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BACKGROUND: Brain activation to motor commands is seen in 15% of clinically unresponsive patients with acute brain injury. This state called cognitive motor dissociation (CMD) is detectable by electroencephalogram (EEG) or functional magnetic resonance imaging, predicts long-term recovery, and is recommended by recent guidelines to support prognostication. However, false negative CMD results are a particular concern, and occult aphasia in clinically unresponsive patients may be a major factor. This study aimed to quantify the impact of aphasia on CMD testing. METHODS: We prospectively studied 61 intensive care unit patients admitted with acute primary intracerebral hemorrhage (ICH) who had behavioral evidence of command following or were able to mimic motor commands. All patients underwent an EEG-based motor command paradigm used to detect CMD and comprehensive aphasia assessments. Logistic regression was used to identify predictors of brain activation, including aphasia types and associations with recovery of independence (Glasgow Outcome Scale-Extended score ≥ 4). RESULTS: Of 61 patients, 50 completed aphasia and the EEG-based motor command paradigm. A total of 72% (n = 36) were diagnosed with aphasia. Patients with impaired comprehension (i.e., receptive or global aphasia) were less likely to show brain activation than those with intact comprehension (odds ratio [OR] 0.23 [95% confidence interval 0.05-0.89], p = 0.04). Brain activation was independently associated with Glasgow Outcome Scale-Extended ≥ 4 by 12 months (OR 2.4 [95% confidence interval 1.2-5.0], p = 0.01) accounting for the Functional Outcome in Patients with Primary ICH score (OR1.3 [95% confidence interval 1.0-1.8], p = 0.01). CONCLUSIONS: Brain activation to motor commands is four times less likely for patients with primary ICH with impaired comprehension. False negative results due to occult receptive aphasia need to be considered when interpreting CMD testing. Early detection of brain activation may help predict long-term recovery in conscious patients with ICH.
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Modern advances in disease genetics have uncovered numerous modifier genes that play a role in the severity of disease expression. One such class of genetic conditions is known as inherited retinal degenerations (IRDs), a collection of retinal degenerative disorders caused by mutations in over 300 genes. A single missense mutation (K42E) in the gene encoding the enzyme dehydrodolichyl diphosphate synthase (DHDDS), which is required for protein N-glycosylation in all cells and tissues, causes DHDDS-IRD (retinitis pigmentosa type 59 (RP59; OMIM #613861)). Apart from a retinal phenotype, however, DHDDS-IRD is surprisingly non-syndromic (i.e., without any systemic manifestations). To explore disease pathology, we selected five glycosylation-related genes for analysis that are suggested to have disease modifier variants. These genes encode glycosyltransferases (ALG6, ALG8), an ER resident protein (DDOST), a high-mannose oligosaccharyl transferase (MPDU1), and a protein N-glycosylation regulatory protein (TNKS). DNA samples from 11 confirmed DHDDS (K42E)-IRD patients were sequenced at the site of each candidate genetic modifier. Quantitative measures of retinal structure and function were performed across five decades of life by evaluating foveal photoreceptor thickness, visual acuity, foveal sensitivity, macular and extramacular rod sensitivity, and kinetic visual field extent. The ALG6 variant, (F304S), was correlated with greater macular cone disease severity and less peripheral rod disease severity. Thus, modifier gene polymorphisms may account for a significant portion of phenotypic variation observed in human genetic disease. However, the consequences of the polymorphisms may be counterintuitively complex in terms of rod and cone populations affected in different regions of the retina.
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Alquil e Aril Transferases , Glucosiltransferases , Proteínas de Membrana , Degeneração Retiniana , Humanos , Genes Modificadores , Glucosiltransferases/genética , Proteínas de Membrana/genética , Mutação , Retina , Degeneração Retiniana/genéticaRESUMO
Purpose: An intravitreally injected antisense oligonucleotide, sepofarsen, was designed to modulate splicing within retinas of patients with severe vision loss due to deep intronic c.2991 + 1655A > G variant in the CEP290 gene. A previous report showed vision improvements following a single injection in one eye with unexpected durability lasting at least 15 months. The current study evaluated durability of efficacy beyond 15 months in the previously treated left eye. In addition, peak efficacy and durability were evaluated in the treatment-naive right eye, and re-injection of the left eye 4 years after the first injection. Observations: Visual function was evaluated with best corrected standard and low-luminance visual acuities, microperimetry, dark-adapted chromatic perimetry, and full-field sensitivity testing. Retinal structure was evaluated with OCT imaging. At the fovea, all visual function measures and IS/OS intensity of the OCT showed transient improvements peaking at 3-6 months, remaining better than baseline at â¼2 years, and returning to baseline by 3-4 years after each single injection. Conclusions and Importance: These results suggest that sepofarsen reinjection intervals may need to be longer than 2 years.
