Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23
Filtrar
1.
J Geriatr Psychiatry Neurol ; 36(3): 201-214, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-35943443

RESUMO

Frontotemporal degeneration (FTD) is an umbrella term encompassing a range of rare neurodegenerative disorders that cause progressive declines in cognition, behavior, and personality. Hearing directly from individuals living with FTD and their care partners is critical in optimizing care, identifying meaningful clinical trial endpoints, and improving research recruitment and retention. The current paper presents a subset of data from the FTD Insights Survey, chronicling the diagnostic journey, symptoms, and the impact of FTD on distress, quality of life, and independence, in the mild to moderate stages of the disease. Survey respondents included 219 individuals diagnosed with FTD and 437 current care partners, representing a range of FTD diagnoses. Around half of survey respondents reported seeing three or more doctors before an FTD diagnosis was given, and a range of prior diagnoses were noted. Most frequently endorsed symptoms tended to be consistent with clinical characteristics of the specific diagnosis, though there was significant variability in symptoms reported within diagnostic categories as well as considerable overlap in symptoms between diagnostic categories. Cognitive and language symptoms of FTD were generally most distressing to the person diagnosed, and a loss of independence was endorsed as affecting quality of life. The distinct perspectives of diagnosed persons and care partners regarding disease impact differed notably for bvFTD/Pick's disease. Participating independently in a range of activities, within the home, outside the home, and with other people, were reported as challenging for people living with FTD, underscoring the degree to which the lives of these individuals are affected even at the mild and moderate stages of disease. Overall, by heeding the perspectives of those living with FTD, we can begin to design more meaningful research studies, provide better care, and develop therapies that improve quality of life.


Assuntos
Demência Frontotemporal , Doenças Neurodegenerativas , Humanos , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/psicologia , Qualidade de Vida , Atrofia
2.
Exp Eye Res ; 171: 48-53, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29499183

RESUMO

The cyclic nucleotide-gated (CNG) channel - composed of CNGA3 and CNGB3 subunits - mediates the influx of cations in cone photoreceptors after light stimulation and thus is a key element in cone phototransduction. Mutations in CNGA3 and CNGB3 are associated with achromatopsia, a rare autosomal recessive retinal disorder. Here, we demonstrate that the presence of an early nonsense mutation in CNGA3 induces the usage of a downstream alternative translation initiation site giving rise to a short CNGA3 isoform. The expression of this short isoform was verified by Western blot analysis and DAB staining of HEK293 cells and cone photoreceptor-like 661W cells expressing CNGA3-GST fusion constructs. Functionality of the short isoform was confirmed by a cellular calcium influx assay. Furthermore, patients carrying an early nonsense mutation were analyzed for residual cone photoreceptor function in order to identify a potential role of the short isoform to modify the clinical outcome in achromatopsia patients. Yet the results suggest that the short isoform is not able to compensate for the loss of the long isoform leaving the biological role of this variant unclear.


Assuntos
Códon sem Sentido/genética , Defeitos da Visão Cromática/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Regulação da Expressão Gênica/fisiologia , Iniciação Traducional da Cadeia Peptídica/genética , Isoformas de Proteínas/genética , Animais , Western Blotting , Linhagem Celular , Defeitos da Visão Cromática/metabolismo , Eletroforese em Gel de Poliacrilamida , Células HEK293/metabolismo , Humanos , Imuno-Histoquímica , Camundongos , Reação em Cadeia da Polimerase , Células Fotorreceptoras Retinianas Cones/metabolismo , Transfecção
3.
Adv Exp Med Biol ; 1074: 237-245, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29721949

RESUMO

Genetic testing of probands in families with an initial diagnosis of autosomal dominant retinitis pigmentosa (adRP) usually confirms the diagnosis, but there are exceptions. We report results of genetic testing in a large cohort of adRP families with an emphasis on exceptional cases including X-linked RP with affected females; homozygous affected individuals in families with heterozygous, dominant disease; and independently segregating mutations in the same family. Genetic testing was conducted in more than 700 families with a provisional or probable diagnosis of adRP. Exceptions to the proposed mode of inheritance were extracted from our comprehensive patient and family database. In a subset of 300 well-characterized families with a probable diagnosis of adRP, 195 (70%) have dominant mutations in known adRP genes but 25 (8%) have X-linked mutations, 3 (1%) have multiple segregating mutations, and 3 (1%) have dominant-acting mutations in genes previously associated with recessive disease. It is currently possible to determine the underlying disease-causing gene and mutation in approximately 80% of families with an initial diagnosis of adRP, but 10% of "adRP" families have a variant mode of inheritance. Informed genetic diagnosis requires close collaboration between clinicians, genetic counselors, and laboratory scientists.


