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1.
Ophthalmic Plast Reconstr Surg ; 40(5): e174-e176, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39240207

RESUMO

Complex congenital lacrimal drainage anomalies are known to be associated with several syndromes and present unique surgical challenges. Duplication of human body structures is uncommon and has been reported in the uterus (uterine didelphys), ureter (duplex ureter), duodenum, transverse colon, and nose. Lacrimal drainage anomalies have been reported in proboscis lateralis. To the best of the authors' knowledge, there are no prior reports on duplication of the lacrimal sac. The present case reports a complex congenital nasolacrimal duct obstruction that was associated with duplication of the lacrimal sac and the presence of 3 canaliculi.


Assuntos
Ducto Nasolacrimal , Humanos , Ducto Nasolacrimal/anormalidades , Ducto Nasolacrimal/cirurgia , Feminino , Obstrução dos Ductos Lacrimais/congênito , Obstrução dos Ductos Lacrimais/diagnóstico , Dacriocistorinostomia/métodos , Aparelho Lacrimal/anormalidades , Aparelho Lacrimal/cirurgia , Aparelho Lacrimal/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/cirurgia
2.
Int Ophthalmol ; 44(1): 367, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39235629

RESUMO

PURPOSE: Crouzon syndrome is a congenital genetic disease caused by mutations of the FGFR2 gene on chromosome 10. It is usually inherited in an autosomal dominant pattern and is one of the most common types of craniosynostosis syndromes. This article focuses on the ophthalmology-related aspects of Crouzon syndrome in order to help diagnose and develop personalized treatment plans. METHODS: A combined systematic search of PubMed electronic database by using Boolean operators AND and OR was conducted, choosing the following keywords: "Crouzon", "craniosynostosis", " eye ", " oculus ", " ocular ", " ophthalmic ", " ophthalmologic ", " ophthalmology ", " globe ", " orbit ", " exophthalmos ", " exorbitism ", " keratopathy ", " visual " etc. After the initial screening of these articles, repetitive literatures were excluded. RESULTS: 47 articles were selected. This article introduces the ocular manifestations, possible pathogenesis and treatment progress in Crouzon syndrome. CONCLUSIONS: The incidence of ocular abnormalities in Crouzon syndrome is very high, such as shallow orbits, exophthalmos, hypertelorism, exposure keratopathy, strabismus, optic neuropathy, ametropia, glaucoma, etc. The pathogenesis of these ocular abnormalities is related to orbital deformities. Most of the treatments are aimed at compensating the abnormal anatomic structure at present.


Assuntos
Disostose Craniofacial , Humanos , Disostose Craniofacial/diagnóstico , Disostose Craniofacial/genética , Oftalmopatias/diagnóstico , Oftalmopatias/terapia , Oftalmopatias/etiologia , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/terapia , Anormalidades do Olho/genética , Mutação
3.
Sci Rep ; 14(1): 20278, 2024 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-39217245

RESUMO

Alterations to cilia are responsible for a wide range of severe disease; however, understanding of the transcriptional control of ciliogenesis remains incomplete. In this study we investigated whether altered cilia-mediated signaling contributes to the pleiotropic phenotypes caused by the Forkhead transcription factor FOXC1. Here, we show that patients with FOXC1-attributable Axenfeld-Rieger Syndrome (ARS) have a prevalence of ciliopathy-associated phenotypes comparable to syndromic ciliopathies. We demonstrate that altering the level of Foxc1 protein, via shRNA mediated inhibition, CRISPR/Cas9 mutagenesis and overexpression, modifies cilia length in vitro. These structural changes were associated with substantially perturbed cilia-dependent signaling [Hedgehog (Hh) and PDGFRα], and altered ciliary compartmentalization of the Hh pathway transcription factor, Gli2. Consistent with these data, in primary cultures of murine embryonic meninges, cilia length was significantly reduced in heterozygous and homozygous Foxc1 mutants compared to controls. Meningeal expression of the core Hh signaling components Gli1, Gli3 and Sufu was dysregulated, with comparable dysregulation of Pdgfrα signaling evident from significantly altered Pdgfrα and phosphorylated Pdgfrα expression. On the basis of these clinical and experimental findings, we propose a model that altered cilia-mediated signaling contributes to some FOXC1-induced phenotypes.


