RESUMO
Pathogenic variants in retinol dehydrogenase 5 (RDH5) attenuate supply of 11-cis-retinal to photoreceptors leading to a range of clinical phenotypes including night blindness because of markedly slowed rod dark adaptation and in some patients, macular atrophy. Current animal models (such as Rdh5-/- mice) fail to recapitulate the functional or degenerative phenotype. Addressing this need for a relevant animal model we present a new domestic cat model with a loss-of-function missense mutation in RDH5 (c.542G > T; p.Gly181Val). As with patients, affected cats have a marked delay in recovery of dark adaptation. In addition, the cats develop a degeneration of the area centralis (equivalent to the human macula). This recapitulates the development of macular atrophy that is reported in a subset of patients with RDH5 mutations and is shown in this paper in seven patients with biallelic RDH5 mutations. There is notable variability in the age at onset of the area centralis changes in the cat, with most developing changes as juveniles but some not showing changes over the first few years of age. There is similar variability in development of macular atrophy in patients and while age is a risk factor, it is hypothesized that genetic modifying loci influence disease severity, and we suspect the same is true in the cat model. This novel cat model provides opportunities to improve molecular understanding of macular atrophy and test therapeutic interventions for RDH5-associated retinopathies.
Assuntos
Degeneração Macular , Doenças Retinianas , Oxirredutases do Álcool/genética , Animais , Atrofia , Gatos , Eletrorretinografia , Humanos , Camundongos , Modelos Animais , Fenótipo , Doenças Retinianas/genéticaRESUMO
PURPOSE: Vitamin A plays a crucial role in rod phototransduction, with deficient levels manifesting as night blindness. Animal models have demonstrated bone dysplasia in the setting of hypovitaminosis A. We present a rare case of bony overgrowth leading to bilateral compressive optic neuropathy, combined with outer retinopathy, in a paediatric patient secondary to isolated vitamin A deficiency. METHODS: A single case report was conducted from Toronto, Canada. RESULTS: A 12-year-old boy with known autism spectrum disorder presented with a 9-month history of progressive painless vision loss. Vision was 20/300 and hand motion in the right and left eye, respectively. Fundus photography demonstrated bilateral optic atrophy and yellow lesions notably in the right eye far periphery. Optical coherence tomography (OCT) imaging demonstrated thinning of the retinal nerve fibre layer, alterations in the ellipsoid zone, as well as retinal pigment epithelium deposits. Computed tomography imaging demonstrated sphenoid bone thickening with narrow optic canals and moderate optic atrophy bilaterally. Full-field electroretinogram (ERG) demonstrated mildly reduced dark adapted (DA) 0.01 b-wave amplitudes and electronegative configuration of DA 3.0 and DA 10.0 ERG; the light adapted ERGs were normal. The patient was treated with pulse vitamin A therapy. Subsequently, the DA ERG normalized, outer retinal changes reversed and vision stabilised; no surgical intervention was conducted. CONCLUSION: This case represents a rare presentation of compressive optic neuropathy with concomitant outer retinopathy secondary to isolated vitamin A deficiency. Despite improvement in outer retinal integrity on OCT imaging and ERG testing results following vitamin A supplementation, no functional improvement was obtained due to severe optic atrophy.
Assuntos
Transtorno do Espectro Autista , Atrofia Óptica , Doenças do Nervo Óptico , Doenças Retinianas , Deficiência de Vitamina A , Animais , Vitamina A , Eletrorretinografia/métodos , Doenças do Nervo Óptico/diagnóstico , Doenças do Nervo Óptico/etiologia , Tomografia de Coerência Óptica/métodosRESUMO
Non-syndromic retinitis pigmentosa (NSRP) is a clinically and genetically heterogeneous group of disorders characterized by progressive degeneration of the rod and cone photoreceptors, often leading to blindness. The evolving association of syndromic genes to cause NSRP and the increasing role of intronic variants in explaining missing heritability in genetic disorders present challenges in establishing conclusive clinical and genetic diagnoses. This study sought to identify and validate the causative genetic variant(s) in a 13-year-old male initially diagnosed with NSRP. Genome sequencing identified a pathogenic missense variant in MVK [NM_000431.3:c.803T>C (p.Ile268Thr)], in trans with a novel intronic variant predicted to create a new donor splice site (c.768+71C>A). Proband cDNA analysis confirmed the inclusion of the first 68 base pairs of intron 8 that resulted in a frameshift in MVK (r.768_769ins[768+1_768+68]) and significantly reduced the expression of reference transcript (17.6%). Patient re-phenotyping revealed ataxia, cerebellar atrophy, elevated urinary mevalonate and LTE4 , in keeping with mild mevalonic aciduria and associated syndromic retinitis pigmentosa. Leakage of reference transcript likely explains the milder phenotype observed in our patient. This is the first association of a deep intronic splice variant to cause MVK-related disorder. This report highlights the importance of variant validation and patient re-phenotyping in establishing accurate diagnosis in the era of genome sequencing.
