RESUMEN
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.
Asunto(s)
Cilios , Enfermedades Renales Quísticas , Enfermedad de Leigh , Mitocondrias , Pez Cebra , Humanos , Pez Cebra/metabolismo , Pez Cebra/genética , Enfermedad de Leigh/genética , Enfermedad de Leigh/metabolismo , Enfermedad de Leigh/patología , Cilios/metabolismo , Cilios/patología , Cilios/genética , Animales , Mitocondrias/metabolismo , Mitocondrias/patología , Mitocondrias/genética , Enfermedades Renales Quísticas/genética , Enfermedades Renales Quísticas/metabolismo , Enfermedades Renales Quísticas/patología , Complejo I de Transporte de Electrón/metabolismo , Complejo I de Transporte de Electrón/genética , Proteínas del Dominio Armadillo/metabolismo , Proteínas del Dominio Armadillo/genética , Retina/metabolismo , Retina/patología , Retina/anomalías , Anomalías del Ojo/genética , Anomalías del Ojo/patología , Anomalías del Ojo/metabolismo , Ratones , Anomalías Múltiples/genética , Anomalías Múltiples/metabolismo , Anomalías Múltiples/patología , Cerebelo/metabolismo , Cerebelo/patología , Cerebelo/anomalías , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , MasculinoRESUMEN
Malignant optic glioma presents a clinical and diagnostic challenge, as early imaging findings overlap with other more common causes of optic nerve enhancement and enlargement, potentially leading to delay in diagnosis. This rare diagnosis carries an extremely poor prognosis, with death usually occurring within 1 year. We present a case of malignant optic glioma that was initially diagnosed as optic neuritis and central retinal vein occlusion, and we emphasize the importance of serial imaging and definitive biopsy to promote early diagnosis and treatment of this entity.
RESUMEN
Historically, visual acuity has been the benchmark for visual function. It is used to measure therapeutic outcomes for vision-related services, products and interventions. Quantitative measurement of suboptimal visual acuity can potentially be corrected optically with proper refraction in some cases, but in many cases of reduced vision there is something else more serious that can potentially impact other aspects of visual function such as contrast sensitivity, color discrimination, peripheral field of view and higher-order visual processing. The measurement of visual acuity typically requires stimuli subject to some degree of standardization or calibration and has thus often been limited to clinical settings. However, we are spending increasing amounts of time interacting with devices that present high-resolution, full color images and video (hereafter, digital media) and can record our responses. Most of these devices can be used to measure visual acuity and other aspects of visual function, not just with targeted testing experiences but from typical device interactions. There is growing evidence that prolonged exposure to digital media can lead to various vision-related issues (eg, computer vision syndrome, dry eye, etc.). Our regular, daily interactions (digital behavior) can also be used to assess our visual function, passively and continuously. This allows us to expand vision health assessment beyond the clinic, to collect vision-related data in the whole range of settings for typical digital behavior from practically any population(s) of interest and to further explore just how our increasingly virtual interactions are affecting our vision. We present a tool that can be easily integrated into digital media to provide insights into our digital behavior.
RESUMEN
BACKGROUND: We describe a 75-year-old woman who experienced vision loss in her left eye due to biopsy-proven giant cell arteritis (GCA). She subsequently developed pachymeningitis causing refractory headaches and bilateral optic neuropathy and maculopathy. METHODS: Case report with literature review. RESULTS: Eighteen months after the initial diagnosis of GCA, imaging studies in our patient demonstrated pachymeningeal enhancement, and meningeal biopsy confirmed lymphoplasmacytic tissue infiltrates with low frequencies of IgG4+ plasma cells. Laboratory investigation revealed the presence of 3 antiretinal antibodies and antimyeloperoxidase antibodies, consistent with autoimmune retinopathy. Treatment with B-cell-depleting anti-CD20 antibodies suppressed meningeal inflammation and prevented further vision loss. CONCLUSIONS: This case illustrates that bilateral vision loss and chronic headaches in patients with GCA may result from retina-directed autoimmunity and pachymeningitis.
