RESUMEN
Mutations in the gene for Norrie disease protein (Ndp) cause syndromic deafness and blindness. We show here that cochlear function in an Ndp knockout mouse deteriorated with age: At P3-P4, hair cells (HCs) showed progressive loss of Pou4f3 and Gfi1, key transcription factors for HC maturation, and Myo7a, a specialized myosin required for normal function of HC stereocilia. Loss of expression of these genes correlated to increasing HC loss and profound hearing loss by 2 mo. We show that overexpression of the Ndp gene in neonatal supporting cells or, remarkably, up-regulation of canonical Wnt signaling in HCs rescued HCs and cochlear function. We conclude that Ndp secreted from supporting cells orchestrates a transcriptional network for the maintenance and survival of HCs and that increasing the level of ß-catenin, the intracellular effector of Wnt signaling, is sufficient to replace the functional requirement for Ndp in the cochlea.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Proteínas del Ojo/fisiología , Células Ciliadas Auditivas/patología , Pérdida Auditiva/patología , Proteínas de Homeodominio/metabolismo , Proteínas del Tejido Nervioso/fisiología , Factor de Transcripción Brn-3C/metabolismo , Factores de Transcripción/metabolismo , Animales , Animales Recién Nacidos , Proteínas de Unión al ADN/genética , Femenino , Células Ciliadas Auditivas/metabolismo , Pérdida Auditiva/etiología , Pérdida Auditiva/metabolismo , Proteínas de Homeodominio/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Transcripción Brn-3C/genética , Factores de Transcripción/genética , Vía de Señalización WntRESUMEN
The mammalian CNS is capable of tolerating chronic hypoxia, but cell type-specific responses to this stress have not been systematically characterized. In the Norrin KO (NdpKO ) mouse, a model of familial exudative vitreoretinopathy (FEVR), developmental hypovascularization of the retina produces chronic hypoxia of inner nuclear-layer (INL) neurons and Muller glia. We used single-cell RNA sequencing, untargeted metabolomics, and metabolite labeling from 13C-glucose to compare WT and NdpKO retinas. In NdpKO retinas, we observe gene expression responses consistent with hypoxia in Muller glia and retinal neurons, and we find a metabolic shift that combines reduced flux through the TCA cycle with increased synthesis of serine, glycine, and glutathione. We also used single-cell RNA sequencing to compare the responses of individual cell types in NdpKO retinas with those in the hypoxic cerebral cortex of mice that were housed for 1 week in a reduced oxygen environment (7.5% oxygen). In the hypoxic cerebral cortex, glial transcriptome responses most closely resemble the response of Muller glia in the NdpKO retina. In both retina and brain, vascular endothelial cells activate a previously dormant tip cell gene expression program, which likely underlies the adaptive neoangiogenic response to chronic hypoxia. These analyses of retina and brain transcriptomes at single-cell resolution reveal both shared and cell type-specific changes in gene expression in response to chronic hypoxia, implying both shared and distinct cell type-specific physiologic responses.
