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1.
Hum Mol Genet ; 31(17): 2934-2950, 2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-35405010

RESUMO

DROSHA encodes a ribonuclease that is a subunit of the Microprocessor complex and is involved in the first step of microRNA (miRNA) biogenesis. To date, DROSHA has not yet been associated with a Mendelian disease. Here, we describe two individuals with profound intellectual disability, epilepsy, white matter atrophy, microcephaly and dysmorphic features, who carry damaging de novo heterozygous variants in DROSHA. DROSHA is constrained for missense variants and moderately intolerant to loss-of-function (o/e = 0.24). The loss of the fruit fly ortholog drosha causes developmental arrest and death in third instar larvae, a severe reduction in brain size and loss of imaginal discs in the larva. Loss of drosha in eye clones causes small and rough eyes in adult flies. One of the identified DROSHA variants (p.Asp1219Gly) behaves as a strong loss-of-function allele in flies, while another variant (p.Arg1342Trp) is less damaging in our assays. In worms, a knock-in that mimics the p.Asp1219Gly variant at a worm equivalent residue causes loss of miRNA expression and heterochronicity, a phenotype characteristic of the loss of miRNA. Together, our data show that the DROSHA variants found in the individuals presented here are damaging based on functional studies in model organisms and likely underlie the severe phenotype involving the nervous system.


Assuntos
Epilepsia , Deficiência Intelectual , MicroRNAs , Microcefalia , Malformações do Sistema Nervoso , Humanos , Deficiência Intelectual/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Microcefalia/genética , Ribonuclease III/genética , Ribonuclease III/metabolismo
2.
Genet Med ; 25(9): 100897, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37191094

RESUMO

PURPOSE: Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)-associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype. METHODS: This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy. RESULTS: All 8 healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death to severe neurologic deficits to normal outcomes. The neuroradiological findings overlapped with ANE but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1: a subset that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family. CONCLUSION: Biallelic variants in RNH1 confer susceptibility to a subtype of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies, such as RNH1, and improve outcomes in the probands and at-risk siblings.


Assuntos
Encefalopatia Aguda Febril , Encefalopatias , Leucoencefalite Hemorrágica Aguda , Criança , Humanos , Leucoencefalite Hemorrágica Aguda/diagnóstico , Leucoencefalite Hemorrágica Aguda/genética , Inflamassomos , Encefalopatias/genética , Fatores de Transcrição , Ribonucleases , Proteínas de Transporte
3.
J Pediatr Hematol Oncol ; 45(4): e464-e470, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36730221

RESUMO

Low-grade gliomas/glioneuronal tumors comprise one-third of all pediatric-type CNS tumors. These tumors are generally caused by activating mutations in the mitogen-activated protein kinase (MAPK) pathway. Targeted drugs, such as trametinib, have shown promise in other cancers and are being utilized in low-grade gliomas. A retrospective chart review was conducted to evaluate radiographic response, visual outcomes, tolerability, and durability of response in progressive circumscribed low-grade gliomas treated with trametinib. Eleven patients were treated with trametinib. The best radiographic response was 2/11 partial response, 3/11 minor response, 3/11 stable disease, and 3/13 progressive disease. In the patients with partial or minor response, the best response was seen after longer durations of therapy; 4 of 5 best responses occurred after at least 9 months of therapy with a median of 21 months. Patients with optic pathway tumors showed at least stable vision throughout treatment, with 3 having improved vision on treatment. Trametinib is effective and well-tolerated in patients with progressive low-grade glioma. Best responses were seen after a longer duration of therapy in those with a positive response. Patients with optic pathway lesions showed stable to improved vision while on treatment.


Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Glioma , Criança , Humanos , Adulto Jovem , Neoplasias Encefálicas/patologia , Estudos Retrospectivos , Glioma/patologia , Piridonas/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico
4.
J Neuroophthalmol ; 43(3): 353-358, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36728098

RESUMO

BACKGROUND: Optic disc drusen (ODD) are calcified deposits in the prelaminar portion of the optic nerve head. Although often asymptomatic, these deposits can cause progressive visual field defects and vision loss. The purpose of this study was to evaluate rates of functional loss in eyes with ODD and to investigate risk factors associated with rates of visual field progression. METHODS: This was a retrospective cohort study including 65 eyes of 43 patients with ODD from the Duke Ophthalmic Registry. All eyes had at least 12 months of follow-up and at least 3 reliable standard automated perimetry (SAP) tests. Linear mixed models were used to estimate rates of SAP mean deviation (MD) loss over time. Univariable and multivariable models were used to assess the effect of clinical variables and intraocular pressure (IOP) on rates of change. RESULTS: Subjects were followed for an average of 7.6 ± 5.3 years. The mean rate of SAP MD change was -0.23 ± 0.26 dB/year, ranging from -1.19 to 0.13 dB/year. Fifty-seven eyes (87.7%) had slow progression (slower than -0.5 dB/year), 6 eyes (9.2%) had moderate progression (between -0.5 dB/year and -1 dB/year), and 2 eyes (3.1%) had fast progression (faster than -1 dB/year). In multivariable models, older age and worse SAP MD at baseline were significantly associated with faster rates of change. Mean IOP was not associated with faster rates of MD change in both univariable and multivariable analyses. CONCLUSIONS: Most eyes with ODD had slow rates of visual field loss over time. Age and baseline severity were significantly associated with faster rates of visual field loss.


Assuntos
Drusas do Disco Óptico , Disco Óptico , Humanos , Campos Visuais , Drusas do Disco Óptico/complicações , Drusas do Disco Óptico/diagnóstico , Estudos Retrospectivos , Disco Óptico/diagnóstico por imagem , Testes de Campo Visual , Pressão Intraocular , Transtornos da Visão/diagnóstico , Transtornos da Visão/etiologia , Progressão da Doença , Seguimentos
5.
Am J Hum Genet ; 103(2): 245-260, 2018 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-30057031

RESUMO

Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals who carry damaging heterozygous variants in IRF2BPL and are affected with neurological symptoms. Five individuals who carry IRF2BPL nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The IRF2BPL bioinformatics signature based on population genomics is consistent with a gene that is intolerant to variation. We show that the fruit-fly IRF2BPL ortholog, called pits (protein interacting with Ttk69 and Sin3A), is broadly detected, including in the nervous system. Complete loss of pits is lethal early in development, whereas partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance. The identified IRF2BPL nonsense variants behave as severe loss-of-function alleles in this model organism, and ectopic expression of the missense variants leads to a range of phenotypes. Taken together, our results show that IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

6.
Retina ; 41(4): 804-811, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32568982

RESUMO

PURPOSE: Deformations of the retina such as staphylomas in myopia or scleral flattening in high intracranial pressure can be challenging to quantify with en face imaging. We describe an optical coherence tomography-based method for the generation of quantitative posterior eye topography maps in normal and pathologic eyes. METHODS: Using "whole eye" optical coherence tomography, we corrected for subjects' optical distortions to generate spatially accurate posterior eye optical coherence tomography volumes and created local curvature (KM, mm-1) topography maps for each consented subject. We imaged nine subjects, three normal, two with myopic degeneration, and four with papilledema including one that was imaged longitudinally. RESULTS: Normal subjects mean temporal KM was 0.0923 mm-1, nasal KM was 0.0927 mm-1, and KM local variability was 0.0162 mm-1. In myopic degeneration, subjects KM local variability was higher at 0.0836 mm-1. In papilledema subjects nasal KM was flatter compared with temporal KM (0.0709 vs. 0.0885 mm-1). Mean intrasession KM repeatability for all subjects was 0.0036 mm-1. CONCLUSION: We have developed an optical coherence tomography based method for quantitative posterior eye topography that offers the ability to analyze local curvature with micron scale resolution and offers the potential to help clinicians and researchers characterize subtle, local retinal deformations earlier in patients and follow their development over time.


