Early occurrence of primary angle-closure glaucoma in a patient with retinitis pigmentosa and CRB1 gene variations / Manifestação precoce de glaucoma de ângulo fechado em paciente com retinopatia por mutação no gene CRB1

ABSTRACT We describe the case of a 15-year-old girl with decreased visual acuity associated with elevated intraocular pressure in both eyes and angle closure on gonioscopy. She also presented attenuation of retinal vessels and optic disc pallor with large excavation in the left eye. Ultrasound biomicroscopy revealed an anteriorly positioned ciliary body and absence of ciliary sulcus, confirming the plateau iris configuration. Spectral-domain optical coherence tomography revealed a bilateral cystoid macular edema. Genetic screening revealed heterozygous variants of the Crumbs homolog 1 (CRB1) gene (c.2843G>A and c.2506C>A). The patient underwent trabeculectomy for intraocular pressure control and topical treatment for macular edema. This case highlights the importance of performing gonioscopy and evaluating intraocular pressure in patients with a shallow anterior chamber despite young age. In addition, it also shows the importance of genetic screening, when available, in elucidating the diagnosis and providing patients and their families' information on the patient's prognosis and possible therapeutic options.

RESUMO Nós descrevemos um caso de uma paciente de 15 anos com queda de acuidade visual e aumento da pressão intraocular em ambos os olhos, juntamente com fechamento angular no exame de gonioscopia. Na fundoscopia a paciente apresentava atenuação dos vasos retinianos, palidez de disco e aumento de escavação em olho esquerdo. Ao exame da biomicroscopia ultrassônica, foi evidenciado corpo ciliar anteriorizado e ausência de sulco ciliar em ambos os olhos, relevando presença de íris em plateau. Ao exame de tomografia de coerência óptica, visualizamos presença de edema macular cistoide bilateral. O screening genético revelou heterozigose no gene CRB1 (c.2843G>A and c.2506C>A), confirmando o diagnóstico de retinose pigmentar. Este caso reforça a importância do exame de gonioscopia e da avaliação da pressão intraocular em pacientes em câmara rasa, mesmo em pacientes jovens. Além disso, mostra a importância do screening genético como ferramenta útil para elucidação diagnóstica.

Analysis of a patient with early-onset retinitis pigmentosa due to novel variants of CRB1 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a patient with early-onset retinitis pigmentosa (RP).@*METHODS@#A patient who had presented at the West China Hospital of Sichuan University on March 10, 2020 was selected as the study subject. The patient and his parents were subjected to whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing and in silico analysis.@*RESULTS@#The patient has featured substantial loss of binocular vision field. Funduscopy revealed characteristic bone spicule-type pigment deposits, as well as attenuated retinal arterioles and pale-appearing optic discs. WES revealed that he has harbored compound missense variants of a RP-associated CRB1 gene, including c.2969T>C (p.Leu990Ser) and c.1816T>C (p.Cys606Arg), which were respectively inherited from his father and mother. Homozygous c.1816T>C (p.Cys606Arg) variant has been identified among RP patients, whilst the c.2969T>C (p.Leu990Ser) variant was unreported previously. Both variants were predicted as likely pathogenic based on the guidelines from the American College of Medical Genetics and Genomics (ACMG).@*CONCLUSION@#The novel compound heterozygous variants of the CRB1 gene probably underlay the early-onset RP in this patient. Above finding has enriched the mutational spectrum of the CRB1 gene.

Analysis of C2ORF71 gene variant in a Chinese patient with retinitis pigmentosa / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a Chinese patient with retinitis pigmentosa (RP).@*METHODS@#Whole exome sequencing (WES) was carried out to screen potential variant in the proband. Candidate variants were determined by taking consideration of clinical phenotype. Sanger sequencing was used to verify the variant in the proband and his parents.@*RESULTS@#The proband was found to harbor compound heterozygous variants of c.8G>A (p.Cys3Tyr) and c.958_959insA (p.Arg320Glnfs*29) in the C2ORF71 gene, which has derived from his father and mother, respectively. Both variants were unreported previously. Based on the ACMG guidelines, they were predicted to be likely pathogenic and pathogenic, respectively.@*CONCLUSION@#The novel compound heterozygous variants of the C2ORF71 gene probably underlay the pathogenesis of RP in the proband. Above finding has enriched the spectrum of C2ORF71 gene mutations and facilitated genetic counseling for the family.