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Ciliopathies manifest from sensory abnormalities to syndromic disorders with multi-organ pathologies, with retinal degeneration a highly penetrant phenotype. Photoreceptor cell death is a major cause of incurable blindness in retinal ciliopathies. To identify drug candidates to maintain photoreceptor survival, we performed an unbiased, high-throughput screening of over 6000 bioactive small molecules using retinal organoids differentiated from induced pluripotent stem cells (iPSC) of rd16 mouse, which is a model of Leber congenital amaurosis (LCA) type 10 caused by mutations in the cilia-centrosomal gene CEP290. We identified five non-toxic positive hits, including the lead molecule reserpine, which maintained photoreceptor development and survival in rd16 organoids. Reserpine also improved photoreceptors in retinal organoids derived from induced pluripotent stem cells of LCA10 patients and in rd16 mouse retina in vivo. Reserpine-treated patient organoids revealed modulation of signaling pathways related to cell survival/death, metabolism, and proteostasis. Further investigation uncovered dysregulation of autophagy associated with compromised primary cilium biogenesis in patient organoids and rd16 mouse retina. Reserpine partially restored the balance between autophagy and the ubiquitin-proteasome system at least in part by increasing the cargo adaptor p62, resulting in improved primary cilium assembly. Our study identifies effective drug candidates in preclinical studies of CEP290 retinal ciliopathies through cross-species drug discovery using iPSC-derived organoids, highlights the impact of proteostasis in the pathogenesis of ciliopathies, and provides new insights for treatments of retinal neurodegeneration.
Leber congenital amaurosis (LCA) is an inherited disease that affects the eyes and causes sight loss in early childhood, which generally gets worse over time. Individuals with this condition have genetic mutations that result in the death of light-sensitive cells, known as photoreceptors, in a region called the retina at the back of the eye. Patients carrying a genetic change in the gene CEP290 account for 20-25% of all LCA. At present, treatment options are only available for a limited number of patients with LCA. One option is to use small molecules as drugs that may target or bypass the faulty processes within the eye to help the photoreceptors survive in many different forms of LCA and other retinal diseases. However, over 90% of new drug candidates fail the first phase of clinical trials for human diseases. This in part due to the candidates having been developed using cell cultures or animal models that do not faithfully reflect how the human body works. Recent advances in cell and developmental biology are now enabling researchers to use stem cells derived from humans to grow retina tissues in a dish in the laboratory. These tissues, known as retinal organoids, behave in a more similar way to retinas in human eyes than those of traditional animal models. However, the methods for making and maintaining human retinal organoids are time-consuming and labor-intensive, which has so far limited their use in the search for new therapies. To address this challenge, Chen et al. developed a large-scale approach to grow retinal organoids from rd16 mutant mice stem cells (which are a good model for LCA caused by mutations to CEP290) and used the photoreceptors from these organoids to screen over 6,000 existing drugs for their ability to promote the survival of photoreceptors. The experiments found that the drug reserpine, which was previously approved to treat high blood pressure, also helped photoreceptors to survive in the diseased organoids. Reserpine also had a similar effect in retinal organoids derived from human patients with LCA and in the rd16 mice themselves. Further experiments suggest that reserpine may help patients with LCA by partially restoring a process by which the body destroys and recycles old and damaged proteins in the cells. The next steps following on from this work will be to perform further tests to demonstrate that this use of reserpine is safe to enter clinical trials as a treatment for LCA and other similar eye diseases.
