RESUMEN
BACKGROUND: Visual impairment (VI) is associated with dementia and other neuropsychiatric outcomes, but previous studies have not considered genetic sources of confounding or effect modification. METHODS: We analysed data from the Health and Retirement Study, an ongoing nationally representative survey of older US adults, a subset of whom underwent genetic testing from 2006 to 2012 (n = 13 465). Using discrete time proportional hazards models and generalised estimating equations, we measured the association between VI and dementia, depression and hallucinations adjusting for demographics and comorbidities, ancestry-specific principal components and polygenic risk scores (PRS) for Alzheimer's disease, major depressive disorder or schizophrenia. Effect modification was assessed using VI-PRS interaction terms and stratified analyses. RESULTS: VI was associated with dementia, depression and hallucinations after adjusting polygenic risk and other confounders. There was no VI-PRS interaction for dementia or depression. However, the association between VI and hallucinations varied by genetic risk of schizophrenia. Within the bottom four quintiles of schizophrenia PRS, VI was not associated with hallucinations among White (OR 1.16, 95% CI: 0.87-1.55) or Black participants (OR 0.96, 95% CI: 0.49-1.89). In contrast, VI was strongly associated with hallucinations among White (OR 2.08, 95% CI: 1.17-3.71) and Black (OR 10.63, 95% CI: 1.74-65.03) participants in the top quintile of schizophrenia PRS. CONCLUSIONS: The association between VI and neuropsychiatric outcomes is not explained by shared genetic risk factors, and there is a significant interaction between VI and polygenic risk of hallucinations in older adults.
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Demencia , Predisposición Genética a la Enfermedad , Alucinaciones , Trastornos Psicóticos , Trastornos de la Visión , Humanos , Masculino , Femenino , Anciano , Demencia/genética , Demencia/epidemiología , Demencia/psicología , Demencia/diagnóstico , Factores de Riesgo , Estados Unidos/epidemiología , Trastornos de la Visión/genética , Trastornos de la Visión/epidemiología , Trastornos de la Visión/psicología , Alucinaciones/genética , Alucinaciones/epidemiología , Alucinaciones/psicología , Alucinaciones/diagnóstico , Trastornos Psicóticos/genética , Trastornos Psicóticos/epidemiología , Trastornos Psicóticos/psicología , Herencia Multifactorial , Medición de Riesgo , Factores de Edad , Persona de Mediana Edad , Anciano de 80 o más Años , Esquizofrenia/genética , Esquizofrenia/epidemiologíaAsunto(s)
Envejecimiento , Epitelio Pigmentado de la Retina , Humanos , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patología , Envejecimiento/genética , Envejecimiento/fisiología , Envejecimiento/metabolismo , Trastornos de la Visión/genética , Trastornos de la Visión/fisiopatología , Animales , GenómicaRESUMEN
BACKGROUND: Cerebral visual impairment (CVI) is the most common form of paediatric visual impairment in developed countries. CVI can arise from a host of genetic or acquired causes, but there has been limited research to date on CVI in the context of genetic disorders. METHODS: We carried out a retrospective analysis of genotypic and phenotypic data for participants with CVI within the DECIPHER database and 100 000 Genomes Project (100KGP). RESULTS: 158 individuals with CVI were identified across both cohorts. Within this group, pathogenic or likely pathogenic sequence variants in 173 genes were identified. 25 of these genes already have known associations with CVI, while the remaining 148 are candidate genes for this phenotype. Gene ontology analysis of the CVI gene sets from both DECIPHER and 100KGP suggests that CVI has a similar degree of genetic heterogeneity to other neurodevelopmental phenotypes, and a strong association with genetic variants converging on ion channels and receptor functions. Individuals with a monogenic disorder and CVI have a higher frequency of epilepsies and severe neurodisability than individuals with a monogenic disorder but not CVI. CONCLUSION: This study supports the availability of genetic testing for individuals with CVI alongside other neurodevelopmental difficulties. It also supports the availability of ophthalmological screening for individuals with genetic diagnoses linked to CVI. Further studies could elaborate on the links between specific genetic disorders, visual maturation and broader neurodevelopmental characteristics.