Asunto(s)
Hipoxia/metabolismo , Neuroglía/metabolismo , Neuronas/metabolismo , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Vitreorretinopatías Exudativas Familiares/genética , Vitreorretinopatías Exudativas Familiares/fisiopatología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/metabolismo , Retina/metabolismo , Retina/fisiología , Neuronas Retinianas/metabolismo , Vasos Retinianos/metabolismo , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodosRESUMEN
BACKGROUND: Hereditary ophthalmic pathology is a genetically heterogeneous group of diseases that occur either as an isolated eye disorder or as a symptom of hereditary syndromes (chromosomal or monogenic). Thus, a diagnostic search in some cases of ophthalmic pathology can be time- and cost-consuming. The most challenging situation can arise when prenatal diagnosis is needed during an ongoing pregnancy. CASE PRESENTATION: A family was referred to the Research Centre for Medical Genetics (RCMG) for childbirth risk prognosis at 7-8 week of gestation because a previous child, a six-year-old boy, has congenital aniridia, glaucoma, retinal detachment, severe psychomotor delay, and lack of speech and has had several ophthalmic surgeries. The affected child had been previously tested for PAX6 mutations and 11p13 copy number variations, which revealed no changes. Considering the lack of pathogenic changes and precise diagnosis for the affected boy, NGS sequencing of clinically relevant genes was performed for the ongoing pregnancy; it revealed a novel hemizygous substitution NM_000266.3(NDP):c.385G > T, p.(Glu129*), in the NDP gene, which is associated with Norrie disease (OMIM #310600). Subsequent Sanger validation of the affected boy and his mother confirmed the identified substitution inherited in X-linked recessive mode. Amniotic fluid testing revealed the fetus was hemizygous for the variant and lead to the decision of the family to interrupt the pregnancy. Complications which developed during the termination of pregnancy required hysterectomy due to medical necessity. CONCLUSIONS: Clinical polymorphism of hereditary ophthalmic pathology can severely complicate establishment of an exact diagnosis and make it time- and cost-consuming. NGS appears to be the method-of-choice in complicated cases, and this could substantially hasten the establishment of a diagnosis and genetic risk estimation.
Asunto(s)
Ceguera/congénito , Proteínas del Ojo/genética , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Proteínas del Tejido Nervioso/genética , Enfermedades del Sistema Nervioso/diagnóstico , Diagnóstico Prenatal/métodos , Degeneración Retiniana/diagnóstico , Espasmos Infantiles/diagnóstico , Sustitución de Aminoácidos , Ceguera/diagnóstico , Ceguera/genética , Ojo/patología , Femenino , Genes Ligados a X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Humanos , Enfermedades del Sistema Nervioso/genética , Embarazo , Degeneración Retiniana/genética , Espasmos Infantiles/genética , Secuenciación del ExomaRESUMEN
BACKGROUND: Norrie disease (ND) is a rare X-linked disorder characterized by bilateral congenital blindness. ND is caused by a mutation in the Norrie disease pseudoglioma (NDP) gene, which encodes a 133-amino acid protein called norrin. Intragenic deletions including NDP and adjacent genes have been identified in ND patients with a more severe neurologic phenotype. We report the biochemical, molecular, clinical and radiological features of two unrelated affected males with a deletion including NDP and MAO genes. METHODS: Biochemical and genetic analyses were performed to understand the atypical phenotype and radiological findings. Biogenic amines in cerebrospinal fluid (CSF) were measured by high-performance liquid chromatography. The coding exons of NDP gene were amplified by polymerase chain reaction. Multiplex ligation-dependent probe amplification and chromosomal microarray were carried out on both affected males. Computed tomography and magnetic resonance imaging were performed on the two patients. RESULTS: In one patient, the serotonin and catecholamine metabolite levels in CSF were virtually undetectable. In both patients, genetic studies revealed microdeletions in the Xp11.3 region, involving the NDP, MAOA and MAOB genes. Radiological examination demonstrated brain and cerebellar atrophy. CONCLUSIONS: We suggest that alterations caused by MAO deficit may remain during the first years of life. Clinical phenotype, biochemical findings and neuroimaging can guide the genetic study in patients with atypical ND and help us to a better understanding of this disease.