Asunto(s)
Ceguera/etiología , Arteritis de Células Gigantes/etiología , Meningitis/complicaciones , Atrofia Óptica/complicaciones , Enfermedades de la Retina/complicaciones , Anciano , Autoanticuerpos/sangre , Autoantígenos/inmunología , Ceguera/diagnóstico , Ceguera/tratamiento farmacológico , Angiografía por Tomografía Computarizada , Femenino , Arteritis de Células Gigantes/diagnóstico , Arteritis de Células Gigantes/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Meningitis/diagnóstico , Meningitis/tratamiento farmacológico , Metotrexato/uso terapéutico , Atrofia Óptica/diagnóstico , Atrofia Óptica/tratamiento farmacológico , Prednisona/uso terapéutico , Retina/inmunología , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/tratamiento farmacológicoRESUMEN
INTRODUCTION: Reading difficulties are common in Parkinson's disease (PD) but not well studied. We report a case of reading difficulties in a 40-year-old man with 6-year history of PD on dopamine replacement therapy. METHODS: We performed detailed neuro-ophthalmic examination and assessment of reading with and without infrared oculography. RESULTS: Clinical examination revealed visual acuity of 20/20, no evidence of vision loss, and normal eye movement and ocular alignment with normal saccades, pursuit, and normal convergence. During King-Devick test, a rapid number reading task performed on a book, patient had normal number reading speed. More detailed study of number and word reading using infrared oculography revealed that while this patient had normal speed and eye movement behavior during number reading, he had dramatic slowing and eye movement abnormality during word reading. The slower reading speed during word reading was due to increased number of progressive saccades, smaller saccade amplitudes, increased number of regressive saccades, and longer fixation durations. CONCLUSIONS: This case nicely illustrated the importance of comprehensive neuro-ophthalmic evaluations in Parkinson's disease and shows that reading difficulties can arise even when there is good visual acuity, ocular motor abilities necessary to read, and accommodation. In this case, reading difficulty was due to higher order ocular motor planning or cognitive abilities involved in word reading since the patient had no difficulty with ocular motor planning while reading numbers. These findings may have important implications towards our understanding of PD and can serve to spark further research in this important area.
Asunto(s)
Dislexia/etiología , Trastornos de la Motilidad Ocular/etiología , Enfermedad de Parkinson/complicaciones , Lectura , Adulto , Progresión de la Enfermedad , Dislexia/diagnóstico , Humanos , MasculinoAsunto(s)
Accidentes de Tránsito , Airbags/efectos adversos , Lesiones Oculares/etiología , Retina/lesiones , Enfermedades de la Retina/etiología , Heridas no Penetrantes/etiología , Electrorretinografía , Lesiones Oculares/diagnóstico , Femenino , Angiografía con Fluoresceína , Humanos , Persona de Mediana Edad , Retina/fisiopatología , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/fisiopatología , Escotoma/diagnóstico , Escotoma/etiología , Escotoma/fisiopatología , Líquido Subretiniano , Tomografía de Coherencia Óptica , Agudeza Visual/fisiología , Heridas no Penetrantes/diagnóstico , Heridas no Penetrantes/fisiopatologíaRESUMEN
Giant cell arteritis (GCA) is an important cause of preventable blindness, most commonly due to anterior ischemic optic neuropathy. Ischemic tissue injury is the end result of a process that begins within the walls of susceptible arteries in which local dendritic cells (DCs) recruit and activate CD4 T cells that, in turn, direct the activity of effector macrophages. In response to the immune attack, the blood vessel forms lumen-stenosing intima. Multiple cascades of excessive T-cell reactivity contribute to the autoimmune features of giant cell arteritis with TH1 and TH17 immunity responsible for the early phase and TH1 immunity promoting chronic-smoldering inflammation. These cascades are only partially overlapping, supporting the concept that a multitude of instigators induce and sustain vascular inflammation. The artery actively participates in the abnormal immune response through endogenous immune sentinels, so-called vascular DCs embedded in the adventitia. Advancing age, the strongest of all risk factors for GCA, contributes to both, the dysfunction of the immune system and the vascular system. Expansion of the therapeutic armamentarium for GCA needs to focus on approaches that mitigate the impact of the aging artery and adapt to the needs of the immunosenescent host.
Asunto(s)
Arteritis de Células Gigantes , Factores de Edad , Células Dendríticas/patología , Células Endoteliales/patología , Femenino , Arteritis de Células Gigantes/diagnóstico , Arteritis de Células Gigantes/genética , Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/terapia , Antígenos HLA/genética , Humanos , Macrófagos/patología , Masculino , Factores de Riesgo , Factores SexualesRESUMEN
Susceptibility for giant cell arteritis increases with chronological age, in parallel with age-related restructuring of the immune system and age-induced remodeling of the vascular wall. Immunosenescence results in shrinkage of the naïve T-cell pool, contraction of T-cell diversity, and impairment of innate immunity. Aging of immunocompetent cells forces the host to take alternative routes for protective immunity and confers risk for pathogenic immunity that causes chronic inflammatory tissue damage. Dwindling immunocompetence is particularly relevant as the aging host is forced to cope with an ever growing infectious load. Immunosenescence coincides with vascular aging during which the arterial wall undergoes dramatic structural changes and medium and large arteries lose their pliability and elasticity. On the molecular level, elastic fibers deteriorate and matrix proteins accumulate biochemical modifications. Thus, the aging process impacts the two major biologic systems that liaise to promote giant cell arteritis; the immune system and the vessel wall niche.
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Envejecimiento/inmunología , Envejecimiento/patología , Vasos Sanguíneos/patología , Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/patología , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/patología , Factores de RiesgoRESUMEN
An otherwise healthy 12-month-old girl presented for evaluation of reduced abduction of the left eye detected at 6 months of age. The remainder of the examination was unremarkable. A special MRI sequence-fast imaging employing steady-state acquisition (FIESTA)-visualized the right but not the left sixth nerve cisternal segment. This is the first reported use of the MRI FIESTA sequence to diagnose aplasia of the sixth cranial nerve.