RESUMO
INTRODUCTION: Infantile nystagmus and foveal hypoplasia associated with AHR gene defects is a newly recognized and rare disorder. Our aim was to present a patient with a novel biallelic AHR pathogenic variant with electrophysiological evidence of chiasmal misrouting. MATERIALS AND METHODS: Complete ocular examination, fundus imaging, visual evoked potentials (VEP) and full-field electroretinography were performed at initial presentation. Genetic testing was performed by whole exome sequencing. RESULTS: Female patient of 6 years old presented a reduced best corrected visual acuity, an infantile nystagmus and a grade III typical foveal hypoplasia without ocular hypopigmentation. A crossed asymmetry was discovered on pattern onset/offset VEP. Genetic testing put in evidence a novel homozygous variant in AHR: c.2242del, p. (Gln748Lysfs*5). During 11-years follow-up period, BCVA gradually improved. There was no evidence of retinal degeneration. CONCLUSION: AHR gene defects could be associated with infantile nystagmus, foveal hypoplasia and chiasmal misrouting.
Assuntos
Eletrorretinografia , Potenciais Evocados Visuais , Fóvea Central , Nistagmo Congênito , Humanos , Feminino , Fóvea Central/anormalidades , Nistagmo Congênito/genética , Nistagmo Congênito/fisiopatologia , Nistagmo Congênito/diagnóstico , Criança , Receptores de Hidrocarboneto Arílico/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Acuidade Visual/fisiologia , Proteínas Repressoras/genética , Tomografia de Coerência ÓpticaRESUMO
Biallelic gene defects in MFSD8 are not only a cause of the late-infantile form of neuronal ceroid lipofuscinosis, but also of rare isolated retinal degeneration. We report clinical and genetic data of seven patients compound heterozygous or homozygous for variants in MFSD8, issued from a French cohort with inherited retinal degeneration, and two additional patients retrieved from a Swiss cohort. Next-generation sequencing of large panels combined with whole-genome sequencing allowed for the identification of twelve variants from which seven were novel. Among them were one deep intronic variant c.998+1669A>G, one large deletion encompassing exon 9 and 10, and a silent change c.750A>G. Transcript analysis performed on patients' lymphoblastoid cell lines revealed the creation of a donor splice site by c.998+1669A>G, resulting in a 140 bp pseudoexon insertion in intron 10. Variant c.750A>G produced exon 8 skipping. In silico and in cellulo studies of these variants allowed us to assign the pathogenic effect, and showed that the combination of at least one severe variant with a moderate one leads to isolated retinal dystrophy, whereas the combination in trans of two severe variants is responsible for early onset severe retinal dystrophy in the context of late-infantile neuronal ceroid lipofuscinosis.
Assuntos
Lipofuscinoses Ceroides Neuronais , Distrofias Retinianas , Éxons/genética , Homozigoto , Humanos , Proteínas de Membrana Transportadoras/genética , Mutação , Lipofuscinoses Ceroides Neuronais/genética , Distrofias Retinianas/genéticaRESUMO
Cyclic nucleotide-gated channel ß1 (CNGB1) encodes the 240-kDa ß subunit of the rod photoreceptor cyclic nucleotide-gated ion channel. Disease-causing sequence variants in CNGB1 lead to autosomal recessive rod-cone dystrophy/retinitis pigmentosa (RP). We herein present a comprehensive review and analysis of all previously reported CNGB1 sequence variants, and add 22 novel variants, thereby enlarging the spectrum to 84 variants in total, including 24 missense variants (two of which may also affect splicing), 21 nonsense, 19 splicing defects (7 at noncanonical positions), 10 small deletions, 1 small insertion, 1 small insertion-deletion, 7 small duplications, and 1 gross deletion. According to the American College of Medical Genetics and Genomics classification criteria, 59 variants were considered pathogenic or likely pathogenic and 25 were variants of uncertain significance. In addition, we provide further phenotypic data from 34 CNGB1-related RP cases, which, overall, are in line with previous findings suggesting that this form of RP has long-term retention of useful central vision despite the early onset of night blindness, which is valuable for patient counseling, but also has implications for it being considered a priority target for gene therapy trials.
