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1.
Hum Genet ; 140(8): 1143-1156, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33974130

RESUMEN

Biallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic-intestinal and retinal-disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.


Asunto(s)
Enfermedades Hereditarias del Ojo/genética , Mucosa Intestinal/metabolismo , Síndromes de Malabsorción/genética , Microvellosidades/patología , Mucolipidosis/genética , Polimorfismo de Nucleótido Simple , Proteínas Qa-SNARE/genética , Células Fotorreceptoras Retinianas Conos/metabolismo , Distrofias Retinianas/genética , Anciano , Anciano de 80 o más Años , Oxidorreductasas de Alcohol/genética , Oxidorreductasas de Alcohol/metabolismo , Animales , Autopsia , Proteínas Co-Represoras/genética , Proteínas Co-Represoras/metabolismo , Enfermedades Hereditarias del Ojo/metabolismo , Enfermedades Hereditarias del Ojo/patología , Femenino , Regulación de la Expresión Génica , Homocigoto , Humanos , Mucosa Intestinal/patología , Síndromes de Malabsorción/metabolismo , Síndromes de Malabsorción/patología , Ratones , Ratones Noqueados , Microvellosidades/genética , Microvellosidades/metabolismo , Mucolipidosis/metabolismo , Mucolipidosis/patología , Fenotipo , Proteínas Qa-SNARE/deficiencia , ARN Mensajero/genética , ARN Mensajero/metabolismo , Células Fotorreceptoras Retinianas Conos/patología , Distrofias Retinianas/metabolismo , Distrofias Retinianas/patología , Rodopsinas Sensoriales/genética , Rodopsinas Sensoriales/metabolismo , Secuenciación del Exoma
2.
Klin Monbl Augenheilkd ; 237(6): 805-823, 2020 Jun.
Artículo en Alemán | MEDLINE | ID: mdl-32303072

RESUMEN

The ophthalmological appraisal differs significantly in the different areas of law, so there are some different causalities and standards of proof and, above all, the assessment is very different. For the three important sub-areas of private accident insurance, statutory accident insurance as well as disability law and social compensation law, there are abstract tabular guidelines which form the essential basis for a comparable and thus fair assessment. The basics of the assessment in these fields of law are presented in a comparative way, with particular emphasis on causality.


Asunto(s)
Testimonio de Experto , Oftalmología , Compensación y Reparación , Evaluación de la Discapacidad , Humanos , Seguro por Accidentes
3.
Klin Monbl Augenheilkd ; 237(3): 239-247, 2020 Mar.
Artículo en Alemán | MEDLINE | ID: mdl-32182628

RESUMEN

The Bardet-Biedl syndrome (BBS) is a rare inherited ciliopathy, which is accompanied by retinal disease, i.e. rod-cone dystrophy (retinitis pigmentosa, RP) and other symptoms, especially truncal obesity, polydactyly, renal abnormalities as well as reduced intelligence or learning difficulties. 25 BBS genes are currently known, and these are responsible for the structure and function of primary cilia. Because ciliary integrity is crucial for numerous pathways of developmental signaling, their dysfunction may cause multisystemic disorders - like BBS. Physicians benefit greatly from new molecular genetic methods that have made genetically heterogeneous conditions diagnostically accessible: By next-generation sequencing (NGS), all BBS-associated genes can be analysed simultaneously in a gene panel. As regards the retinal phenotype, genotype-phenotype correlations are not significant. Besides classical autosomal recessive inheritance, oligogenic/triallelic traits have been reported, but these seem to play a minor role, if any (as a growing number of large-scale NGS-based studies suggests). In the absence of causal therapy, the mainstay of ophthalmological endeavour is focused on visual rehabilitation with low vision aids, use of the white cane and training to develop everyday life skills.


Asunto(s)
Síndrome de Bardet-Biedl , Retinitis Pigmentosa , Estudios de Seguimiento , Estudios de Asociación Genética , Humanos , Fenotipo
4.
Fortschr Neurol Psychiatr ; 86(1): 28-36, 2018 01.
Artículo en Alemán | MEDLINE | ID: mdl-29342484

RESUMEN

The requirements regarding visual functioning needed for driving ability are stipulated in Annex 6 of the German driving licence regulations: In case of a visual disorder an ophthalmological assessment is essential: It is of crucial importance for the examining ophthalmologist to exhaust all ocular-medical possibilities to enable the applicant to maintain or regain his driving permission. In the overwhelming majority of the cases this is eminently feasible.However, there is no way to attest driving ability in a patient suffering acute one-sided visual loss for a period of 3 months on the basis of legal recommendations. Concerning oculomotor disturbances, the expansion of the diplopic central visual field and the subjective restriction caused thereby are important: the central 20 degree area must be free of diplopia.According to the German driving license regulations, absolute homonymous visual field defects such as hemianopsia or quadrantic defects affecting the visual centre are incompatible with driving an automobile. Even training measures causing the patient to experience a sense of smooth orientation do nothing to mitigate this fact.Dealing with serious disturbances of visual function, as a matter of principle an ophthalmologist should provide an additional expertise before a positive decision on driving ability is made.