Assuntos
Miopia Degenerativa/diagnóstico por imagem , Papiledema/diagnóstico por imagem , Segmento Posterior do Olho/diagnóstico por imagem , Tomografia de Coerência Óptica , Adulto , Técnicas de Diagnóstico Oftalmológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miopia Degenerativa/patologia , Papiledema/patologia , Segmento Posterior do Olho/patologia , Retina/diagnóstico por imagem
7.
J Neuroophthalmol ; 41(1): 54-59, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31609845

RESUMO

BACKGROUND: Giant cell arteritis (GCA) is an important diagnostic consideration in elderly patients with vision changes. Superficial temporal artery biopsy (TAB) has long been considered the gold standard diagnostic approach for GCA, but MRI has gained interest as an alternative diagnostic modality. Although most of the literature has focused on imaging abnormalities of branches of the external carotid artery, there have been a few reports of GCA-related inflammatory involvement of the orbit and internal carotid arteries (ICAs) on MRI. METHODS: This was a retrospective cross-sectional study of patients undergoing TAB at a single tertiary referral center over a 5-year period. Patients who had undergone contrast-enhanced MRI of the brain and orbits within 1 month of biopsy were included. Fifty-four TAB-positive and 78 TAB-negative patients were reviewed, with the MRI studies of 7 TAB-positive and 6 TAB-negative patients deemed adequate for interpretation. MRI studies were reviewed by 2 masked neuroradiologists, and the findings were correlated with biopsy results and clinical findings. RESULTS: Intracranial ICA vessel wall enhancement was identified in 6 of 7 TAB-positive patients (sensitivity 86%), compared with 2 of 6 TAB-negative patients (specificity 67%). Optic nerve sheath enhancement was identified in 5 of 7 TAB-positive patients (sensitivity 71%) and in 2 of 6 TAB-negative patients (specificity 67%), bilateral in all such cases. The combination of both abnormal imaging findings was observed in 5 of 7 TAB-positive patients (sensitivity 71%) and in none of the 6 TAB-negative patients (specificity 100%). CONCLUSIONS: Intracranial ICA and optic nerve sheath enhancement were observed in a majority of patients with TAB-proven GCA, and the combination of these findings was highly specific for GCA. Identification of these abnormalities on MRI should raise concern for GCA and prompt a thorough review of systems, laboratory testing, and consideration of TAB in patients with ocular complaints potentially consistent with ischemia.


Assuntos
Artéria Carótida Interna/diagnóstico por imagem , Arterite de Células Gigantes/diagnóstico , Doenças do Nervo Óptico/diagnóstico por imagem , Artérias Temporais/patologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , Estudos Transversais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e Especificidade
8.
Graefes Arch Clin Exp Ophthalmol ; 258(1): 89-98, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31758259

RESUMO

PURPOSE: Compared with fluorescein angiography (FA), the gold standard for diagnosing choroidal neovascularization (CNV) activity, optical coherence tomography angiography (OCTA) is non-invasive without risks associated with fluorescein dye use, and may be especially advantageous in the diagnosis and monitoring of children with CNV. METHODS: Eight eyes from eight patients aged 12 months to 18 years were imaged with the investigational Spectralis OCTA (version 6.9, Heidelberg Engineering, Heidelberg, Germany) and the RTVue XR Avanti (Optovue Inc., Fremont, CA, USA). Two patients were imaged during examination under anesthesia while six patients were imaged in the clinic. Demographic information, ocular characteristics, treatment history, and imaging studies (color photos, fluorescein angiography, OCT) were collected and reviewed. RESULTS: Three eyes had active CNV while five had quiescent CNV at the time of imaging. CNV was idiopathic or secondary to trauma, retinal vascular dysgenesis versus retinopathy of prematurity, pigmentary retinopathy, Best vitelliform macular dystrophy, panuveitis, morning glory disc anomaly, and optic disc drusen. OCTA of two active CNV demonstrated presence of a main trunk with multiple fine capillaries, vessel loops, and anastomoses. OCTA was repeated after treatment for two CNV and demonstrated a decrease in size with loss of fine capillaries, vessel loops, and anastomoses. For the third active CNV, OCTA verified flow in the CNV complex despite the uncertainty of FA hyperfluorescence in the setting of grossly abnormal retinal vasculature. The five quiescent CNV all lacked fine capillaries, vessel loops, and anastomoses on OCTA. CONCLUSION: OCTA demonstrates morphological differences between active and quiescent pediatric CNV.