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Fenotipo , Humanos , Femenino , Masculino , Estudios de Asociación Genética/métodos , Estudios Retrospectivos , Niño , Predisposición Genética a la Enfermedad , Ceguera Cortical/genética , Ceguera Cortical/diagnóstico , Pruebas Genéticas , Genotipo , Trastornos de la Visión/genética , Trastornos de la Visión/diagnóstico , Bases de Datos Genéticas , Preescolar , AdolescenteRESUMEN
INTRODUCTION: Heimler syndrome (HS) is a rare disorder that includes sensorineural hearing loss (SNHL), nail abnormalities, and enamel hypoplasia. Patients with this syndrome can also exhibit ocular manifestations. At present, only a few cases of HS have been reported, existing knowledge of this syndrome is limited, and many cases have been misdiagnosed or even missed. This is the first report of Heimler syndrome with blurred vision as the first complaint, which was diagnosed by genetic analysis in the ophthalmology department. CASE DESCRIPTION: An 8-year-old girl complained of bilateral visual blur and night blindness from birth. Ophthalmic examinations revealed bilateral retinitis pigmentosa with cystoid macular edema, visual impairment with hyperopia and astigmatism. Hearing test revealed bilateral severe sensorineural hearing loss. Dental examinations revealed enamel hypoplasia. In addition, whole-exome sequencing (WES) identified two pathogenic variants in PEX1: the previously reported missense variant c.2966T > C (p.I989â T), and the novel frameshift variant c.1671_1672del (p.G558Sfs*33). CONCLUSION: Heimler syndrome is caused by compound heterozygous PEX1 pathogenic variants, c.2966T > C (p.I989â T) and c.1671_1672del (p.G558Sfs*33), which contributed to the diversity of clinical and genetic profiles in this patient. The main clinical manifestations include bilateral retinitis pigmentosa with cystoid macular edema, sensorineural hearing loss, and enamel hypoplasia. Systemic examinations are suggested for patients suspected of having pigmentary retinal dystrophy, especially combined with hearing-related impairments. Genetic testing can help us to make a definitive diagnosis.
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Amelogénesis Imperfecta , Pérdida Auditiva Sensorineural , Uñas Malformadas , Humanos , Femenino , Niño , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/diagnóstico , Uñas Malformadas/genética , Uñas Malformadas/diagnóstico , Amelogénesis Imperfecta/genética , Amelogénesis Imperfecta/diagnóstico , Agudeza Visual , Heterocigoto , Análisis Mutacional de ADN , Secuenciación del Exoma , Tomografía de Coherencia Óptica , Trastornos de la Visión/genética , Trastornos de la Visión/diagnóstico , Proteínas de la Membrana/genética , ADN/genética , ATPasas Asociadas con Actividades Celulares DiversasRESUMEN
OBJECTIVE: To analyze the clinical data and genetic characteristics of a child with CLN1 neuronal ceroid lipofuscinosis in conjunct with Hereditary hyperferritinemia cataract syndrome (HHCS). METHODS: A child who was admitted to the PICU of the First Affiliated Hospital of Zhengzhou University in November 2020 was selected as the study subject. Clinical data of the child was collected. Genetic testing was carried out for the child, and the result was analyzed in the light of literature review to explore the clinical and genetic characteristics to facilitate early identification. RESULTS: The patient, a 3-year-old male, had mainly presented with visual impairment, progressive cognitive and motor regression, and epilepsy. Cranial magnetic resonance imaging revealed deepened sulci in bilateral cerebral hemispheres, and delayed myelination. The activity of palmitoyl protein thioesterase was low (8.4 nmol/g/min, reference range: 132.2 ~ 301.4 nmol/g/min), whilst serum ferritin was increased (2417.70 ng/mL, reference range: 30 ~ 400 ng/ml). Fundoscopy has revealed retinal pigment degeneration. Whole exome sequencing revealed that he has harbored c.280A>C and c.124-124+3delG compound heterozygous variants of the PPT1 gene, which were respectively inherited from his father and mother. Neither variant has been reported previously. The child has also harbored a heterozygous c.-160A>G variant of the FTL gene, which was inherited from his father. Based on the clinical phenotype and results of genetic testing, the child was diagnosed as CLN1 and HHCS. CONCLUSION: The compound heterozygous variants of the PPT1 gene probably underlay the disorders in this child. For children with CLN1 and rapidly progressing visual impairment, ophthalmological examination should be recommended, and detailed family history should be taken For those suspected for HHCS, genetic testing should be performed to confirm the diagnosis.