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Ciliopatias , Reserpina , Camundongos , Animais , Reserpina/farmacologia , Reserpina/metabolismo , Proteostase , Antígenos de Neoplasias/genética , Proteínas do Citoesqueleto/metabolismo , Retina/metabolismo , Células Fotorreceptoras/metabolismo , Ciliopatias/tratamento farmacológico , Ciliopatias/genética , Ciliopatias/metabolismoRESUMO
Purpose: Blue cone monochromacy (BCM) is an X-linked retinopathy due to mutations in the OPN1LW/OPN1MW gene cluster. Symptoms include reduced visual acuity and disturbed color vision. We studied BCM color vision to determine outcome measures for future clinical trials. Methods: Patients with BCM and normal-vision participants were examined with Farnsworth-Munsell (FM) arrangement tests and the Color Assessment and Diagnosis (CAD) test. A retrospective case series in 36 patients with BCM (ages 6-70) was performed with the FM D-15 test. A subset of six patients also had Roth-28 Hue and CAD tests. Results: All patients with BCM had abnormal results for D-15, Roth-28, and CAD tests. With D-15, there was protan-deutan confusion and no bimodal tendency. Roth-28 results reinforced that finding. There was symmetry in color vision metrics between the two eyes and coherence between sessions with the arrangement tests and CAD. Severe abnormalities in red-green sensitivity with CAD were expected. Unexpected were different levels of yellow-blue results with two patterns of abnormal thresholds: moderate elevation in two younger patients and severe elevation in four patients ≥35 years. Coefficients of repeatability and intersession means were tabulated for all test modalities. Conclusions: Given understanding of advantages, disadvantages, and complexities of interpretation of results, both an arrangement test and CAD should be useful monitors of color vision through a clinical trial in BCM. Translational Relevance: Our pilot studies in BCM of arrangement and CAD tests indicated both were clinically feasible and interpretable in the context of this cone gene disease.
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Defeitos da Visão Cromática , Visão de Cores , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Defeitos da Visão Cromática/diagnóstico , Defeitos da Visão Cromática/genética , Avaliação de Resultados em Cuidados de SaúdeRESUMO
The only approved retinal gene therapy is for biallelic RPE65 mutations which cause a recessive retinopathy with a primary molecular defect located at the retinal pigment epithelium (RPE). For a distinct recessive RPE disease caused by biallelic BEST1 mutations, a pre-clinical proof-of-concept for gene therapy has been demonstrated in canine eyes. The current study was undertaken to consider potential outcome measures for a BEST1 clinical trial in patients demonstrating a classic autosomal recessive bestrophinopathy (ARB) phenotype. Spatial distribution of retinal structure showed a wide expanse of abnormalities including large intraretinal cysts, shallow serous retinal detachments, abnormalities of inner and outer segments, and an unusual prominence of the external limiting membrane. Surrounding the central macula extending from 7 to 30 deg eccentricity, outer nuclear layer was thicker than expected from a cone only retina and implied survival of many rod photoreceptors. Co-localized however, were large losses of rod sensitivity despite preserved cone sensitivities. The dissociation of rod function from rod structure observed, supports a large treatment potential in the paramacular region for biallelic bestrophinopathies.
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Bestrofinas , Degeneração Retiniana , Animais , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina , Bestrofinas/genética , Mutação , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/patologia , Degeneração Retiniana/genética , Degeneração Retiniana/terapia , HumanosRESUMO
Purpose: The purpose of this study was to evaluate rod and cone function and outer retinal structure within macular lesions, and surrounding extralesional areas of patients with autosomal dominant Best vitelliform macular dystrophy caused by BEST1 mutations. Methods: Seventeen patients from seven families were examined with dark- and light-adapted chromatic perimetry and optical coherence tomography. Subsets of patients had long-term follow-up (14-22 years, n = 6) and dark-adaptation kinetics measured (n = 5). Results: Within central lesions with large serous retinal detachments, rod sensitivity was severely reduced but visual acuity and cone sensitivity were relatively retained. In surrounding extralesional areas, there was a mild but detectable widening of the subretinal space in some patients and some retinal areas. Available evidence was consistent with subretinal widening causing slower dark-adaptation kinetics. Over long-term follow-up, some eyes showed formation of de novo satellite lesions at retinal locations that years previously demonstrated subretinal widening. A subclinical abnormality consisting of a retina-wide mild thickening of the outer nuclear layer was evident in many patients and thickening increased in the subset of patients with long-term follow-up. Conclusions: Outcome measures for future clinical trials should include evaluations of rod sensitivity within central lesions and quantitative measures of outer retinal structure in normal-appearing regions surrounding the lesions.