Asunto(s)
Ceguera/congénito , Proteínas del Ojo/genética , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Monoaminooxidasa/genética , Proteínas del Tejido Nervioso/genética , Enfermedades del Sistema Nervioso/diagnóstico , Degeneración Retiniana/diagnóstico , Espasmos Infantiles/diagnóstico , Adolescente , Aminas Biogénicas/líquido cefalorraquídeo , Ceguera/diagnóstico , Ceguera/diagnóstico por imagen , Ceguera/genética , Ceguera/patología , Cerebelo/patología , Corteza Cerebral/patología , Preescolar , Ojo/patología , Eliminación de Gen , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico por imagen , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Humanos , Masculino , Enfermedades del Sistema Nervioso/diagnóstico por imagen , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/patología , Neurotransmisores/líquido cefalorraquídeo , Degeneración Retiniana/diagnóstico por imagen , Degeneración Retiniana/genética , Degeneración Retiniana/patología , Espasmos Infantiles/diagnóstico por imagen , Espasmos Infantiles/genética , Espasmos Infantiles/patologíaRESUMEN
BACKGROUND: Presumably, progression of developmental retinal vascular disorders is mainly driven by persistent ischemia/hypoxia. An investigation into vision-threatening retinal ischemia remains important. Our aim was to evaluate, in relation to retinal ischemia, protective effects and mechanisms of Dendrobium nobile Lindley (DNL) and its bibenzyl component moscatilin. The therapeutic mechanisms included evaluations of levels of placental growth factor (PLGF) and Norrie disease protein (NDP). METHODS: An oxygen glucose deprivation (OGD) model involved cells cultured in DMEM containing 1% O2, 94% N2 and 0 g/L glucose. High intraocular pressure (HIOP)-induced retinal ischemia was created by increasing IOP to 120 mmHg for 60 min in Wistar rats. The methods included electroretinogram (ERG), histopathology, MTT assay and biochemistry. RESULTS: When compared with cells cultured in DMEM containing DMSO (DMSO+DMEM), cells subjected to OGD and pre-administrated with DMSO (DMSO+OGD) showed a significant reduction in the cell viability and NDP expression. Moreover, cells that received OGD and 1 h pre-administration of 0.1 µM moscatilin (Pre-OGD Mos 0.1 µM) showed a significant counteraction of the OGD-induced decreased cell viability. Furthermore, compared with the DMSO+OGD group (44.54 ± 3.15%), there was significant elevated NDP levels in the Pre-OGD Mos 0.1 µM group (108.38 ± 29.33%). Additionally, there were significant ischemic alterations, namely reduced ERG b-wave, less numerous retinal ganglion cells, decreased inner retinal thickness, and reduced/enhanced amacrine's ChAT/Müller's GFAP or vimentin immunolabelings. Moreover, there were significantly increased protein levels of HIF-1α, VEGF, PKM2, RBP2 and, particularly, PLGF (pg/ml; Sham vs. Vehicle: 15.11 ± 1.58 vs. 39.53 ± 5.25). These ischemic effects were significantly altered when 1.0 g/Kg/day DNL (DNL1.0 + I/R or I/R+ DNL1.0) was applied before and/or after ischemia, but not vehicle (Vehicle+I/R). Of novelty and significance, the DNL1.0 action mechanism appears to be similar to that of the anti-PLGF Eylea [PLGF (pg/ml); DNL1.0 vs. Eylea+I/R: 19.93 ± 2.24 vs. 6.44 ± 0.60]. CONCLUSIONS: DNL and moscatilin are able to protect against retinal ischemic/hypoxic changes respectively by downregulating PLGF and upregulating NDP. Progression of developmental retinal vascular disorders such as Norrie disease due to persistent ischemia/hypoxia might be thus prevented.
Asunto(s)
Compuestos de Bencilo/farmacología , Hipoxia de la Célula/efectos de los fármacos , Dendrobium/química , Extractos Vegetales/farmacología , Sustancias Protectoras/farmacología , Retina/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Factor de Crecimiento Placentario/genética , Factor de Crecimiento Placentario/metabolismo , Sustancias Protectoras/química , Ratas , Ratas Wistar , Retina/citología , Enfermedades de la Retina/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
PURPOSE: NDP-related retinopathies are a group of X-linked disorders characterized by degenerative and proliferative changes of the neuroretina, occasionally accompanied with varying degrees of mental retardation and sensorineural hearing loss. NDP is the predominant gene associated with NDP-related retinopathies. The purpose of this study was to report the clinical and genetic findings in three unrelated patients diagnosed with NDP-related retinopathies. METHODS: The patients underwent complete ophthalmic examination followed by genetic analyses. NDP gene was screened by direct sequencing approach. Targeted resequencing of several other ocular genes was carried out in patient samples that either indicated NDP gene deletion or tested negative for NDP mutation. Gene quantitation analysis was performed using real-time PCR. RESULTS: The whole NDP gene was deleted in patient I, while a missense NDP mutation, c.205T>C, was identified in patient II, and both had classical Norrie disease ocular phenotype (with no other systemic defects). Patient III who was diagnosed with familial exudative vitreoretinopathy did not show any mutation in the known candidate genes as well as in other ocular genes tested. CONCLUSIONS: The patient with whole NDP gene deletion did not exhibit any apparent extraocular defects (like mental retardation or sensorineural hearing loss) during his first decade of life, and this is considered to be a notable finding. Our study also provides evidence emphasizing the need for genetic testing which could eliminate ambiguities in clinical diagnosis and detect carrier status, thereby aiding the patient and family members during genetic counseling.