Assuntos
Distrofias de Cones e Bastonetes/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Estudos de Coortes , Distrofias de Cones e Bastonetes/classificação , Distrofias de Cones e Bastonetes/epidemiologia , Distrofias de Cones e Bastonetes/patologia , Análise Mutacional de DNA , Estudos de Associação Genética , Humanos , MutaçãoRESUMO
Pathogenic variants in CRB1 lead to diverse recessive retinal disorders from severe Leber congenital amaurosis to isolated macular dystrophy. Until recently, no clear phenotype-genotype correlation and no appropriate mouse models existed. Herein, we reappraise the phenotype-genotype correlation of 50 patients with regards to the recently identified CRB1 isoforms: a canonical long isoform A localized in Müller cells (12 exons) and a short isoform B predominant in photoreceptors (7 exons). Twenty-eight patients with early onset retinal dystrophy (EORD) consistently had a severe Müller impairment, with variable impact on the photoreceptors, regardless of isoform B expression. Among them, two patients expressing wild type isoform B carried one variant in exon 12, which specifically damaged intracellular protein interactions in Müller cells. Thirteen retinitis pigmentosa patients had mainly missense variants in laminin G-like domains and expressed at least 50% of isoform A. Eight patients with the c.498_506del variant had macular dystrophy. In one family homozygous for the c.1562C>T variant, the brother had EORD and the sister macular dystrophy. In contrast with the mouse model, these data highlight the key role of Müller cells in the severity of CRB1-related dystrophies in humans, which should be taken into consideration for future clinical trials.
Assuntos
Células Ependimogliais/patologia , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Degeneração Macular/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Distrofias Retinianas/patologia , Retinose Pigmentar/patologia , Adolescente , Idade de Início , Processamento Alternativo , Criança , Pré-Escolar , Células Ependimogliais/metabolismo , Proteínas do Olho/química , Feminino , Estudos de Associação Genética , Humanos , Lactente , Degeneração Macular/genética , Degeneração Macular/metabolismo , Masculino , Proteínas de Membrana/química , Modelos Moleculares , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/química , Mutação Puntual , Distrofias Retinianas/genética , Distrofias Retinianas/metabolismo , Retinose Pigmentar/genética , Retinose Pigmentar/metabolismo , Estudos Retrospectivos , Deleção de Sequência , Adulto JovemRESUMO
Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of TTLL5. Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct USH2A variants, which might explain the observed rod involvement. Our study highlights the role of TTLL5 in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in TTLL5, previously undetected by classical sequencing methods. In addition, variable phenotypes in TTLL5-associated patients might be due to the presence of additional gene defects.
Assuntos
Proteínas de Transporte/genética , Distrofias de Cones e Bastonetes/genética , Oftalmopatias Hereditárias/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação/genética , Distrofias Retinianas/genética , Adulto , Idoso , Criança , Pontos de Quebra do Cromossomo , Simulação por Computador , Distrofias de Cones e Bastonetes/fisiopatologia , Variações do Número de Cópias de DNA/genética , Eletrorretinografia , Oftalmopatias Hereditárias/fisiopatologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Distrofias Retinianas/fisiopatologiaRESUMO
The autosomal dominant progressive bifocal chorioretinal atrophy (PBCRA) disease locus has been mapped to chromosome 6q14-16.2 that overlaps the North Carolina macular dystrophy (NCMD) locus MCDR1. NCMD is a nonprogressive developmental macular dystrophy, in which variants upstream of PRDM13 have been implicated. Whole genome sequencing was performed to interrogate structural variants (SVs) and single nucleotide variants (SNVs) in eight individuals, six affected individuals from two families with PBCRA, and two individuals from an additional family with a related developmental macular dystrophy. A SNV (chr6:100,046,804T>C), located 7.8 kb upstream of the PRDM13 gene, was shared by all PBCRA-affected individuals in the disease locus. Haplotype analysis suggested that the variant arose independently in the two families. The two affected individuals from Family 3 were screened for rare variants in the PBCRA and NCMD loci. This revealed a de novo variant in the proband, 21 bp from the first SNV (chr6:100,046,783A>C). This study expands the noncoding variant spectrum upstream of PRDM13 and suggests altered spatio-temporal expression of PRDM13 as a candidate disease mechanism in the phenotypically distinct but related conditions, NCMD and PBCRA.