Homozygosity Mapping and Targeted Sanger Sequencing Identifies Three Novel CRB1 [Crumbs homologue 1] Mutations in Iranian Retinal Degeneration Families

Background: Inherited retinal diseases [IRDs] are a group of genetic disorders with high degrees of clinical, genetic and allelic heterogeneity. IRDs generally show progressive retinal cell death resulting in gradual vision loss

IRDs constitute a broad spectrum of disorders including retinitis pigmentosa and Leber congenital amaurosis. In this study, we performed genotyping studies to identify the underlying mutations in three Iranian families

Methods: Having employed homozygosity mapping and Sanger sequencing, we identified the underlying mutations in the crumbs homologue 1 gene. The CRB1 protein is a part of a macromolecular complex with a vital role in retinal cell polarity, morphogenesis, and maintenance

Results: We identified a novel homozygous variant [c.1053-1061del; p.Gly352-Cys354del] in one family, a combination of a novel [c.2086T>C; p.Cys696Arg] and a known variant [c.2234C>T, p.Thr745Met] in another family and a homozygous novel variant [c.3090T>A; p.Asn!030Lys] in a third family

Conclusion: This study shows that mutations in CRB1 are relatively common in Iranian non-syndromic IRD patients

Caracterización clínica del síndrome de Usher. Provincia Holguín / Usher syndrome clinical characterization. Holguin province

Fundamento: El síndrome de Usher es una enfermedad determinada genéticamente, con una gran heterogeneidad clínica y genética; está caracterizada por hipoacusia neurosensorial de moderada a severa, retinosis pigmentaria progresiva y puede acompañarse de alteración vestibular. Por la alta prevalencia de esta enfermedad en la provincia de Holguín, se considera necesario este estudio. Objetivo: Caracterizar clínicamente todos los enfermos con diagnóstico clínico de síndrome de Usher en la provincia Holguín, en el período de enero del 2009 a enero del 2016. Metodología: Se realizó un estudio descriptivo, retrospectivo, tipo serie de casos, a los 53 pacientes con diagnóstico clínico de síndrome de Usher en la provincia Holguín. La muestra estuvo formada por los 53 enfermos residentes en la provincia. Se revisaron los registros del Centro Provincial de Retinosis Pigmentaria y las historias clínicas de estos pacientes; se recogieron los datos de interés en un instrumento que se confeccionó para ello. Las variables estudiadas fueron el sexo, la edad, edad del diagnóstico de la hipoacusia y severidad, edad del diagnóstico de la retinosis pigmentaria y los resultados de las pruebas audiológicas, lo que permitió conocer la función vestibular. Resultados: Se caracterizó clínicamente el 100 % de los enfermos estudiados. Predominó el sexo masculino (60,37 %). El 80 % presentó la retinosis pigmentaria en la primera infancia y la hipoacusia congénita profunda en 67,92 %. Las pruebas vestibulares demostraron que el 71,70 % presenta síndrome de Usher tipo II y el 28,30 % tiene el tipo I. Conclusiones: Predominó el sexo masculino, la hipoacusia precedió a la alteración visual. Se logró caracterizar clínicamente a estos afectados. Prevaleció el síndrome de Usher tipo II.