Assuntos
Retinose Pigmentar/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 10/genética , Proteínas da Matriz Extracelular/genética , Proteínas do Olho/genética , Feminino , Dosagem de Genes , Genes Dominantes , Genes Ligados ao Cromossomo X , Ligação Genética , Hexoquinase/genética , Humanos , Masculino , Linhagem , Retinose Pigmentar/diagnóstico
4.
Mol Vis ; 23: 470-481, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28761320

RESUMO

PURPOSE: With recent availability of next-generation sequencing (NGS), it is becoming more common to pursue disease-targeted panel testing rather than traditional sequential gene-by-gene dideoxy sequencing. In this report, we describe using NGS to identify multiple disease-causing mutations that contribute concurrently or independently to retinal dystrophy in three relatively small families. METHODS: Family members underwent comprehensive visual function evaluations, and genetic counseling including a detailed family history. A preliminary genetic inheritance pattern was assigned and updated as additional family members were tested. Family 1 (FAM1) and Family 2 (FAM2) were clinically diagnosed with retinitis pigmentosa (RP) and had a suspected autosomal dominant pedigree with non-penetrance (n.p.). Family 3 (FAM3) consisted of a large family with a diagnosis of RP and an overall dominant pedigree, but the proband had phenotypically cone-rod dystrophy. Initial genetic analysis was performed on one family member with traditional Sanger single gene sequencing and/or panel-based testing, and ultimately, retinal gene-targeted NGS was required to identify the underlying cause of disease for individuals within the three families. Results obtained in these families necessitated further genetic and clinical testing of additional family members to determine the complex genetic and phenotypic etiology of each family. RESULTS: Genetic testing of FAM1 (n = 4 affected; 1 n.p.) identified a dominant mutation in RP1 (p.Arg677Ter) that was present for two of the four affected individuals but absent in the proband and the presumed non-penetrant individual. Retinal gene-targeted NGS in the fourth affected family member revealed compound heterozygous mutations in USH2A (p. Cys419Phe, p.Glu767Serfs*21). Genetic testing of FAM2 (n = 3 affected; 1 n.p.) identified three retinal dystrophy genes (PRPH2, PRPF8, and USH2A) with disease-causing mutations in varying combinations among the affected family members. Genetic testing of FAM3 (n = 7 affected) identified a mutation in PRPH2 (p.Pro216Leu) tracking with disease in six of the seven affected individuals. Additional retinal gene-targeted NGS testing determined that the proband also harbored a multiple exon deletion in the CRX gene likely accounting for her cone-rod phenotype; her son harbored only the mutation in CRX, not the familial mutation in PRPH2. CONCLUSIONS: Multiple genes contributing to the retinal dystrophy genotypes within a family were discovered using retinal gene-targeted NGS. Families with noted examples of phenotypic variation or apparent non-penetrant individuals may offer a clue to suspect complex inheritance. Furthermore, this finding underscores that caution should be taken when attributing a single gene disease-causing mutation (or inheritance pattern) to a family as a whole. Identification of a disease-causing mutation in a proband, even with a clear inheritance pattern in hand, may not be sufficient for targeted, known mutation analysis in other family members.


Assuntos
Proteínas da Matriz Extracelular/genética , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Periferinas/genética , Proteínas de Ligação a RNA/genética , Retinose Pigmentar/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Análise Mutacional de DNA , Proteínas do Olho/genética , Feminino , Testes Genéticos , Proteínas de Homeodomínio/genética , Humanos , Padrões de Herança , Masculino , Proteínas Associadas aos Microtúbulos , Pessoa de Meia-Idade , Linhagem , Transativadores/genética , Adulto Jovem
5.
Mol Vis ; 22: 1239-1247, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27777503

RESUMO

PURPOSE: To identify the underlying cause of disease in a large family with North Carolina macular dystrophy (NCMD). METHODS: A large four-generation family (RFS355) with an autosomal dominant form of NCMD was ascertained. Family members underwent comprehensive visual function evaluations. Blood or saliva from six affected family members and three unaffected spouses was collected and DNA tested for linkage to the MCDR1 locus on chromosome 6q12. Three affected family members and two unaffected spouses underwent whole exome sequencing (WES) and subsequently, custom capture of the linkage region followed by next-generation sequencing (NGS). Standard PCR and dideoxy sequencing were used to further characterize the mutation. RESULTS: Of the 12 eyes examined in six affected individuals, all but two had Gass grade 3 macular degeneration features. Large central excavation of the retinal and choroid layers, referred to as a macular caldera, was seen in an age-independent manner in the grade 3 eyes. The calderas are unique to affected individuals with MCDR1. Genome-wide linkage mapping and haplotype analysis of markers from the chromosome 6q region were consistent with linkage to the MCDR1 locus. Whole exome sequencing and custom-capture NGS failed to reveal any rare coding variants segregating with the phenotype. Analysis of the custom-capture NGS sequencing data for copy number variants uncovered a tandem duplication of approximately 60 kb on chromosome 6q. This region contains two genes, CCNC and PRDM13. The duplication creates a partial copy of CCNC and a complete copy of PRDM13. The duplication was found in all affected members of the family and is not present in any unaffected members. The duplication was not seen in 200 ethnically matched normal chromosomes. CONCLUSIONS: The cause of disease in the original family with MCDR1 and several others has been recently reported to be dysregulation of the PRDM13 gene, caused by either single base substitutions in a DNase 1 hypersensitive site upstream of the CCNC and PRDM13 genes or a tandem duplication of the PRDM13 gene. The duplication found in the RFS355 family is distinct from the previously reported duplication and provides additional support that dysregulation of PRDM13, not CCNC, is the cause of NCMD mapped to the MCDR1 locus.