Assuntos
Regiões 5' não Traduzidas , Distrofias Hereditárias da Córnea/diagnóstico , Distrofias Hereditárias da Córnea/genética , Predisposição Genética para Doença , Histona-Lisina N-Metiltransferase/genética , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/genética , Fatores de Transcrição/genética , Adulto , Biologia Computacional/métodos , Feminino , Estudos de Associação Genética/métodos , Loci Gênicos , Haplótipos , Humanos , Família Multigênica , Linhagem , Sequenciamento Completo do GenomaRESUMO
Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30-50% of the cases, the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked structural variants, by variants in intronic, promoter or more distant regulatory regions, and represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB), show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of the gene-coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that seven of the 189 CACNA1F-related cases have intronic and synonymous disease-causing variants leading to missplicing as validated by minigene approaches. These findings highlight that gene-locus sequencing may be a very efficient method in detecting disease-causing variants in clinically well-characterized patients with a diagnosis of IRD, like icCSNB.
Assuntos
Canais de Cálcio Tipo L/genética , Oftalmopatias Hereditárias/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação , Miopia/genética , Cegueira Noturna/genética , Análise de Sequência de DNA/métodos , Predisposição Genética para Doença , Hemizigoto , Humanos , Íntrons , Masculino , Linhagem , Splicing de RNA , Mutação SilenciosaRESUMO
In this study, we report a novel duplication causing North Carolina macular dystrophy (NCMD) identified applying whole genome sequencing performed on eight affected members of two presumed unrelated families mapping to the MCDR1 locus. In our families, the NCMD phenotype was associated with a 98.4 kb tandem duplication encompassing the entire CCNC and PRDM13 genes and a common DNase 1 hypersensitivity site. To study the impact of PRDM13 or CCNC dysregulation, we used the Drosophila eye development as a model. Knock-down and overexpression of CycC and CG13296, Drosophila orthologues of CCNC and PRDM13, respectively, were induced separately during eye development. In flies, eye development was not affected, while knocking down either CycC or CG13296 mutant models. Overexpression of CycC also had no effect. Strikingly, overexpression of CG13296 in Drosophila leads to a severe loss of the imaginal eye-antennal disc. This study demonstrated for the first time in an animal model that overexpression of PRDM13 alone causes a severe abnormal retinal development. It is noteworthy that mutations associated with this autosomal dominant foveal developmental disorder are frequently duplications always including an entire copy of PRDM13, or variants in one DNase 1 hypersensitivity site at this locus.
Assuntos
Distrofias Hereditárias da Córnea/genética , Ciclina C/genética , Histona-Lisina N-Metiltransferase/genética , Adulto , Animais , Mapeamento Cromossômico , Cromossomos Humanos Par 6 , Distrofias Hereditárias da Córnea/metabolismo , Ciclina C/metabolismo , Drosophila melanogaster , Proteínas do Olho/genética , Feminino , Ligação Genética , Haplótipos , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Masculino , Domínios PR-SET , Linhagem , Sequenciamento Completo do GenomaRESUMO
CEP290 mutations cause a spectrum of ciliopathies, including Leber congenital amaurosis. Milder retinal diseases have been ascribed to exclusion of CEP290 mutant exons through basal exon skipping (BES) and/or nonsense-associated altered splicing (NAS). Here, we report two siblings with some preserved vision despite biallelism for presumably severe CEP290 mutations: a maternal splice site change in intron 18 (c.1824 + 3A > G) and a paternal c.6869dup (p.Asn2290Lysfs∗6) in exon 50 that introduces a premature termination codon (PTC) within the same exon. Analyzing mRNAs from fibroblasts of the two siblings, we detected no BES or NAS which could have enabled the production of PTC-free CEP290 isoforms from the paternal allele. In contrast, we reveal partial alteration of exon 18 donor splice site, allowing the transcription of some correctly spliced CEP290 mRNAs from the maternal allele which likely account for the mild retinal disease. This observation adds further variability to the mechanisms underlying CEP290 pleiotropy.