Assuntos
Deficiência de Mevalonato Quinase , Retinose Pigmentar , Masculino , Humanos , Deficiência de Mevalonato Quinase/genética , Linhagem , Retinose Pigmentar/genética , Mutação , ÍntronsRESUMO
Certain combinations of common variants in exon 3 of OPN1LW and OPN1MW, the genes encoding the apo-protein of the long- and middle-wavelength sensitive cone photoreceptor visual pigments in humans, induce splicing defects and have been associated with dyschromatopsia and cone dysfunction syndromes. Here we report the identification of a novel exon 3 haplotype, G-C-G-A-T-T-G-G (referring to nucleotide variants at cDNA positions c.453, c.457, c.465, c.511, c.513, c.521, c.532, and c.538) deduced to encode a pigment with the amino acid residues L-I-V-V-A at positions p.153, p.171, p.174, p.178, and p.180, in OPN1LW or OPN1MW or both in a series of seven patients from four families with cone dysfunction. Applying minigene assays for all observed exon 3 haplotypes in the patients, we demonstrated that the novel exon 3 haplotype L-I-V-V-A induces a strong but incomplete splicing defect with 3-5% of residual correctly spliced transcripts. Minigene splicing outcomes were similar in HEK293 cells and the human retinoblastoma cell line WERI-Rb1, the latter retaining a cone photoreceptor expression profile including endogenous OPN1LW and OPN1MW gene expression. Patients carrying the novel L-I-V-V-A haplotype presented with a mild form of Blue Cone Monochromacy or Bornholm Eye Disease-like phenotype with reduced visual acuity, reduced cone electroretinography responses, red-green color vision defects, and frequently with severe myopia.
Assuntos
Defeitos da Visão Cromática , Opsinas de Bastonetes/genética , Defeitos da Visão Cromática/genética , Defeitos da Visão Cromática/metabolismo , Éxons/genética , Células HEK293 , Haplótipos , Humanos , Células Fotorreceptoras Retinianas Cones/metabolismo , Opsinas de Bastonetes/metabolismoRESUMO
OBJECTIVE: To report the clinical and novel electrophysiological features in a child with POLG-related sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO). METHODS: The proband, a male child of Indian descent, underwent serial systemic and ophthalmological evaluations from birth until 14 years of age. Eye examinations included visual acuity and extraocular movement assessments, fundus photography, spectral domain optical coherence tomography and full-field electroretinography (ERG). Detailed genetic testing was also performed. RESULTS: The child carried a homozygous mutation in POLG (c.911T > G/p.Leu304Arg) and manifested systemic features such as seizures, headaches, areflexia, hypotonia, myopathy and vomiting. The child's distance visual acuity was 0.50 and 0.40 LogMAR in the right and left eyes, respectively. Bilateral ophthalmoplegia and ptosis were observed at 5 years of age. The dark-adapted (DA) ERG responses to 2.29 cd s m-2 and 7.6 cd s m-2 stimuli showed a markedly reduced b/a ratio; an electronegative configuration was noted to a DA 7.6 ERG. CONCLUSION: This is the first documented case of an electronegative ERG in a POLG-related disorder consistent with generalized rod ON-bipolar dysfunction. The rest of the proband's systemic and ophthalmological features were consistent with SANDO but some features overlapped with other POLG-related disorders such as Alpers-Huttenlocher syndrome and autosomal dominant progressive external ophthalmoplegia demonstrating the wide phenotypic overlap expected due to POLG mutations.