Assuntos
Cílios , Anormalidades do Olho , Oftalmopatias Hereditárias , Fatores de Transcrição Forkhead , Fenótipo , Transdução de Sinais , Cílios/metabolismo , Cílios/patologia , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Humanos , Animais , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Anormalidades do Olho/metabolismo , Camundongos , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/metabolismo , Oftalmopatias Hereditárias/patologia , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/genética , Segmento Anterior do Olho/anormalidades , Segmento Anterior do Olho/metabolismo , Segmento Anterior do Olho/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Ciliopatias/genética , Ciliopatias/metabolismo , Ciliopatias/patologia , Feminino , Masculino , Proteína Gli2 com Dedos de Zinco/metabolismo , Proteína Gli2 com Dedos de Zinco/genética , Mutação
4.
Invest Ophthalmol Vis Sci ; 65(10): 14, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39110587

RESUMO

Purpose: Fabry disease is an X-linked lysosomal storage disorder that results in multi-systemic renal, cardiovascular, and neuropathological damage, including in the eyes. We evaluated anterior segment ocular abnormalities based on age, sex (male and female), and genotype (wild-type, knockout [KO] male, heterozygous [HET] female, and KO female) in a rat model of Fabry disease. Methods: The α-Gal A KO and WT rats were divided into young (6-24 weeks), adult (25-60 weeks), and aged (61+ weeks) groups. Intraocular pressure (IOP) was measured. Eyes were clinically scored for corneal and lens opacity as well as evaluated for corneal epithelial integrity and tear break-up time (TBUT). Anterior chamber depth (ACD) and central corneal thickness (CCT) using anterior segment-optical coherence tomography (AS-OCT). Results: The Fabry rats showed an age-dependent increase in IOP, predominantly in the male genotype. TBUT was decreased in both male and female groups with aging. Epithelial integrity was defective in KO males and HET females with age. However, it was highly compromised in KO females irrespective of age. Corneal and lens opacities were severely affected irrespective of sex or genotype in the aging Fabry rats. AS-OCT quantification of CCT and ACD also demonstrated age-dependent increases but were more pronounced in Fabry versus WT genotypes. Conclusions: Epithelial integrity, corneal, and lens opacities worsened in Fabry rats, whereas IOP and TBUT changes were age-dependent. Similarly, CCT and ACD were age-related but more pronounced in Fabry rats, providing newer insights into the anterior segment ocular abnormalities with age, sex, and genotype in a rat model of Fabry disease.


Assuntos
Segmento Anterior do Olho , Modelos Animais de Doenças , Doença de Fabry , Pressão Intraocular , Tomografia de Coerência Óptica , Animais , Doença de Fabry/genética , Doença de Fabry/patologia , Doença de Fabry/fisiopatologia , Feminino , Masculino , Ratos , Segmento Anterior do Olho/patologia , Segmento Anterior do Olho/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Pressão Intraocular/fisiologia , Fatores Sexuais , Envelhecimento/fisiologia , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , alfa-Galactosidase/genética
5.
Eur J Obstet Gynecol Reprod Biol ; 301: 70-76, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39106617

RESUMO

BACKGROUND: Complete cryptophthalmos, congenital aphakia, and corneal vascularization are relatively uncommon congenital eye malformations during the fetal period. Herein, we report a case of a fetus with complete cryptophthalmos, congenital aphakia, and corneal vascularization in both eyes and review previous prenatal reports of related cases. CASE PRESENTATION: The patient was a 27-year-old pregnant woman, gravida 2, para 1, who was referred to our hospital for consultation at 23 weeks of gestation due to a diagnosis of fetal right renal agenesis at an external hospital. The ultrasound system of our hospital diagnosed the fetus with complete cryptophthalmos, congenital aphakia, and corneal vascularization, which was verified under the postnatal water basin test, anatomical and pathological sections. CONCLUSIONS: Fetal ocular malformations are often associated with malformations of other organs, and if ultrasound findings are associated with such malformations, attention should be paid to the ocular examination to avoid missing the diagnosis.


Assuntos
Afacia , Anormalidades do Olho , Ultrassonografia Pré-Natal , Humanos , Feminino , Gravidez , Adulto , Anormalidades do Olho/diagnóstico por imagem , Afacia/diagnóstico por imagem , Neovascularização da Córnea/diagnóstico por imagem , Córnea/diagnóstico por imagem , Córnea/anormalidades
6.
Prog Retin Eye Res ; 102: 101288, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39097141