Assuntos
Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular/genética , Códon sem Sentido , Proteínas do Citoesqueleto/genética , Éxons , Splicing de RNA , Doenças Retinianas/genética , Humanos , Mutação , IrmãosRESUMO
INTRODUCTION: CABP4-related retinal dysfunction is a cone-rod synaptic transmission disorder with electronegative electroretinogram (ERG) waveform. It is a rare retinal dysfunction that can be classified into the incomplete form of congenital stationary night blindness. Absent foveal reflex and overall foveal thinning were previously reported, but in most cases the fundus appearance was described as nearly normal. We report here peculiar macular changes in a patient of French ancestry harbouring CABP4 mutations. METHODS: Complete ocular examination and full-field ERG were performed at the initial presentation and follow-up. Multimodal fundus imagining, including spectral-domain optical coherence tomography, colour, infrared reflectance and short-wavelength autofluorescence photographs, was performed during follow-up visits. RESULTS: A 7-month-old infant was addressed to our department for visual unresponsiveness and nystagmus. ERG had an electronegative waveform, even for light-adapted stimuli, thus supporting the diagnosis of photoreceptor-bipolar cell transmission disorder. Genetic investigations discovered a compound heterozygous mutation in CABP4: c.646C > T, p.Arg216*/c.673C > T, p.Arg225*. Multimodal fundus imaging, performed at follow-up visits, showed fine radial folds at the vitreomacular interface and dark foveal dots in both eyes. Optic coherence tomography revealed a focal foveal ellipsoid zone gap. DISCUSSION: Initial presentation was misleading with Leber congenital amaurosis. The electronegative ERG waveform reoriented the genetic investigations and thus establishing a correct diagnosis. To the best of our knowledge, the peculiar fundus changes observed in our patient were never reported before. We hypothesized that a foveal ellipsoid zone interruption discovered in our patient could reflect mostly a cone dysfunction. It was unclear whether the fine radial folds in both maculae were linked with high hyperopia or were an intrinsic feature of the retinal disease. CONCLUSION: CABP4-related retinal disease is a cone-rod system disorder with possible foveal abnormalities.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Oftalmopatias Hereditárias/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Mutação , Miopia/diagnóstico , Cegueira Noturna/diagnóstico , Células Fotorreceptoras de Vertebrados/patologia , Doenças Retinianas/diagnóstico , Doenças Retinianas/genética , Eletrorretinografia , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/fisiopatologia , Angiofluoresceinografia , França/epidemiologia , Fundo de Olho , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Humanos , Lactente , Masculino , Miopia/genética , Miopia/fisiopatologia , Cegueira Noturna/genética , Cegueira Noturna/fisiopatologia , Linhagem , Doenças Retinianas/fisiopatologia , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos , Acuidade Visual , População Branca/genéticaRESUMO
Congenital stationary night blindness (CSNB) is a heterogeneous retinal disorder characterized by visual impairment under low light conditions. This disorder is due to a signal transmission defect from rod photoreceptors to adjacent bipolar cells in the retina. Two forms can be distinguished clinically, complete CSNB (cCSNB) or incomplete CSNB; the two forms are distinguished on the basis of the affected signaling pathway. Mutations in NYX, GRM6, and TRPM1, expressed in the outer plexiform layer (OPL) lead to disruption of the ON-bipolar cell response and have been seen in patients with cCSNB. Whole-exome sequencing in cCSNB patients lacking mutations in the known genes led to the identification of a homozygous missense mutation (c.1807C>T [p.His603Tyr]) in one consanguineous autosomal-recessive cCSNB family and a homozygous frameshift mutation in GPR179 (c.278delC [p.Pro93Glnfs(∗)57]) in a simplex male cCSNB patient. Additional screening with Sanger sequencing of 40 patients identified three other cCSNB patients harboring additional allelic mutations in GPR179. Although, immunhistological studies revealed Gpr179 in the OPL in wild-type mouse retina, Gpr179 did not colocalize with specific ON-bipolar markers. Interestingly, Gpr179 was highly concentrated in horizontal cells and Müller cell endfeet. The involvement of these cells in cCSNB and the specific function of GPR179 remain to be elucidated.
