RESUMEN
Idebenone, the only approved treatment for Leber hereditary optic neuropathy (LHON), promotes recovery of visual function in up to 50% of patients, but we can neither predict nor understand the non-responders. Idebenone is reduced by the cytosolic NAD(P)H oxidoreductase I (NQO1) and directly shuttles electrons to respiratory complex III, bypassing complex I affected in LHON. We show here that two polymorphic variants drastically reduce NQO1 protein levels when homozygous or compound heterozygous. This hampers idebenone reduction. In its oxidized form, idebenone inhibits complex I, decreasing respiratory function in cells. By retrospectively analyzing a large cohort of idebenone-treated LHON patients, classified by their response to therapy, we show that patients with homozygous or compound heterozygous NQO1 variants have the poorest therapy response, particularly if carrying the m.3460G>A/MT-ND1 LHON mutation. These results suggest consideration of patient NQO1 genotype and mitochondrial DNA mutation in the context of idebenone therapy.
Asunto(s)
Atrofia Óptica Hereditaria de Leber , Ubiquinona/análogos & derivados , Humanos , Atrofia Óptica Hereditaria de Leber/tratamiento farmacológico , Atrofia Óptica Hereditaria de Leber/genética , Atrofia Óptica Hereditaria de Leber/metabolismo , Antioxidantes/uso terapéutico , Antioxidantes/farmacología , Estudios Retrospectivos , Ubiquinona/farmacología , Ubiquinona/uso terapéutico , Ubiquinona/metabolismo , Complejo I de Transporte de Electrón/genética , NAD(P)H Deshidrogenasa (Quinona)/genética , NAD(P)H Deshidrogenasa (Quinona)/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders caused by mutations in at least 100 genes. However, approximately 60% of cases with axonal neuropathies (CMT2) still remain without a genetic diagnosis. We aimed at identifying novel disease genes responsible for CMT2. METHODS: We performed whole exome sequencing and targeted next generation sequencing panel analyses on a cohort of CMT2 families with evidence for autosomal recessive inheritance. We also performed functional studies to explore the pathogenetic role of selected variants. RESULTS: We identified rare, recessive variants in the MYO9B (myosin IX) gene in two families with CMT2. MYO9B has not yet been associated with a human disease. MYO9B is an unconventional single-headed processive myosin motor protein with signaling properties, and, consistent with this, our results indicate that a variant occurring in the MYO9B motor domain impairs protein expression level and motor activity. Interestingly, a Myo9b-null mouse has degenerating axons in sciatic nerves and optic nerves, indicating that MYO9B plays an essential role in both peripheral nervous system and central nervous system axons, respectively. The degeneration observed in the optic nerve prompted us to screen for MYO9B mutations in a cohort of patients with optic atrophy (OA). Consistent with this, we found compound heterozygous variants in one case with isolated OA. CONCLUSIONS: Novel or very rare variants in MYO9B are associated with CMT2 and isolated OA.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth , Miosinas , Animales , Humanos , Ratones , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Mutación/genética , Linaje , Fenotipo , Proteínas , Nervio Ciático/patología , Miosinas/genéticaRESUMEN
Congenital Stationary Night Blindness type 2 (CSNB2) and Aland island Eye Disease (AIED) associated with CACNA1F mutation demonstrate a significant phenotype overlapping. We report two cases with different clinical presentation carrying two novel mutations in CACNA1F gene. Subjects underwent a complete neurophtahlmological examination associated with structural and electrofunctional insight. Next Generation Sequencing (NGS) analysis of 31 genes previously associated with retinal dystrophy (RD) was performed. Messenger RNAs derived from probands 'peripheral blood samples were analyzed by RT-PCR and cDNA sequencing. The neuro-ophthalmological examinations revealed different clinical, structural and morphological presentations, more severe in patient 1 compared with patient 2. Molecular analysis revealed, that both patients had the hemizygous form of two novel mutations in CACNA1F gene. Patient 1 presented a duplication (c.425dupC) in exon 4, resulting in shifting of the reading frame with the insertion of a premature Stop codon. In Patient 2 variant c.5156G > C localized in the donor's splicing site of exon 43 was identified. Complementary DNA sequencing demonstrated skipping of exon 43 with a deletion of 55 amino acids that causes a frame shift with insertion of a Stop codon. These findings suggest that the effect and the localization of the mutations in the CACNA1F gene can explain different clinical phenotypes. Clinical spectrum is more severe and resembles the AIED phenotype when the mutation affects the first part of the protein, while it is more similar to CSNB2 if the mutation is localized at the end of the protein. Genetic testing results to be an essential tool to provide more accurate diagnosis and prognosis in patients with inherited retinal degenerative disorders and could help, in the future, to develop more specific therapeutic strategies.