Assuntos
Corioide/irrigação sanguínea , Neovascularização de Coroide/diagnóstico , Angiofluoresceinografia/métodos , Vasos Retinianos/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Adolescente , Capilares/diagnóstico por imagem , Criança , Pré-Escolar , Corioide/diagnóstico por imagem , Feminino , Fundo de Olho , Humanos , Lactente , Masculino
9.
Graefes Arch Clin Exp Ophthalmol ; 258(9): 2039-2049, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32472201

RESUMO

PURPOSE: To detect retinal features and abnormalities on optical coherence tomography (OCT) without pupil dilation and relate these to brain injury in infants with a clinical diagnosis of hypoxic ischemic encephalopathy (HIE). METHODS: Under an institutional review board-approved protocol, we imaged eight infants without pharmacologic mydriasis, using handheld, non-contact spectral-domain (Leica Microsystems, IL) or investigational swept-source OCT at the bedside in an intensive care nursery, after birth (depending on primary clinical care team permission based on health status) and weekly until discharge. The newborn infant with HIE is neurologically unstable; therefore, pharmacologic mydriasis and stimulation with visible light for retinal examination are usually avoided. We analyzed images for retinal pathologies, central foveal thickness, and retinal nerve fiber layer (RNFL) thickness at the papillomacular bundle and compared them to historical controls and published normative data, HIE clinical assessment, and abnormalities on brain magnetic resonance imaging (MRI). RESULTS: On OCT, three of eight infants had bilateral multiple small macular and perimacular cystoid spaces; two of these three infants also had pronounced retinal ganglion cell layer thinning and severe brain injury on MRI and the third had bilateral paracentral acute middle maculopathy and mild brain injury on MRI. Other findings in HIE infant eyes included abnormally thin fovea and thin RNFL and markers of retinal immaturity such as the absence of sub-foveal photoreceptor development and sub-foveal fluid. CONCLUSIONS: Bedside handheld OCT imaging within the first 2 weeks of life revealed retinal injury in infants with HIE-related brain injury. Future studies may determine the relationship between acute/subacute retinal abnormalities and brain injury severity and neurodevelopmental outcomes in HIE.


Assuntos
Encéfalo/patologia , Fóvea Central/patologia , Hipóxia-Isquemia Encefálica/diagnóstico , Imageamento por Ressonância Magnética/métodos , Doenças Retinianas/diagnóstico , Tomografia de Coerência Óptica/métodos , Feminino , Idade Gestacional , Humanos , Hipóxia-Isquemia Encefálica/complicações , Recém-Nascido , Masculino , Doenças Retinianas/etiologia , Estudos Retrospectivos
10.
Ophthalmology ; 126(12): 1703-1711, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31548134

RESUMO

PURPOSE: To assess macular vasculature in healthy infants and children using OCT angiography (OCTA). DESIGN: Prospective cross-sectional study. PARTICIPANTS: One hundred thirty-five normal maculae of 89 healthy infants and children (mean age, 8.5±5.3 years; range, 9 weeks-17 years) treated at the Duke University Eye Center. METHODS: We imaged 135 maculae of 89 pediatric patients using the standard Spectralis tabletop and investigational Spectralis with Flex module devices, both equipped with investigational OCTA software (Heidelberg Engineering, Heidelberg, Germany). OCT angiography images of the superficial vascular complex (SVC) and deep vascular complex (DVC) were analyzed for foveal avascular zone (FAZ) area and superficial and deep vessel density. We assessed effects of age, gender, race, axial length (AL), and central subfield thickness on FAZ and vessel density. Patients with both eyes imaged were assessed for agreement between the FAZ and vessel densities of the left and right eyes. MAIN OUTCOME MEASURES: The FAZ area, as well as vessel area density (VAD) and vessel length density (VLD) in the SVC and DVC. RESULTS: The FAZ varied significantly with race; white patients showed a significantly smaller FAZ than black patients (mean difference, 0.11 mm2; P = 0.004). The FAZ did not vary with age, gender, or AL (P > 0.05). In the SVC, VAD and VLD varied significantly with age (P < 0.001) and AL (R2 = 0.46; P < 0.001) but not gender (P > 0.05). The SVC VLD was significantly different between races and ethnicities (P = 0.037), but VAD was not (P < 0.05). In the DVC, VAD and VLD also varied significantly with age (P < 0.001) and AL (R2 = 0.46; P < 0.001) but not gender or race (P > 0.05). There was excellent agreement between the right and left eyes for FAZ (intraclass correlation [ICC], 0.97), SVC VLD (ICC, 1.00), and DVC VLD (ICC, 1.00). CONCLUSIONS: Quantitative studies of pediatric perifoveal vasculature should consider age, race, and AL. In eyes with unilateral disease, the perifoveal vasculature in the unaffected eye may be used as a control comparison because there is excellent agreement between eyes.