RESUMO

Development of the anterior segment of the eye requires reciprocal sequential interactions between the arising tissues, facilitated by numerous genetic factors. Disruption of any of these processes results in congenital anomalies in the affected tissue(s) leading to anterior segment disorders (ASD) including aniridia, Axenfeld-Rieger anomaly, congenital corneal opacities (Peters anomaly, cornea plana, congenital primary aphakia), and primary congenital glaucoma. Current understanding of the genetic factors involved in ASD remains incomplete, with approximately 50% overall receiving a genetic diagnosis. While some genes are strongly associated with a specific clinical diagnosis, the majority of known factors are linked with highly variable phenotypic presentations, with pathogenic variants in FOXC1, CYP1B1, and PITX2 associated with the broadest spectrum of ASD conditions. This review discusses typical clinical presentations including associated systemic features of various forms of ASD; the latest functional data and genotype-phenotype correlations related to 25 ASD factors including newly identified genes; promising novel candidates; and current and emerging treatments for these complex conditions. Recent developments of interest in the genetics of ASD include identification of phenotypic expansions for several factors, discovery of multiple modes of inheritance for some genes, and novel mechanisms including a growing number of non-coding variants and alleles affecting specific domains/residues and requiring further studies.


Assuntos
Segmento Anterior do Olho , Anormalidades do Olho , Estudos de Associação Genética , Humanos , Segmento Anterior do Olho/anormalidades , Anormalidades do Olho/genética , Anormalidades do Olho/fisiopatologia , Fenótipo , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/fisiopatologia
7.
Pediatr Neurol ; 160: 38-44, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39181021

RESUMO

BACKGROUND: Biallelic SUFU variants have originally been linked to Joubert syndrome, comprising cerebellar abnormalities, dysmorphism, and polydactyly. In contrast, heterozygous truncating variants have recently been associated with developmental delay and ocular motor apraxia, but only a limited number of patients have been reported. Here, we aim to delineate further the mild end of the phenotypic spectrum related to SUFU haploinsufficiency. METHODS: Nine individuals (from three unrelated families) harboring truncating SUFU variants were investigated, including two previously reported individuals (from one family). We provide results from a comprehensive assessment comprising neuroimaging, neuropsychology, video-oculography, and genetic testing. RESULTS: We identified three inherited or de novo truncating variants in SUFU (NM_016169.4): c.895C>T p.(Arg299∗), c.71dup p.(Ala25Glyfs∗23), and c.71del p.(Pro24Argfs∗72). The phenotypic expression showed high variability both between and within families. Clinical features include motor developmental delay (seven of nine), axial hypotonia (five of nine), ocular motor apraxia (three of nine), and cerebellar signs (three of nine). Four of the six reported children had macrocephaly. Neuropsychological and developmental assessments revealed mildly delayed language development in the youngest children, whereas general cognition was normal in all variant carriers. Subtle but characteristic SUFU-related neuroimaging abnormalities (including superior cerebellar dysplasia, abnormalities of the superior cerebellar peduncles, rostrally displaced fastigium, and vermis hypoplasia) were observed in seven of nine individuals. CONCLUSIONS: Our data shed further light on the mild but recognizable features of SUFU haploinsufficiency and underline its marked phenotypic variability, even within families. Notably, neurodevelopmental and behavioral abnormalities are mild compared with Joubert syndrome and seem to be well compensated over time.


Assuntos
Deficiências do Desenvolvimento , Haploinsuficiência , Fenótipo , Humanos , Masculino , Feminino , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/fisiopatologia , Adolescente , Cerebelo/diagnóstico por imagem , Cerebelo/anormalidades , Apraxias/diagnóstico por imagem , Apraxias/genética , Apraxias/fisiopatologia , Apraxias/congênito , Doenças Renais Císticas/genética , Doenças Renais Císticas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/fisiopatologia , Neuroimagem , Anormalidades do Olho/genética , Anormalidades do Olho/diagnóstico por imagem , Retina/diagnóstico por imagem , Retina/anormalidades , Síndrome de Cogan
8.
BMJ Case Rep ; 17(8)2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-39214587

RESUMO

A girl in middle childhood presented with glaucoma in her right eye along with segmental haemangiomas on the right side of the face and neck. Magnetic resonance angiography of the brain showed hypoplasia of the right internal carotid artery, leading to the diagnosis of posterior fossa malformations, haemangioma, arterial anomalies, cardiac defects and eye abnormalities (PHACE) syndrome. High-definition anterior segment ocular coherence tomography (AS-OCT) of the right eye showed an absence of Schlemm's canal and a hyperreflective membrane over the trabecular meshwork. The presence of this angle dysgenesis on AS-OCT, a novel finding in this disease, explained the elevated intraocular pressure in the right eye. The embryological basis for the development of angle dysgenesis might help better understand the pathogenesis of PHACE syndrome.