Background: Usher syndrome is a genetically determined disease with great clinical and genetic heterogeneity. This disease is characterized by sensorineural hearing loss of moderate to severe, progressive pigmentosa retinitis and may be accompanied by vestibular alteration. At the high prevalence of this disease in the province of Holguin, this study is considered necessary. Objective: To characterize all patients clinically with clinical diagnosis of Usher syndrome in Holguin province, in the period from January 2009 to January 2016. Methodology: A series types of retrospective cases, descriptive study with 53 patients with clinical diagnosis of Usher syndrome in Holguin province was conducted. The sample consisted of 53 patients residing in the province. Provincial records Pigmentosa Retinitis Pigmentosa Center and the medical records of these patients were reviewed, the data of interest are collected in an instrument that was drawn up for these. The variables studied were sex, age, age at diagnosis of hearing loss and severity, age of diagnosis of pigmentosa retinitis and the results of the audiological tests, allowing knowing the vestibular function. Results: It was possible to clinically characterize 100 % of the patients studied, predominantly male in a 60.37 %. 80 % had pigmentosa retinitis in early childhood and profound congenital hearing loss in 67.92 %. Vestibular tests showed that 71. 70 % have Usher syndrome type II and 28.30 % have the type I. Conclusions: mainly males, hearing loss preceded visual impairment. It was possible to clinically characterize those affected. It prevailed Usher syndrome type II.

Estudo clínico e padrão de herança em pacientes com retinose pigmentar / Clinical study and pattern of inheritance in patients with retinitis pigmentosa

OBJETIVO: Realizar análise epidemiológica de pacientes com retinose pigmentar (RP), caracterizando aspectos clínicos da doença e o padrão de herança encontrado em nosso meio, de acordo com a presença ou não de síndrome de Usher. MÉTODOS: Foram estudados 155 pacientes com RP, tendo sido a amostra dividida em 2 grupos: grupo 1 (n=130), com pacientes diagnosticados com RP clássica, sem associação com alterações sistêmicas; e grupo 2 (n=25), com pacientes diagnosticados com Síndrome de Usher (USH). Foram caracterizados aspectos clínicos da doença (sexo, idade, sintomas oculares, acuidade visual, alterações do segmento anterior e posterior e alterações em exames complementares) e o padrão de herança encontrado. Os dados foram obtidos através de anamnese, exame oftalmológico completo e exames subsidiários (campo visual manual, eletrorretinograma, retinografia simples e fluorescente), no período de fevereiro de 2003 a dezembro de 2009. Foi utilizado o programa SPSS versão 13.0 para análise dos dados estatísticos. RESULTADOS: A herança autossômica recessiva foi a forma mais comumente encontrada (76,2% no grupo 1), mas em proporção maior do que a de outros trabalhos da literatura. Um menor número de casos com padrão recessivo ligado ao X (1,5%) também foi notado no grupo 1. Não houve diferença estatisticamente significante entre as características clínicas entre os dois grupos. CONCLUSÃO: O padrão de herança encontrado nos pacientes com RP clássica foi similar ao encontrado em outros trabalhos. As características clínicas foram semelhantes nos dois grupos estudados.

OBJECTIVE: To make an epidemiological analysis of patients with retinitis pigmentosa (RP), characterizing clinical aspects of the disease and the pattern of inheritance found in the population studied, according to the presence or not of Usher Syndrome. METHODS: 155 patients with RP were studied and the sample was divided into two groups: group 1 (n = 130) with patients diagnosed with classical RP not associated with systemic symptoms; and group 2 (n = 25) with patients diagnosed with Usher syndrome (USH). We characterized clinical aspects of the disease (sex, age, ocular symptoms, visual acuity and anterior and posterior segment changes) and the pattern of inheritance. Data were obtained through medical history, complete ophthalmic examination and complementary exams (manual visual field, electroretinogram, retinography and fluorescent angiography) for the period of February 2003 to December 2009. We used SPSS version 13.0 for statistical data analysis. RESULTS: The autosomal recessive inheritance was the most commonly found (76.2% in group 1), but in greater proportion than that of other studies. A smaller number of cases with X-linked recessive pattern (1.5%) was also noted in group 1. There was no statistically significant difference between the clinical characteristics of the two groups. CONCLUSION: The pattern of inheritance found in patients with classical RP was similar to that found in other studies. Clinical characteristics were similar in both groups.