Assuntos
Macula Lutea/irrigação sanguínea , Vasos Retinianos/anatomia & histologia , Adolescente , Fatores Etários , Comprimento Axial do Olho/anatomia & histologia , Criança , Pré-Escolar , Estudos Transversais , Etnicidade , Feminino , Angiofluoresceinografia , Voluntários Saudáveis , Humanos , Lactente , Macula Lutea/diagnóstico por imagem , Masculino , Microvasos , Estudos Prospectivos , Vasos Retinianos/diagnóstico por imagem , Tomografia de Coerência Óptica , Acuidade Visual
11.
Retina ; 39(1): 98-110, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29190238

RESUMO

PURPOSE: To explore vitreoretinal pathologies and their longitudinal changes visible on handheld optical coherence tomography (OCT) of young children with familial exudative vitreoretinopathy. METHODS: The authors retrospectively analyzed handheld OCT images for vitreoretinal interface and retinal abnormalities and optic nerve head (ONH) elevation. RESULTS: From 26 eyes of 16 children (mean age 32 months) with familial exudative vitreoretinopathy, 10 had ONH dragging on photographs, and in these, handheld OCT revealed temporal and anterior retinal displacement, prominent vitreopapillary adhesion or traction, and retinal nerve fiber layer thickening at ONH margins with adjacent retinal elevation. Despite a nearly normal photographic appearance, handheld OCT revealed ONH elevation with vitreopapillary traction (6/16 eyes), ONH edema (1/16 eye), and retinal vascular protrusion (5/16 eyes). Handheld OCT-visualized vitreous abnormalities (18/26 eyes) were more prevalent at higher stages of disease. Handheld OCT-visualized elevation of ONH and the retina worsened over time in nine eyes and improved in 5/6 eyes after vitrectomy. CONCLUSION: Handheld OCT can detect early ONH, retinal, and vitreous changes in eyes with familial exudative vitreoretinopathy. Contraction of strongly adherent vitreous in young patients with familial exudative vitreoretinopathy appears to cause characteristic ONH dragging and tractional complications without partial posterior vitreous detachment. Vitreopapillary dragging may be visible only on OCT and may progress in the absence of obvious retinal change on conventional examination.


Assuntos
Vitreorretinopatias Exsudativas Familiares/diagnóstico , Angiofluoresceinografia/métodos , Disco Óptico/patologia , Retina/patologia , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Criança , Pré-Escolar , Progressão da Doença , Feminino , Seguimentos , Fundo de Olho , Humanos , Lactente , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de Tempo , Corpo Vítreo/patologia
12.
Genet Med ; 20(4): 464-469, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28914269

RESUMO

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.