Assuntos
Coartação Aórtica , Anormalidades do Olho , Glaucoma , Síndromes Neurocutâneas , Humanos , Feminino , Síndromes Neurocutâneas/diagnóstico por imagem , Síndromes Neurocutâneas/complicações , Síndromes Neurocutâneas/diagnóstico , Coartação Aórtica/diagnóstico por imagem , Coartação Aórtica/complicações , Coartação Aórtica/diagnóstico , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/complicações , Anormalidades do Olho/diagnóstico , Glaucoma/diagnóstico , Tomografia de Coerência Óptica/métodos , Hemangioma/complicações , Hemangioma/diagnóstico por imagem , Artéria Carótida Interna/anormalidades , Artéria Carótida Interna/diagnóstico por imagem , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/complicações , Angiografia por Ressonância Magnética
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(8): 957-961, 2024 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-39097279

RESUMO

OBJECTIVE: To explore the clinical characteristics and genetic basis for a fetus with Joubert syndrome. METHODS: A pregnant woman who had visited Suzhou Municipal Hospital on February 26, 2021 was selected as the study subject. The fetus and her parents were subjected to whole exome sequencing (WES), and candidate variants were verified by Sanger sequencing. cDNA analysis of her father and RNA sequencing of her sister were also carried out. RESULTS: The fetus was found to harbor compound heterozygous variants of the TCTN1 gene, namely c.624G>A and c.96dupA (p.Glu33Argfs*49), which were inherited from her father and mother, respectively. Her sister also carried the paternal c.624G>A variant, and mRNA transcripts with the c.624G>A variant of the TCTN1 gene were not detected by cDNA analysis of her father and RNA sequencing of her sister. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.624G>A and c.96dupA variants were both classified as likely pathogenic (PVS1+PM2_Supporting). CONCLUSION: The compound heterozygous variants of the TCTN1 gene probably underlay the pathogenesis in this fetus. Above finding has also expanded the mutational spectrum of the TCTN1 gene.


Assuntos
Anormalidades Múltiplas , Cerebelo , Anormalidades do Olho , Feto , Doenças Renais Císticas , Adulto , Feminino , Humanos , Masculino , Gravidez , Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Sequenciamento do Exoma , Anormalidades do Olho/genética , Feto/anormalidades , Heterozigoto , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Mutação , Retina/anormalidades , Diagnóstico Pré-Natal
10.
Ophthalmic Plast Reconstr Surg ; 40(4): e125-e128, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38967579

RESUMO

Ablepharon-macrostomia syndrome is a rare disorder characterized by TWIST2 mutations and anterior lamellar dysgenesis. Timely intervention is critical to prevent exposure keratopathy, corneal ulceration, and permanent vision loss. We report a novel approach to multiplanar eyelid reconstruction in ablepharon-macrostomia syndrome involving use of a modified reverse hatchet flap in 1 lower eyelid along with division at the eyelid margin, recession of the eyelid retractors in conjunction with preputial skin grafting for anterior lamellar restoration in the other 3 eyelids.


Assuntos
Blefaroplastia , Anormalidades do Olho , Pálpebras , Macrostomia , Retalhos Cirúrgicos , Humanos , Macrostomia/cirurgia , Pálpebras/cirurgia , Pálpebras/anormalidades , Anormalidades do Olho/cirurgia , Blefaroplastia/métodos , Masculino , Anormalidades Múltiplas/cirurgia , Feminino , Procedimentos de Cirurgia Plástica/métodos
11.
Medicine (Baltimore) ; 103(29): e39082, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39029032

RESUMO

BACKGROUND: Mowat-Wilson syndrome (MWS) is a rare genetic condition resulting in multiple congenital anomalies, including facial dysmorphism, structural anomalies of the internal organs, functional disorders, and, although less commonly, ocular abnormalities. To present a child with MWS and eye abnormalities. METHODS: A 3-year-old boy was born at 37 weeks of pregnancy with dysmorphic features, neurodevelopmental disorders, genetically confirmed MWS, nystagmus, strabismus, and suspicion of congenital glaucoma. Ophthalmic examination was carried out under general anesthesia; eyeball ultrasound and electrophysiological examination (flash visual evoked potentials) were also performed. RESULTS: The examinations revealed nystagmus, a normal response of pupils to light in both eyes, and normal intraocular pressure, that is, 17 and 18 mm Hg in the right and left eye, respectively. Corneal thickness was 606 µm in the right eye and 588 µm in the left eye. Gonioscopy revealed displacement of Schwalbe line anterior to the limbus of the cornea (posterior embryotoxon). Fundus examination revealed a pink optic disk with a cup-to-disc ratio of 0.5, macular pigment regrouping, and normal blood vessels. Flash visual evoked potentials: P2 latency was normal. P2 amplitude from the left hemisphere was reduced to 50%, and P2 amplitude over the right hemisphere was normal. CONCLUSION: Children with genetically determined congenital anomalies need regular ophthalmic checkups to accurately assess the eye and determine the prospects of vision function development.