Síndrome de Usher de tipo II: caracterización oftalmológica, auditiva y genética de una familia consanguínea / Type II Usher syndrome: ophthalmological, auditory, and genetic characterization of a consanguineous family

Se caracterizó a una familia consanguínea de 25 miembros, 3 de los cuales padecían el síndrome de Usher de tipo II, a través del estudio auditivo, oftalmológico y genético en el Centro de Retinosis Pigmentaria de Santiago de Cuba. Los pacientes (2 varones y 1 fémina) tenían en común: aparición de la enfermedad en la etapa juvenil, mala visión nocturna, campos visuales reducidos, hipoacusia neurosensorial y resultados normales en las pruebas vestibulares; asimismo, en genética molecular, la electroforesis en gel de poliacrilamida reveló la presencia del marcador D1S237, estrechamente ligado al gen USH2 en el cromosoma 1. Esa caracterización permitirá aplicar la terapia génica y los implantes, tanto de células madre como cocleares, según corresponda.

A consanguineous family of 25 members, 3 of whom suffered from type II Usher syndrome was characterized through the auditory, ophthalmologic, and genetic study in the Retinitis Pigmentosa Center from Santiago de Cuba. The patients (2 males and a female) had in common: occurrence of the illness during youth, bad night vision, reduced visual fields, neurosensorial hypoakusia, and normal results in the vestibular tests; also, in molecular genetics, electrophoresis in polyacrilamide gel revealed the presence of the D1S237 marker, closely linked to the gene USH2 in chromosome 1. That characterization will allow to apply the genic therapy and both implants, mother cells and cochlear, as it corresponds.

Aspectos genético-sociales de la retinosis pigmentaria / Social-genetic aspects of the pigmentary retinosis

La Retinosis pigmentaria es una enfermedad de origen genético a la que se le asocian múltiples problemas sociales relacionados con su origen. Objetivo: describir ciertos aspectos genético-sociales de la Retinosis pigmentaria importantes para su manejo y prevención. Método: se realizó un estudio descriptivo transversal en el Centro de Retinosis Pigmentaria de Camagüey, desde octubre de mil novecientos noventa y uno hasta Julio de dos mil ocho, con doscientos nueve pacientes afectados por esta enfermedad. Los datos se extrajeron de las historias clínicas de genética, los cuales fueron vertidos en un modelo de recolección y luego procesados estadísticamente por medio de técnicas descriptivas. Resultados: de las dosciento nueve familias, ciento trece casos índices eran del sexo femenino y noventa y seis del masculino. Se halló consanguinidad en cincuenta y tres familias con herencia definida. El grado de parentesco más frecuente fue el de primos hermanos. Hubo una fuerte asociación estadística entre la consanguinidad y la herencia autosómica recesiva, que fue a su vez el modo de herencia más frecuente. Hubo un mayor número de mujeres estudiadas y pesquisadas que de hombres. Las formas sindrómicas de la enfermedad se presentaron en dieciséis familias (7,65 por ciento). El síndrome Usher resultó ser el más frecuente. Conclusiones: la naturaleza hereditaria, la presencia de consanguinidad, y las formas sindrómicas de la enfermedad son importantes aspectos genético-sociales relacionados con la retinosis pigmentaria, por lo que el estudio de los mismos debe profundizarse con vistas a la prevención y manejo de la enfermedad.

Pigmentary retinosis is a disease of genetic origin to which is associated multiple social problems related with its origin. Objective: to describe certain important social-genetic aspects of the Pigmentary retinosis for their management and prevention. Method: a cross-sectional descriptive study at the Pigmentary Retinosis Center of Camagüey was performed, from October 1991 to July 2008, with 209 patients affected by this disease. Data were extracted of the genetics´ clinical histories, which were poured in a summary model and then statistically processed by means of descriptive techniques. Results: of the 209 families, one-hundred thirteen index cases were of the female sex and ninety-six of the masculine one. Consanguinity in fifty-three families with defined inheritance was found. The most frequent family relationship was that of first cousins. There was a b statistical association among consanguinity and recessive autosomal inheritance that was in turn the most frequent way of inheritance. There was a bigger number of studied and investigated women than men. Syndromic forms of the disease were presented in sixteen families (7,65 percent). The Usher’s syndrome turned out to be the most frequent one. Conclusions: the hereditary nature, the presence of consanguinity and the syndromic forms of the disease are important social-genetic aspects related with pigmentary retinosis, for what its study should be deepened with a view to the prevention and management of the disease.