Assuntos
Distrofias Hereditárias da Córnea/genética , Proteínas do Olho/genética , Histona-Lisina N-Metiltransferase/genética , Mutação , Sequências de Repetição em Tandem/genética , Fatores de Transcrição/genética , Adulto , Idoso , Criança , Pré-Escolar , Mapeamento Cromossômico , Distrofias Hereditárias da Córnea/diagnóstico , Feminino , Ligação Genética , Humanos , Masculino , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia
6.
Adv Exp Med Biol ; 854: 193-200, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26427411

RESUMO

Whole-genome linkage mapping identified a region on chromosome 10q21.3-q22.1 with a maximum LOD score of 3.0 at 0 % recombination in a six-generation family with autosomal dominant retinitis pigmentosa (adRP). All known adRP genes and X-linked RP genes were excluded in the family by a combination of methods. Whole-exome next-generation sequencing revealed a missense mutation in hexokinase 1, HK1 c.2539G > A, p.Glu847Lys, tracking with disease in all affected family members. One severely-affected male is homozygous for this region by linkage analysis and has two copies of the mutation. No other potential mutations were detected in the linkage region nor were any candidates identified elsewhere in the genome. Subsequent testing detected the same mutation in four additional, unrelated adRP families, for a total of five mutations in 404 probands tested (1.2 %). Of the five families, three are from the Acadian population in Louisiana, one is French Canadian and one is Sicilian. Haplotype analysis of the affected chromosome in each family and the homozygous individual revealed a rare, shared haplotype of 450 kb, suggesting an ancient founder mutation. HK1 is a widely-expressed gene, with multiple, abundant retinal transcripts, coding for hexokinase 1. Hexokinase catalyzes phosphorylation of glucose to glusose-6-phospate, the first step in glycolysis. The Glu847Lys mutation is in a highly-conserved site, outside of the active site or known functional sites.


Assuntos
Cromossomos Humanos Par 10/genética , Predisposição Genética para Doença/genética , Hexoquinase/genética , Mutação de Sentido Incorreto , Retinose Pigmentar/genética , Sequência de Bases , Análise Mutacional de DNA , Exoma/genética , Saúde da Família , Feminino , Genes Dominantes , Genótipo , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Linhagem , Retinose Pigmentar/diagnóstico , Homologia de Sequência do Ácido Nucleico
7.
Ophthalmology ; 122(4): 833-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25556114

RESUMO

PURPOSE: To determine whether annual decline in visual field sensitivity is greater in the transition zone at the edge of the frequency-domain optical coherence tomography (fdOCT) inner segment ellipsoid zone (EZ) than at other locations in the visual field. DESIGN: Prospective, longitudinal, observational study. PARTICIPANTS: Forty-four patients with X-linked retinitis pigmentosa (XLRP) resulting from a mutation in the RPGR gene. METHODS: Static perimetric fields (Humphrey 30-2; Carl Zeiss Meditec, Dublin, CA) were obtained annually for 4 years. Beginning with year 2, fdOCT scans were obtained annually with a Heidelberg Spectralis HRA + OCT (Heidelberg Engineering, Heidelberg, Germany). MAIN OUTCOME MEASURES: The rate of visual field decline at locations near the edge of the EZ compared with the rates for the macula and in the mid periphery. RESULTS: Sensitivity just inside and outside the edge of the EZ declined at rates of 0.84 and 0.92 dB/year, respectively. By comparison, average sensitivity in the macula and mid periphery declined by 0.38 and 0.61 dB/year, respectively. CONCLUSIONS: The edge of the EZ in each patient with XLRP indicates a transition zone between relatively healthy and relatively degenerate retina. The annual loss of sensitivity in the transition zone is more rapid than it is elsewhere in the retina.


Assuntos
Proteínas do Olho/genética , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Mutação , Retina/fisiopatologia , Retinose Pigmentar/fisiopatologia , Transtornos da Visão/fisiopatologia , Campos Visuais/fisiologia , Adolescente , Adulto , Criança , Feminino , Seguimentos , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Masculino , Estudos Prospectivos , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genética , Sensibilidade e Especificidade , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Testes de Campo Visual , Adulto Jovem
8.
Hum Genet ; 133(3): 331-45, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24154662

RESUMO

Retinitis pigmentosa (RP) is a devastating form of retinal degeneration, with significant social and professional consequences. Molecular genetic information is invaluable for an accurate clinical diagnosis of RP due to its high genetic and clinical heterogeneity. Using a gene capture panel that covers 163 of the currently known retinal disease genes, including 48 RP genes, we performed a comprehensive molecular screening in a collection of 123 RP unsettled probands from a wide variety of ethnic backgrounds, including 113 unrelated simplex and 10 autosomal recessive RP (arRP) cases. As a result, 61 mutations were identified in 45 probands, including 38 novel pathogenic alleles. Interestingly, we observed that phenotype and genotype were not in full agreement in 21 probands. Among them, eight probands were clinically reassessed, resulting in refinement of clinical diagnoses for six of these patients. Finally, recessive mutations in CLN3 were identified in five retinal degeneration patients, including four RP probands and one cone-rod dystrophy patient, suggesting that CLN3 is a novel non-syndromic retinal disease gene. Collectively, our results underscore that, due to the high molecular and clinical heterogeneity of RP, comprehensive screening of all retinal disease genes is effective in identifying novel pathogenic mutations and provides an opportunity to discover new genotype-phenotype correlations. Information gained from this genetic screening will directly aid in patient diagnosis, prognosis, and treatment, as well as allowing appropriate family planning and counseling.