Asunto(s)
Anomalías Múltiples , Ceguera/congénito , ADN/genética , Proteínas del Ojo/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Mutación Missense , Proteínas del Tejido Nervioso/genética , Enfermedades del Sistema Nervioso/genética , Retina/diagnóstico por imagen , Enfermedades de la Retina/genética , Espasmos Infantiles/genética , Ceguera/diagnóstico , Ceguera/genética , Ceguera/metabolismo , Niño , Preescolar , Análisis Mutacional de ADN , Proteínas del Ojo/metabolismo , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/metabolismo , Humanos , Lactante , Masculino , Microscopía Acústica , Proteínas del Tejido Nervioso/metabolismo , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/metabolismo , Linaje , Fenotipo , Reacción en Cadena en Tiempo Real de la Polimerasa , Retina/metabolismo , Degeneración Retiniana , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/metabolismo , Estudios Retrospectivos , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/metabolismoRESUMEN
We report a case of Norrie disease, diagnosed by prenatal ultrasound, confirmed by Sanger sequencing of the DNP gene from the aborted fetal cord blood and histologically. Prenatal ultrasound revealed no abnormality in either eye at 22+1 and 31+4 gestational weeks, but at 36+5 gestational weeks both eyes had massive vitreous cavity opacities with complete retinal detachment. Norrie disease was initially suspected because of an older male sibling with the disease. To our knowledge, prenatal ultrasound diagnosis of Norrie disease has been previously described only one case in 1993 in a 34-week-old fetus. The normal eye development until after 31 + 4 gestational weeks provides insight into the first manifestation and then the rapid progression of the eye disease.
Asunto(s)
Ceguera/congénito , Anomalías del Ojo/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades del Sistema Nervioso/diagnóstico , Espasmos Infantiles/diagnóstico , Adulto , Ceguera/diagnóstico , Ceguera/diagnóstico por imagen , Ceguera/genética , Análisis Mutacional de ADN , Anomalías del Ojo/diagnóstico por imagen , Anomalías del Ojo/genética , Proteínas del Ojo/genética , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico por imagen , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Edad Gestacional , Humanos , Masculino , Proteínas del Tejido Nervioso/genética , Enfermedades del Sistema Nervioso/diagnóstico por imagen , Enfermedades del Sistema Nervioso/genética , Linaje , Embarazo , Diagnóstico Prenatal , Degeneración Retiniana , Desprendimiento de Retina/congénito , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/diagnóstico por imagen , Espasmos Infantiles/diagnóstico por imagen , Espasmos Infantiles/genética , Ultrasonografía Doppler en Color , Ultrasonografía PrenatalRESUMEN
Persistent hyperplastic primary vitreous is a spectrum of congenital ocular abnormalities characterized by leukocoria, microphthalmia, cataracts, extensive intravitreal hemorrhage, persistence of the hyaloid artery, glaucoma, and retinal detachment. It might be isolated or associated with congenital syndromes such as trisomy 13, Walker-Warburg syndrome, and Norrie disease. We present 2 cases of persistent hyperplastic primary vitreous diagnosed by prenatal sonography in the early third trimester. Bilateral hyperechoic lenses and retinal nonattachment were detected in the sonographic examination of the first case, whereas irregular echogenic bands between the lenses and posterior walls of the eyes were prominent in the second case. In both of the cases, ocular findings were accompanied by intracranial findings, including severe hydrocephalus, an abnormal gyral pattern, and cerebellar hypoplasia, suggesting the diagnosis of Walker-Warburg syndrome. We also present a review of the literature regarding the prenatal diagnosis of this malformation.