Assuntos
Doenças Retinianas , Células Fotorreceptoras Retinianas Bastonetes/patologia , Adolescente , DNA Polimerase gama/genética , Eletrorretinografia , Humanos , Masculino , Mutação , Tomografia de Coerência ÓpticaRESUMO
PURPOSE: Determining the role of DYNC2H1 variants in nonsyndromic inherited retinal disease (IRD). METHODS: Genome and exome sequencing were performed for five unrelated cases of IRD with no identified variant. In vitro assays were developed to validate the variants identified (fibroblast assay, induced pluripotent stem cell [iPSC] derived retinal organoids, and a dynein motility assay). RESULTS: Four novel DYNC2H1 variants (V1, g.103327020_103327021dup; V2, g.103055779A>T; V3, g.103112272C>G; V4, g.103070104A>C) and one previously reported variant (V5, g.103339363T>G) were identified. In proband 1 (V1/V2), V1 was predicted to introduce a premature termination codon (PTC), whereas V2 disrupted the exon 41 splice donor site causing incomplete skipping of exon 41. V1 and V2 impaired dynein-2 motility in vitro and perturbed IFT88 distribution within cilia. V3, homozygous in probands 2-4, is predicted to cause a PTC in a retina-predominant transcript. Analysis of retinal organoids showed that this new transcript expression increased with organoid differentiation. V4, a novel missense variant, was in trans with V5, previously associated with Jeune asphyxiating thoracic dystrophy (JATD). CONCLUSION: The DYNC2H1 variants discussed herein were either hypomorphic or affecting a retina-predominant transcript and caused nonsyndromic IRD. Dynein variants, specifically DYNC2H1 variants are reported as a cause of non syndromic IRD.
Assuntos
Síndrome de Ellis-Van Creveld , Degeneração Retiniana , Dineínas do Citoplasma/genética , Síndrome de Ellis-Van Creveld/genética , Éxons , Humanos , Mutação , Linhagem , Retina , Degeneração Retiniana/genéticaRESUMO
OBJECTIVE: To report a unique retinal signaling defect in GNB5-related disease. METHODS: A 3-year-old female child underwent detailed systemic and ophthalmological evaluation. The eye examination included fundus photography, spectral domain optical coherence tomography and an extended protocol full-field electroretinography (ERG) including the ISCEV recommended standard steps. The dark-adapted (DA) ERGs were performed to a series of white flashes (range 0.006-30.0 cd s m-2) and two red flashes. The DA ERGs to higher stimulus intensities (3.0, 10.0 and 30.0 cd s m-2) were tested using a range of inter-stimulus intervals (ISI) of up to 60 s. In addition to standard light-adapted (LA) ERGs, a short-duration (0.5 s) LA 3.0 30-Hz flicker ERG and a long-duration LA ON-OFF ERG were also performed. Genetic testing included microarray, mitochondrial genome testing and whole exome sequencing. RESULTS: The child was diagnosed to have status epilepticus and bradycardia at 6 months of age. Subsequently, she was diagnosed to have global developmental delay and hypotonia. On ophthalmological evaluation, the child fixes and follows light. Fundus evaluation showed mild optic disk pallor; macular SD-OCT was normal. The dim flash DA ERGs (DA 0.006 and DA 0.01 cd s m-2) were non-detectable. DA red flash ERGs showed the presence of an x-wave (cone component) and no rod component. The DA 3.0, 10.0 and 30.0 ERGs showed electronegative configuration regardless of the ISI; the averaged a-wave amplitude (4 flashes) was smaller at shorter ISI but became normal at a prolonged ISI (60 s). The LA 30-Hz flicker ERG was severely reduced but detectable for the initial 0.5 s; this became non-detectable after 5 s of averaging. The LA 3.0 2-Hz ERG showed markedly reduced a- and b-wave amplitudes and a reduced b:a ratio; the LA ON-OFF ERGs were non-detectable. WES identified a homozygous null mutation in G protein subunit beta 5 (GNB5; c.1032C>A/p.Tyr344*). CONCLUSION: This report identifies for the first time a unique retinopathy associated with biallelic mutations in GNB5. The observed phenotype is consistent with a dual retinal signaling defect reminiscent of features of bradyopsia and rod ON-bipolar dysfunction.