Asunto(s)
Conducción de Automóvil/legislación & jurisprudencia , Conducción de Automóvil/psicología , Enfermedades del Sistema Nervioso/psicología , Trastornos de la Visión/psicología , Alemania , Hemianopsia/complicaciones , Humanos , Concesión de Licencias , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Nervio Oculomotor/psicología , Oftalmólogos , Trastornos de la Visión/diagnóstico , Trastornos de la Visión/terapia , Pruebas de Visión , Pruebas del Campo Visual
6.
Am J Hum Genet ; 93(1): 110-7, 2013 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-23746546

RESUMEN

The majority of the genetic causes of autosomal-recessive (ar) cone-rod dystrophy (CRD) are currently unknown. A combined approach of homozygosity mapping and exome sequencing revealed a homozygous nonsense mutation (c.565C>T [p.Glu189*]) in RAB28 in a German family with three siblings with arCRD. Another homozygous nonsense mutation (c.409C>T [p.Arg137*]) was identified in a family of Moroccan Jewish descent with two siblings affected by arCRD. All five affected individuals presented with hyperpigmentation in the macula, progressive loss of the visual acuity, atrophy of the retinal pigment epithelium, and severely reduced cone and rod responses on the electroretinogram. RAB28 encodes a member of the Rab subfamily of the RAS-related small GTPases. Alternative RNA splicing yields three predicted protein isoforms with alternative C-termini, which are all truncated by the nonsense mutations identified in the arCRD families in this report. Opposed to other Rab GTPases that are generally geranylgeranylated, RAB28 is predicted to be farnesylated. Staining of rat retina showed localization of RAB28 to the basal body and the ciliary rootlet of the photoreceptors. Analogous to the function of other RAB family members, RAB28 might be involved in ciliary transport in photoreceptor cells. This study reveals a crucial role for RAB28 in photoreceptor function and suggests that mutations in other Rab proteins may also be associated with retinal dystrophies.


Asunto(s)
Genes Recesivos , Retinitis Pigmentosa/genética , Proteínas de Unión al GTP rab/genética , Adolescente , Adulto , Empalme Alternativo , Animales , Niño , Mapeo Cromosómico , Cilios/metabolismo , Cilios/patología , Codón sin Sentido/genética , Regulación de la Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Homocigoto , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Linaje , Cilio Conector de los Fotorreceptores/metabolismo , Cilio Conector de los Fotorreceptores/patología , Prenilación de Proteína , Transporte de Proteínas , Ratas , Retina/enzimología , Retina/patología , Epitelio Pigmentado de la Retina/enzimología , Epitelio Pigmentado de la Retina/patología , Células Fotorreceptoras Retinianas Bastones/enzimología , Células Fotorreceptoras Retinianas Bastones/patología , Retinitis Pigmentosa/enzimología , Retinitis Pigmentosa/patología , Agudeza Visual , Proteínas de Unión al GTP rab/metabolismo
7.
Ophthalmology ; 123(6): 1375-85, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26976702