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Canales de Calcio Tipo L , Enfermedades Genéticas Ligadas al Cromosoma X , Miopía , Ceguera Nocturna , Albinismo Ocular , Canales de Calcio Tipo L/genética , Enfermedades Hereditarias del Ojo , Finlandia , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Humanos , Mutación , Miopía/diagnóstico , Miopía/genética , Ceguera Nocturna/diagnóstico , Ceguera Nocturna/genética , FenotipoRESUMEN
Visuo-motor adaptation to optical prisms (Prism Adaptation, PA), displacing the visual scene laterally, is a behavioral method used for the experimental investigation of visuomotor plasticity, and, in clinical settings, for temporarily ameliorating and rehabilitating unilateral spatial neglect. This study investigated the building up of PA, and the presence of the typically occurring subsequent Aftereffects (AEs) in a brain-damaged patient (TMA), suffering from apperceptive agnosia and a right visual half-field defect, with bilateral atrophy of the parieto-occipital cortices, regions involved in PA and AEs. Base-Right prisms and control neutral lenses were used. PA was achieved by repeated pointing movements toward three types of stimuli: visual, auditory, and bimodal audio-visual. The presence and the magnitude of AEs were assessed by proprioceptive, visual, visuo-proprioceptive, and auditory-proprioceptive straight-ahead pointing tasks. The patient's brain connectivity was investigated by Diffusion Tensor Imaging (DTI). Unlike control participants, TMA did not show any adaptation to prism exposure, but her AEs were largely preserved. These findings indicate that AEs may occur even in the absence of PA, as indexed by the reduction of the pointing error, showing a dissociation between the classical measures of PA and AEs. In the PA process, error reduction, and its feedback, may be less central to the building up of AEs, than the sensorimotor pointing activity per se.
RESUMEN
BACKGROUND: GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results. METHODS: Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies. RESULTS: Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed. CONCLUSION: An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy.
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Redes Comunitarias/estadística & datos numéricos , Enfermedad de Moyamoya , Neuroimagen , Accidente Cerebrovascular/complicaciones , Adolescente , Adulto , Anciano , Isquemia Encefálica/complicaciones , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Humanos , Lactante , Recién Nacido , Italia , Masculino , Persona de Mediana Edad , Enfermedad de Moyamoya/diagnóstico por imagen , Enfermedad de Moyamoya/epidemiología , Enfermedad de Moyamoya/genética , Fenotipo , Estudios Retrospectivos , Adulto JovenRESUMEN
Pain occurs with optic neuropathies associated with inflammatory central nervous system diseases (MS and NMO), idiopathic intracranial hypertension and spontaneous hypotension, giant cell arteritis, immunomediated systemic diseases, compressive lesions, or infective disorders. Pain can precede the onset of visual loss in acute optic neuritis, it can be irradiated to the orbital region in giant cell arteritis and parasellar compressive optic neuropathies, or it may be located to the back of the eye with posterior scleritis. History of symptoms together with complete neuro-ophthalmological examination must guide the differential diagnosis and neuroimaging. Painful visual loss due to different pathophysiological mechanisms requires specific treatment and prognosis.