Assuntos
Subunidades beta da Proteína de Ligação ao GTP/genética , Mutação , Doenças Retinianas/genética , Pré-Escolar , Adaptação à Escuridão/fisiologia , Eletrorretinografia/métodos , Oftalmopatias Hereditárias , Feminino , Humanos , Fenótipo , Estimulação Luminosa , Doenças Retinianas/diagnóstico , Doenças Retinianas/fisiopatologia , Tomografia de Coerência Óptica , Visão Ocular/genética , Sequenciamento do ExomaRESUMO
Achromatopsia is an autosomal recessive disorder characterized by cone photoreceptor dysfunction. We recently identified activating transcription factor 6 (ATF6) as a genetic cause of achromatopsia. ATF6 is a key regulator of the unfolded protein response. In response to endoplasmic reticulum (ER) stress, ATF6 migrates from the ER to Golgi to undergo regulated intramembrane proteolysis to release a cytosolic domain containing a basic leucine zipper (bZIP) transcriptional activator. The cleaved ATF6 fragment migrates to the nucleus to transcriptionally up-regulate protein-folding enzymes and chaperones. ATF6 mutations in patients with achromatopsia include missense, nonsense, splice site, and single-nucleotide deletion or duplication changes found across the entire gene. Here, we comprehensively tested the function of achromatopsia-associated ATF6 mutations and found that they group into three distinct molecular pathomechanisms: class 1 ATF6 mutants show impaired ER-to-Golgi trafficking and diminished regulated intramembrane proteolysis and transcriptional activity; class 2 ATF6 mutants bear the entire ATF6 cytosolic domain with fully intact transcriptional activity and constitutive induction of downstream target genes, even in the absence of ER stress; and class 3 ATF6 mutants have complete loss of transcriptional activity because of absent or defective bZIP domains. Primary fibroblasts from patients with class 1 or class 3 ATF6 mutations show increased cell death in response to ER stress. Our findings reveal that human ATF6 mutations interrupt distinct sequential steps of the ATF6 activation mechanism. We suggest that increased susceptibility to ER stress-induced damage during retinal development underlies the pathology of achromatopsia in patients with ATF6 mutations.
Assuntos
Fator 6 Ativador da Transcrição/metabolismo , Defeitos da Visão Cromática/genética , Defeitos da Visão Cromática/metabolismo , Mutação/genética , Morte Celular/genética , Linhagem Celular , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/genética , Fibroblastos/metabolismo , Complexo de Golgi/metabolismo , Células HEK293 , Humanos , Chaperonas Moleculares/metabolismo , Transcrição Gênica/genéticaRESUMO
Congenital stationary night blindness (CSNB) is a heterogeneous group of non-progressive inherited retinal disorders with characteristic electroretinogram (ERG) abnormalities. Riggs and Schubert-Bornschein are subtypes of CSNB and demonstrate distinct ERG features. Riggs CSNB demonstrates selective rod photoreceptor dysfunction and occurs due to mutations in genes encoding proteins involved in rod phototransduction cascade; night blindness is the only symptom and eye examination is otherwise normal. Schubert-Bornschein CSNB is a consequence of impaired signal transmission between the photoreceptors and bipolar cells. Schubert-Bornschein CSNB is subdivided into complete CSNB with an ON bipolar signaling defect and incomplete CSNB with both ON and OFF pathway involvement. Both subtypes are associated with variable degrees of night blindness or photophobia, reduced visual acuity, high myopia, and nystagmus. Whole-exome sequencing of a family screened negative for mutations in genes associated with CSNB identified biallelic mutations in the guanine nucleotide-binding protein subunit beta-3 gene (GNB3). Two siblings were compound heterozygous for a deletion (c.170_172delAGA [p.Lys57del]) and a nonsense mutation (c.1017G>A [p.Trp339(∗)]). The maternal aunt was homozygous for the nonsense mutation (c.1017G>A [p.Trp339(∗)]). Mutational analysis of GNB3 in a cohort of 58 subjects with CSNB identified a sporadic case individual with a homozygous GNB3 mutation (c.200C>T [p.Ser67Phe]). GNB3 encodes the ß subunit of G protein heterotrimer (Gαßγ) and is known to modulate ON bipolar cell signaling and cone transducin function in mice. Affected human subjects showed an unusual CSNB phenotype with variable degrees of ON bipolar dysfunction and reduced cone sensitivity. This unique retinal disorder with dual anomaly in visual processing expands our knowledge about retinal signaling.