Assuntos
Exoma , Mutação , Miopia/genética , Cegueira Noturna/genética , Receptores Acoplados a Proteínas G/genética , Alelos , Animais , Eletrorretinografia/métodos , Oftalmopatias Hereditárias , Feminino , Doenças Genéticas Ligadas ao Cromossomo X , Heterogeneidade Genética , Técnicas de Genotipagem/métodos , Heterozigoto , Homozigoto , Humanos , Masculino , Camundongos , Fenótipo , Polimorfismo de Nucleotídeo Único , Estrutura Terciária de Proteína , Proteoglicanas/genética , Receptores de Glutamato Metabotrópico/genética , Retina/anormalidades , Canais de Cátion TRPM/genéticaRESUMO
OBJECTIVES: The aim of this study was to find, using spectral domain-optical coherence tomography (SD-OCT), retinal imaging biomarkers differentiating neuromyelitis optica spectrum disorder (NMOSD), multiple sclerosis (MS) and healthy controls (HCs). MATERIALS AND METHODS: The population was composed of patients with NMOSD (n=23) or MS (n=110) and of HCs (n=75). Evaluation criteria were retinal thickness/volume, visual acuity, low contrast vision acuity and Expanded Disability Status Scale score. RESULTS: Considering all eyes and after statistical adjustments including the number of optic neuritis (ON) episodes, we found that NMOSD patients did not have significantly more retinal atrophy than MS patients; whereas MS non-optic neuritis (NON) eyes had thinner temporal (p=0.032) and temporo-superior peripapillary retinal nerve fibre layer (pRNFL; p=0.011) thicknesses than NMOSD NON eyes; in addition, NMOSD NON eyes presented significant naso-inferior pRNFL (p=0.024), temporal pRNFL (p=0.039), macular ganglion cell complex (p=0.004) and ganglion cell layer (p=0.002) atrophy vs HC eyes. We identified significant correlations between visual and clinical disability and retinal thicknesses in both diseases. CONCLUSION: OCT may help to differentiate NMOSD and MS by focusing on the NON eyes (temporal pRNFL atrophy more severe in MS). Moreover, we discuss the possibility of a retinal degenerative process independent of ON in NMOSD.
Assuntos
Esclerose Múltipla/patologia , Neuromielite Óptica/patologia , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica/métodos , Adulto , Atrofia/patologia , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Oligocone trichromacy (OT) is an uncommon cone dysfunction disorder, the mechanism of which remains poorly understood. OT has been thought to be non-progressive, but its long-term visual outcome has been seldom reported in the literature. Our aim was to present two OT patients followed at our institution over 18 years. MATERIALS AND METHODS: Complete ocular examination, color vision, visual fields, and full-field electroretinography (ERG) were performed at initial presentation and follow-up. Spectral-domain optical coherence tomography (OCT) was performed during follow-up when available at our institution. RESULTS: Initial ocular examination showed satisfactory visual acuities with normal fundus examination and near-to-normal color vision. However, computerized perimetry demonstrated a ring-shaped scotoma around fixation, and ERG showed a profound cone dysfunction. The discrepancy between preserved color vision and profound cone dysfunction leads to the diagnosis of OT. Subsequent follow-ups over 18 years showed subtle degradation of visual acuities along with progression of the myopia in both patients and slight worsening of color vision in one patient. Initial OCT revealed a focal interruption of the ellipsoid line along with decreased thickness of the perifoveal macula. Subsequent OCT imaging performed 2 years later did not show any macular changes. CONCLUSION: Although OT is known to be a non-progressive cone dysfunction, our results suggest that subtle degradation of the visual function might happen over time.
