RESUMEN
Leptomeningeal carcinomatosis (LC) refers to diffuse seeding of the leptomeninges by tumor metastases. The clinical presentation may differ and the diagnosis may be difficult especially when cancer has not yet been diagnosed. We report a case of LC, where the clinical picture and a specific change in cerebrospinal fluid suggested the diagnosis of a prion disease.
Asunto(s)
Síndrome de Creutzfeldt-Jakob/fisiopatología , Carcinomatosis Meníngea/diagnóstico , Carcinomatosis Meníngea/fisiopatología , Autopsia , Encéfalo/metabolismo , Encéfalo/patología , Corteza Cerebral/patología , Electroencefalografía , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Queratinas/metabolismo , Antígeno Ki-67/metabolismo , Imagen por Resonancia Magnética , Persona de Mediana EdadRESUMEN
This paper deals with an unusual case of Alzheimer's disease with early onset, no family history, myoclonus, tonic generalized seizures and pseudo-periodic spikes on EEG. The demise occurred after 8 years of progressive cognitive deterioration; the pathological examination showed "Pick-like" atrophy, neurofibrillary tangles, senile plaques, congophilic angiopathy and cerebellar amyloid plaques. The genetical research could not support the hypothesis of a mutation of Presenilin 1 and 2 genes. Anyway, the peculiarity of the phenotype is worthy to be described even in the absence of specific molecular findings.
Asunto(s)
Enfermedad de Alzheimer , Adulto , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Encéfalo/patología , Electroencefalografía , Femenino , Humanos , Ovillos Neurofibrilares/patología , Placa Amiloide/etiología , Tomógrafos Computarizados por Rayos XAsunto(s)
CADASIL/diagnóstico por imagen , Ecocardiografía Transesofágica/métodos , Foramen Oval Permeable/diagnóstico por imagen , Ultrasonografía Doppler Transcraneal/métodos , Malformaciones Arteriovenosas/diagnóstico por imagen , CADASIL/complicaciones , Diagnóstico Diferencial , Foramen Oval Permeable/complicaciones , HumanosRESUMEN
PURPOSE: The hypothesis addressed by this study is that a glutamine synthetase (GS) deficiency in neoplastic astrocytes is a possible molecular basis associated with seizure generation in glioblastoma multiforme (GBM). METHODS: Quantitative Western blot analysis of GS was performed in 20 individuals operated for malignant glioma. RESULTS: The levels of GS in patients with GBM and epilepsy were significantly lower (range 0.04-1.15; mean 0.35 +/- 0.36; median 0.25) than in non-epileptic GBM individuals (range 0.78-3.97; mean 1.64 +/- 0.99; median 1.25; P = 0.002). No relationship has been found between histological features (i.e. necrosis, gliosis, stroma, inflammatory cells, giant cells, and haemosiderine) and GS expression or epilepsy. DISCUSSION: Even though the epileptogenesis in glioma is multifactorial, it is conceivable that a down-regulation of GS may have an important pro-epileptogenic role in GBM, through the slowing of glutamate-glutamine cycle. This study suggests that seizures in GBM are coupled with a highly localized enzyme deficiency. The manipulation of GS activity might constitute a novel principle for inhibiting seizures in patients with glioma epilepsy.
Asunto(s)
Neoplasias Encefálicas/enzimología , Epilepsia/enzimología , Epilepsia/etiología , Glioblastoma/complicaciones , Glioblastoma/enzimología , Glutamato-Amoníaco Ligasa/metabolismo , Adulto , Anciano , Western Blotting , Neoplasias Encefálicas/complicaciones , Femenino , Glioblastoma/patología , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
CADASIL/epidemiología , Foramen Oval Permeable/epidemiología , CADASIL/genética , Comorbilidad , Genotipo , Humanos , FenotipoRESUMEN
Cerebral developmental venous anomalies (DVAs) are generally considered as anatomical variants of the venous system without clinical importance. We report the case of a 15-year-old girl with recurrent episodes of migraine-like headache who presented with subacute vertigo and ataxia associated with intense occipital pain. Magnetic resonance imaging (MRI) showed a DVA with signal modifications of the surrounding brain parenchyma in the left cerebellar hemisphere. The patient's ataxia regressed completely within about 2 months. On a follow-up MRI 4 years later the venous malformation and the parenchymal abnormalities were unchanged. We attribute the patient's focal neurological dysfunction to regional changes in the brain parenchyma, possibly secondary to venous hypertension. Our report provides evidence that also uncomplicated DVAs can become symptomatic and supports the role of the venous congestion within the DVA territory in pathogenesis of some brain parenchymal abnormalities associated with DVAs.
Asunto(s)
Ataxia/complicaciones , Venas Cerebrales/anomalías , Trastornos Migrañosos/complicaciones , Adolescente , Ataxia/patología , Angiografía Cerebral/métodos , Venas Cerebrales/fisiopatología , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Trastornos Migrañosos/patologíaRESUMEN
Point mutations in mtDNA-encoded tRNA genes frequently cause isolated myopathies but rarely cause the facioscapulohumeral phenotype. We report on a patient affected with chronic progressive weakness of facioscapulohumeral/peroneal muscles whose muscle biopsy showed a mitochondrial myopathy. mtDNA direct sequencing and RFLP analysis revealed a heteroplasmic transition T12313C which disrupts a conserved site in the T Psi C stem of the tRNA(Leu(CUN)) gene and fulfills the accepted criteria of pathogenicity. A partial deletion of the nuclear DNA D4Z4 region with residual repeat sizes of 25 kb was also found in the patient and in her mother. This is the first reported case of mitochondrial myopathy/facioscapulohumeral muscular dystrophy (FSHD) "double trouble".