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Distrofia Macular Viteliforme , Humanos , Distrofia Macular Viteliforme/diagnóstico , Distrofia Macular Viteliforme/genética , Proteínas do Olho/genética , Tomografia de Coerência Óptica/métodos , Testes de Campo Visual , Mutação , Bestrofinas/genéticaRESUMO
Background and Objectives: There have been numerous reports of neurologic manifestations identified in hospitalized patients infected with SARS-CoV-2, the virus that causes COVID-19. Here, we identify the spectrum of associated neurologic symptoms and diagnoses, define the time course of their development, and examine readmission rates and mortality risk posthospitalization in a multiethnic urban cohort. Methods: We identify the occurrence of new neurologic diagnoses among patients with laboratory-confirmed SARS-CoV-2 infection in New York City. A retrospective cohort study was performed on 532 cases (hospitalized patients with new neurologic diagnoses within 6 weeks of positive SARS-CoV-2 laboratory results between March 1, 2020, and August 31, 2020). We compare demographic and clinical features of the 532 cases with 532 controls (hospitalized COVID-19 patients without neurologic diagnoses) in a case-control study with one-to-one matching and examine hospital-related data and outcomes of death and readmission up to 6 months after acute hospitalization in a secondary case-only analysis. Results: Among the 532 cases, the most common new neurologic diagnoses included encephalopathy (478, 89.8%), stroke (66, 12.4%), and seizures (38, 7.1%). In the case-control study, cases were more likely than controls to be male (58.6% vs 52.8%, p = 0.05), had baseline neurologic comorbidities (36.3% vs 13.0%, p < 0.0001), and were to be treated in an intensive care unit (62.0% vs 9.6%, p < 0.0001). Of the 394 (74.1%) cases who survived acute hospitalization, more than half (220 of 394, 55.8%) were readmitted within 6 months, with a mortality rate of 23.2% during readmission. Discussion: Hospitalized patients with SARS-CoV-2 and new neurologic diagnoses have significant morbidity and mortality postdischarge. Further research is needed to define the effect of neurologic diagnoses during acute hospitalization on longitudinal post-COVID-19-related symptoms including neurocognitive impairment.
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Signaling of vision to the brain starts with the retinal phototransduction cascade which converts visible light from the environment into chemical changes. Vision impairment results when mutations inactivate proteins of the phototransduction cascade. A severe monogenically inherited blindness, Leber congenital amaurosis (LCA), is caused by mutations in the GUCY2D gene, leading to a molecular defect in the production of cyclic GMP, the second messenger of phototransduction. We studied two patients with GUCY2D-LCA who were undergoing gene augmentation therapy. Both patients had large deficits in rod photoreceptor-based night vision before intervention. Within days of therapy, rod vision in both patients changed dramatically; improvements in visual function and functional vision in these hyper-responding patients reached more than 3 log10 units (1000-fold), nearing healthy rod vision. Quick activation of the complex molecular pathways from retinal photoreceptor to visual cortex and behavior is thus possible in patients even after being disabled and dormant for decades.
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Purpose: To understand consequences of reconstituting cone photoreceptor function in congenital binocular blindness resulting from mutations in the centrosomal protein 290 (CEP290) gene. Design: Phase 1b/2 open-label, multicenter, multiple-dose, dose-escalation trial. Participants: A homogeneous subgroup of 5 participants with light perception (LP) vision at the time of enrollment (age range, 15-41 years) selected for detailed analyses. Medical histories of 4 participants were consistent with congenital binocular blindness, whereas 1 participant showed evidence of spatial vision in early life that was later lost. Intervention: Participants received a single intravitreal injection of sepofarsen (160 or 320 µg) into the study eye. Main Outcome Measures: Full-field stimulus testing (FST), visual acuity (VA), and transient pupillary light reflex (TPLR) were measured at baseline and for 3 months after the injection. Results: All 5 participants with LP vision demonstrated severely abnormal FST and TPLR findings. At baseline, FST threshold estimates were 0.81 and 1.0 log cd/m2 for control and study eyes, respectively. At 3 months, study eyes showed a large mean improvement of -1.75 log versus baseline (P < 0.001), whereas untreated control eyes were comparable with baseline. Blue minus red FST values were not different than 0 (P = 0.59), compatible with cone mediation of remnant vision. At baseline, TPLR response amplitude and latency estimates were 0.39 mm and 0.72 seconds, respectively, for control eyes, and 0.28 mm and 0.78 seconds, respectively, for study eyes. At 3 months, study eyes showed a mean improvement of 0.44 mm in amplitude and a mean acceleration of 0.29 seconds in latency versus baseline (P < 0.001), whereas control eyes showed no significant change versus baseline. Specialized tests performed in 1 participant confirmed and extended the standardized results from all 5 participants. Conclusions: By subjective and objective evidence, intravitreal sepofarsen provides improvement of light sensitivity for individuals with LP vision. However, translation of increased light sensitivity to improved spatial vision may occur preferentially in those with a history of visual experience during early neurodevelopment. Interventions for congenital lack of spatial vision in CEP290-associated Leber congenital amaurosis may lead to better results if performed before visual cortex maturity.