Asunto(s)
Vítreo Primario Hiperplásico Persistente/diagnóstico por imagen , Ultrasonografía Prenatal , Adulto , Diagnóstico Diferencial , Resultado Fatal , Femenino , Humanos , Recién Nacido , Masculino , Cuerpo Vítreo/diagnóstico por imagen , Adulto JovenRESUMEN
Developmental malformations of the vitreoretinal vasculature are a heterogeneous group of conditions with various modes of inheritance, and include familial exudative vitreoretinopathy (FEVR), persistent fetal vasculature (PFV), and Norrie disease. We investigated a large consanguineous kindred with multiple affected individuals exhibiting variable phenotypes of abnormal vitreoretinal vasculature, consistent with the three above-mentioned conditions and compatible with autosomal recessive inheritance. Exome sequencing identified a novel c.542G > T (p.C181F) apparently mutation in the TSPAN12 gene that segregated with the ocular disease in the family. The TSPAN12 gene was previously reported to cause dominant and recessive FEVR, but has not yet been associated with other vitreoretinal manifestations. The intra-familial clinical variability caused by a single mutation in the TSPAN12 gene underscores the complicated phenotype-genotype correlation of mutations in this gene, and suggests that there are additional genetic and environmental factors involved in the complex process of ocular vascularization during embryonic development. Our study supports considering PFV, FEVR, and Norrie disease a spectrum of disorders, with clinical and genetic overlap, caused by mutations in distinct genes acting in the Norrin/ß-catenin signaling pathway.
Asunto(s)
Ceguera/congénito , Enfermedades del Sistema Nervioso/genética , Vítreo Primario Hiperplásico Persistente/genética , Fenotipo , Mutación Puntual/genética , Espasmos Infantiles/genética , Tetraspaninas/genética , Secuencia de Bases , Ceguera/genética , Biología Computacional , Exoma/genética , Enfermedades Hereditarias del Ojo , Vitreorretinopatías Exudativas Familiares , Genes Recesivos , Enfermedades Genéticas Ligadas al Cromosoma X , Humanos , Datos de Secuencia Molecular , Degeneración Retiniana , Enfermedades de la Retina/genética , Análisis de Secuencia de ADNRESUMEN
Purpose: To describe a case of early-term planned delivery of a fetus with Norrie disease. Methods: A retrospective chart review was performed. Results: A fetus with an older sibling with bilateral blindness from Norrie disease had positive NPD genetic testing on chorionic villus sampling. Transabdominal fetal ophthalmic ultrasound found bilateral total retinal detachments (RDs) at 32 weeks gestational age. The fetus was delivered at 37 weeks and had an examination under anesthesia, which showed bilateral inoperable RDs. Conclusions: Transabdominal fetal ophthalmic ultrasound was able to identity bilateral total RDs in utero. Further study is warranted on preterm or early-term delivery if a fetus has evidence of RD in utero.
RESUMEN
Detailed binding experiments reveal new insights into the Norrin/Wnt signaling pathway that helps to control vascularization in the retina.