Assuntos
Doença de Hirschsprung , Deficiência Intelectual , Microcefalia , Humanos , Masculino , Pré-Escolar , Microcefalia/genética , Microcefalia/diagnóstico , Deficiência Intelectual/genética , Doença de Hirschsprung/genética , Doença de Hirschsprung/diagnóstico , Doença de Hirschsprung/fisiopatologia , Fácies , Potenciais Evocados Visuais/fisiologia , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Anormalidades do Olho/fisiopatologia
12.
AJNR Am J Neuroradiol ; 45(8): 1070-1075, 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-38991766

RESUMO

BACKGROUND AND PURPOSE: Morning glory disc anomaly (MGDA) is a congenital malformation characterized by a funnel-shaped optic disc excavation with radiating vessels and a central glial tuft. Imaging is essential to evaluate associated cephalocele and steno-occlusive vasculopathy. The goal of this study was to assess optic nerve, chiasmatic, and sphenoid bone morphology in MGDA. MATERIALS AND METHODS: This retrospective study examined all subjects with funduscopically confirmed MGDA diagnosed and imaged with brain MR imaging between 2008 and 2023. RESULTS: Thirty-two children met inclusion criteria. Ocular involvement was unilateral in 29 subjects and bilateral in 3. Segmental optic nerve enlargement ipsilateral to the MGDA was seen in 21 subjects, with 3 also demonstrating a segmental reduction in the size of the ipsilateral optic nerve. Segmental reduction in the size of the ipsilateral optic nerve was present in 3 additional subjects, one with bilateral MGDA. The optic chiasm appeared asymmetrically thickened in 21 subjects, often with deformity. The optic nerves appeared normal in signal intensity in all subjects, with faint peripheral chiasmatic enhancement in 4 of 20 patients who received contrast. Optic nerve findings were stable in 15 subjects with multiple examinations. A persistent craniopharyngeal canal was identified in 17 subjects with sphenoid cephalocele in 1 and mild inferior pituitary gland displacement in 4. Tubular or nodular nasopharyngeal lesions were seen in 10 subjects. One subject had an off-midline sphenoid bone cleft, midbrain deformity, and abnormal thickening of and enhancement around the left oculomotor nerve; the oculomotor nerve finding was present in 1 additional patient. CONCLUSIONS: MGDA often manifests with ipsilateral optic nerve thickening, leading to a potential misdiagnosis as optic glioma. MGDA is also commonly associated with a persistent craniopharyngeal canal with variable pituitary gland and infundibular deformity, cephalocele, and tubular or nodular nasopharyngeal lesions.


Assuntos
Imageamento por Ressonância Magnética , Disco Óptico , Humanos , Feminino , Masculino , Estudos Retrospectivos , Criança , Imageamento por Ressonância Magnética/métodos , Disco Óptico/diagnóstico por imagem , Disco Óptico/anormalidades , Disco Óptico/patologia , Pré-Escolar , Adolescente , Lactente , Fenótipo , Osso Esfenoide/diagnóstico por imagem , Osso Esfenoide/anormalidades , Osso Esfenoide/patologia , Quiasma Óptico/diagnóstico por imagem , Quiasma Óptico/anormalidades , Quiasma Óptico/patologia , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/patologia
13.
J Clin Invest ; 134(13)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38949024

RESUMO

Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.


Assuntos
Cílios , Doenças Renais Císticas , Doença de Leigh , Mitocôndrias , Peixe-Zebra , Humanos , Peixe-Zebra/metabolismo , Peixe-Zebra/genética , Doença de Leigh/genética , Doença de Leigh/metabolismo , Doença de Leigh/patologia , Cílios/metabolismo , Cílios/patologia , Cílios/genética , Animais , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitocôndrias/genética , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Doenças Renais Císticas/patologia , Complexo I de Transporte de Elétrons/metabolismo , Complexo I de Transporte de Elétrons/genética , Proteínas do Domínio Armadillo/metabolismo , Proteínas do Domínio Armadillo/genética , Retina/metabolismo , Retina/patologia , Retina/anormalidades , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Anormalidades do Olho/metabolismo , Camundongos , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Cerebelo/metabolismo , Cerebelo/patologia , Cerebelo/anormalidades , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Masculino
14.
Eye (Lond) ; 38(11): 2216-2223, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38971922