Assuntos
Defeitos da Visão Cromática/diagnóstico , Células Fotorreceptoras Retinianas Cones/patologia , Adolescente , Criança , Defeitos da Visão Cromática/fisiopatologia , Eletrorretinografia , Feminino , Angiofluoresceinografia , Seguimentos , Humanos , Linhagem , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos , Acuidade Visual/fisiologia , Testes de Campo Visual , Campos Visuais/fisiologiaRESUMO
PURPOSE: To assess the frequency of and to characterize the clinical spectrum and optical coherence tomography findings of vitelliform macular dystrophy linked to IMPG1 and IMPG2, 2 new causal genes expressed in the interphotoreceptor matrix. DESIGN: Retrospective epidemiologic, clinical, electrophysiologic, and molecular genetic study. PARTICIPANTS: The database of a national referral center specialized in genetic sensory diseases was screened for patients with a macular vitelliform dystrophy without identified mutation or small deletion or large rearrangement in BEST1 and PRPH2 genes. Forty-nine families were included. METHODS: Clinical, imaging, and electro-oculogram findings were reviewed. Mutation screening of IMPG1 and IMPG2 genes were performed systematically. MAIN OUTCOME MEASURES: Frequency, inheritance, and clinical pattern of vitelliform dystrophy associated with IMPG1 and IMPG2 mutations were characterized. RESULTS: IMPG1 was the causal gene in 3 families (IMPG1 1-3, 11 patients) and IMPG2 in a fourth family (2 patients). With an autosomal dominant transmission, families 1 and 2 had the c.713TâG (p.Leu238Arg) mutation in IMPG1 and family 4 had the c.3230GâT (p.Cys1077Phe) mutation in IMPG2. Patients with IMPG1 or IMPG2 mutations had a late onset and moderate visual impairment (mean visual acuity, 20/40; mean age of onset, 42 years), even in the sporadic case of family 3 with a presumed recessive transmission (age at onset, 38 years; mean visual acuity, 20/50). Drusen-like lesions adjacent to the vitelliform deposits were observed in 9 of 13 patients. The vitelliform material was above the retinal pigment epithelium (RPE) at any stage of the macular dystrophy, and this epithelium was well preserved and maintained its classical reflectivity on spectral-domain optical coherence tomography (SD-OCT). Electro-oculogram results were normal or borderline in 9 cases. CONCLUSIONS: IMPG1 and IMPG2 are new causal genes in 8% of families negative for BEST1 and PRPH2 mutations. These genes should be screened in adult-onset vitelliform dystrophy with (1) moderate visual impairment, (2) drusen-like lesions, (3) normal reflectivity of the RPE line on SD-OCT, and (4) vitelliform deposits located between ellipsoid and interdigitation lines on SD-OCT. These clinical characteristics are not observed in the classical forms of BEST1 or PRPH2 vitelliform dystrophies.
Assuntos
Proteínas da Matriz Extracelular/genética , Proteínas do Olho/genética , Predisposição Genética para Doença , Mutação , Proteoglicanas/genética , Distrofia Macular Viteliforme , Adulto , Idoso , Estudos de Casos e Controles , Eletroculografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Epitélio Pigmentado da Retina/patologia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual , Distrofia Macular Viteliforme/genética , Distrofia Macular Viteliforme/patologia , Distrofia Macular Viteliforme/fisiopatologiaRESUMO
CNGB1 gene mutations are a well-known cause of autosomal recessive retinitis pigmentosa (RP), which was recently associated with olfactory dysfunction. The purpose of this study was to report the molecular spectrum and the ocular and olfactory phenotypes of a multiethnic cohort with CNGB1-associated RP. A cross-sectional case series was conducted at two ophthalmic genetics referral centers. Consecutive patients with molecularly confirmed CNGB1-related RP were included. All patients underwent a complete ophthalmological examination complemented by psychophysical olfactory evaluation. Fifteen patients (10 families: 8 Portuguese, 1 French, and 1 Turkish), mean aged 57.13 ± 15.37 years old (yo), were enrolled. Seven disease-causing variants were identified, two of which are reported for the first time: c.2565_2566del and c.2285G > T. Although 11/15 patients reported onset of nyctalopia before age 10, diagnosis was only established after 30 yo in 9/15. Despite widespread retinal degeneration being present in 14/15 probands, a relatively preserved visual acuity was observed throughout follow-up. Olfactory function was preserved in only 4/15 patients, all of whom carried at least one missense variant. Our study supports previous reports of an autosomal recessive RP-olfactory dysfunction syndrome in association with certain disease-causing variants in the CNGB1 gene and expands the mutational spectrum of CNGB1-related disease by reporting two novel variants.