Asunto(s)
Proteínas del Ojo , Proteínas del Tejido Nervioso , Retina , Vía de Señalización Wnt , Proteínas del Ojo/metabolismo , Proteínas del Ojo/genética , Humanos , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Retina/metabolismo , Animales , Unión ProteicaRESUMEN
A number of congenital and inherited diseases present with both ocular and psychiatric features. The genetic inheritance and phenotypic variants play a key role in disease severity. Early recognition of the signs and symptoms of those disorders is critical to earlier intervention and improved prognosis. Typically, the associations between these two medical subspecialties of ophthalmology and psychiatry are poorly understood by most practitioners so we hope to provide a narrative review to improve the identification and management of these disorders. We conducted a comprehensive review of the literature detailing the diseases with ophthalmic and psychiatric overlap that were more widely represented in the literature. Herein, we describe the clinical features, pathophysiology, molecular biology, diagnostic tests, and the most recent approaches for the treatment of these diseases. Recent studies have combined technologies for ocular and brain imaging such as optical coherence tomography (OCT) and functional imaging with genetic testing to identify the genetic basis for eye-brain connections. Additional work is needed to further explore these potential biomarkers. Overall, accurate, efficient, widely distributed and non-invasive tests that can help with early recognition of these diseases will improve the management of these patients using a multidisciplinary approach.
Asunto(s)
Oftalmología , Psiquiatría , Humanos , Pruebas GenéticasRESUMEN
Purpose: To describe a novel case of Norrie disease and X-linked Kabuki syndrome caused by a microdeletion encompassing multiple genes on the X chromosome. Observations: A 3-day-old boy born at full term had bilateral retrolental fibrovascular plaques. Surgery with lensectomy and vitrectomy revealed bilateral, closed funnel retinal detachments consistent with a clinical diagnosis of Norrie disease. In addition, the baby had congenital heart defects, hearing loss, and dysmorphic facies. His mother carried a clinical diagnosis of Kabuki syndrome. Genetic testing of the baby revealed an Xp11.3 microdeletion that included the NDP and KDM6A genes, confirming the baby had both Norrie disease and X-linked Kabuki syndrome. The mother was found via ultrawide-field fluorescein angiography to have asymptomatic peripheral retinal vascular anomalies, consistent with NDP-associated familial exudative vitreoretinopathy (FEVR). Conclusions and importance: This is the first reported case of Norrie disease together with X-linked Kabuki syndrome. Contiguous gene deletions may explain some of the variable systemic involvement in Norrie disease.
RESUMEN
Avascular peripheral retina in an infant is a common characteristic of numerous pediatric retinal vascular disorders and often presents a diagnostic challenge to the clinician. In this review, key features of each disease in the differential diagnosis, from retinopathy of prematurity, familial exudative vitreoretinopathy, Coats disease, incontinentia pigmenti, Norrie disease, and persistent fetal vasculature, to other rare hematologic conditions and telomere disorders, will be discussed by expert ophthalmologists in the field.
Asunto(s)
Flujo Sanguíneo Regional , Retina , Enfermedades de la Retina , Vasos Retinianos , Niño , Humanos , Lactante , Recién Nacido , Diagnóstico Diferencial , Retina/anomalías , Retina/anatomía & histología , Enfermedades de la Retina/congénito , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/patología , Vasos Retinianos/anomalías , Vasos Retinianos/patologíaRESUMEN
PURPOSE: To report the concurrent presentation and management of IQCB1-associated Leber Congenital Amaurosis and NDP-associated Familial Exudative Vitreoretinopathy (FEVR). MATERIALS AND METHODS: A 6-month-old Caucasian infant presented with poor visual response, high hypermetropia, and infantile-nystagmus with a provisional diagnosis of Leber Congenital Amaurosis based on clinical findings. Genetic counseling and testing were performed with a 285 gene retinal dystrophy panel (Blueprint Genetics). Clinical characteristics, presentation, ancillary testing results, and management are described. RESULTS: Two previously reported heterozygous pathogenic variants in ICQB1 were identified (c.1518_1519del (p.His506Glnfs*13) and c.1381C>T, p.Arg461*) segregating in trans. In addition, a variation of uncertain significance (VUS) was found in NDP (c.280C>T; p.His94Tyr). Fluorescein angiography was performed demonstrating peripheral avascularity and retinal telangiectasia without frank neovascularization. Peripheral ablative laser was applied to the avascular zone. CONCLUSIONS: The NDP VUS likely represents a pathogenic variant given the FEVR phenotype in addition to retinal degeneration, creating a rare dual phenotype. The combination of low oxygen demand from the IQCB1-associated retinal degeneration and NDP variant may have led to a more attenuated FEVR presentation with uncertain prognosis. A molecular diagnosis informed ocular and renal surveillance, as well as the recurrence risk for future offspring.