Assuntos
Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Glicoproteínas de Membrana/genética , Chaperonas Moleculares/genética , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genética , Alelos , Biologia Computacional , Éxons , Genes Recessivos , Testes Genéticos , Genótipo , Humanos , Glicoproteínas de Membrana/metabolismo , Chaperonas Moleculares/metabolismo , Mutação , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes , Análise de Sequência de DNA
9.
Ophthalmol Retina ; 4(5): 510-520, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31953110

RESUMO

PURPOSE: X-linked retinitis pigmentosa can manifest in female carriers with widely variable severity, whereas others remain unaffected. The contribution of X-chromosome inactivation (XCI) to phenotypic variation has been postulated but not demonstrated. Furthermore, the impact of genotype and genetic modifiers has been demonstrated in affected males but has not been well established in female carriers. The purpose of this study was to describe the scope of clinical phenotype in female carriers with mutations in RPGR and quantify the contribution of genotype, genetic modifiers, and XCI to phenotypic severity. DESIGN: Cohort study. PARTICIPANTS: Seventy-seven female carriers with RPGR mutations from 41 pedigrees. METHODS: Coding single nucleotide polymorphisms were sequenced in candidate genetic modifier genes encoding known RPGR-interacting proteins. X-chromosome inactivation ratios were determined in genomic DNA isolated from blood (n = 42) and saliva (n = 20) using methylation status of X-linked polymorphic repeats. These genetic data were compared with disease severity based on quantitative clinical parameters. MAIN OUTCOME MEASURES: Visual acuity, Humphrey visual field (HVF) results, full-field electroretinography results, and dark adaptation. RESULTS: Most individuals at all ages were mildly affected or unaffected, whereas those who progressed to moderate or severe vision loss were older than 30 years. RPGR genotype was not associated with clinical severity. The D1264N variant in RPGRIP1L was associated with more severe disease. Skewed XCI toward inactivation of the normal RPGR allele was associated with more severe disease. The XCI ratio in both blood and saliva was a predictor of visual function as measured by HVF diameter, rod amplitude, flicker amplitude, and flicker implicit time. For carriers with extreme XCI skewing of 80:20 or more, 57% were affected severely compared with 8% for those with XCI of less than 80:20 (P = 0.002). CONCLUSIONS: Female carriers with mutations in RPGR demonstrate widely variable clinical severity. X-chromosome inactivation ratios correlate with clinical severity and may serve as a predictor of clinically significant disease. Because RPGR gene therapy trials are underway, a future imperative exists to determine which carriers require intervention and when to intervene. X-chromosome inactivation analysis may be useful for identifying candidates for early intervention.


Assuntos
Cromossomos Humanos X/genética , DNA/genética , Adaptação à Escuridão/fisiologia , Proteínas do Olho/genética , Mutação , Retinose Pigmentar/genética , Acuidade Visual , Adolescente , Adulto , Idoso , Biomarcadores , Criança , Estudos de Coortes , Análise Mutacional de DNA , Eletrorretinografia , Proteínas do Olho/metabolismo , Feminino , Genótipo , Fatores de Troca do Nucleotídeo Guanina , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/metabolismo , Adulto Jovem
10.
JAMA Ophthalmol ; 136(8): 849-856, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29879277

RESUMO

Importance: There are no approved drug treatments for autosomal dominant retinitis pigmentosa, a relentlessly progressive cause of adult and childhood blindness. Objectives: To evaluate the potential efficacy and assess the safety of orally administered valproic acid (VPA) in the treatment of autosomal dominant retinitis pigmentosa. Design, Setting, and Participants: Multicenter, phase 2, prospective, interventional, placebo-controlled, double-masked randomized clinical trial. The study took place in 6 US academic retinal degeneration centers. Individuals with genetically characterized autosomal dominant retinitis pigmentosa were randomly assigned to receive treatment or placebo for 12 months. Analyses were intention-to-treat. Interventions: Oral VPA 500 mg to 1000 mg daily for 12 months or placebo. Main Outcomes and Measures: The primary outcome measure was determined prior to study initiation as the change in visual field area (assessed by the III4e isopter, semiautomated kinetic perimetry) between baseline and month 12. Results: The mean (SD) age of the 90 participants was 50.4 (11.6) years. Forty-four (48.9%) were women, 87 (96.7%) were white, and 79 (87.8%) were non-Hispanic. Seventy-nine participants (87.8%) completed the study (42 [95.5%] received placebo and 37 [80.4%] received VPA). Forty-two (46.7%) had a rhodopsin mutation. Most adverse events were mild, although 7 serious adverse events unrelated to VPA were reported. The difference between the VPA and placebo arms for mean change in the primary outcome was -150.43 degree2 (95% CI, -290.5 to -10.03; P = .035). Conclusions and Relevance: This negative value indicates that the VPA arm had worse outcomes than the placebo group. This study brings to light the key methodological considerations that should be applied to the rigorous evaluation of treatments for these conditions. This study does not provide support for the use of VPA in the treatment of autosomal dominant retinitis pigmentosa. Trial Registration: ClinicalTrials.gov Identifier: NCT01233609.