Assuntos
Transtornos do Olfato , Retinose Pigmentar , Humanos , Estudos Transversais , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Retinose Pigmentar/genética , Retinose Pigmentar/diagnóstico , Mutação , Fenótipo , Transtornos do Olfato/genéticaRESUMO
Night vision requires signaling from rod photoreceptors to adjacent bipolar cells in the retina. Mutations in the genes NYX and GRM6, expressed in ON bipolar cells, lead to a disruption of the ON bipolar cell response. This dysfunction is present in patients with complete X-linked and autosomal-recessive congenital stationary night blindness (CSNB) and can be assessed by standard full-field electroretinography (ERG), showing severely reduced rod b-wave amplitude and slightly altered cone responses. Although many cases of complete CSNB (cCSNB) are caused by mutations in NYX and GRM6, in approximately 60% of the patients the gene defect remains unknown. Animal models of human diseases are a good source for candidate genes, and we noted that a cCSNB phenotype present in homozygous Appaloosa horses is associated with downregulation of TRPM1. TRPM1, belonging to the family of transient receptor potential channels, is expressed in ON bipolar cells and therefore qualifies as an excellent candidate. Indeed, mutation analysis of 38 patients with CSNB identified ten unrelated cCSNB patients with 14 different mutations in this gene. The mutation spectrum comprises missense, splice-site, deletion, and nonsense mutations. We propose that the cCSNB phenotype in these patients is due to the absence of functional TRPM1 in retinal ON bipolar cells.
Assuntos
Genes Recessivos , Mutação , Cegueira Noturna/congênito , Cegueira Noturna/genética , Canais de Cátion TRPM/genética , Eletrorretinografia , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Modelos Genéticos , Cegueira Noturna/fisiopatologia , Núcleo Familiar , LinhagemRESUMO
The objective of this study was to determine the main causal diagnosis for spinocerebellar ataxia (SCA) in a geographically defined population of ataxia patients and to suggest a rational basis for choosing appropriate clinical and paraclinical assessments. Given the many aetiologies responsible for SCA, the diagnosis requires the performance of a wide range of paraclinical analyses. At present, there is no consensus on the diagnostic value of these examinations. Furthermore, most of the currently available data gathered by reference centres suffer from selection bias. We performed a prospective study of consecutive cerebellar ataxia patients referred by their family doctors to a university hospital in northern France. Multiple system atrophy and obvious secondary causes (e.g. alcoholism) were excluded by our screening process. The patient's family members were also assessed. Of the 204 patients examined, 47% presented autosomal dominant ataxia and 33% presented sporadic ataxia. Autosomal recessive ataxia was rare (8%) and age at onset was significantly earlier for this condition than for other forms. An aetiological diagnosis was established in 44% of patients, a plausible hypothesis could be formed in 13% of cases, and no diagnosis was made in the remaining 44%. Established diagnoses included SCA1, SCA2, SCA3 and SCA6 mutations, Friedreich's ataxia, and one rare case of ataxia associated with anti-glutamic acid decarboxylase antibodies. Two families presented ataxia associated with autosomal, dominant, optic atrophy with an OPA1 mutation. Mitochondrial diseases were suspected in about 10% of patients. In SCA, reliable determination of the transmission mode always requires the assessment of family members. Mitochondrial disease may be an emerging cause of ataxia. Metabolite assays appeared to be of little value when systematically performed and so should be prescribed only by metabolic disorder specialists in selected cases of sporadic and recessive ataxia. Ophthalmological examination was the most helpful physiological assessment.