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Neuritis Óptica/fisiopatología , Dolor/fisiopatología , Humanos , Neuritis Óptica/complicaciones , Neuritis Óptica/diagnóstico , Neuritis Óptica/terapia , Dolor/complicaciones , Dolor/diagnóstico , Manejo del DolorAsunto(s)
Depresión/diagnóstico , Depresión/etiología , Cefalea/epidemiología , Cefalea/etiología , Seudotumor Cerebral/complicaciones , Seudotumor Cerebral/epidemiología , Adulto , Estudios Transversales , Depresión/epidemiología , Femenino , Cefalea/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Seudotumor Cerebral/diagnóstico por imagen , Seudotumor Cerebral/psicología , Escalas de Valoración Psiquiátrica , Índice de Severidad de la EnfermedadRESUMEN
The visual system is involved in different ways in migraine. Visual auras are the most common form of migraine aura. It may consist of positive or negative visual symptoms and cortical spreading depression is felt to be the phenomenon that underlies it. Even in migraine without aura, vision it is not totally excluded given that one of the major criteria for the diagnosis of migraine is photophobia. In persistent visual aura, patients refer symptoms defined as visual snow and television static. In retinal migraine unilateral decreased vision or complete visual loss occurs. Ophthalmoplegic migraine is characterized by palsy of one among the three ocular motor nerves. Migraine visual aura, particularly when occurring without headache, is a diagnosis of exclusion. Imaging studies and laboratory tests should exclude neurologic disease, included seizures and central nervous system tumor, ocular pathologies, carotid or cardiac disease, thrombosis and connective tissue disease.
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Migraña con Aura/diagnóstico , Migraña con Aura/fisiopatología , Trastornos de la Visión/diagnóstico , Trastornos de la Visión/fisiopatología , Corteza Visual/fisiología , Diagnóstico Diferencial , Humanos , Migraña con Aura/epidemiología , Fotofobia/diagnóstico , Fotofobia/epidemiología , Fotofobia/fisiopatología , Trastornos de la Visión/epidemiologíaRESUMEN
PURPOSE: To investigate the role of orbital color Doppler ultrasound (OCDUS) in the diagnosis of carotid-cavernous fistula (CCF) with anterior drainage and particularly whether a negative OCDUS could avoid an invasive diagnostic cerebral angiography (DSA). MATERIALS AND METHODS: Twenty-two consecutive patients with ophthalmic signs suspecting CCF were submitted to ophthalmologic examination, OCDUS and DSA. CCF diagnosis with OCDUS was based on the finding of a reversed, arterialized and low-resistive-index (RI <0.5) blood flow in the superior ophthalmic vein (SOV). Sensibility, specificity, PPV, NPV, and accuracy of OCDUS were calculated considering both patients and eyes, using DSA as gold standard. RESULTS: DSA demonstrated 20 CCFs in 18 patients. Considering the patients, in 18/22 CCF diagnosis was positive at OCDUS and DSA while 4/22 were negative at both. Considering the eyes, in 24/43 CCF diagnosis was positive at both DSA and OCDUS (total eyes = 43, due to one case of SOV thrombosis). In 19/43 eyes diagnosis was negative at both OCDUS and DSA. So sensitivity, specificity, PPV, NPV, and accuracy of OCDUS in the patients and eyes analysis were all 100 %. CONCLUSIONS: OCDUS is a reliable, noninvasive tool in the diagnosis of CCF; a negative OCDUS could avoid an invasive DSA in patients suspected for anterior-draining CCF.
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Fístula del Seno Cavernoso de la Carótida/diagnóstico por imagen , Ultrasonografía Doppler en Color , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Adaptation to optical prisms displacing the visual scene laterally is a widely investigated instance of visuo-motor plasticity, also because prism adaptation (PA) has been extensively used as a treatment for right-brain-damaged patients suffering from left spatial neglect. The lateral visual displacement brought about by prisms, as indexed by a pointing error in the direction of the displacement, is progressively corrected through repeated pointings: after prism removal, a shift in the direction opposite to the prism-induced deviation occurs in visual, proprioceptive, and visuo-proprioceptive straight-ahead tasks (aftereffects, AEs). The cerebellum and the posterior parietal cortex (PPC) are key components of the bilateral cerebral network subserving the AEs, and the reduction of the pointing error during prism exposure in PA. We report the experimental study of a patient with bilateral occipital and left cerebellar damage, who showed a preserved reduction of the pointing errors to rightward displacing prisms, but not the leftward AEs in the proprioceptive straight-ahead task; instead, visual-proprioceptive and visual AEs were preserved. Anodal transcranial Direct Current Stimulation (tDCS) over the left PPC restored the leftward proprioceptive AEs, and anodal tDCS over the left cerebellum abolished the rightward deviation. Conversely, stimulation over the right PPC or the right cerebellum was ineffective. These results provide novel evidence for neuromodulatory effects of tDCS on defective AEs, through the stimulation over dedicated cortical regions.