Assuntos
Oftalmopatias Hereditárias/etiologia , Genes Recessivos/genética , Doenças Genéticas Ligadas ao Cromossomo X/etiologia , Proteínas Heterotriméricas de Ligação ao GTP/genética , Mutação/genética , Miopia/etiologia , Cegueira Noturna/etiologia , Alelos , Sequência de Aminoácidos , Animais , Estudos de Casos e Controles , Eletrorretinografia , Oftalmopatias Hereditárias/patologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Genótipo , Proteínas Heterotriméricas de Ligação ao GTP/química , Homozigoto , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Miopia/patologia , Cegueira Noturna/patologia , Linhagem , Fenótipo , Conformação Proteica , Homologia de Sequência de Aminoácidos , Acuidade Visual/genéticaRESUMO
Bardet Biedl syndrome (BBS) is a multisystem genetically heterogeneous ciliopathy that most commonly leads to obesity, photoreceptor degeneration, digit anomalies, genito-urinary abnormalities, as well as cognitive impairment with autism, among other features. Sequencing of a DNA sample from a 17-year-old female affected with BBS did not identify any mutation in the known BBS genes. Whole-genome sequencing identified a novel loss-of-function disease-causing homozygous mutation (K102*) in C8ORF37, a gene coding for a cilia protein. The proband was overweight (body mass index 29.1) with a slowly progressive rod-cone dystrophy, a mild learning difficulty, high myopia, three limb post-axial polydactyly, horseshoe kidney, abnormally positioned uterus and elevated liver enzymes. Mutations in C8ORF37 were previously associated with severe autosomal recessive retinal dystrophies (retinitis pigmentosa RP64 and cone-rod dystrophy CORD16) but not BBS. To elucidate the functional role of C8ORF37 in a vertebrate system, we performed gene knockdown in Danio rerio and assessed the cardinal features of BBS and visual function. Knockdown of c8orf37 resulted in impaired visual behavior and BBS-related phenotypes, specifically, defects in the formation of Kupffer's vesicle and delays in retrograde transport. Specificity of these phenotypes to BBS knockdown was shown with rescue experiments. Over-expression of human missense mutations in zebrafish also resulted in impaired visual behavior and BBS-related phenotypes. This is the first functional validation and association of C8ORF37 mutations with the BBS phenotype, which identifies BBS21. The zebrafish studies hereby show that C8ORF37 variants underlie clinically diagnosed BBS-related phenotypes as well as isolated retinal degeneration.
Assuntos
Síndrome de Bardet-Biedl/genética , Predisposição Genética para Doença , Proteínas/genética , Distrofias Retinianas/genética , Adolescente , Animais , Síndrome de Bardet-Biedl/patologia , Modelos Animais de Doenças , Feminino , Humanos , Células de Kupffer/metabolismo , Células de Kupffer/patologia , Mutação , Degeneração Retiniana/genética , Degeneração Retiniana/patologia , Distrofias Retinianas/patologia , Peixe-Zebra/genéticaRESUMO
PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.
Assuntos
Estudos de Associação Genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Testes Genéticos , Análise de Sequência de DNA , Sequenciamento Completo do Genoma , Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Exoma , Feminino , Estudos de Associação Genética/métodos , Estudos de Associação Genética/normas , Testes Genéticos/métodos , Testes Genéticos/normas , Variação Genética , Humanos , Masculino , Anotação de Sequência Molecular , Fenótipo , Análise de Sequência de DNA/métodos , Análise de Sequência de DNA/normas , Sequenciamento do Exoma/métodos , Sequenciamento do Exoma/normas , Sequenciamento Completo do Genoma/métodos , Sequenciamento Completo do Genoma/normasRESUMO
PURPOSE: The full-field electroretinogram (ff-ERG) is a widely used clinical tool to evaluate generalized retinal function by recording electrical potentials generated by the cells in the retina in response to flash stimuli and requires mydriasis. The purpose of this study was to determine the intra-visit reliability and diagnostic capability of a handheld, mydriasis-free ERG, RETeval (LKC Technologies, Gaithersburg, MD, USA), in comparison with the standard clinical ff-ERG by measuring responses recommended by the International Society for Clinical Electrophysiology of Vision (ISCEV). METHODS: This prospective, cross-sectional study included 35 patients recruited at the Hospital for Sick Children (median age = 17, range 11 months-69 years) who had undergone a clinical ff-ERG according to ISCEV standards. For RETeval (n = 35), pupils were undilated in most (n = 29) and sensor strip electrodes were placed under the inferior orbital rim. Stimulus settings on RETeval were equivalent to those used in the clinical ERG. Fifty-seven control participants (median age = 22, range 8-65 years) underwent undilated RETeval ERG to establish standard values for comparison. Patient waveform components with amplitudes < 5th percentile, or implicit times > 95th percentile of normal relative to control data were classified as abnormal for the RETeval system. RESULTS: The RETeval system demonstrated a high degree of within-visit reliability for amplitudes (ICC = 0.82) and moderate reliability for implicit times (ICC = 0.53). Cohen's Kappa analysis revealed a substantial level of agreement between the diagnostic capability of RETeval in comparison with clinical ff-ERG (k = 0.82), with a sensitivity and specificity of 1.00 and 0.82, respectively. Pearson's correlations for clinical ERG versus RETeval demonstrated a positive correlation for amplitudes across the rod (r = 0.65) and cone (r = 0.74) ERG waveforms. Bland-Altman plots showed no bias between the mean differences across all amplitude and implicit time parameters of the two systems. CONCLUSIONS: The present study demonstrated that RETeval is a reliable tool with reasonable accuracy in comparison with the clinical ERG. The portable nature of RETeval system enables its incorporation at resource-limited centers where the ff-ERG is not readily available. The avoidance of sedation and pupillary dilation are added advantages of RETeval ERG.