Assuntos
Predisposição Genética para Doença/genética , Padrões de Herança/genética , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/etiologia , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ataxias Espinocerebelares/genética , Adulto JovemRESUMO
AIMS: To describe genetic and clinical findings in a French family affected by best vitelliform macular dystrophy (BVMD). METHODS: We screened eight at-risk members of a family, including a BVMD-affected proband, by direct sequencing of 11 bestrophin-1 (BEST1) exons. Individuals underwent ophthalmic examination and autofluorescent fundus imaging, indocyanine green angiography, electro-oculogram (EOG), electroretinogram (ERG), multifocal ERG, optical coherence tomography (OCT), and where possible, spectral domain OCT. RESULTS: The sequence analysis of the BEST1 gene revealed one previously unknown mutation, c.15C>A (p.Y5X), in two family members and one recently described mutation, c.430A>G (p.S144G), in five family members. Fundus examination and electrophysiological responses provided no evidence of the disease in the patient carrying only the p.Y5X mutation. Three patients with the p.S144G mutation did not show any preclinical sign of BVMD except altered EOGs. Two individuals of the family exhibited a particularly severe phenotype of multifocal BVMD-one individual carrying the p.S144G mutation heterozygously and one individual harboring both BEST1 mutations (p.S144G inherited from his mother and p.Y5X from his father). Both of these family members had multifocal vitelliform autofluorescent lesions combined with abnormal EOG, and the spectral domain OCT displayed a serous retinal detachment. In addition, ERGs demonstrated widespread retinal degeneration and multifocal ERGs showed a reduction in the central retina function, which could be correlated with the decreased visual acuity and visual field scotomas. CONCLUSIONS: A thorough clinical evaluation found no pathological phenotype in the patient carrying the isolated p.Y5X mutation. The patients carrying the p.S144G variation in the protein exhibited considerable intrafamilial phenotypic variability. Two young affected patients in this family exhibited an early onset, severe, multifocal BVMD with a diffuse distribution of autofluorescent deposits throughout the retina and rapid evolution toward the loss of central vision. The other genetically affected relatives had only abnormal EOGs and displayed no or extremely slow electrophysiological evolution.
Assuntos
Canais de Cloreto/genética , Proteínas do Olho/genética , Mutação , Distrofia Macular Viteliforme/genética , Adolescente , Adulto , Alelos , Bestrofinas , Criança , Eletroculografia/métodos , Eletrorretinografia/métodos , Éxons , Saúde da Família , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Retina/patologia , Análise de Sequência de DNA , Tomografia de Coerência Óptica/métodosRESUMO
PURPOSE: To evaluate a genetic approach of BEST1 and PRPH2 screening according to age of onset, family history, and Arden ratio in patients with juvenile vitelliform macular dystrophy (VMD2) or adult-onset vitelliform macular dystrophy (AVMD), which are characterized by autofluorescent deposits. DESIGN: Clinical, electrophysiologic, and molecular retrospective study. PARTICIPANTS: The database of a clinic specialized in genetic sensory diseases was screened for patients with macular vitelliform dystrophy. Patients with an age of onset less than 40 years were included in the VMD2 group (25 unrelated patients), and patients with an age of onset more than 40 years were included in the AVMD group (19 unrelated patients). METHODS: Clinical, fundus photography, and electro-oculogram (EOG) findings were reviewed. Mutation screening of BEST1 and PRPH2 genes was systematically performed. MAIN OUTCOME MEASURES: Relevance of age of onset, family history, and Arden ratio were reviewed. RESULTS: Patients with VMD2 carried a BEST1 mutation in 60% of the cases. Seven novel mutations in BEST1 (p.V9L, p.F80V, p.I73V, p.R130S, pF298C, pD302A, and p.179delN) were found. Patients with VMD2 with a positive family history or a reduced Arden ratio carried a BEST1 mutation in 70.5% of cases and in 83% if both criteria were fulfilled. Patients with AVMD carried a PRPH2 mutation in 10.5% of cases and did not carry a BEST1 mutation. The probability of finding a PRPH2 mutation increased in the case of a family history (2/5 patients). Electro-oculogram was normal in 3 of 15 patients with BEST1 mutations and reduced in the 3 patients with PRPH2 mutations. CONCLUSIONS: Age of onset is a major criterion to distinguish VMD2 from AVMD. Electro-oculogram is not as relevant because decreased or normal Arden ratios have been associated with mutations in both genes and diseases. A positive family history increased the probability of finding a mutation. BEST1 screening should be recommended to patients with an age of onset less than 40 years, and PRPH2 screening should be recommended to patients with an age of onset more than 40 years. For an onset between 30 and 40 years, PRPH2 can be screened if no mutation has been detected in BEST1. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.