Mutation identification in a 5-generation pedigree with autosomal dominant retinitis pigmentosa / 华中科技大学学报（医学）（英德文版）

An extended 5-generation family has been investigated in which 32 of the 111 family members were diagnosed as having retinitis pigmentosa (RP). The proband was a 58-year old male in whom night-blindness was first observed in early childhood, with almost loss of vision by 52 years of age. The symptoms observed in other family members included night-blindness, impaired vision and visual field loss. Dementia, digital abnormalities, deaf-mutism and mental retardation were variously diagnosed in a number of individuals with RP. The affected and unaffected family members were tested for mutations in a range of candidate genes. The 8 exons of three candidate genes have been analyzed by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and DNA sequencing techniques. A novel mutation was identified in the rhodopsin gene at codon 52 of exon 1 (TTC-TAC) that resulted in a substitution of Phe to Tyr.

Psychosis in a patient with Usher syndrome: a case report

The present report is the case of a 26-year-old man, born with Usher syndrome. The patient had had a significant hearing impairment since birth and had developed retinitis pigmentosa. He had originally been diagnosed with a depressive disorder and treated with antidepressants, with no subsequent improvement in his mental state. Following a deterioration in his mental state he was admitted for reassessment at the Queen Elizabeth Psychiatric Hospital, Birmingham, and antidepressants were stopped. It subsequently became apparent from observations, interviews with the patient and information from the patient's carers and relatives that he had a psychotic illness. Treatment was started with the antipsychotic drug risperidone, after which he showed significant improvement. The association between Usher syndrome and psychosis is discussed

Screening for homozygosity by descent in families with autosomal recessive retinitis pigmentosa.

Retinitis pigmentosa (RP) is a genetically heterogeneous disease and an important cause of blindness in the state of Andhra Pradesh in India. In an attempt to identify the disease locus in families with the recessive form of the disease, we used the approach of screening for homozygosity by descent in offspring of consanguineous and nonconsanguineous families with RP. Microsatellite markers closely flanking 21 known candidate genes for RP were genotyped in parents and affected offspring to determine whether there was homozygosity at these loci that was shared by affected individuals of a family. This screening approach may be a rapid preliminary method to test known loci for possible cosegregation with disease.

RPE65 gene: multiplex PCR and mutation screening in patients from India with retinal degenerative diseases.

We used multiplex PCR follwed by sequencing to screen for mutations in the 14 exons of the RPE65 gene in early-childhood-onset autosomal recessive retinitis pigmentosa (arRP) and Leber's congenital amaurosis (LCA) patients. The RPE65 protein is believed to play an important role in the metabolism of vitamin A in the visual cycle and mutations identified in the gene could have implications for vitamin A-based therapeutic intervention. We were able to identify a homozygous mutation (AAT --> AAG) in exon 9 in an arRP patient and a heterozygous missense transversion (AAT --> AAG) also in exon 9 of an LCA patient. We also identified a polymorphism in exon 10 (GAG --> GAA) in an arRP as well as an LCA patient. Mutation screening would be greatly facilitated by multiplex PCR which could cut down costs, labour and time involved. The nucleotide changes observed in this study could be de novo. Though a larger study has been undertaken, from the preliminary results it appears that in India the RPE65 gene seems to be less involved in causation of LCA.

Mutation analysis of codons 345 and 347 of rhodopsin gene in Indian retinitis pigmentosa patients.

More than 100 mutations have been reported till date in the rhodopsin gene in patients with retinitis pigmentosa. The present study was undertaken to detect the reported rhodopsin gene point mutations in Indian retinitis pigmentosa patients. We looked for presence or absence of codon 345 and 347 mutations in exon 5 of the gene using the technique of allele-specific polymerase chain reaction by designing primers for each mutation. We have examined 100 patients from 76 families irrespective of genetic categories. Surprisingly, in our sample the very widely reported highly frequent mutations of codon 347 (P --> S/A/R/Q/L/T) were absent while the codon 345 mutation V --> M was seen in three cases in one family (autosomal dominant form) and in one sporadic case (total two families). This is the first report on codon 345 and 347 mutation in Indian retinitis pigmentosa subjects.

