Caracterización fenotípica de la retinitis pigmentaria asociada a sordera / Phenotypic characterization of retinitis pigmentosa associated with deafness

Introducción. El síndrome de Usher es una alteración genética caracterizada por la asociación de retinitis pigmentaria y sordera. Sin embargo, hay casos con familias en las cuales, a pesar de presentarse dicha asociación, no se puede diagnosticar un síndrome de Usher ni ninguno otro. Objetivo. Reevaluar fenotípicamente a 103 familias con diagnóstico previo de posible síndrome de Usher o retinitis pigmentaria asociada con sordera. Materiales y métodos. Se revisaron las historias clínicas de 103 familias con un posible diagnóstico clínico de síndrome de Usher o retinitis pigmentaria asociada con sordera. Se seleccionaron las familias cuyo diagnóstico clínico no correspondía a un síndrome de Usher típico. Los afectados fueron valorados oftalmológica y audiológicamente. Se analizaron variables demográficas y clínicas. Resultados. Se reevaluaron 14 familias cuyo diagnóstico clínico no correspondía al de síndrome de Usher. De las familias con diagnóstico inicial de síndrome de Usher típico, el 13,6 % recibieron uno posterior de "retinitis pigmentaria asociada con sordera" de "otro síntoma ocular asociado con hipoacusia',' o en forma aislada en una misma familia, de "retinitis pigmentaria" o "hipoacusia'.' Conclusiones. Es fundamental el estudio familiar en los casos en que la clínica no concuerda con el diagnóstico de síndrome de Usher típico. En los pacientes con retinitis pigmentaria asociada con sordera, el diagnóstico clínico acertado permite enfocar los análisis moleculares y, así, establecer un diagnóstico diferencial. Es necesario elaborar guías de nomenclatura en los casos con estos hallazgos atípicos para orientar a médicos e investigadores en cuanto a su correcto manejo.

Introduction: There are several syndromes that associate retinitis pigmentosa with deafness or hearing loss. The most frequent is Usher syndrome, a genetic disorder of autosomal recessive inheritance, which, in some cases, is accompanied by vestibular dysfunction. However, there are cases of families that despite having retinitis pigmentosa associated with deafness, cannot be classified as Usher or other syndromes due to additional findings. Objective: To reassess the phenotypes of 103 families previously diagnosed as possible Usher syndrome and/or retinitis pigmentosa associated with deafness. Materials and methods: We conducted a descriptive and retrospective study by reviewing the medical records of 103 families with a probable clinical diagnosis of Usher syndrome and/or retinitis pigmentosa associated with deafness. Families whose clinical diagnosis did not correspond to the typical Usher syndrome were selected and evaluated ophthalmologically and audiologically. Demographic and clinical variables were analyzed. Results: We selected and then reevaluated 14 families and 55 individuals as they did not correspond to a clinical diagnosis of Usher syndrome; 13.6% of the families initially considered to have typical Usher syndrome were later diagnosed with retinitis pigmentosa associated with deafness, another ocular symptom associated with hearing loss, retinitis pigmentosa, or isolated hearing loss in the same family. Conclusions: Family studies are essential in cases where the symptoms do not match the typical Usher' syndrome. In the cases of retinitis pigmentosa associated with deafness, a correct clinical diagnosis allows for focusing on the molecular analyses to establish a differential diagnosis. The need for nomenclature guidelines on these atypical findings is relevant to aid physicians and researchers in the best approach to these cases.

Usher syndrome with methylmalonic acidemia and homocysteine in an infant / 中华围产医学杂志

A case of Usher syndrome with methylmalonic acidemia and homocysteine is reported. The patient was a two-month-old and small for gestational age male infant hospitalized for "feeding difficulties" during the neonatal period. The baby boy presented hypotonia, microcephaly, and hearing loss after birth. Genetic test found compound heterozygous mutations of c.482G>A and c.567dup in MMACHC, and both were pathogenic mutations inherited from his parents. Moreover, the patient also had compound heterozygous variants at c.2802T>G and c.14017T>C of USH2A gene. The former was suspected to be pathogenic, and the latter was of unknown clinical significance. Both were from the parents. Usher syndrome and methylmalonic acidemia with homocysteine were clinically diagnosed. Followed up to the age of two, the child was found with moderate mental retardation, while the physical development was comparable to that of the same age group.