RESUMEN

PURPOSE: To elucidate the functional effect of the ABCA4 variant c.5461-10T→C, one of the most frequent variants associated with Stargardt disease (STGD1). DESIGN: Case series. PARTICIPANTS: Seventeen persons with STGD1 carrying ABCA4 variants and 1 control participant. METHODS: Haplotype analysis of 4 homozygotes and 11 heterozygotes for c.5461-10T→C and sequence analysis of the ABCA4 gene for a homozygous proband. Fibroblasts were reprogrammed from 3 persons with STGD1 into induced pluripotent stem cells, which were differentiated into photoreceptor progenitor cells (PPCs). The effect of the c.5461-10T→C variant on RNA splicing by reverse-transcription polymerase chain reaction was analyzed using PPC mRNA. In vitro assays were performed with minigene constructs containing ABCA4 exon 39. We analyzed the natural history and ophthalmologic characteristics of 4 persons homozygous for c.5461-10T→C. MAIN OUTCOME MEASURES: Haplotype and rare variant data for ABCA4, RNA splice defects, age at diagnosis, visual acuity, fundus appearance, visual field, electroretinography (ERG) results, fluorescein angiography results, and fundus autofluorescence findings. RESULTS: The frequent ABCA4 variant c.5461-10T→C has a subtle effect on splicing based on prediction programs. A founder haplotype containing c.5461-10T→C was found to span approximately 96 kb of ABCA4 and did not contain other rare sequence variants. Patient-derived PPCs showed skipping of exon 39 or exons 39 and 40 in the mRNA. HEK293T cell transduction with minigenes carrying exon 39 showed that the splice defects were the result of the c.5461-10T→C variant. All 4 subjects carrying the c.5461-10T→C variant in a homozygous state showed a young age of STGD1 onset, with low visual acuity at presentation and abnormal cone ERG results. All 4 demonstrated severe cone-rod dystrophy before 20 years of age and were legally blind by 25 years of age. CONCLUSIONS: The ABCA4 variant c.5461-10T→C is located on a founder haplotype lacking other disease-causing rare sequence variants. In vitro studies revealed that it leads to mRNA exon skipping and ABCA4 protein truncation. Given the severe phenotype in persons homozygous for this variant, we conclude that this variant results in the absence of ABCA4 activity.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Empalme Alternativo , Exones/genética , Degeneración Macular/congénito , Células Fotorreceptoras de Vertebrados/fisiología , ARN Mensajero/genética , Células Madre/fisiología , Adulto , Análisis Mutacional de ADN , Electrorretinografía , Femenino , Fibroblastos/metabolismo , Angiografía con Fluoresceína , Células HEK293 , Haplotipos , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Degeneración Macular/diagnóstico , Degeneración Macular/genética , Degeneración Macular/fisiopatología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Sitios de Empalme de ARN/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Enfermedad de Stargardt , Transfección , Agudeza Visual/fisiología , Campos Visuales/fisiología , Adulto Joven
9.
Mol Vis ; 20: 753-9, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24940029

RESUMEN

PURPOSE: The gene encoding nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) was recently found to be mutated in a subset of patients with Leber congenital amaurosis (LCA) with macular atrophy. The aim of this study was to determine the occurrence and frequency of NMNAT1 mutations and associated phenotypes in different types of inherited retinal dystrophies. METHODS: DNA samples of 161 patients with LCA without genetic diagnosis were analyzed for variants in NMNAT1 using Sanger sequencing. Variants in exon 5 of NMNAT1, which harbors the majority of the previously identified mutations, were screened in 532 additional patients with retinal dystrophies. This cohort encompassed 108 persons with isolated or autosomal recessive cone-rod dystrophy (CRD), 271 with isolated or autosomal recessive retinitis pigmentosa (RP), and 49 with autosomal dominant RP, as well as 104 persons with LCA in whom the causative mutation was previously identified. RESULTS: Compound heterozygous alterations were found in six patients with LCA and in one person with early-onset RP. All except one carried the common p.E257K variant on one allele. Macular atrophy was absent in one patient, who carried this variant in combination with a truncating mutation on the other allele. The p.E257K alteration was also found in a heterozygous state in five individuals with LCA and one with RP while no mutation was detected on the other allele. Two individuals with LCA carried other NMNAT1 variants in a heterozygous state, whereas no NMNAT1 variants in exon 5 were identified in individuals with CRD. The p.E257K variant was found to be enriched in a heterozygous state in individuals with LCA (0.94%) compared to Caucasian controls (0.18%), although the difference was statistically insignificant (p=0.12). CONCLUSIONS: Although macular atrophy can occur in LCA and CRD, no NMNAT1 mutations were found in the latter cohort. NMNAT1 variants were also not found in a large group of patients with sporadic or autosomal recessive RP. The enrichment of p.E257K in a heterozygous state in patients with LCA versus controls suggests that this allele could act as a modifier in other genetic subtypes of LCA.


Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Heterocigoto , Amaurosis Congénita de Leber/enzimología , Amaurosis Congénita de Leber/genética , Nicotinamida-Nucleótido Adenililtransferasa/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Adulto Joven
10.
Hum Mutat ; 34(11): 1537-1546, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23946133

RESUMEN

This study was undertaken to investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early-onset retinal dystrophy (EORD), and autosomal recessive retinitis pigmentosa (arRP); to delineate the ocular phenotypes; and to provide an overview of all published LCA5 variants in an online database. Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging were possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of retinitis pigmentosa (RP) were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were prescreened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of retinal pigment epithelium. One of the families with a milder phenotype harbored a homozygous splice site mutation; a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1,008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for ∼2% of disease in this cohort, and the majority of LCA5 mutations are likely null. The LCA5 protein truncating mutations are predominantly associated with LCA. However, in two families with the milder EORD, the LCA5 gene analysis revealed a homozygous splice site mutation in one and a stop mutation in combination with a missense mutation in a second family, suggesting that this milder phenotype is due to residual function of lebercilin and expanding the currently known phenotypic spectrum to include the milder early onset RP. Some patients have remaining foveal cone structures (intact IS/OS junctions on OCT imaging) and remaining visual acuities, which may bode well for upcoming treatment trials.


Asunto(s)
Proteínas del Ojo/genética , Estudios de Asociación Genética , Amaurosis Congénita de Leber/genética , Proteínas Asociadas a Microtúbulos/genética , Mutación , Retinitis Pigmentosa/genética , Adolescente , Adulto , Alelos , Niño , Preescolar , Consanguinidad , Femenino , Angiografía con Fluoresceína , Genotipo , Humanos , Lactante , Recién Nacido , Amaurosis Congénita de Leber/diagnóstico , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Retina/patología , Retinitis Pigmentosa/diagnóstico , Adulto Joven
11.
PLoS One ; 16(9): e0256985, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34473779

RESUMEN

This multicenter, open-label study aimed to determine the safety and functional outcome of a high-addition segmented refractive bifocal intraocular lens (IOL) in late inactive age-related macular degeneration (AMD). Twenty eyes of 20 patients were enrolled and followed until 12 months after the intervention. Patients underwent cataract surgery with implantation of a LS-313 MF80 segmented refractive bifocal intraocular lens with a near addition of +8.0 D (Teleon Surgical Vertriebs GmbH, Berlin, Germany). The main outcome measures were distance corrected near visual acuity (DCNVA) and safety as determined by intra- and post-operative complications. Secondary outcomes included distance corrected visual acuity (CDVA), uncorrected distance visual acuity (UDVA), uncorrected near visual acuity (UNVA), the need for magnification to read newspaper, preferred reading distance, speed and performance (logRAD), as well as patient satisfaction. Mean DCNVA improved from 0.95 (±0.19) to 0.74 (±0.35) logMAR, until 6 months after surgery, P<0.05. CDVA improved from 0.70 (±0.23) to 0.59 (±0.30) logMAR, UDVA from 0.94 (±0.25) to 0.69 (±0.34) logMAR, UNVA from 1.08 (±0.19) to 0.87 (±0.43) logMAR. The mean need for magnification decreased from 2.9- to 2.3-fold, preferred reading distance from 23 to 20 cm. No intraoperative complications occurred during any of the surgeries. One patient lost > 2 lines of CDVA between 6 and 12 months, in another case, the study IOL was exchanged for a monofocal one due to dysphotopsia and decreased CDVA. Implantation of a segmented refractive bifocal IOL with +8.0 D addition improves near and distance vision in patients with late AMD and has a satisfactory safety profile.


Asunto(s)
Extracción de Catarata/efectos adversos , Extracción de Catarata/métodos , Implantación de Lentes Intraoculares/efectos adversos , Implantación de Lentes Intraoculares/métodos , Lentes Intraoculares , Degeneración Macular/cirugía , Diseño de Prótesis , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Degeneración Macular/diagnóstico por imagen , Masculino , Proyectos Piloto , Complicaciones Posoperatorias , Lectura , Refracción Ocular , Tomografía de Coherencia Óptica/métodos , Resultado del Tratamiento , Agudeza Visual
12.
Prog Retin Eye Res ; 27(5): 536-48, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18723109