Assuntos
Anticonvulsivantes/uso terapêutico , Retinose Pigmentar/tratamento farmacológico , Ácido Valproico/uso terapêutico , Transtornos da Visão/tratamento farmacológico , Administração Oral , Adulto , Idoso , Anticonvulsivantes/administração & dosagem , Método Duplo-Cego , Eletrorretinografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Retina/fisiopatologia , Retinose Pigmentar/genética , Retinose Pigmentar/fisiopatologia , Rodopsina/genética , Ácido Valproico/administração & dosagem , Transtornos da Visão/fisiopatologia , Acuidade Visual/fisiologia , Testes de Campo Visual , Campos Visuais/fisiologia
12.
Invest Ophthalmol Vis Sci ; 57(2): 349-59, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26842753

RESUMO

PURPOSE: We determined the phenotypic variation, disease progression, and potential modifiers of autosomal dominant retinal dystrophies caused by a splice site founder mutation, c.828+3A>T, in the PRPH2 gene. METHODS: A total of 62 individuals (19 families) harboring the PRPH2 c.828+3A>T mutation, had phenotype analysis by fundus appearance, electrophysiology, and visual fields. The PRPH2 haplotypes in trans were sequenced for potential modifying variants and generalized estimating equations (GEE) used for statistical analysis. RESULTS: Several distinct phenotypes caused by the PRPH2 c.828+3A>T mutation were observed and fell into two clinical categories: Group I (N = 44) with mild pattern dystrophies (PD) and Group II (N = 18) with more severe cone-rod dystrophy (CRD), retinitis pigmentosa (RP), and central areolar chorioretinal dystrophy (CACD). The PRPH2 Gln304-Lys310-Asp338 protein haplotype in trans was found in Group I only (29.6% vs. 0%), whereas the Glu304-Lys310-Gly338 haplotype was predominant in Group II (94.4% vs. 70.4%). Generalized estimating equations analysis for PD versus the CRD/CACD/RP phenotypes in individuals over 43 years alone with the PRPH2 haplotypes in trans and age as predictors, adjusted for correlation within families, confirmed a significant effect of haplotype on severity (P = 0.03) with an estimated odds ratio of 7.16 (95% confidence interval [CI] = [2.8, 18.4]). CONCLUSIONS: The PRPH2 c.828+3A>T mutation results in multiple distinct phenotypes likely modified by protein haplotypes in trans; the odds of having the CACD/RP-like phenotype (versus the PD phenotype) are 7.16 times greater with a Glu304-Lys310-Gly338 haplotype in trans. Further functional studies of the modifying haplotypes in trans and PRPH2 splice variants may offer therapeutic targets.


Assuntos
Efeito Fundador , Mutação , Periferinas/genética , Sítios de Splice de RNA/genética , Distrofias Retinianas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Adaptação à Escuridão , Progressão da Doença , Eletrorretinografia , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Polimorfismo Conformacional de Fita Simples , Retina/fisiopatologia , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/fisiopatologia , Acuidade Visual/fisiologia , Campos Visuais/fisiologia , Adulto Jovem
13.
Am J Ophthalmol ; 140(5): 858-867, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16214101

RESUMO

PURPOSE: To evaluate the clinical features associated with the RP10 form of autosomal-dominant retinitis pigmentosa in 11 affected members of various ages from one family with a defined IMPDH1 mutation (Asp226Asn). DESIGN: Prospective, observational case series. METHODS: Visual function assessment included visual acuity, color vision, visual field, dark adaptometry, full-field electroretinography (ffERG), and multifocal electroretinography (mfERG). Ophthalmologic examinations, fundus photography, and optical coherence tomographic scans were also performed. Blood samples were obtained to screen for basic immune function. RESULTS: Visual acuity was slightly reduced in the teenage years and substantially reduced in association with cystoid macular edema (CME) at all ages. Color defects were observed in three patients (one teen, two adults). Dark-adapted thresholds were elevated. Visual fields were markedly constricted by age 40 (

Assuntos
IMP Desidrogenase/genética , Mutação de Sentido Incorreto , Retinose Pigmentar/genética , Adolescente , Adulto , Defeitos da Visão Cromática/genética , Defeitos da Visão Cromática/patologia , Eletrorretinografia , Feminino , Genes Dominantes , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Estudos Prospectivos , Retinose Pigmentar/enzimologia , Retinose Pigmentar/patologia , Tomografia de Coerência Óptica , Transtornos da Visão/genética , Transtornos da Visão/patologia , Acuidade Visual , Campos Visuais
14.
JAMA Ophthalmol ; 133(5): 511-7, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25675413