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Adaptación Fisiológica/fisiología , Lóbulo Parietal/fisiología , Trastornos de la Percepción/terapia , Recuperación de la Función/fisiología , Estimulación Transcraneal de Corriente Directa/métodos , Lesiones Encefálicas/complicaciones , Cerebelo/patología , Lateralidad Funcional , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Trastornos de la Percepción/etiología , Trastornos de la Percepción/patología , Estimulación Luminosa , Pruebas del Campo Visual , Campos Visuales/fisiologíaRESUMEN
A 43-year-old woman experienced a worsening of her usual headache. As a right hemifacial hypoesthesia had appeared, the patient underwent a brain MRI that revealed a giant cavernoma localized at the left meso-diencephalic region (figure, A and B). After the operation, an involuntary ocular oscillation known as see-saw nystagmus developed (video on the Neurology® Web site at www.neurology.org). See-saw nystagmus consists of alternating phases of intorsion of the elevating eye and extorsion of the descending eye.(1) The patient displayed a right head tilt with left hypertropia referred to as "ocular tilt reaction" (figure, C)-a phenomenon related to the imbalance in the graviceptive pathways between vestibular nuclei and the interstitial nucleus of Cajal (figure, D).(2.)
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Encéfalo/patología , Nistagmo Patológico/diagnóstico , Adulto , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Neuroimagen/métodos , Neurología/educación , Nistagmo Patológico/etiologíaRESUMEN
OBJECTIVE: To report the use of rituximab to treat thyroid-associated orbitopathy (TAO) in a patient with a concomitant B-cell organ-specific autoimmune disorder-the stiff person syndrome (SPS). METHODS: We present a case report and a review of the related literature. RESULTS: A 62-year-old man with SPS, latent autoimmune diabetes of the adult, and Graves-Basedow disease was referred to our medical center because of bilateral TAO. An ophthalmologic examination documented asymmetric bilateral NOSPECS (N = no signs or symptoms; O = only signs, no symptoms; S = soft tissue involvement; P = proptosis; E = extraocular muscle involvement; C = corneal involvement; and S = sight loss) class IV TAO (left eye>right eye) with a clinical activity score of 5 on a scale of 7. Magnetic resonance imaging of the orbits documented bilateral exophthalmos (left eye>right eye) due to retrobulbar fibroadipose infiltration, bilateral increase of extrinsic ocular muscle thickness, and enhancement of the left inferior rectus muscle on T2-weighted sequences. Because of concomitant incapacitating SPS and diet-controlled latent autoimmune diabetes of the adult, we excluded long-term corticosteroid therapy as an option and considered the use of rituximab, a mouse-human chimeric monoclonal antibody targeting the CD20 protein on pre-B and mature B lymphocytes. Rituximab was administered in accordance with the protocol for rheumatoid arthritis. During the subsequent 4 months, clinical signs and symptoms of TAO dramatically resolved (clinical activity score = 0 of 7) with a sustained improvement of the spastic paraparesis. The glutamic acid decarboxylase antibody titer remained high, and glycemic control and first-phase insulin secretion did not change. CONCLUSION: Treatment of active TAO with rituximab should be considered when standard intravenous pulse glucocorticoid treatment is contraindicated or ineffective and when SPS or other organ-specific autoimmune disorders with involvement of humoral autoimmunity are present, inasmuch as more than 1 disease may benefit from the use of this chimeric monoclonal antibody.