Retinose pigmentar sem pigmento / Retinilis pigmentosa sine pigmento

A retinose pigmentar é uma doença hereditária degenerativa primária da retina, que apresenta um quadro clínico clássico. Neste trabalho apresentamos dois casos atípicos (irmäos) de retinose pigmentar sem pigmento

Retinosis pigmentaria: Análisis genético / Pigmentary retinopathy. Genetic analysis

Se realizó una revisión retrospectiva en el Servicio de Genética de la APEC de 38 pacientes con Dx. de Retinosis pigmentaria, que acudieron en el periodo comprendido entre Septiembre de 1995 y Diciembre de 1996. Se evaluó la frecuencia de las diferentes formas hereditarias y su comparación con otras poblaciones, la edad de inicio, la capacidad visual actual y la incidencia de catarata en cada grupo. Se confirma que la evolución y el pronóstico son variables según el patrón hereditario, siendo generalmente más severa la forma autosómica recesiva y los casos esporádicos. Las formas autosómico dominantes son heterogéneas y las formas sindromáticas varían según el síndrome en cuestión. El estudio clínico y familiar son nuestra base para asesoramiento genético

A genetic analysis of retinitis pigmentosa.

The data consists of sixty probands affected with Retinitis pigmentosa. Syndromic cases were found in five percent of the RP probands. Segregation analysis was carried out on proband sibship data. The ascertainment probability was estimated at 0.5517. Analysis of the data by parental mating types of proband sibships indicated the presence of dominant forms of RP (2.05%). Analysis of proband sibships indicated the presence of low risk families in the Normal x Normal matings (45%) and in the consanguineous matings (40%). The hypothesis of recessive inheritance could be confirmed only in multiplex sibships (p = 0.383 +/- 0.0793). Data on proband matings though incomplete conformed in general to autosomal recessive gene hypothesis.

Treinta y siete casos de retinitis pigmentosa en una familia / 37 cases of retinitis pigmentosa in a family

Se estudian 6 generaciones de una familia afectados de retinitis pigmentosa pesquisados a partir de un caso índice. Se analiza su tipo de herencia, signos y síntomas oftalmológicos y estudio electrorretinográfico. Se encuentra una retinitis pigmentosa autosómica dominante. Las características oftalmológicas tienen topografía inicial variada, electrorretinograma ausente y complicaciones oftalmológicas asociadas como catarata y glaucoma. Se observan un cambio en la historia natural de la enfermedad en las últimas generaciones, lo que sugiere una influencia ambiental

Implication of some environmental factors in development of genetic abnormalities associated with some eye disorders in Sharkia, Egypt

A retrospective case-control study was carried out in Sharkia Governorate upon 55 cases with congenital cataract, glaucoma and retinitis pigmentosa and 20 healthy persons as a control group. This study was intended to investigate the mode of inheritance, implication of prenatal environmental exposure and other personal risk factors in development of these serious eye disorders. The subjects were examined according to the following protocol; [1] an interview for recording the relevant personal and family data, [2] complete medical an ophthalmological examinationX3] family pedigree was constructed for each case and, [4] peripheral lymphocyte haryotyping was done for detection of chromosomal abnormalities. The main findings are as follows: [1] the mode of inheritance in primary congenital glaucoma was multifactorial, in congenital cataract as autosmal dominant and recessive and in retinitis pigmentosa it can follow autosomal dominant and recessive, [2] a significant higher prevalence of chromosomal abberration among cases when compared with control, [3] 66.7% of cases with chromosomal abberration had a prenatal history of exposure to some environmental hazards [P<0.01]. [4]; a history of parental exposure to environmental hazards were reported by 2.6% of all cases with congenital eye disorder