RESUMO

OBJECTIVES: This prospective cohort study aimed to investigate the ocular outcomes of universal eye screening in newborns and assess the relationship between different perinatal risk factors and various ocular abnormalities in infants who do not meet the criteria for retinopathy of prematurity (ROP) screening. METHODS: An universal eye screening questionnaire was utilised to screen newborn babies who did not meet the ROP screening criteria within 72 h of birth at a public and private hospital between June 2016 and April 2018. The questionnaire covered demographic characteristics, neonatal history, and eye examination findings. A trained retina specialist conducted comprehensive anterior and posterior segment examinations utilising a binocular indirect ophthalmoscope. RESULTS: Out of the 1795 newborns screened, 55.2% were male, and 44.8% were female. The most prevalent ocular abnormality observed was retinal haemorrhage (RH), with a prevalence of 10.64% (95% CI: 9.25-12.16%). The prevalence of non-RH abnormality was 7.5% (95% CI: 6.34-8.84%). The retinal haemorrhages were associated with normal vaginal deliveries (OR: 9.91; 95% CI: 6.71-14.64, p-value < 0.001), while non-RH abnormalities were associated with pre-term babies (OR: 4.87; 95% CI: 3.03-7.83, p < 0.001), consanguinity (OR: 2.20; 95% CI: 1.28-3.8, p < 0.001), low birth weight (OR: 0.22; 95% CI: 0.14-0.34, p < 0.001) and systemic abnormalities (OR: 3.08; 95% CI: 1.94-4.91, p < 0.001). CONCLUSIONS: Sight-threatening ocular pathology in newborns may be linked to perinatal risk factors such as preterm birth, low birth weight, consanguinity, and systemic abnormalities. Accordingly, it may be prudent to consider specialized ocular screening protocols for neonates within this high-risk cohort in future prospective studies.


Assuntos
Triagem Neonatal , Retinopatia da Prematuridade , Humanos , Recém-Nascido , Feminino , Estudos Prospectivos , Fatores de Risco , Retinopatia da Prematuridade/diagnóstico , Retinopatia da Prematuridade/epidemiologia , Triagem Neonatal/métodos , Masculino , Prevalência , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/epidemiologia , Idade Gestacional , Inquéritos e Questionários , Oftalmoscopia , Seleção Visual/métodos , Recém-Nascido Prematuro
15.
Int J Mol Sci ; 25(14)2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39063141

RESUMO

KIAA0586 variants have been associated with a wide range of ciliopathies, mainly Joubert syndrome (JS, OMIM #616490) and short-rib thoracic dysplasia syndrome (SRTD, OMIM #616546). However, the hypothesis that this gene is involved with hydrolethalus syndrome (HSL, OMIM #614120) and orofaciodigital syndrome IV (OMIM #258860) has already been raised. Ciliopathies' clinical features are often overlapped despite differing in phenotype severity. Besides KIAA0586, HYLS1 and KIF7 are also known for being causative of ciliopathies, indicating that all three genes may have similar or converging genomic pathways. Overall, the genotypic and phenotypic spectrum of ciliopathies becomes wider and conflicting while more and more new variants are added to this group of disorders' molecular pot. In this case report we discuss the first Brazilian individual clinically diagnosed with hydrolethalus syndrome and molecular findings that demonstrate the role of KIAA0586 as a causative gene of a group of genetic disorders. Also, recent reports on individuals with intronic and exonic variants combined leading to ciliopathies support our patient's molecular diagnosis. At the same time, we discuss variable expressivity and overlapping features in ciliopathies.


Assuntos
Anormalidades Múltiplas , Cerebelo , Anormalidades do Olho , Doenças Renais Císticas , Fenótipo , Retina , Humanos , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Doenças Renais Císticas/genética , Anormalidades Múltiplas/genética , Retina/anormalidades , Retina/patologia , Retina/metabolismo , Cerebelo/anormalidades , Cerebelo/patologia , Ciliopatias/genética , Masculino , Mutação , Feminino , Proteínas de Ciclo Celular
16.
J Cell Sci ; 137(13)2024 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-38841887