RESUMEN

The advances in retinal imaging technologies have led to enormous innovation towards diagnostic in current ophthalmology, enabling the practitioner to detect early retinal changes and to document treatment effects. While, in the past, retinoscopy, visual acuity testing and perimetry played the major role in functional diagnostics, today, laser-based systems like laser scanning imaging systems especially for fluorescein-angiography, optical coherence tomography, electrodiagnostic systems and the analysis of retinal vessels may be used as well. However, the challenge to correlate subjective alterations or clinical changes with visual function, still remains. Micro- or fundus perimetry offers the option to test retinal sensitivity while directly observing the fundus. In this paper, we review the literature encompassing the results of more than 25 years of fundus perimetry, i.e. perimetry under simultaneous visualization of the fundus. During this time, results on known diseases and reproducibility of the technique were published, but a lot of work was also performed on the combination of different examination methods, allowing a synopsis of long-term results and new approaches by combining different methods and improving each of them. The first part of this review attends to improvements of the method. The second part addresses the clinical and diagnostic values. The final part is dedicated to diagnostic and long-term observation of fundus perimetric results beginning with common and rare diseases like age-related macular degeneration, macular holes and diabetic retinopathy, various types of macular dystrophies ending with challenges in conventional perimetry like glaucoma and malingering. Due to the experience and progress in the field of fundus perimetry and retinal imaging, the method has long passed its role of observing and has all the potential for prediction, early detection and treatment-monitoring of macular diseases.


Asunto(s)
Fondo de Ojo , Mácula Lútea/fisiología , Pruebas del Campo Visual , Campos Visuales/fisiología , Animales , Humanos , Enfermedades de la Retina/fisiopatología , Trastornos de la Visión/fisiopatología
13.
Ophthalmologe ; 116(11): 1058-1063, 2019 Nov.
Artículo en Alemán | MEDLINE | ID: mdl-30927070

RESUMEN

PURPOSE: Landolt rings are commonly used for the measurement of visual acuity, especially for legal purposes. For multiple reasons, in clinical practice these optotypes are not in use and not practical. Therefore, the difference between visual acuity tested with Landolt rings as opposed to numbers was evaluated. METHODS: Visual acuity measurements of 2335 eyes from 1394 patients (aged 5-98 years, median 51 years) were retrospectively analyzed at the Low Vision Department of the University of Heidelberg. The patients had a broad range of ophthalmological disorders. In all patients the measurement of visual acuity was performed with numbers as well as Landolt rings according to DIN 58220. Visual acuity was determined in LogMAR and compared between the two optotypes. RESULTS: Correlation between both optotypes was high with r2 = 0.927 but there was a pronounced mean difference in visual acuity of 0.13 ± 0.14 LogMAR. Using numbers, visual acuity was 0.13 LogMAR higher, somewhat more than one line. These differences were mostly independent of visual acuity and increased slightly with age; however, the variations were greater for lower visual acuity. CONCLUSION: Whereas in clinical practice visual acuity is typically determined using numbers and early treatment diabetic retinopathy study (ETDRS) charts are the gold standard for a scientific assessment of visual acuity, only the use of Landolt rings enables an examination without the influence of form recognition. The use of Landolt rings is therefore valid for legal reasons in Europe according to EN ISO 8596 and in Germany according to DIN 58220. Comparing Landolt rings with the Snellen E chart or LEA symbols, these results confirm previous reports that visual acuity measured with Landolt rings results in lower visual acuity. On average visual acuity is approximately one line worse than when tested with numbers, a fact that has to be taken into account when comparing different examination results. This may be explained by incorrect correlation of the used numbers exceeding the allowed difference in eligibility of 0.05 LogMAR. Hence, it is important for legal assessment to measure visual acuity correctly with Landolt rings.


Asunto(s)
Pruebas de Visión , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Alemania , Humanos , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Agudeza Visual , Adulto Joven
14.
Invest Ophthalmol Vis Sci ; 59(8): 3220-3231, 2018 07 02.
Artículo en Inglés | MEDLINE | ID: mdl-29971439