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BACKGROUND: Inherited retinal degenerations (IRDs) affect daylight and night vision to different degrees. In the current work, we devise a method to quantify mobility under dark-adapted conditions in patients with severe childhood blindness due to Leber congenital amaurosis (LCA). Mobility thresholds from two different LCA genotypes are compared to dark-adapted vision measurements using the full-field stimulus test (FST), a conventional desktop outcome measure of rod vision. METHODS: A device consisting of vertical LED strips on a plane resembling a beaded curtain was programmed to produce a rectangular pattern target defining a 'door' of varying luminance that could appear at one of three positions. Mobility performance was evaluated by letting the subject walk from a fixed starting position ~ 4 m away from the device with instructions to touch the door. Success was defined as the subject touching within the 'door' area. Ten runs were performed and the process was repeated for different levels of luminance. Tests were performed monocularly in dark-adapted and dilated eyes. Results from LCA patients with the GUCY2D and CEP290 genotypes and normal subjects were analyzed using logistic regression to estimate the mobility threshold for successful navigation. The relation of thresholds for mobility, FST and visual acuity were quantified using linear regression. RESULTS: Normal subjects had mobility thresholds near limits of dark-adapted rod vision. GUCY2D-LCA patients had a wide range of mobility thresholds from within 1 log of normal to greater than 8 log abnormal. CEP290-LCA patients had abnormal mobility thresholds that were between 5 and 6 log from normal. Sensitivity loss estimates using FST related linearly to the mobility thresholds which were not correlated with visual acuity. CONCLUSIONS: The mobility task we developed can quantify functional vision in severely disabled patients with LCA. Taken together with other outcome measures of rod and cone photoreceptor-mediated vision, dark-adapted functional vision should provide a more complete understanding of the natural history and effects of treatment in patients with LCA.
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Amaurose Congênita de Leber , Degeneração Retiniana , Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular/genética , Criança , Proteínas do Citoesqueleto/genética , Adaptação à Escuridão , Humanos , Amaurose Congênita de Leber/diagnóstico , Amaurose Congênita de Leber/genética , Mutação , Células Fotorreceptoras Retinianas Cones , Visão OcularRESUMO
Blue cone monochromacy (BCM) is an X-linked retinal disorder characterized by low vision, photoaversion, and poor color discrimination. BCM is due to the lack of long-wavelength-sensitive and middle-wavelength-sensitive cone photoreceptor function and caused by mutations in the OPN1LW/OPN1MW gene cluster on Xq28. Here, we investigated the prevalence and the landscape of submicroscopic structural variants (SVs) at single-base resolution in BCM patients. We found that about one-third (n = 73) of the 213 molecularly confirmed BCM families carry an SV, most commonly deletions restricted to the OPN1LW/OPN1MW gene cluster. The structure and precise breakpoints of the SVs were resolved in all but one of the 73 families. Twenty-two families-all from the United States-showed the same SV, and we confirmed a common ancestry of this mutation. In total, 42 distinct SVs were identified, including 40 previously unreported SVs, thereby quadrupling the number of precisely mapped SVs underlying BCM. Notably, there was no "region of overlap" among these SVs. However, 90% of SVs encompass the upstream locus control region, an essential enhancer element. Its minimal functional extent based on deletion mapping in patients was refined to 358 bp. Breakpoint analyses suggest diverse mechanisms underlying SV formation as well as in one case the gene conversion-based exchange of a 142-bp deletion between opsin genes. Using parsimonious assumptions, we reconstructed the composition and copy number of the OPN1LW/OPN1MW gene cluster prior to the mutation event and found evidence that large gene arrays may be predisposed to the occurrence of SVs at this locus.