RESUMO

Centrosomal proteins play pivotal roles in orchestrating microtubule dynamics, and their dysregulation leads to disorders, including cancer and ciliopathies. Understanding the multifaceted roles of centrosomal proteins is vital to comprehend their involvement in disease development. Here, we report novel cellular functions of CEP41, a centrosomal and ciliary protein implicated in Joubert syndrome. We show that CEP41 is an essential microtubule-associated protein with microtubule-stabilizing activity. Purified CEP41 binds to preformed microtubules, promotes microtubule nucleation and suppresses microtubule disassembly. When overexpressed in cultured cells, CEP41 localizes to microtubules and promotes microtubule bundling. Conversely, shRNA-mediated knockdown of CEP41 disrupts the interphase microtubule network and delays microtubule reassembly, emphasizing its role in microtubule organization. Further, we demonstrate that the association of CEP41 with microtubules relies on its conserved rhodanese homology domain (RHOD) and the N-terminal region. Interestingly, a disease-causing mutation in the RHOD domain impairs CEP41-microtubule interaction. Moreover, depletion of CEP41 inhibits cell proliferation and disrupts cell cycle progression, suggesting its potential involvement in cell cycle regulation. These insights into the cellular functions of CEP41 hold promise for unraveling the impact of its mutations in ciliopathies.


Assuntos
Proliferação de Células , Microtúbulos , Humanos , Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Centrossomo/metabolismo , Retina/metabolismo , Retina/patologia , Retina/anormalidades , Ciliopatias/metabolismo , Ciliopatias/genética , Ciliopatias/patologia , Cerebelo/metabolismo , Cerebelo/anormalidades , Cerebelo/patologia , Doenças Renais Císticas/metabolismo , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Cílios/metabolismo , Cílios/patologia , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Animais , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Anormalidades do Olho/metabolismo , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Ligação Proteica , Ciclo Celular/genética , Células HEK293
17.
J Zoo Wildl Med ; 55(2): 322-329, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38875189

RESUMO

Panamanian golden frog (PGF) (Atelopus zeteki) is a critically endangered species. The Maryland Zoo in Baltimore houses two groups of PGF originating from distinct geographic locations as an assurance colony, with the goal of upholding genetics for future release of individuals back to their native environment. The purpose of this cross-sectional study was to characterize the prevalence of ocular abnormalities in these two zoo-housed populations of PGF as well as to establish normal parameters for selected diagnostic tests in these groups. Twenty-five females and 25 males were randomly selected from each group (100 PGF; 200 eyes in total) to undergo ocular examination using slit lamp biomicroscopy and direct ophthalmoscopy. Endodontic absorbent paper point test (EAPPT) and intraocular pressure (IOP) and Rose Bengal stain diagnostic tests were also performed. Reference ranges for tear production (EAPPT, 0.5-3 mm/min) and IOP (14-26 mmHg) were calculated in the nondiseased PGF eyes (n = 160 eyes). Rose Bengal stain uptake was negative on all eyes. In total, 40 eyes of 30 PGF were found to have some form of ocular abnormality (28% of PGF, 20% of eyes). The most frequently observed ocular abnormalities were cataract (9% of PGF, 6% of eyes) and keratitis (nonlipid keratopathy; 10% of PGF, 5.5% of eyes). There was no significant difference in overall ocular abnormality prevalence between the two groups studied (P = 0.37) or between the sexes (P = 0.76). The median age of an eye with cataract and keratitis (nonlipid keratopathy) was 10.35 and 7.7 yr, respectively. Ocular abnormalities are common in these two populations of PGF. Documentation of these ocular abnormalities and establishment of diagnostic reference ranges have not previously been published and may be important for maintaining the health of this endangered species.


Assuntos
Anuros , Animais , Feminino , Masculino , Prevalência , Estudos Transversais , Animais de Zoológico , Anormalidades do Olho/veterinária , Anormalidades do Olho/epidemiologia , Anormalidades do Olho/diagnóstico , Valores de Referência , Espécies em Perigo de Extinção , Oftalmopatias/veterinária , Oftalmopatias/epidemiologia , Oftalmopatias/diagnóstico , Baltimore/epidemiologia
18.
Int J Mol Sci ; 25(11)2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38892036

RESUMO

The extracellular matrix is a complex network of proteins and other molecules that are essential for the support, integrity, and structure of cells and tissues within the human body. The genes ZNF469 and PRDM5 each produce extracellular-matrix-related proteins that, when mutated, have been shown to result in the development of brittle cornea syndrome. This dysfunction results from aberrant protein function resulting in extracellular matrix disruption. Our group recently identified and published the first known associations between variants in these genes and aortic/arterial aneurysms and dissection diseases. This paper delineates the proposed effects of mutated ZNF469 and PRDM5 on various essential extracellular matrix components, including various collagens, TGF-B, clusterin, thrombospondin, and HAPLN-1, and reviews our recent reports associating single-nucleotide variants to these genes' development of aneurysmal and dissection diseases.