Assuntos
Adaptação à Escuridão/fisiologia , Eletrorretinografia/métodos , Retina/fisiopatologia , Doenças Retinianas/classificação , Adolescente , Adulto , Idoso , Criança , Estudos Transversais , Eletrorretinografia/instrumentação , Feminino , Humanos , Lactente , Luz , Masculino , Pessoa de Meia-Idade , Midriáticos/administração & dosagem , Estimulação Luminosa , Estudos Prospectivos , Pupila/efeitos dos fármacos , Valores de Referência , Reprodutibilidade dos Testes , Doenças Retinianas/fisiopatologia , Adulto JovemRESUMO
X-linked retinoschisis (XLRS) is a vitreo-retinal degeneration caused by mutations in the RS1 gene which encodes the protein retinoschisin (RS1), required for the structural and functional integrity of the retina. Data are presented from a group of 38 XLRS patients from Moorfields Eye Hospital (London, UK) who had one of 18 missense mutations in RS1. Patients were grouped based on mutation severity predicted by molecular modeling: mild (class I), moderate (intermediate) and severe (class II). Most patients had an electronegative scotopic bright flash electroretinogram (ERG) (reduced b/a-wave ratio) in keeping with predominant inner retinal dysfunction. An association between the type of structural RS1 alterations and the severity of b/a-wave reduction was found in all but the oldest group of patients, significant in patients aged 15-30 years. Severe RS1 missense changes were associated with a lower ERG b/a ratio than were mild changes, suggesting that the extent of inner retinal dysfunction is influenced by the effect of the mutations on protein structure. The majority of class I mutations showed no changes involving cysteine residues. Class II mutations caused severe perturbations due to the removal or insertion of cysteine residues or due to changes in the hydrophobic core. The ERG b/a ratio in intermediate cases was abnormal but showed significant variability, possibly related to the role of proline or arginine residues. We also conducted a second study, using a completely independent cohort, to indicate a genotype-ERG phenotype correlation.
Assuntos
Proteínas do Olho/química , Proteínas do Olho/genética , Mutação de Sentido Incorreto , Retinosquise/fisiopatologia , Adolescente , Adulto , Estudos de Coortes , Eletrorretinografia , Proteínas do Olho/metabolismo , Feminino , Variação Genética , Genótipo , Humanos , Modelos Moleculares , Fenótipo , Conformação Proteica , Estabilidade Proteica , Retina/metabolismo , Retina/fisiopatologia , Retinosquise/genética , Adulto JovemRESUMO
PURPOSE: To identify the genetic cause of autosomal-dominant pattern dystrophy (PD) of the retinal pigment epithelium (RPE) in two families. METHODS AND RESULTS: Two families with autosomal-dominant PD were identified. Eight members of family 1 (five affected) were subjected to whole-genome SNP genotyping; multipoint genome-wide linkage analysis identified 7 regions of potential linkage, and genotyping four additional individuals from family 1 resulted in a maximum logarithm of odds score of 2.09 observed across four chromosomal regions. Exome sequencing of two affected family 1 members identified 15 shared non-synonymous rare coding sequence variants within the linked regions; candidate genes were prioritised and further analysed. Sanger sequencing confirmed a novel heterozygous missense variant (E79K) in orthodenticle homeobox 2 (OTX2) that segregated with the disease phenotype. Family 2 with PD (two affected) harboured the same missense variant in OTX2. A shared haplotype of 19.68â cM encompassing OTX2 was identified between affected individuals in the two families. Within the two families, all except one affected demonstrated distinct 'patterns' at the macula. In vivo structural retinal imaging showed discrete areas of RPE-photoreceptor separation at the macula in all cases. Electroretinogram testing showed generalised photoreceptor degeneration in three cases. Mild developmental anomalies were observed, including optic nerve head dysplasia (four cases), microcornea (one case) and Rathke's cleft cyst (one case); pituitary hormone levels were normal. CONCLUSIONS: This is the first report implicating OTX2 to underlie PD. The retinal disease resembles conditional mice models that show slow photoreceptor degeneration secondary to loss of Otx2 function in the adult RPE.