Assuntos
Exoma , Estudos de Associação Genética , Predisposição Genética para Doença , Técnicas de Diagnóstico Molecular , Alelos , Biópsia , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Genótipo , Humanos , Lactente , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/normas , Fenótipo , Polimorfismo de Nucleotídeo Único , Doenças Raras/diagnóstico , Doenças Raras/genética , Sequenciamento do Exoma , Sequenciamento Completo do Genoma
13.
J Hum Genet ; 63(12): 1211-1222, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30250212

RESUMO

Mitochondrial dysfunction lies behind many neurodegenerative disorders, owing largely to the intense energy requirements of most neurons. Such mitochondrial dysfunction may work through a variety of mechanisms, from direct disruption of the electron transport chain to abnormal mitochondrial biogenesis. Recently, we have identified biallelic mutations in the mitochondrial flavoprotein "ferredoxin reductase" (FDXR) gene as a novel cause of mitochondriopathy, peripheral neuropathy, and optic atrophy. In this report, we expand upon those results by describing two new cases of disease-causing FDXR variants in patients with variable severity of phenotypes, including evidence of an inflammatory response in brain autopsy. To investigate the underlying pathogenesis, we examined neurodegeneration in a mouse model. We found that Fdxr mutant mouse brain tissues share pathological changes similar to those seen in patient autopsy material, including increased astrocytes. Furthermore, we show that these abnormalities are associated with increased levels of markers for both neurodegeneration and gliosis, with the latter implying inflammation as a major factor in the pathology of Fdxr mutations. These data provide further insight into the pathogenic mechanism of FDXR-mediated central neuropathy, and suggest an avenue for mechanistic studies that will ultimately inform treatment.


Assuntos
Alelos , Proteínas Ferro-Enxofre/genética , Mutação , Doenças Neurodegenerativas/genética , Oxirredutases/genética , Animais , Encéfalo/enzimologia , Encéfalo/patologia , Feminino , Humanos , Inflamação/enzimologia , Inflamação/genética , Inflamação/patologia , Proteínas Ferro-Enxofre/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/patologia , Oxirredutases/metabolismo
16.
J Neuroophthalmol ; 37(3): 311-313, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-27548636

RESUMO

Endodermal cysts, also known as neurogenic, neuroenteric, foregut, bronchogenic, respiratory, epithelial, teratomatous, or gastrocytoma cysts, can be found in the central nervous system, predominantly in the subarachnoid space of the cervical and thoracic spinal cord. We describe a child with an endodermal cyst of the third nerve and highlight neuroimaging findings, pathological correlation, clinical course, and patient management.


Assuntos
Cistos do Sistema Nervoso Central/diagnóstico , Neoplasias dos Nervos Cranianos/diagnóstico , Imageamento por Ressonância Magnética/métodos , Doenças do Nervo Oculomotor/diagnóstico , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos
17.
J Neuroophthalmol ; 37(2): 126-132, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27787461

RESUMO

Fulminant idiopathic intracranial hypertension (FIIH) is a subtype of idiopathic intracranial hypertension (IIH) characterized by rapid, severe, progressive vision loss. Surgical intervention is often performed either as a cerebrospinal fluid (CSF) shunt procedure or an optic nerve sheath fenestration or, at times, both. These surgical procedures carry a significant risk of morbidity and failure. We present 2 patients in whom a temporary lumbar drain was successfully used in the management of medically undertreated pediatric FIIH, and circumvented the need for surgical intervention.


Assuntos
Derivações do Líquido Cefalorraquidiano/métodos , Pseudotumor Cerebral/cirurgia , Baixa Visão/etiologia , Acuidade Visual , Doença Aguda , Adolescente , Feminino , Humanos , Pseudotumor Cerebral/complicações , Pseudotumor Cerebral/diagnóstico , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica , Baixa Visão/diagnóstico , Baixa Visão/fisiopatologia
19.
J Neuroophthalmol ; 36(4): 402-403, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27468120

RESUMO

Nonglaucomatous cupping is commonly encountered in neuro-ophthalmic practice. However, the progression of clinical and imaging findings over time has not been well described. We present serial fundus photographs and spectral domain optical coherence tomography from a pediatric patient with neuromyelitis optic spectrum disorder, which demonstrated progression of both cupping and optic atrophy in the setting of normal intraocular pressure.


Assuntos
Atrofia Óptica/diagnóstico , Disco Óptico/patologia , Tomografia de Coerência Óptica/métodos , Criança , Feminino , Humanos , Pressão Intraocular , Acuidade Visual
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