Assuntos
Matriz Extracelular , Fatores de Transcrição , Humanos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/genética , Instabilidade Articular/genética , Instabilidade Articular/congênito , Histona-Lisina N-Metiltransferase/genética , Distrofias Hereditárias da Córnea/genética , Distrofias Hereditárias da Córnea/patologia , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patologia , Aneurisma Aórtico/genética , Mutação , Proteínas de Ligação a DNA/genética , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/patologia , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Anormalidades do Olho , Anormalidades da Pele
19.
Sci Rep ; 14(1): 14380, 2024 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-38909058

RESUMO

Inherited and developmental eye diseases are quite diverse and numerous, and determining their genetic cause is challenging due to their high allelic and locus heterogeneity. New molecular approaches, such as whole exome sequencing (WES), have proven to be powerful molecular tools for addressing these cases. The present study used WES to identify the genetic etiology in ten unrelated Mexican pediatric patients with complex ocular anomalies and other systemic alterations of unknown etiology. The WES approach allowed us to identify five clinically relevant variants in the GZF1, NFIX, TRRAP, FGFR2 and PAX2 genes associated with Larsen, Malan, developmental delay with or without dysmorphic facies and autism, LADD1 and papillorenal syndromes. Mutations located in GZF1 and NFIX were classified as pathogenic, those in TRRAP and FGFR2 were classified as likely pathogenic variants, and those in PAX2 were classified as variants of unknown significance. Protein modeling of the two missense FGFR2 p.(Arg210Gln) and PAX2 p.(Met3Thr) variants showed that these changes could induce potential structural alterations in important functional regions of the proteins. Notably, four out of the five variants were not previously reported, except for the TRRAP gene. Consequently, WES enabled the identification of the genetic cause in 40% of the cases reported. All the syndromes reported herein are very rare, with phenotypes that may overlap with other genetic entities.


Assuntos
Sequenciamento do Exoma , Anormalidades do Olho , Fator de Transcrição PAX2 , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Humanos , Masculino , Feminino , Criança , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Fator de Transcrição PAX2/genética , Pré-Escolar , Anormalidades do Olho/genética , Lactente , Mutação , Adolescente , Predisposição Genética para Doença
20.
Cells Dev ; 179: 203926, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38729574

RESUMO

The periocular mesenchyme (POM) is a transient migratory embryonic tissue derived from neural crest cells (NCCs) and paraxial mesoderm that gives rise to most of the structures in front of the eye. Morphogenetic defects of these structures can impair aqueous humor outflow, leading to elevated intraocular pressure and glaucoma. Mutations in collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) cause Gould syndrome - a multisystem disorder often characterized by variable cerebrovascular, ocular, renal, and neuromuscular manifestations. Approximately one-third of individuals with COL4A1 and COL4A2 mutations have ocular anterior segment dysgenesis (ASD), including congenital glaucoma resulting from abnormalities of POM-derived structures. POM differentiation has been a major focus of ASD research, but the underlying cellular mechanisms are still unclear. Moreover, earlier events including NCC migration and survival defects have been implicated in ASD; however, their roles are not as well understood. Vascular defects are among the most common consequences of COL4A1 and COL4A2 mutations and can influence NCC survival and migration. We therefore hypothesized that NCC migration might be impaired by COL4A1 and COL4A2 mutations. In this study, we used 3D confocal microscopy, gross morphology, and quantitative analyses to test NCC migration in Col4a1 mutant mice. We show that homozygous Col4a1 mutant embryos have severe embryonic growth retardation and lethality, and we identified a potential maternal effect on embryo development. Cerebrovascular defects in heterozygous Col4a1 mutant embryos were present as early as E9.0, showing abnormal cerebral vasculature plexus remodeling compared to controls. We detected abnormal NCC migration within the diencephalic stream and the POM in heterozygous Col4a1 mutants whereby mutant NCCs formed smaller diencephalic migratory streams and POMs. In these settings, migratory NCCs within the diencephalic stream and POM localize farther away from the developing vasculature. Our results show for the first time that Col4a1 mutations lead to cranial NCCs migratory defects in the context of early onset defective angiogenesis without affecting cell numbers, possibly impacting the relation between NCCs and the blood vessels during ASD development.


Assuntos
Movimento Celular , Colágeno Tipo IV , Modelos Animais de Doenças , Anormalidades do Olho , Mutação , Crista Neural , Crista Neural/metabolismo , Crista Neural/patologia , Animais , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Movimento Celular/genética , Camundongos , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Mutação/genética , Segmento Anterior do Olho/anormalidades , Segmento Anterior do Olho/patologia
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