RESUMEN

Purpose: To assess the occurrence and the disease expression of the common p.Asn1868Ile variant in patients with Stargardt disease (STGD1) harboring known, monoallelic causal ABCA4 variants. Methods: The coding and noncoding regions of ABCA4 were sequenced in 67 and 63 STGD1 probands respectively, harboring monoallelic ABCA4 variants. In case p.Asn1868Ile was detected, segregation analysis was performed whenever possible. Probands and affected siblings harboring p.Asn1868Ile without additional variants in cis were clinically evaluated retrospectively. Two asymptomatic siblings carrying the same ABCA4 variants as their probands were clinically examined. The penetrance of p.Asn1868Ile was calculated using allele frequency data of ABCA4 variants in non-Finnish European individuals. Results: The p.Asn1868Ile variant was found in cis with known variants in 14/67 probands. In 27/67 probands, we identified p.Asn1868Ile without additional variants in cis, in combination with known, mainly severe ABCA4 variants. In 23/27 probands, the trans configuration was established. Among 27 probands and 6/7 STGD1 siblings carrying p.Asn1868Ile, 42% manifested late-onset disease (>44 years). We additionally identified four asymptomatic relatives carrying a combination of a severe variant and p.Asn1868Ile; ophthalmologic examination in two persons did not reveal STGD1. Based on ABCA4 allele frequency data, we conservatively estimated the penetrance of p.Asn1868Ile, when present in trans with a severe variant, to be below 5%. Conclusions: A significant fraction of genetically unexplained STGD1 cases carries p.Asn1868Ile as a second variant. Our findings suggest exceptional differences in disease expression or even nonpenetrance of this ABCA4 variant, pointing toward an important role for genetic or environmental modifiers in STGD1.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Degeneración Macular/congénito , Mutación , Polimorfismo de Nucleótido Simple , Adulto , Edad de Inicio , Anciano , Electrorretinografía , Femenino , Angiografía con Fluoresceína , Frecuencia de los Genes , Prueba de Complementación Genética , Humanos , Degeneración Macular/diagnóstico , Degeneración Macular/genética , Degeneración Macular/fisiopatología , Masculino , Persona de Mediana Edad , Linaje , Penetrancia , Estudios Retrospectivos , Análisis de Secuencia de ADN , Hermanos , Enfermedad de Stargardt , Tomografía de Coherencia Óptica , Agudeza Visual/fisiología
15.
Invest Ophthalmol Vis Sci ; 48(8): 3788-95, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17652753

RESUMEN

PURPOSE: To assess changes of the light increment sensitivity (LIS) of the macular area in patients with type 2 idiopathic macular telangiectasia (IMT). METHODS: Fifty-eight eyes of 30 patients were examined in a cross-sectional study. All eyes were assigned to group A (early disease stages) or group B (late disease stages with retinal pigment clumping or vascular membranes). Investigation of visual function included visual acuity and fundus-related microperimetry. RESULTS: Thirty-seven and 16 eyes were assigned to group A and group B, respectively. Temporal to the fovea, each eye of group B had an absolute scotoma. Topographically, the areas with reduced LIS correlated well with the angiographically hyperfluorescent areas or retinal pigmentations and showed a sharp demarcation from areas with normal LIS. However, within areas with angiographic alterations, at least some test locations exhibited preserved LIS in group B eyes; in 51% of group A eyes, none of those test locations showed abnormal LIS. Group A eyes that showed marked LIS reduction revealed common abnormalities: either hyporeflective spaces between the neurosensory retina and the retinal pigment epithelium in OCT imaging or atrophic areas, both topographically related to the scotoma. Visual acuity was correlated with foveal LIS but not with the LIS temporal to the fovea. CONCLUSIONS: Long-standing morphologic macular alterations from type 2 IMT are associated with topographically related functional impairment. Eyes with profound parafoveal scotomas can exhibit relatively preserved visual acuity. Therefore, testing for retinal light sensitivity should be included as an additional outcome measure for future interventional studies.


Asunto(s)
Mácula Lútea/irrigación sanguínea , Mácula Lútea/patología , Índice de Severidad de la Enfermedad , Telangiectasia/patología , Anciano , Anciano de 80 o más Años , Estudios Transversales , Progresión de la Enfermedad , Femenino , Angiografía con Fluoresceína , Humanos , Mácula Lútea/fisiopatología , Masculino , Persona de Mediana Edad , Pigmentos Retinianos/metabolismo , Escotoma/patología , Escotoma/fisiopatología , Telangiectasia/fisiopatología , Tomografía de Coherencia Óptica , Agudeza Visual
16.
Invest Ophthalmol Vis Sci ; 48(12): 5690-8, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18055821

RESUMEN

PURPOSE: Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) cause severe visual impairment early in life. Thus far, mutations in 13 genes have been associated with autosomal recessive LCA and juvenile RP. The purpose of this study was to use homozygosity mapping to identify mutations in known LCA and juvenile RP genes. METHODS: The genomes of 93 consanguineous and nonconsanguineous patients with LCA and juvenile RP were analyzed for homozygous chromosomal regions by using SNP microarrays. This patient cohort was highly selected, as mutations in the known genes had been excluded with the LCA mutation chip, or a significant number of LCA genes had been excluded by comprehensive mutation analysis. Known LCA and juvenile RP genes residing in the identified homozygous regions were analyzed by sequencing. Detailed ophthalmic examinations were performed on the genotyped patients. RESULTS: Ten homozygous mutations, including seven novel mutations, were identified in the CRB1, LRAT, RPE65, and TULP1 genes in 12 patients. Ten patients were from consanguineous marriages, but in two patients no consanguinity was reported. In 10 of the 12 patients, the causative mutation was present in the largest or second largest homozygous segment of the patient's genome. CONCLUSIONS: Homozygosity mapping using SNP microarrays identified mutations in a significant proportion (30%) of consanguineous patients with LCA and juvenile RP and in a small number (3%) of nonconsanguineous patients. Significant homozygous regions which did not map to known LCA or juvenile RP genes and may be instrumental in identifying novel disease genes were detected in 33 patients.