Novel compound heterozygous mutations in the PCDH15 gene in a family affected with Usher syndrome type 1F with retinitis pigmentosa sine pigmento / 中华眼底病杂志

Objective:To identify the causative gene in a family affected with Usher syndrome (USH) with retinitis pigmentosa sine pigmento (RPSP) and to analyze the genotype-phenotype correlation.Methods:A retrospective clinical study. A 9-year-old girl with RPSP type 1F USH diagnosed in the ophthalmology clinic of Henan Provincial People's Hospital in November 2019 and her parents were included in the study. The patient had bilateral night blindness for more than 4 years, she suffered from hearing loss 7 years, and is currently binaural sensorineural deafness. The best corrected visual acuity in both eyes was 0.5 +. There was showed no obvious pigmentation on the fundus. The visual acuity of the peripheral field of vision decreased. Optical coherence tomography showed that the outer layer of the peripheral retina became thinner and the ellipsoid band disappeared. On electroretinogram examination, the rod and cone system response was severely decreased. The clinical phenotype of the parents of the child were normal. The peripheral venous blood of the child and his parents were extracted, the whole genome DNA was extracted, the custom developed targeted capture kit (PS400) was used, and the next-generation sequencing technology was used to detect genetic mutations. The suspected pathogenic mutation sites were verified by Sanger; co-segregation was performed among family members. The pathogenicity of variants were evaluated according to the interpretation standards and guidelines of sequence variants. Bioinformatics techniques were used to assess the impact of variants on encoded proteins. Results:The results of genetic testing showed that the proband detected the PCDH15 gene c.4109dupA (p.K1370fs) (M1), c.17dupA (p.Y6_L7delinsX) (M2) compound heterozygous mutation sites, verified by Sanger sequencing, the mutations were in the family in a state of co-segregation. According to the evaluation of sequence variation interpretation standards and guidelines, M1 and M2 were pathogenic variants of the PCDH15 gene. M1 led to a complete change in the transmembrane structure of the encoded protein, and M2 caused the gene to only translate 6 amino acids, which predicted that the PCDH15 protein cannot be synthesized. According to the clinical phenotype, gene mutation pathogenicity and protein structure prediction, the final clinical diagnosis was PCDH15-related type 1F. Conclusions:PCDH15 genes c.4109dupA and c.17dupA are the pathogenic mutation sites of USH in this family. These compound heterozygous new mutations lead to the failure of normal synthesis of PCDH15 protein, which leads to ocular and ear manifestations.

Valoración clínica, epidemiológica y del diagnóstico de Enfermería del síndrome de Usher / Clinical, epidemiological and nursing diagnostic evaluation of Usher syndrome

RESUMEN Introducción: El síndrome de Usher es un heterogéneo grupo de enfermedades hereditarias, que se manifiesta clínicamente por asociar pérdida auditiva neurosensorial con la ceguera, hecho este que hace que los pacientes que lo padecen requieran de cuidados de Enfermería especiales. Objetivo: valorar clínica, epidemiológica y del diagnóstico de Enfermería con síndrome de Usher, en Pinar del Río entre los años 2016 y 2018. Métodos: investigación observacional, descriptiva y transversal. El universo estuvo conformado por 63 pacientes y la muestra por 55 que cumplieron los criterios de inclusión. Las variables analizadas fueron: edad, sexo, agudeza visual central mejor corregida, tipo de pérdida auditiva neurosensorial, forma clínica del síndrome de Usher y diagnóstico de Enfermería. Resultados: el 56,3 % de los pacientes fueron masculinos, el 60% de los pacientes presentaron USH Tipo II, el 38,2 % presentó valores de la agudeza visual central mejor corregida entre 0,7 -1,0, en el 43,6 % de los pacientes la pérdida auditiva neurosensorial fue moderada; el 100 % de los casos presentaron como diagnóstico de Enfermería deterioro de la habilidad de traslación, seguido del deterioro de la integridad tisular y riesgo de caída (85,5 %). Conclusiones: el sexo masculino predominó en la evaluación y el grupo etario de 61 años y más, con una agudeza visual central mejor corregida entre 0,7-1,0 y una pérdida auditiva neurosensorial moderada; y la forma clínica de Usher II la más frecuente, así como el diagnóstico de Enfermería de deterioro de la habilidad de traslación.

ABSTRACT Introduction: Usher syndrome is a heterogeneous group of hereditary diseases, which manifests itself clinically by associating sensorineural hearing loss with blindness, a fact that makes patients suffering from this disease require special nursing care. Objective: to assess the clinical, epidemiological and nursing diagnostic status of Usher syndrome in Pinar del Río between 2016 and 2018. Methods: observational, descriptive and cross-sectional research. The target group consisted of 63 patients and the sample of 55 who met the inclusion criteria. The variables analyzed were: age, gender, best corrected central visual acuity, type of sensorineural hearing loss, clinical type of Usher syndrome and nursing diagnosis. Results: 56,3 % of patients were male, 60 % of patients suffered from Usher Type II, 38,2 % presented values of central visual acuity better corrected between 0,7 -1,0, in 43,6 % of patients the sensorineural hearing loss was moderate; 100 % of cases presented as a nursing diagnosis the deterioration of the ability of movement, followed by deterioration of tissue integrity and risk of falling (85,5 %). Conclusions: male gender predominated in the assessment and the age group of 61 years and older, with better corrected central visual acuity between 0.7-1.0 and moderate sensorineural hearing loss; and the clinical type of Usher II was the most frequent, as well as the diagnosis of nursing involving impaired ability to move.