RESUMO

IMPORTANCE: Screening for splice site mutation c.828+3A>T in the peripherin 2 (PRPH2) gene should be a high priority in families with highly variable retinal dystrophies. The correction of missplicing is a potential therapeutic target. OBJECTIVE: To determine the prevalence, genetic origin, and molecular mechanism of a donor c.828+3A>T mutation in the PRPH2 (peripherin 2, retinal degeneration slow) gene in individuals with retinal dystrophies. DESIGN, SETTING, AND PARTICIPANTS: Case-control study that took place at the University of Texas Health Science Center, the University of Iowa, and the Retina Foundation of the Southwest, from January 1, 1987, to August 1, 2014, including affected individuals from 200 families with a diagnosis of autosomal dominant retinitis pigmentosa, 35 families with unspecified macular dystrophies, and 116 families with pattern dystrophy. Participants were screened for the c.828+3A>T mutation by restriction-enzyme digest, single-strand conformational polymorphism screening, or bidirectional sequencing. Haplotypes of polymorphic markers flanking the PRPH2 locus and sequence variants within the gene were determined by denaturing gel electrophoresis or automated capillary-based cycle sequencing. The effect of the splice site mutation on the PRPH2 transcript was analyzed using NetGene2, a splice prediction program and by the reverse transcription polymerase chain reaction of illegitimate transcripts from peripheral white blood cells. MAIN OUTCOMES AND MEASURES: Results of testing for splice site mutation, haplotypes, and alternate transcripts. RESULTS: The PRPH2 mutation was found in 97 individuals of 19 independently ascertained families with a clinical diagnosis of retinitis pigmentosa, macular dystrophy, and/or pattern dystrophy. All affected individuals also shared a rare haplotype of approximately 644 kilobase pairs containing the c.828+3A>T mutation, which extends from the short tandem repeat polymorphism D6S282 to c.1013G>A (rs434102, a single-nucleotide polymorphism) in exon 3 of PRPH2, suggesting this mutation is from a common ancestor and is a founder mutation. It has a prevalence of 2% in families diagnosed as having autosomal dominant retinitis pigmentosa and 10% in families with variable clinical diagnosis of pattern, macular, and retinal dystrophies. Individuals with the c.828+3A>T mutation expressed a PRPH2 transcript not found in control participants and that was consistent with abnormal splicing. CONCLUSIONS AND RELEVANCE: The PRPH2 c.828+3A>T splice site mutation is a frequent cause of inherited retinal dystrophies and is owing to the founder effect. The likely cause of disease is the missplicing of the PRPH2 message that results in a truncated protein product. Identifying the genetic etiology assists in more accurate management and possible future therapeutic options.


Assuntos
Efeito Fundador , Mutação , Periferinas/genética , Sítios de Splice de RNA/genética , Distrofias Retinianas/genética , Sequência de Bases , Estudos de Casos e Controles , Ligação Genética , Humanos , Dados de Sequência Molecular , Polimorfismo Conformacional de Fita Simples , Distrofias Retinianas/epidemiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA
15.
Invest Ophthalmol Vis Sci ; 56(11): 6646-53, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26469750

RESUMO

PURPOSE: Docosahexaenoic acid (DHA) was supplemented in a single-site, placebo-controlled, randomized clinical trial designed to slow vision loss associated with X-linked retinitis pigmentosa (XLRP); the DHAX Trial. We previously reported no significant differences between supplemented and placebo groups in intent-to-treat analysis of primary ERG outcomes. Assessed herein are hypothesis-generating measures of ancillary visual function outcomes in participants fully adhering to trial protocol. METHODS: Male participants with XLRP (range, 7-31 years) received 30 mg DHA/kg/d (n = 29) or placebo (n = 22) for 4 years. Visual outcomes were measured annually and red blood cell (RBC) DHA determined every 6 months. RESULTS: Oral DHA supplementation increased mean RBC-DHA levels by 4-fold (P < 0.0001) over placebo. No group differences in progression were found for visual acuity (P = 0.11), shape discrimination (P = 0.18), or fundus appearance (P = 0.70). Optical coherence tomography (OCT) became available during year 2 of the trial; no group differences were seen in ellipsoid zone constriction (P = 0.87) over 2 years. Yearly rates of progression were reduced for dark-adapted thresholds (P = 0.06) and visual field sensitivity for foveal, macular, peripheral, total, and ellipsoid zone regions by DHA supplementation (P = 0.039, P = 0.031, P < 0.0001, P < 0.0001, and P = 0.033). Rates of visual field sensitivity decline were dependent on RBC-DHA (P = 0.046 to <0.0001). CONCLUSIONS: Supplementation of DHA significantly elevated blood DHA levels and reduced the rate of progression in final dark-adapted thresholds and visual field sensitivity. From the relationship between RBC-DHA and the rate of field sensitivity loss, we can extrapolate that an RBC-DHA level of 17% could minimize the decline in field sensitivity. (ClinicalTrials.gov number, NCT00100230.)


Assuntos
Ácidos Docosa-Hexaenoicos/uso terapêutico , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Retinose Pigmentar/tratamento farmacológico , Adolescente , Adulto , Criança , Progressão da Doença , Percepção de Forma/efeitos dos fármacos , Fundo de Olho , Humanos , Masculino , Retinose Pigmentar/genética , Campos Visuais/efeitos dos fármacos , Adulto Jovem
16.
Invest Ophthalmol Vis Sci ; 55(8): 4958-66, 2014 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-25015354