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Enfermedades Hereditarias del Ojo , Amaurosis Congénita de Leber , Enfermedades de la Retina , Distrofias Retinianas , Humanos , Vitreorretinopatías Exudativas Familiares , Enfermedades de la Retina/complicaciones , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/genética , Amaurosis Congénita de Leber/complicaciones , Amaurosis Congénita de Leber/diagnóstico , Amaurosis Congénita de Leber/genética , Enfermedades Hereditarias del Ojo/diagnóstico , Enfermedades Hereditarias del Ojo/genética , Fenotipo , Mutación , Linaje , Análisis Mutacional de ADN , Proteínas de Unión a Calmodulina/genéticaRESUMEN
Familial Exudative Vitreoretinopathy (FEVR), Norrie disease, and persistent fetal vascular syndrome (PFVS) are extremely rare retinopathies that are clinically distinct but are unified by abnormal retinal endothelial cell function, and subsequent irregular retinal vascular development and/or aberrant inner blood-retinal-barrier (iBRB) function. The early angiogenesis of the retina and its iBRB is a delicate process that is mediated by the canonical Norrin Wnt-signaling pathway in retinal endothelial cells. Pathogenic variants in genes that play key roles within this pathway, such as NDP, FZD4, TSPAN12, and LRP5, have been associated with the incidence of these retinal diseases. Recent efforts to further elucidate the etiology of these conditions have not only highlighted their multigenic nature but have also resulted in the discovery of pathological variants in additional genes such as CTNNB1, KIF11, and ZNF408, some of which operate outside of the Norrin Wnt-signaling pathway. Recent discoveries of FEVR-linked variants in two other Catenin genes (CTNND1, CTNNA1) and the Endoplasmic Reticulum Membrane Complex Subunit-1 gene (EMC1) suggest that we will continue to find additional genes that impact the neural retinal vasculature, especially in multi-syndromic conditions. The goal of this review is to briefly highlight the current understanding of the roles of their encoded proteins in retinal endothelial cells to understand the essential functional mechanisms that can be altered to cause these very rare pediatric retinal vascular diseases.
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Enfermedades de la Retina , Enfermedades Vasculares , Humanos , Niño , Vitreorretinopatías Exudativas Familiares/metabolismo , Células Endoteliales/metabolismo , Tetraspaninas/metabolismo , Enfermedades de la Retina/metabolismo , Enfermedades Vasculares/metabolismo , Receptores Frizzled/genética , Receptores Frizzled/metabolismo , Proteínas de Unión al ADN/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Norrie disease (ND; OMIM 310600), a rare X-linked recessive genetic disorder, is characterized by congenital blindness and occasionally, sensorineural hearing loss, and developmental delay. The congenital blindness of ND patients is almost untreatable; thus, hearing is particularly important for them. However, the mechanism of hearing loss of ND patients is unclear, and no good treatment is available except wearing hearing-aid. Therefore, revealing the mechanism of hearing loss in ND patients and exploring effective treatment methods are greatly important. In addition, as a serious monogenic genetic disease, convenient gene identification method is important for ND patients and their family members, as well as prenatal diagnosis and preimplantation genetic diagnosis to block intergenerational transmission of pathogenic genes. In this study, a Norrie family with two male patients was reported. This pedigree was ND caused by large fragment deletion of NDP (norrin cystine knot growth factor NDP) gene. In addition to typical severe ophthalmologic and audiologic defects, the patients showed new pathological features of endolymphatic hydrops (EH), and they also showed acoustic nerves abnormal as described in a very recent report. PCR methods were developed to analyze and diagnose the variation of the family members. This study expands the understanding of the clinical manifestation and pathogenesis of ND and provides a new idea for the treatment of patients in this family and a convenient method for the genetic screen for this ND family.