Assuntos
Genes Dominantes , Mutação , Fatores de Transcrição Otx/genética , Distrofias Retinianas/genética , Distrofias Retinianas/patologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Biologia Computacional , Análise Mutacional de DNA , Exoma , Feminino , Ligação Genética , Genótipo , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Fatores de Transcrição Otx/química , Linhagem , Polimorfismo de Nucleotídeo Único , Conformação Proteica , Distrofias Retinianas/diagnóstico , Alinhamento de Sequência , Testes Visuais , Adulto JovemRESUMO
Standard automated perimetery is considered the gold standard for evaluating a patient's visual field. However, it is costly and requires a fixed testing environment. In response, perimetric devices using virtual reality (VR) headsets have emerged as an alternative way to measure visual fields in patients. This systematic review aims to characterize both novel and established VR headsets in the literature and explore their potential applications within visual field testing. A search was conducted using MEDLINE, Embase, CINAHL, and the Core Collection (Web of Science) for articles published until January 2023. Subject headings and keywords related to virtual reality and visual field were used to identify studies specific to this topic. Records were first screened by title/abstract and then by full text using predefined criteria. Data was extracted accordingly. A total of 2404 records were identified from the databases. After deduplication and the two levels of screening, 64 studies describing 36 VR headset perimetry devices were selected for extraction. These devices encompassed various visual field measurement techniques, including static and kinetic perimetry, with some offering vision rehabilitation capabilities. This review reveals a growing consensus that VR headset perimetry devices perform comparably to, or even better than, standard automated perimetry. They are better tolerated by patients in terms of gaze fixation, more cost-effective, and generally more accessible for patients with limited mobility.
Assuntos
Doenças do Sistema Nervoso , Realidade Virtual , Humanos , Testes de Campo Visual , Campos Visuais , Fixação OcularRESUMO
BACKGROUND/AAIMS: Congenital stationary night blindness (CSNB) is an inherited retinal disease that is often associated with high myopia and can be caused by pathological variants in multiple genes, most commonly CACNA1F, NYX and TRPM1. High myopia is associated with retinal degeneration and increased risk for retinal detachment. Slowing the progression of myopia in patients with CSNB would likely be beneficial in reducing risk, but before interventions can be considered, it is important to understand the natural history of myopic progression. METHODS: This multicentre, retrospective study explored CSNB caused by variants in CACNA1F, NYX or TRPM1 in patients who had at least 6 measurements of their spherical equivalent of refraction (SER) before the age of 18. A mixed-effect model was used to predict progression of SER overtime and differences between genotypes were evaluated. RESULTS: 78 individuals were included in this study. All genotypes showed a significant myopic predicted SER at birth (-3.076D, -5.511D and -5.386D) for CACNA1F, NYX and TRPM1 respectively. Additionally, significant progression of myopia per year (-0.254D, -0.257D and -0.326D) was observed for all three genotypes CACNA1F, NYX and TRPM1, respectively. CONCLUSIONS: Patients with CSNB tend to be myopic from an early age and progress to become more myopic with age. Patients may benefit from long-term myopia slowing treatment in the future and further studies are indicated. Additionally, CSNB should be considered in the differential diagnosis for early-onset myopia.
RESUMO
Purpose: To describe the clinical, electrophysiological and genetic spectrum of inherited retinal diseases associated with variants in the PRPH2 gene. Methods: A total of 241 patients from 168 families across 15 sites in 9 countries with pathogenic or likely pathogenic variants in PRPH2 were included. Records were reviewed for age at symptom onset, visual acuity, full-field ERG, fundus colour photography, fundus autofluorescence (FAF), and SD-OCT. Images were graded into six phenotypes. Statistical analyses were performed to determine genotype-phenotype correlations. Results: The median age at symptom onset was 40 years (range, 4-78 years). FAF phenotypes included normal (5%), butterfly pattern dystrophy, or vitelliform macular dystrophy (11%), central areolar choroidal dystrophy (28%), pseudo-Stargardt pattern dystrophy (41%), and retinitis pigmentosa (25%). Symptom onset was earlier in retinitis pigmentosa as compared with pseudo-Stargardt pattern dystrophy (34 vs 44 years; P = 0.004). The median visual acuity was 0.18 logMAR (interquartile range, 0-0.54 logMAR) and 0.18 logMAR (interquartile range 0-0.42 logMAR) in the right and left eyes, respectively. ERG showed a significantly reduced amplitude across all components (P < 0.001) and a peak time delay in the light-adapted 30-Hz flicker and single-flash b-wave (P < 0.001). Twenty-two variants were novel. The central areolar choroidal dystrophy phenotype was associated with 13 missense variants. The remaining variants showed marked phenotypic variability. Conclusions: We described six distinct FAF phenotypes associated with variants in the PRPH2 gene. One FAF phenotype may have multiple ERG phenotypes, demonstrating a discordance between structure and function. Given the vast spectrum of PRPH2 disease our findings are useful for future clinical trials.