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Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Oftalmopatía de Graves/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Autoanticuerpos/sangre , Contraindicaciones , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/dietoterapia , Diabetes Mellitus Tipo 1/inmunología , Glucocorticoides , Oftalmopatía de Graves/complicaciones , Oftalmopatía de Graves/inmunología , Oftalmopatía de Graves/terapia , Humanos , Factores Inmunológicos/efectos adversos , Masculino , Persona de Mediana Edad , Paraparesia Espástica/complicaciones , Paraparesia Espástica/tratamiento farmacológico , Paraparesia Espástica/inmunología , Rituximab , Síndrome de la Persona Rígida/complicaciones , Síndrome de la Persona Rígida/tratamiento farmacológico , Síndrome de la Persona Rígida/inmunología , Resultado del TratamientoRESUMEN
OBJECT: Nonfunctioning pituitary adenomas (NFPAs) are benign tumors of the pituitary gland that typically cause visual and/or hormonal dysfunction. Surgery is the treatment of choice, but patients remain at risk for tumor recurrence for several years afterwards. The authors evaluate the early results of surgery and the long-term risk of tumor recurrence in patients with NFPAs. METHODS: Between 1990 and 2005, 491 previously untreated patients with NFPA underwent surgery at the Università Vita-Salute. Determinations of recurrence or growth of the residual tumor tissue during the follow-up period were based on neuroradiological criteria. RESULTS: Residual tumor after surgery was detected in 173 patients (36.4%). Multivariate analysis showed that invasion of the cavernous sinus, maximum tumor diameter, and absence of tumor apoplexy were associated with an unfavorable surgical outcome. At least 2 sets of follow-up neuroimaging studies were obtained in 436 patients (median follow-up 53 months). Tumors recurred in 83 patients (19.0%). When tumor removal appeared complete, younger age at surgery was associated with a risk of tumor recurrence. In patients with incomplete tumor removal, adjunctive postoperative radiotherapy had a marked protective effect against growth of residual tumor. CONCLUSIONS: Complete surgical removal of NFPAs can be safely achieved in > 50% of cases. Visual symptoms and, less frequently, pituitary function may improve after surgery. However, tumor can recur in patients after apparently complete surgical removal. In patients with incomplete tumor removal, radiation therapy is the most effective adjuvant therapy for preventing residual tumor growth.
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Adenoma/cirugía , Recurrencia Local de Neoplasia/etiología , Neoplasias Hipofisarias/cirugía , Adenoma/patología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/prevención & control , Neoplasia Residual , Neoplasias Hipofisarias/patología , Medición de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECT: Treatment options for patients with cavernous sinus meningiomas (CSMs) include microsurgical tumor resection, radiotherapy, and radiosurgery. Gamma Knife surgery (GKS) is increasingly being used because it is associated with lower mortality and morbidity rates than microsurgery. The purpose of this study was to assess the role of GKS in the treatment of CSM and to thoroughly analyze the clinical response to GKS. METHODS: Between January 2001 and December 2005, 123 patients (25 men and 98 women; mean age 62.6 +/- 11 years, range 31-86 years) who underwent treatment for CSMs were included in this study. Of these, 41 patients underwent microsurgery before GKS, whereas the remaining 82 had GKS as a first-line therapy after a diagnosis was made based on magnetic resonance imaging findings. Dysfunction in cranial nerves (CNs) II, III, IV, V, and VI was noted in 74 patients at the time of GKS. The mean tumor volume was 7.99 cm(3) (0.7-30.5 cm(3)). The mean prescription dose to the tumor margin was 13.8 +/- 1.1 Gy (range 10-20 Gy). RESULTS: The overall tumor control rate was 98.4% with a median follow-up of 36 months. The actuarial tumor control rate at 5 years was 90.5%. A reduction in tumor volume was observed in 53 patients (43.1%), whereas in 68 patients (55.3%) no volumetric variation was recorded. Of the 74 patients who presented with CN deficits, improvement was noted in 23 (31.1%). CONCLUSIONS: Gamma Knife surgery is a useful treatment for CSM both as a first- or second-line therapy. It is a safe and effective treatment for tumors located close to the optic pathways.