Asunto(s)
Ceguera/genética , Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Retinitis Pigmentosa/genética , Ceguera/congénito , Niño , Preescolar , Consanguinidad , Análisis Mutacional de ADN , Femenino , Perfilación de la Expresión Génica , Genotipo , Homocigoto , Humanos , Lactante , Recién Nacido , Masculino , Linaje , Retinitis Pigmentosa/congénito
17.
Mol Genet Genomic Med ; 5(5): 531-552, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28944237

RESUMEN

BACKGROUND: Combined retinal degeneration and sensorineural hearing impairment is mostly due to autosomal recessive Usher syndrome (USH1: congenital deafness, early retinitis pigmentosa (RP); USH2: progressive hearing impairment, RP). METHODS: Sanger sequencing and NGS of 112 genes (Usher syndrome, nonsyndromic deafness, overlapping conditions), MLPA, and array-CGH were conducted in 138 patients clinically diagnosed with Usher syndrome. RESULTS: A molecular diagnosis was achieved in 97% of both USH1 and USH2 patients, with biallelic mutations in 97% (USH1) and 90% (USH2), respectively. Quantitative readout reliably detected CNVs (confirmed by MLPA or array-CGH), qualifying targeted NGS as one tool for detecting point mutations and CNVs. CNVs accounted for 10% of identified USH2A alleles, often in trans to seemingly monoallelic point mutations. We demonstrate PTC124-induced read-through of the common p.Trp3955* nonsense mutation (13% of detected USH2A alleles), a potential therapy target. Usher gene mutations were found in most patients with atypical Usher syndrome, but the diagnosis was adjusted in case of double homozygosity for mutations in OTOA and NR2E3, genes implicated in isolated deafness and RP. Two patients with additional enamel dysplasia had biallelic PEX26 mutations, for the first time linking this gene to Heimler syndrome. CONCLUSION: Targeted NGS not restricted to Usher genes proved beneficial in uncovering conditions mimicking Usher syndrome.

18.
Invest Ophthalmol Vis Sci ; 47(3): 1167-76, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16505055

RESUMEN

PURPOSE: To test the efficiency of a microarray chip as a diagnostic tool in a cohort of northwestern European patients with Leber congenital amaurosis (LCA) and to perform a genotype-phenotype analysis in patients in whom pathologic mutations were identified. METHODS: DNAs from 58 patients with LCA were analyzed using a microarray chip containing previously identified disease-associated sequence variants in six LCA genes. Mutations identified by chip analysis were confirmed by sequence analysis. On identification of one mutation, all protein coding exons of the relevant genes were sequenced. In addition, sequence analysis of the RDH12 gene was performed in 22 patients. Patients with mutations were phenotyped. RESULTS: Pathogenic mutations were identified in 19 of the 58 patients with LCA (32.8%). Four novel sequence variants were identified. Mutations were most frequently found in CRB1 (15.5%), followed by GUCY2D (10.3%). The p.R768W mutation was found in 8 of 10 GUCY2D alleles, suggesting that it is a founder mutation in the northwest of Europe. In early childhood, patients with AIPL1 or GUCY2D mutations show normal fundi. Those with AIPL1-associated LCA progress to an RP-like fundus before the age of 8, whereas patients with GUCY2D-associated LCA still have relatively normal fundi in their mid-20s. Patients with CRB1 mutations present with distinct fundus abnormalities at birth and consistently show characteristics of RP12. Pathogenic GUCY2D mutations result in the most severe form of LCA. CONCLUSIONS: Microarray-based mutation detection allowed the identification of 32% of LCA sequence variants and represents an efficient first-pass screening tool. Mutations in CRB1, and to a lesser extent, in GUCY2D, underlie most LCA cases in this cohort. The present study establishes a genotype-phenotype correlation for AIPL1, CRB1, and GUCY2D.