RESUMO

PURPOSE: Docosahexaenoic acid (DHA) continues to be evaluated and recommended as treatment and prophylaxis for various diseases. We recently assessed efficacy of high-dose DHA supplementation to slow vision loss in patients with X-linked retinitis pigmentosa (XLRP) in a randomized clinical trial. Because DHA is a highly unsaturated fatty acid, it could serve as a target for free-radical induced oxidation, resulting in increased oxidative stress. Biosafety was monitored during the 4-year trial to determine whether DHA supplementation was associated with identifiable risks. METHODS: Males (n = 78; 7-31 years) meeting entry criteria were enrolled. The modified intent-to-treat cohort (DHA = 33; placebo = 27) adhered to the protocol ≥ 1 year. Participants were randomized to an oral dose of 30 mg/kg/d DHA or placebo plus a daily multivitamin. Comprehensive metabolic analyses were assessed for group differences. Treatment-emergent adverse events including blood chemistry metabolites were recorded. RESULTS: By year 4, supplementation elevated plasma and red blood cell-DHA 4.4- and 3.6-fold, respectively, compared with the placebo group (P < 0.00001). Over the trial duration, no significant differences between DHA and placebo groups were found for vitamin A, vitamin E, platelet aggregation, antioxidant activity, lipoprotein cholesterol, or oxidized LDL levels (all P > 0.14). Adverse events were transient and not considered severe (e.g., gastrointestinal [GI] irritability, blood chemistry alterations). One participant was unable to tolerate persistent GI discomfort. CONCLUSIONS: Long-term, high-dose DHA supplementation to patients with XLRP was associated with limited safety risks in this 4-year trial. Nevertheless, GI symptoms should be monitored in all patients taking high dose DHA especially those with personal or family history of GI disturbances. (ClinicalTrials.gov number, NCT00100230.).


Assuntos
Ácidos Docosa-Hexaenoicos/administração & dosagem , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Retinose Pigmentar/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Criança , Cromatografia Líquida de Alta Pressão , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/farmacocinética , Relação Dose-Resposta a Droga , Eletrorretinografia , Seguimentos , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Humanos , Masculino , Retinose Pigmentar/genética , Retinose Pigmentar/metabolismo , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
17.
JAMA Ophthalmol ; 132(7): 866-73, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24805262

RESUMO

IMPORTANCE: X-linked retinitis pigmentosa is a severe inherited retinal degenerative disease with a frequency of 1 in 100,000 persons. Because no cure is available for this orphan disease and treatment options are limited, slowing of disease progression would be a meaningful outcome. OBJECTIVE: To determine whether high-dose docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid, slows progression of X-linked retinitis pigmentosa measured by cone electroretinography (ERG). DESIGN, SETTING, AND PARTICIPANTS: A 4-year, single-site, randomized, placebo-controlled, double-masked phase 2 clinical trial at a research center specializing in medical retina. Seventy-eight male patients diagnosed as having X-linked retinitis pigmentosa were randomized to DHA or placebo. Data were omitted for 2 patients with non-X-linked retinitis pigmentosa and 16 patients who were unable to follow protocol during the first year. The remaining participants were tested annually and composed a modified intent-to-treat cohort (DHA group, n = 33; placebo group, n = 27). INTERVENTIONS: All participants received a multivitamin and were randomly assigned to oral DHA (30 mg/kg/d) or placebo. MAIN OUTCOMES AND MEASURES: The primary outcome was the rate of loss of cone ERG function. Secondary outcomes were rod and maximal ERG amplitudes and cone ERG implicit times. Capsule counts and red blood cell DHA levels were assessed to monitor adherence. RESULTS: Average (6-month to 4-year) red blood cell DHA levels were 4-fold higher in the DHA group than in the placebo group (P < .001). There was no difference between the DHA and placebo groups in the rate of cone ERG functional loss (0.028 vs 0.022 log µV/y, respectively; P = .30). No group differences were evident for change in rod ERG (P = .27), maximal ERG (P = .65), or cone implicit time (no change over 4 years). The rate of cone loss (ie, event rate) was markedly reduced compared with rates in previous studies. No severe treatment-emergent adverse events were found. CONCLUSIONS AND RELEVANCE: Long-term DHA supplementation was not effective in slowing the loss of cone or rod ERG function associated with X-linked retinitis pigmentosa. Participant dropout and lower-than-expected disease event rate limited power to detect statistical significance. A larger sample size, longer trial, and attainment of a target blood DHA level (13%) would be desirable. While DHA supplementation at 30 mg/kg/d does not present serious adverse effects, routine monitoring of gastrointestinal tolerance is prudent. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00100230.


Assuntos
Ácidos Docosa-Hexaenoicos/administração & dosagem , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Retinose Pigmentar/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Cápsulas , Criança , Cromatografia Gasosa , Progressão da Doença , Ácidos Docosa-Hexaenoicos/sangue , Ácidos Docosa-Hexaenoicos/uso terapêutico , Método Duplo-Cego , Eletrorretinografia , Membrana Eritrocítica/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Humanos , Masculino , Células Fotorreceptoras Retinianas Cones/fisiologia , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/fisiopatologia , Resultado do Tratamento , Adulto Jovem
18.
Invest Ophthalmol Vis Sci ; 54(2): 1411-6, 2013 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-23372056