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Defeitos da Visão Cromática , Opsinas de Bastonetes , Defeitos da Visão Cromática/genética , Deleção de Genes , Humanos , Família Multigênica/genética , Células Fotorreceptoras Retinianas Cones , Opsinas de Bastonetes/genéticaRESUMO
CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 ( NCT03140969 ), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit-risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development.
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Amaurose Congênita de Leber , Adulto , Antígenos de Neoplasias/genética , Cegueira/genética , Proteínas de Ciclo Celular/genética , Criança , Proteínas do Citoesqueleto/metabolismo , Humanos , Amaurose Congênita de Leber/tratamento farmacológico , Amaurose Congênita de Leber/genética , Oligonucleotídeos Antissenso/efeitos adversos , Visão OcularRESUMO
Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing" variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as "likely disease-causing" according to ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.
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Defeitos da Visão Cromática , Canais de Cátion Regulados por Nucleotídeos Cíclicos , Defeitos da Visão Cromática/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Humanos , Mutação , Células Fotorreceptoras Retinianas ConesRESUMO
Disease mechanisms have become better understood in previously incurable forms of early-onset severe retinal dystrophy, such as Leber congenital amaurosis (LCA). This has led to novel treatments and clinical trials that have shown some success. Standard methods to measure vision were difficult if not impossible to perform in severely affected patients with low vision and nystagmus. To meet the need for visual assays, we devised a psychophysical method, which we named full-field stimulus testing (FST). From early versions based on an automated perimeter, we advanced FST to a more available light-emitting diode platform. The journey from invention to use of such a technique in our inherited retinal degeneration clinic is reviewed and many of the lessons learned over the 15 years of application of FST are explained. Although the original purpose and application of FST was to quantify visual thresholds in LCA, there are rare opportunities for FST also to be used beyond LCA to measure aspects of vision in other inherited retinal degenerations; examples are given. The main goal of the current review, however, remains to enable investigators studying and treating LCA to understand how to best use FST and how to reduce artefact and confounding complexities so the test results become more valuable to the understanding of LCA diseases and results of novel interventions.
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Oftalmopatias Hereditárias , Amaurose Congênita de Leber , Distrofias Retinianas , Criança , Humanos , Amaurose Congênita de Leber/diagnóstico , Amaurose Congênita de Leber/genética , Amaurose Congênita de Leber/terapia , Mutação , Avaliação de Resultados em Cuidados de Saúde , RetinaRESUMO
Purpose: The purpose of this study was to compare the natural history of visual function change in cohorts of patients affected with retinal degeneration due to biallelic variants in Bardet-Biedl syndrome genes: BBS1 and BBS10. Methods: Patients were recruited from nine academic centers from six countries (Belgium, Canada, France, New Zealand, Switzerland, and the United States). Inclusion criteria were: (1) female or male patients with a clinical diagnosis of retinal dystrophy, (2) biallelic disease-causing variants in BBS1 or BBS10, and (3) measures of visual function for at least one visit. Retrospective data collected included genotypes, age, onset of symptoms, and best corrected visual acuity (VA). When possible, data on refractive error, fundus images and autofluorescence (FAF), optical coherence tomography (OCT), Goldmann kinetic perimetry (VF), electroretinography (ERG), and the systemic phenotype were collected. Results: Sixty-seven individuals had variants in BBS1 (n = 38; 20 female patients and 18 male patients); or BBS10 (n = 29; 14 female patients and 15 male patients). Missense variants were the most common type of variants for patients with BBS1, whereas frameshift variants were most common for BBS10. When ERGs were recordable, rod-cone dystrophy (RCD) was observed in 82% (23/28) of patients with BBS1 and 73% (8/11) of patients with BBS10; cone-rod dystrophy (CORD) was seen in 18% of patients with BBS1 only, and cone dystrophy (COD) was only seen in 3 patients with BBS10 (27%). ERGs were nondetectable earlier in patients with BBS10 than in patients with BBS1. Similarly, VA and VF declined more rapidly in patients with BBS10 compared to patients with BBS1. Conclusions: Retinal degeneration appears earlier and is more severe in BBS10 cases as compared to those with BBS1 variants. The course of change of visual function appears to relate to genetic subtypes of BBS.