Novel mutations in the USH2A gene in a family affected with Usher syndrome type 2 / 中华眼底病杂志

Objective To identify the pathogenic genes and mutations in a family with Usher syndrome type 2.Methods A three-generation family including 7 individuals was enrolled in this study.There were 2 male patients and 5 unaffected individuals.All participants was underwent related ophthalmologic examination,including best corrected visual acuity,slit-lamp,indirect ophthalmoscopy,electroretinogram (ERG),optical coherence tomography and visual field test.DNA was extracted from 3 ml peripheral venous blood of all participants.A total of 136 hereditary retinal disease target genes were screened and the DNA sequence was performed by Next-generation sequence analysis.Then the suspected mutations compared with databases to identify the suspected mutations,which should be verified with non-affected family members and 100 normal subjects by PCR and Sanger sequence.Results The sequence result showed that 2 patients,the proband and his brother,carried complex heterozygous mutations in the USH2A gene:c.5459T＞C (p.M1820T) in exon 27,c.802G ＞A (p.G268R) in exon 5 and c.1190T＞A (p.I397K) in exon 7.The c.5459T ＞ C and c.1190T ＞A mutations in USH2A have not been reported in the literature and database.Although their mother carried c.5459T＞C (p.M1820T) and c.802G＞A (p.G268R),and their father carried c.1190T＞A (p.I397K) heterozygous mutations,the parents did not present phenotype.These mutations were not detected in other normal family members.The result was supported by co-segregation analysis.Conclusion The heterozygous mutations c.5459T＞C (p.M1820T),c.1190T＞A (p.I397K) and c.802G＞A (p.G268R) in USH2A gene cause Usher syndrome in this family.

Outcomes of Late Implantation in Usher Syndrome Patients

Abstract Introduction Usher syndrome (US) is an autosomal recessive disorder characterized by hearing loss and progressive visual impairment. Some deaf Usher syndrome patients learn to communicate using sign language. During adolescence, as they start losing vision, they are usually referred to cochlear implantation as a salvage for their new condition. Is a late implantation beneficial to these children? Objective The objective of this study is to describe the outcomes of US patients who received cochlear implants at a later age. Methods This is a retrospective study of ten patients diagnosed with US1. We collected pure-tone thresholds and speech perception tests from pre and one-year post implant. Results Average age at implantation was 18.9 years (5-49). Aided average thresholds were 103 dB HL and 35 dB HL pre and one-year post implant, respectively. Speech perception was only possible to bemeasured in four patients preoperatively, who scored 13.3; 26.67; 46% vowels and 56% 4-choice. All patients except one had some kind of communication. Two were bilingual. After one year of using the device, seven patients were able to perform the speech tests (from four-choice to close set sentences) and three patients abandoned the use of the implant. Conclusion We observed that detection of sounds can be achieved with late implantation, but speech recognition is only possible in patients with previous hearing stimulation, since it depends on the development of hearing skills and the maturation of the auditory pathways.

Current research in the genes and proteins related with Usher syndrome / 中华眼底病杂志

Usher syndrome (USH) is an autosomal recessive hereditary disease,characterized as retinitis pigmentosa and deafness.According to the severity of hearing loss,presence or absence of vestibular dysfunction,Usher syndrome is divided into 3 clinical subtypes..USH1,USH2 and USH3.Due to the genetically heterogeneous,it is important and valuable to find out the gene mutations in USH patients,which will be helpful to prenatal diagnosis,early intervention and gene therapy.Till now,the following 13 USH-related chromosomal loci were reported in the literature:USH1B,USH1C,USH1D (CDH23 gene),USH1F (PCDH15 gene),USH1G (SANS gene),USH1E,USH1H,USH1J and USH1K,USH2A,USH2C,USH2D and USH3 (CLRN1 gene).Ten out of all 13 loci have been located and identified.But more mechanisms should be further investigated,such as the relationship between the locus of gene mutations and clinical symptoms,how the modified protein structures and functions trigger clinical symptoms.

Análisis Molecular de las Mutaciones 2299delG y C759F en Individuos Colombianos con Retinitis Pigmentosa e Hipoacusia Neurosensorial / Molecular analyses of 2299delG and C759F mutations in Colombian Retinitis Pigmentosa and Sensorineural hearing loss affected individuals

Determinar la presencia de las mutaciones 2299delG y C759F en 37 individuos colombianos no relacionados con asociación de RP e hipoacusia neurosensorial. Materiales y métodos: análisis de secuencia directa del exón 13 del gen USH2A en todos los individuos seleccionados para el estudio. Resultados: la mutación 2299delG fue observada únicamente en individuos con Síndrome de Usher tipo II, mientras que la mutación C759F, no fue observada en ninguno de los individuos del estudio...

To determine the presence of 2299delG and C759F mutations in 37 non-related subjects from Colombia suffering from RP and sensorineural deafness. Materials and methods: Exon 13 of USH2A gene was directly sequenced in all subjects selected for the study. Results: In this work, the 2299delG mutation was only observed in subjects suffering from Usher syndrome type II while the C759F mutation was not detected in any subject...

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.