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Eletrorretinografia , Periferinas , Fenótipo , Distrofias Retinianas , Acuidade Visual , Humanos , Periferinas/genética , Pessoa de Meia-Idade , Adulto , Masculino , Feminino , Adolescente , Distrofias Retinianas/genética , Distrofias Retinianas/fisiopatologia , Distrofias Retinianas/diagnóstico , Idoso , Acuidade Visual/fisiologia , Criança , Adulto Jovem , Pré-Escolar , Tomografia de Coerência Óptica , Mutação , Angiofluoresceinografia , Estudos de Associação Genética , Estudos Retrospectivos , Análise Mutacional de DNA , DNA/genética , LinhagemRESUMO
PURPOSE: To compare the clinical phenotype and detailed electroretinographic parameters in X-linked retinoschisis (XLRS). DESIGN: Retrospective, comparative study. PARTICIPANTS: Fifty-seven patients (aged 1-67 years) with molecularly confirmed XLRS were clinically ascertained. METHODS: Pattern electroretinography (PERG) and full-field electroretinography (ERG), incorporating international standard recordings, were performed in 44 cases. Thirteen patients, mostly pediatric, were tested using a simplified ERG protocol. On-Off and S-cone ERGs were performed in most adults. Fundus autofluorescence (FAF) imaging and optical coherence tomography (OCT) were available in 17 and 21 cases, respectively. MAIN OUTCOME MEASURES: The clinical and electrophysiologic data associated with different types of mutation in the RS1 gene. RESULTS: Forty-three patients had missense changes (group A), and 14 patients had nonsense, splice-site, or frame-shifting mutations in the RS1 gene (group B). The mean best-corrected visual acuity was better in group A than in group B (0.34 and 0.21, respectively). Fundus examination revealed foveal schisis in approximately half of both groups. The bright-flash dark-adapted (DA) ERG (11.0 candela.sec.m(-2)) waveform was electronegative in 62% of group A eyes and 100% of group B eyes. The photopic 30-Hz flicker ERG was delayed in all group B eyes and all except 6 group A eyes. On-Off ERG b-waves were subnormal in 39% of group A and 89% of group B eyes; d-waves were delayed in 14 eyes (group A = 10, group B = 4). S-cone ERGs were abnormal in 50% of both groups. The PERG was abnormal in 88% of group A and 100% of group B eyes. A spoke-wheel pattern of high and low intensity was the most common FAF abnormality observed. The OCT showed intraretinal schitic cavities in the majority of eyes. CONCLUSIONS: There is profound phenotypic variability in patients with XLRS. Most patients have DA bright-flash ERGs with a low b:a ratio in keeping with inner retinal dysfunction. Generalized cone system dysfunction is common and associated with an abnormal On-response and less frequent additional Off-response involvement. Nonsense, splice-site, or frame-shifting mutations in RS1 consistently caused electronegative bright-flash ERG, delayed flicker response, and abnormal PERG; missense mutations result in a wider range of ERG abnormalities.
Assuntos
Proteínas do Olho/genética , Mutação , Retina/fisiopatologia , Retinosquise/genética , Retinosquise/fisiopatologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Adaptação à Escuridão , Eletrorretinografia , Feminino , Angiofluoresceinografia , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fenótipo , Estimulação Luminosa , Estudos Retrospectivos , Tomografia de Coerência Óptica , Adulto JovemRESUMO
PURPOSE: To review three inherited retinal disorders associated with diagnostic or pathognomonic electroretinogram (ERG) abnormalities: cone dystrophy with supernormal rod ERG (KCNV2), enhanced S-cone syndrome (NR2E3), and bradyopsia (RGS9/R9AP). METHODS: A review of clinical details, genetic basis, and electrophysiological features in these disorders and a brief summary of the standard and nonstandard ERG techniques required to identify the disorders. RESULTS: The electrophysiological features in each of these three disorders are pathognomonic such that the responsible gene can be specified. The results from nonstandard electrophysiological testing in excess of international standards are necessary to describe the pathognomonic changes in cone dystrophy with supernormal rod ERG and bradyopsia. The clinical phenotype in the disorders can be variable. Mutations in NR2E3 may additionally be associated with phenotypes other than enhanced S-cone syndrome. CONCLUSION: : Characteristic ERG changes enable the diagnosis of cone dystrophy with supernormal rod ERG, enhanced S-cone syndrome, and bradyopsia and accurate genetic screening. This review highlights the need for additional nonstandard ERGs to make the diagnosis in two of these disorders.