RESUMEN
A Norrie disease protein gene (NDP) variant, c.174 + 1G > A, was found in a Chinese family through next-generation sequencing and verified with Sanger sequencing. A case of Norrie disease was reported in the first child, and the symptoms were consistent with the results of gene sequencing. The child's mother, who was pregnant at the time, was found to be a carrier of the identified pathogenic variant. To determine if the fetus carried the same disease-causing variant, prenatal examination and prenatal diagnosis were conducted. The fetus had biocular vitreous abnormalities and complete retinal abnormalities. Genetic testing showed that the fetus had maternally inherited the NDP gene variant found in the proband. It was concurrently confirmed that the NDP gene variant led to the deletion of 246 bp at the 3' end of exon 2, resulting in the deletion of the initiation codon and the occurrence of disease. Our study suggests that the diagnosis of rare diseases through next-generation sequencing, combined with prenatal ultrasound and prenatal diagnosis, can help families with known familial genetic diseases. Furthermore, the findings of this study broaden the known genetic spectrum of Norrie disease.
RESUMEN
Purpose: To explore the genetic defects in two Chinese families with X-linked Norrie disease (ND). Methods: We analyzed two Chinese families with ND at molecular level through clinical exome sequencing and the variations were identified by Sanger sequencing. Results: Two genetic variations were found in the NDP gene by clinical exome sequencing, a partial deletion of 801 bp contained the whole exon 2 and a missense variant (164G>A) within codon 55 that resulted in the interchange of cysteine by phenylalanine. Clinical findings were more severe in the patients who presented the missense variant. Conclusion: We report two genetic variations in the NDP gene in Chinese that extend the mutational and phenotypic spectra of NDP gene, and also demonstrate the feasibility of clinical exome sequencing in application of molecular diagnosis.
Asunto(s)
Pueblos del Este de Asia , Degeneración Retiniana , Humanos , Secuenciación del Exoma , Linaje , Proteínas del Ojo/genética , Proteínas del Tejido Nervioso/genéticaRESUMEN
Aims and Rationale: The inner retina is supplied by three intraretinal capillary plexi whereas the outer retina is supplied by the choroidal circulation: NDP is essential for normal intraretinal vascularisation. Pathogenic variants in NDP (Xp11.3) may result in either a severe retinal phenotype associated with hearing loss (Norrie Disease) or a moderate retinal phenotype (Familial Exudative Vitreoretinopathy, FEVR). However, little is known about whether the nature or location of the NDP variant is predictive of severity. In this systematic review we summarise all reported NDP variants and draw conclusions about whether the nature of the NDP variant is predictive of the severity of the resulting ocular pathology and associated hearing loss and intellectual disability. Findings: 201 different variants in the NDP gene have been reported as disease-causing. The pathological phenotype that may result from a disease-causing NDP variant is quite diverse but generally comprises a consistent cluster of features (retinal hypovascularisation, exudation, persistent foetal vasculature, tractional/exudative retinal detachment, intellectual disability and hearing loss) that vary predictably with severity. Previous reviews have found no clear pattern in the nature of NDP mutations that cause either FEVR or Norrie disease, with the exception that mutations affecting cysteine residues have been associated with Norrie Disease and that visual loss amongst patients with Norrie disease tends to be more severe if the NDP mutation results in an early termination of translation as opposed to a missense related amino acid change. A key limitation of previous reviews has been variability in the case definition of Norrie disease and FEVR amongst authors. We thus reclassified patients into two groups based only on the severity of their retinal disease. Of the reported pathogenic variants that have been described in more than one patient, we found that any given variant caused an equivalent severity of retinopathy each time it was reported with very few exceptions. We therefore conclude that specific NDP mutations generally result in a consistent retinal phenotype each time they arise. Reports by different authors of the same variant causing either FEVR or Norrie disease conflict primarily due to variability in the authors' respective case definitions rather than true differences in disease severity.