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Chaperoninas/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação de Sentido Incorreto/genética , Distrofias Retinianas/fisiopatologia , Acuidade Visual/fisiologia , Adolescente , Adulto , Síndrome de Bardet-Biedl/genética , Síndrome de Bardet-Biedl/fisiopatologia , Criança , Pré-Escolar , Eletrorretinografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Óptica , Refração Ocular/fisiologia , Retina/fisiopatologia , Distrofias Retinianas/genética , Estudos Retrospectivos , Tomografia de Coerência Óptica , Testes de Campo Visual , Campos Visuais/fisiologiaRESUMO
Purpose: To investigate the validity and reliability of macular rod photoreceptor function measurement with a microperimeter. Methods: Macular sensitivity in dark-adapted retinitis pigmentosa (RP) patients (22 eyes; 9-67 years of age) and controls (five eyes; 22-55 years of age) was assessed with a modified Humphrey field analyzer (mHFA), as well as a scotopic microperimeter (Nidek MP-1S). Sensitivity loss (SL) was estimated at rod-mediated locations. All RP eyes were re-evaluated at a second visit 6 months later. The dynamic range of the MP-1S was expanded with a range of neutral-density filters (NDFs). Results: In controls, a 4 NDF was used at all macular locations tested. In patients with RP, 0 to 3 NDFs were used, depending on the local disease severity. At rod-mediated locations (n = 281), SL estimates obtained with the MP-1S were highly correlated (r = 0.80) with those of the mHFA. The inter-perimeter difference of SL averaged less than 3 decibels (dB) with all NDFs, except those with most severe locations evaluated with a 0 NDF, where the difference averaged more than 6 dB. The results were similar on the second visit. Conclusions: The MP-1S estimates of SL are highly correlated with those of the mHFA over a wide range of disease severity replicated at two visits; however, there was an unexplained bias in the magnitude of SL estimated by the MP-1S especially at loci with severe disease. Translational Relevance: MP-1S scotopic microperimetry can be used to evaluate changes to macular rod function, but evaluation of treatment potential by quantitative comparison of SL to retinal structure will be more challenging.
Assuntos
Retinose Pigmentar , Testes de Campo Visual , Humanos , Reprodutibilidade dos Testes , Retina , Retinose Pigmentar/diagnósticoRESUMO
Despite major progress in the discovery of causative genes, many individuals and families with inherited retinal degenerations (IRDs) remain without a molecular diagnosis. We applied whole exome sequencing to identify the genetic cause in a family with an autosomal dominant IRD. Eye examinations were performed and affected patients were studied with electroretinography and kinetic and chromatic static perimetry. Sequence variants were analyzed in genes (n = 271) associated with IRDs listed on the RetNet database. We applied a stepwise filtering process involving the allele frequency in the control population, in silico prediction tools for pathogenicity, and evolutionary conservation to prioritize the potential causal variant(s). Sanger sequencing and segregation analysis were performed on the proband and other family members. The IRD in this family is expressed as a widespread progressive retinal degeneration with maculopathy. A novel heterozygous variant (c.200A > T) was identified in the ARL3 gene, leading to the substitution of aspartic acid to valine at position 67. The Asp67 residue is evolutionary conserved, and the change p.Asp67Val is predicted to be pathogenic. This variant was segregated in affected members of the family and was absent from an unaffected individual. Two previous reports of a de novo missense mutation in the ARL3 gene, each describing a family with two affected generations, are the only examples to date of autosomal dominant IRD associated with this photoreceptor gene. Our results, identifying a novel pathogenic variant in ARL3 in a four-generation family with a dominant IRD, augment the evidence that the ARL3 gene is another cause of non-syndromic retinal degeneration.
RESUMO
Inherited retinal diseases (IRDs) are at the forefront of innovative gene-specific treatments because of the causation by single genes, the availability of microsurgical access for treatment delivery, and the relative ease of quantitative imaging and vision measurement. However, it is not always easy to choose a priori, from scores of potential measures, an appropriate subset to evaluate efficacy outcomes considering the wide range of disease stages with different phenotypic features. This article reviews measurements of visual function and retinal structure that our group has used over the past three decades to understand the natural history of IRDs. We include measures of light sensitivity, retinal structure, mapping of natural fluorophores, evaluation of pupillary light reflex, and oculomotor control. We provide historical context and examples of applicability. We also review treatment trial outcomes using these measures of function and structure.