RESUMO

PURPOSE: We determined the fraction of families in a well-characterized cohort with a provisional diagnosis of autosomal dominant retinitis pigmentosa (adRP) that have disease-causing mutations in the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene or the retinitis pigmentosa 2 (RP2) gene. METHODS: Families with a provisional clinical diagnosis of adRP, and a pedigree consistent with adRP but no male-to-male transmission were selected from a cohort of 258 families, and tested for mutations in the RPGR and RP2 genes with di-deoxy sequencing. To facilitate testing of RPGR in "adRP" families that had no male members available for testing, the repetitive and purine-rich ORF15 of RPGR was subcloned and sequenced in heterozygous female subjects from 16 unrelated families. RESULTS: Direct sequencing of RPGR and RP2 allowed for identification of a disease-causing mutation in 21 families. Of these "adRP" families 19 had RPGR mutations, and two had RP2 mutations. Subcloning and sequencing of ORF15 of RPGR in female subjects identified one additional RPGR mutation. Of the 22 mutations identified, 15 have been reported previously. CONCLUSIONS: These data show that 8.5% (22 in 258) of families thought to have adRP truly have X-linked retinitis pigmentosa (XLRP). These results have substantive implications for calculation of recurrence risk, genetic counseling, and potential treatment options, and illustrate the importance of screening families with a provisional diagnosis of autosomal inheritance and no male-to-male transmission for mutations in X-linked genes. Mutations in RPGR are one of the most common causes of all forms of retinitis pigmentosa.


Assuntos
DNA/genética , Proteínas do Olho/genética , Genes Ligados ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Mutação , Retinose Pigmentar/genética , Adulto , Eletrorretinografia , Proteínas do Olho/metabolismo , Feminino , Proteínas de Ligação ao GTP , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Fatores de Troca do Nucleotídeo Guanina , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/metabolismo
19.
Am Orthopt J ; 62: 90-8, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22848117

RESUMO

INTRODUCTION AND PURPOSE: A number of studies have evaluated visual acuity (VA) of special needs children, but no analyses of the parents' perception of VA testing or the utilization of VA test results by pediatric ophthalmologists have been reported. PATIENTS AND METHODS: Special needs children referred for an initial VA test (Teller Acuity Cards) during a 2-year period were enrolled (n = 309). Within the overall cohort, twenty consecutive parents whose child attended during a 6-week period completed a Parent Questionnaire before and after VA testing. Also, 58 parents of infants with cortical visual impairment (CVI) completed the Parental Stress Index-Short Form (PSI-SF) before VA testing and 3 months later. Referring pediatric ophthalmologists (n = 12) completed a Physician Questionnaire. RESULTS: VA testing was associated with parents reporting increased knowledge scores and decreased concerns about their children's vision on the Parent Questionnaire. VA testing was also associated with reduced Total and Parental Distress subscale scores on the PSI-SF by parents of infants with CVI. Ophthalmologists reported that VA results were useful in diagnosis and clinical management and provided new information to parents, Early Childhood Intervention programs, schools, and social agencies. CONCLUSION: VA testing is of benefit in children with special needs to both their parents and ophthalmologists, providing quantitative information about visual impairment and reducing stress experienced by parents.


Assuntos
Avaliação da Deficiência , Crianças com Deficiência/reabilitação , Transtornos da Visão/fisiopatologia , Testes Visuais , Acuidade Visual , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pais/psicologia , Prevalência , Estudos Retrospectivos , Estresse Psicológico , Inquéritos e Questionários , Estados Unidos/epidemiologia , Transtornos da Visão/epidemiologia , Transtornos da Visão/reabilitação
20.
PLoS One ; 6(8): e23021, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21857984

RESUMO

Mutations in RPGR account for over 70% of X-linked retinitis pigmentosa (XlRP), characterized by retinal degeneration and eventual blindness. The clinical consequences of RPGR mutations are highly varied, even among individuals with the same mutation: males demonstrate a wide range of clinical severity, and female carriers may or may not be affected. This study describes the phenotypic diversity in a cohort of 98 affected males from 56 families with RPGR mutations, and demonstrates the contribution of genetic factors (i.e., allelic heterogeneity and genetic modifiers) to this diversity. Patients were categorized as grade 1 (mild), 2 (moderate) or 3 (severe) according to specific clinical criteria. Patient DNAs were genotyped for coding SNPs in 4 candidate modifier genes with products known to interact with RPGR protein: RPGRIP1, RPGRIP1L, CEP290, and IQCB1. Family-based association testing was performed using PLINK. A wide range of clinical severity was observed both between and within families. Patients with mutations in exons 1-14 were more severely affected than those with ORF15 mutations, and patients with predicted null alleles were more severely affected than those predicted to make RPGR protein. Two SNPs showed association with severe disease: the minor allele (N) of I393N in IQCB1 (p = 0.044) and the common allele (R) of R744Q in RPGRIP1L (p = 0.049). These data demonstrate that allelic heterogeneity contributes to phenotypic diversity in XlRP and suggest that this may depend on the presence or absence of RPGR protein. In addition, common variants in 2 proteins known to interact with RPGR are associated with severe disease in this cohort.


Assuntos
Proteínas do Olho/genética , Genes Modificadores/genética , Heterogeneidade Genética , Mutação , Retinose Pigmentar/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Alelos , Antígenos de Neoplasias/genética , Proteínas de Ligação a Calmodulina/genética , Proteínas de Ciclo Celular , Estudos de Coortes , Proteínas do Citoesqueleto , Análise Mutacional de DNA , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Predisposição Genética para Doença/genética , Variação Genética , Genótipo , Haplótipos , Humanos , Proteínas de Neoplasias/genética , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Retinose Pigmentar/patologia , Índice de Gravidade de Doença
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA