fentanyl and midazolam and subjected to peribulbar anesthesia. There were no complications during surgery. After finishing the procedure, the patient reported lack of vision in the contralateral eye. Akinesia of the muscles innervated by the cranial nerve pairs III and VI, ptosis, and medium-sized pupils unresponsive to light stimulus were observed. Four hours after anesthesia, complete recovery of vision and eyelid and eyeball movements was seen in the non-operated eye. CONCLUSIONS: During peribulbar anesthesia, structures located in the intraconal space can be accidentally hit leading to complications such as described in the above report. Following the technical guidelines and using appropriate size needles may reduce the risk of such complication, but not completely.

Molecular Screening of 43 Brazilian Families Diagnosed with Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy.

Leber congenital amaurosis (LCA) is a severe disease that leads to complete blindness in children, typically before the first year of life. Due to the clinical and genetic heterogeneity among LCA and other retinal diseases, providing patients with a molecular diagnosis is essential to assigning an accurate clinical diagnosis. Using our gene panel that targets 300 genes that are known to cause retinal disease, including 24 genes reported to cause LCA, we sequenced 43 unrelated probands with Brazilian ancestry. We identified 42 unique variants and were able to assign a molecular diagnosis to 30/43 (70%) Brazilian patients. Among these, 30 patients were initially diagnosed with LCA or a form of early-onset retinal dystrophy, 17 patients harbored mutations in LCA-associated genes, while 13 patients had mutations in genes that were reported to cause other diseases involving the retina.

Charles Miller Fisher: the 65th anniversary of the publication of his groundbreaking study "Transient Monocular Blindness Associated with Hemiplegia" / Charles Miller Fisher: 65 anos da publicação de seu estudo inovador "Cegueira monocular transitória associada com hemiplegia"

ABSTRACT Charles Miller Fisher is considered the father of modern vascular neurology and one of the giants of neurology in the 20th century. This historical review emphasizes Prof. Fisher's magnificent contribution to vascular neurology and celebrates the 65th anniversary of the publication of his groundbreaking study, "Transient Monocular Blindness Associated with Hemiplegia."

RESUMO Charles Miller Fisher é considerado o pai da neurologia vascular moderna, e um dos gigantes da neurologia no século XX. Esta revisão histórica enfatiza a magnífica contribuição de Miller Fisher na neurologia vascular, particularmente com a celebração dos 65 anos de publicação do seu estudo inovador intitulado "Cegueira monocular transitória associada com hemiplegia".

Amaurosis congénita de Leber RPE-65, seguimiento a 7 años.

Leber congenital amaurosis is a retinal dystrophy with several forms of presentation due to its genetic variability. Case of a female girl followed up from 4 to 11 years old is presented, with positive clinical data of nyctalopia, myopia and choroid ocular fundus. Electroretinogram was not measurable in all phases but diagnostic was confirmed by RPE65 mutation genetic study. RPE65 Leber congenital amaurosis is particularly important as it has been researched for a gene therapy treatment with good functional outcomes up to now, awaiting to offer hope and a better quality of life to people with this disease.