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Catarata , Lipofuscinosis Ceroideas Neuronales , Preescolar , Humanos , Masculino , Catarata/genética , Pruebas Genéticas , Mutación , Lipofuscinosis Ceroideas Neuronales/diagnóstico , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/patología , Trastornos de la Visión/genéticaRESUMEN
The association between dystonia and early-onset epileptic encephalopathy (EOEE) may have a genetic basis. Phosphatidylinositol glycan biosynthesis class A protein (PIGA) germline mutations have been described in the last decade and associated with refractory EOEEs. Dysmorphisms and visceral abnormalities have also been reported. Here, we present the case of a now 8-month-old child who was evaluated for dystonia, visual impairment, and developmental delay at 2 months of age, followed by refractory focal seizures when he was 4 months old. The remaining examination was normal, besides an accelerated linear growth. His brain magnetic resonance and an extensive metabolic investigation failed to show any abnormalities. At 7 months of age, the exome sequencing found a hemizygous PIGA pathogenic variant-c.1352T > C (p.(Ile451Thr). Seizures improved after the association of carbamazepine with levetiracetam and the beginning of the ketogenic diet. To our knowledge, this is the first time the phenotype associated with this specific mutation is described. Our patient had the singularity of manifesting with remarkable dystonia, over 2 months before the onset of seizures. We also point to the utility of the gene sequencing approach in the diagnosis of patients with dystonia and EOEEs, since identification of the genetic cause may help in patient's management and families' empowerment.
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Mutación , Trastornos de la Visión , Humanos , Masculino , Lactante , Trastornos de la Visión/genética , Trastornos de la Visión/etiología , Espasmos Infantiles/genética , Espasmos Infantiles/complicaciones , Distonía/genética , Distonía/etiología , Distonía/tratamiento farmacológico , Proteínas de la Membrana/genética , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/complicacionesRESUMEN
RESUMEN: El objetivo de este estudio fue describir la frecuencia genotípica y alélica del ACTN3 R577X y ECA I/D en atletas ciegos de fútbol 5. Se incluyó una metodología descriptiva con una muestra de 63 deportistas ciegos (28,0±5,8 años), todos varones, de equipos de fútbol 5 de alto rendimiento. El polimorfismo se determinó mediante la reacción en cadena de la polimerasa en tiempo real (RT-PCR). La estadística fue descriptiva realizada a partir de las medidas de frecuencia de genotipos y alelos. La frecuencia genotípica de la ACTN3 en los deportistas presentó la siguiente distribución: el 28,6 % con genotipo RR, el 54 % con RX y el 17,4 % con XX y frecuencia alélica del 55,6 % para el alelo R y del 44,4 % para el alelo X. En cuanto a la ECA I/D, la frecuencia genotípica fue del 63,5 % para el genotipo ID, del 22,2 % para el DD y del 14,3 % para el II. La frecuencia alélica presentó prevalencia del alelo D con el 53,9 %. El estudio constató una predominancia de los genotipos y alelos representativos de las modalidades de fuerza y velocidad para ACTN3 R577X y ECA I/D de atletas de fútbol 5.
SUMMARY: The aim of this study was to describe the genotypic and allele frequency of ACTN3 R577X and ACE I/D in blind athletes of 5-a-side football performance. A descriptive methodology was included with a sample of 63 blind male athletes (28.0 ±5.8 years) of football teams with a 5-a-side performance rating. The polymorphism was determined by means by of real-time Polymerase Chain Reaction (rt-PCR). Statistics were descriptive based on the measures of frequency of genotypes and alleles. The genotypic frequency of ACTN3 by the athletes presented the following distribution: 28.6 % with RR genotype, 54 % with RX and 17.4 % XX and allele frequency of 55.6 % for the R allele and 44.4 % for the X allele. As for ACE I/D, the genotype frequency was 63.5 % for genotype ID, 22.2 % for DD and 14.3 % for II. The allele frequency showed a predominance of the D allele with 53.9 %. The study found for ACTN3 R577X and ACE I/ D of blind athletes of 5-a-side football, a predominance of genotypes and alleles representative of strength and speed modalities.