Asunto(s)
Ceguera/congénito , Ceguera/genética , Proteínas Portadoras/genética , Proteínas del Ojo/genética , Guanilato Ciclasa/genética , Proteínas de la Membrana/genética , Mutación , Proteínas del Tejido Nervioso/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Receptores de Superficie Celular/genética , Proteínas Adaptadoras Transductoras de Señales , Oxidorreductasas de Alcohol/genética , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas/métodos , Genotipo , Humanos , Lactante , Masculino , Fenotipo , Retinitis Pigmentosa/congénito , Retinitis Pigmentosa/genética , cis-trans-Isomerasas
19.
Am J Ophthalmol ; 142(1): 17-30, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16815247

RESUMEN

PURPOSE: To evaluate the autologous translocation of peripheral choroid and retinal pigment epithelium (RPE) in 45 eyes of 43 patients with age-related macular degeneration (AMD). DESIGN: Prospective nonrandomized study. METHODS: All patients had visual loss due to AMD (n = 5 classic membranes, n = 14 occult, n = 2 mixed, n = 16 pigment epithelial detachment (PED), n = 5 subretinal hemorrhage, n = 3 geographic atrophy). After extraction of the neovascular complex, an autologous peripheral full-thickness explant of RPE, Bruch membrane, and choroid was translocated from the midperiphery to the macula. RESULTS: Preoperative distant visual acuity ranged from 20/800 to 20/40. Reading vision ranged from 1.4 logarithm of reading acuity determination (logRAD) to 0.5 logRAD (0.04 to 0.32 Snellen equivalent). Revision surgery was required in 22 eyes as a result of proliferative vitreoretinopathy (PVR), retinal detachment, macular pucker, or vitreous hemorrhage. In eight patients, the patch was renewed. At six months, distant visual acuity ranged from light perception to 20/50 (increase of 15 letters in four eyes). Reading vision ranged from 1.4 to 0.4 logRAD. Visual outcome was unrelated to the type of AMD. Vascularization of the transplant was visible on indocyanine green (ICG) angiography in 40 of 42 eyes. In most patients, autofluorescence of the pigment epithelium was coincident with revascularization of the graft. Fixation on the patch was positively related to visual acuity. CONCLUSIONS: Autologous translocation of a full-thickness transplant of choroid and RPE usually results in a vascularized and functioning graft. Vascularization was even achieved in patients with geographic atrophy. Fixation stability and microperimetry before the patch translocation may be helpful in selecting patients who will profit from surgery.


Asunto(s)
Coroides/trasplante , Degeneración Macular/cirugía , Epitelio Pigmentado Ocular/trasplante , Anciano , Lámina Basal de la Coroides/trasplante , Coroides/irrigación sanguínea , Colorantes , Femenino , Angiografía con Fluoresceína , Humanos , Verde de Indocianina , Degeneración Macular/diagnóstico , Masculino , Neovascularización Fisiológica , Complicaciones Posoperatorias , Estudios Prospectivos , Reoperación , Trasplante Autólogo , Agudeza Visual , Pruebas del Campo Visual , Campos Visuales
20.
Eur J Hum Genet ; 24(3): 459-62, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26153215

RESUMEN

Several genes have been implicated in the autosomal recessive form of cone-rod dystrophy (CRD), but the majority of cases remain unsolved. We identified a homozygous interval comprising two known genes associated with the autosomal recessive form of CRD, namely RAB28 and PROM1, in a consanguineous family with clinical evidence of CRD. Both genes proved to be mutation negative upon sequencing of exons and canonical splice sites but whole-genome sequencing revealed a private variant located deep in intron 18 of PROM1. In silico and functional analyses of this variant using minigenes as splicing reporters revealed the integration of a pseudoexon in the mutant transcript, thereby leading to a premature termination codon and presumably resulting in a functional null allele. This is the first report of a deep intronic variant that acts as a splicing mutation in PROM1. The detection of such variants escapes the exon-focused techniques typically used in genetic analyses. Sequencing the entire genomic regions of known disease genes might identify more causal mutations in the autosomal recessive form of CRD.


Asunto(s)
Antígenos CD/genética , Exones/genética , Predisposición Genética a la Enfermedad , Genoma Humano , Glicoproteínas/genética , Intrones/genética , Mutación/genética , Péptidos/genética , Retinitis Pigmentosa/genética , Antígeno AC133 , Secuencia de Aminoácidos , Antígenos CD/química , Secuencia de Bases , Análisis Mutacional de ADN , Femenino , Glicoproteínas/química , Células HEK293 , Homocigoto , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Péptidos/química , Empalme del ARN/genética
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