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Humanos , Masculino , Adulto , Fútbol , Trastornos de la Visión/genética , Paratletas , Polimorfismo Genético , Actinina/genética , Ceguera/genética , Reacción en Cadena de la Polimerasa , Peptidil-Dipeptidasa A/genética , Frecuencia de los Genes , GenotipoRESUMEN
OBJECTIVE: Juvenile Neuronal Ceroid-Lipofuscinosis (JNCL, CLN 3, Batten Disease) (OMIM #204200) belongs to the most common group of neurodegenerative disorders of childhood. We report the clinical data and molecular analysis of a large Brazilian family. METHOD: Family composed of two consanguineous couples and thirty-two children. Clinical data of ten JNCL patients and molecular analyses on 13 participants were obtained. RESULTS: The large 1.02 kb deletion was detected. The most severe phenotype, with autistic behavior, tics and parkinsonism was seen in a 12-year-old female and a milder phenotype in a 14-year-old male. Nyctalopia was the first symptom in one deceased child. The visual loss of six patients has been first observed in the school and not at home. CONCLUSION: The report highlights the phenotypical intrafamily variation in 10 affected children of this family. The molecular investigation of this large family in our metabolic center turned possible the diagnosis, right approach and genetic counseling.
OBJETIVO: Lipofuscinose Ceróide Neuronal Juvenil (JNCL, CLN 3, Doença de Batten) (OMIM # 204200) pertence ao grupo mais comum de doenças neurodegenerativas na infância. É causada por mutações no gene CLN3, com padrão de herança recessiva. A deleção de 1,02 kb é a mutação mais comum. Relatamos os dados clínicos e análise molecular de uma família consanguínea numerosa. MÉTODO: Família composta por dois casais consanguíneos e trinta e duas crianças. Foram obtidos dados clínicos de dez pacientes e análises moleculares de 13 participantes. RESULTADOS: Foi detectada deleção de 1,02 kb. O fenótipo mais grave, com comportamento autista, tiques e parkinsonismo foi visto em uma paciente do sexo feminino de 12 anos e o fenótipo mais leve em um paciente do sexo masculino de 14 anos. Nictalopia foi o primeiro sintoma de uma criança falecida. A perda visual de seis pacientes foi observada pela primeira vez na escola e não em casa. CONCLUSÃO: Destaca-se a variação fenotípica intrafamiliar em 10 pacientes. A investigação molecular desta família numerosa tornou possível o diagnóstico, a abordagem correta e aconselhamento genético.
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Adolescente , Niño , Femenino , Humanos , Masculino , Consanguinidad , Eliminación de Gen , Lipofuscinosis Ceroideas Neuronales/genética , Brasil , Causas de Muerte , Electroforesis en Gel de Agar , Exones/genética , Ceguera Nocturna/genética , Linaje , Fenotipo , Trastornos de la Visión/genéticaRESUMEN
Se presenta un paciente de baja estatura braquidactilia, metacarpos y falanges anchos, defectos del tabique ventricular, esferofaquia, extopia lentis y glaucoma. Su madre muestra signos similares pero atenuados. Ambos padres eram primos
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Preescolar , Humanos , Masculino , Anomalías Múltiples , Trastornos de la Visión/genética , SíndromeRESUMEN
Diversos erros inatos do metabolismo, entre os quais a galactosemia, a homocistinúria, a doença de Lowe, as mucopolissacaridoses e as dislipidoses, podem levar à deficiência visual. A detecçäo desses distúrbios permite, em determinados casos, que afetados e familiares se beneficiem de medidas preventivas e/ou terapêuticas. Visando à identificaçäo de distúrbios metabólicos, 160 deficientes visuais foram estudados através de inúmeras técnicas bioquímicas de triagem e diagnóstico. Com o objetivo de testar a eficiência dos métodos de triagem empregados, 71 desses pacientes foram submetidos a uma reavaliaçäo cuidadosa. Em nenhum dos estudos foi detectados um erro inato do metabolismo relacionado com deficiência visual. Na avaliaçäo inicial foi identificado um caso de cistinúria. Na reavaliaçäo, esse diagnóstico foi confirmado e foram detectados distúrbios metabólicos intermitentes (glicosúria renal e frutosúria essencial) em 2 pacientes. Esses resultados indicam que a prevalência de erros inatos do metabolismo que têm manifestaçöes oculares é baixa em deficientes visuais, e que a triagem rotineira é eficiente para a detecçäo de anormalidades metabólicas persistentes