Asunto(s)
Eliminación de Gen , Distrofia Muscular Facioescapulohumeral/genética , ARN de Transferencia de Leucina/genética , Secuencia de Bases , Biopsia , ADN Mitocondrial/genética , Femenino , Humanos , Persona de Mediana Edad , Datos de Secuencia Molecular , Músculo Esquelético/patología , Distrofia Muscular Facioescapulohumeral/patología , Conformación de Ácido Nucleico , Fenotipo , Polimorfismo de Longitud del Fragmento de Restricción , ARN de Transferencia de Leucina/químicaRESUMEN
Quality of life (QoL), as defined by the Short Form 36, has previously been shown to be abnormal in patients with Charcot-Marie-Tooth disease (CMT), both for Physical Composite Scores (PCS) and Mental Composite Scores (MCS). We have now extended these observations in a multicenter evaluation of 89 patients with Charcot-Marie-Tooth disease type 1A, the most common form of CMT. Both the PCS and MCS were abnormal also in this cohort, compared with the Italian population at large. In particular, the ability to ambulate independently as well as toe and heel walk correlated well with QoL measures in our patients.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/fisiopatología , Enfermedad de Charcot-Marie-Tooth/psicología , Calidad de Vida/psicología , Adolescente , Adulto , Anciano , Enfermedad de Charcot-Marie-Tooth/epidemiología , Estudios de Cohortes , Electrofisiología , Femenino , Humanos , Italia/epidemiología , Masculino , Persona de Mediana EdadRESUMEN
The term "mitochondrial diseases" (MD) refers to a group of disorders related to respiratory chain dysfunction. Clinical features are usually extremely heterogeneous because MD may involve several tissues with different degrees of severity. Muscle and brain are mostly affected, probably because of their high dependence on oxidative metabolism. Muscle can be the only affected tissue or involved as a part of a multi-system disease; ragged red fibers, accumulation of structurally altered mitochondria and cytochrome-c-oxidase (COX) negative fibers are the main pathological features. In mitochondrial encephalopathies, central nervous system (CNS) structures are affected according to different patterns of distribution and severity. Characteristic lesions are neuronal loss, vasculo-necrotic changes, gliosis, demyelination and spongy degeneration. In accordance with either grey matter or white matter involvement two main groups of diseases may be distinguished. Neuronal loss and vasculo-necrotic multifocal lesions are the common features of grey matter involvement; demyelination and spongy degeneration occur when white matter is affected, often associated with less severe lesions of the grey structures. Grey matter lesions are prevalent in MERRF, MELAS, Alpers and Leigh syndromes. White matter involvement is always seen in Kearns-Sayre syndrome and was recently described in mtDNA depletion syndrome linked to dGK mutations and in the rare conditions associated with complex I and II deficiency. In this review we describe the main histopathological features of muscle and CNS lesions in mitochondrial diseases.
Asunto(s)
Sistema Nervioso Central/patología , Enfermedades Mitocondriales/patología , Músculos/patología , Encéfalo/patología , Encefalopatías Metabólicas/genética , Encefalopatías Metabólicas/patología , ADN Mitocondrial/genética , Humanos , Enfermedades Mitocondriales/genética , Encefalomiopatías Mitocondriales/genética , Encefalomiopatías Mitocondriales/patología , Miopatías Mitocondriales/genética , Miopatías Mitocondriales/patología , MutaciónRESUMEN
Ataxia oculomotor apraxia type 1 (AOA1) is the most common form of autosomal recessive ataxia in Japan, and the second in Portugal after Friedreich ataxia. AOA1 is typically characterized by early-onset cerebellar ataxia, oculomotor apraxia, hypoalbuminemia, hypercholesterolemia and late axonal sensori-motor neuropathy. AOA1 is associated with the aprataxin gene (APTX) encoding a protein involved in DNA repair. We characterized a novel homozygous missense mutation of APTX in a 34 year-old female patient born from consanguineous parents. The mutation, a Val230Gly caused by a c.689 T>G substitution, involved the histidine-triad (HIT) domain of the protein, affected a phylogenetically conserved amino acid and was absent in the control population. We described the clinical and neurophysiological features, the findings at structural and functional brain imaging, and the pathological picture of the sural nerve biopsy. The report emphasized the genetical and phenotypical heterogeneity of AOA1 by demonstrating atypical features such as absence of oculomotor apraxia and signs of pyramidal involvement. Expression studies by Western blotting on fibroblasts demonstrated that the homozygous Val230Gly mutation was associated with decreased levels of APTX indicating a loss-of-function mechanism.
Asunto(s)
Apraxias/genética , Ataxia Cerebelosa/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Proteínas Nucleares/genética , Trastornos de la Motilidad Ocular/genética , Adulto , Neuropatía Alcohólica/genética , Neuropatía Alcohólica/patología , Neuropatía Alcohólica/fisiopatología , Sustitución de Aminoácidos , Apraxias/metabolismo , Apraxias/fisiopatología , Atrofia/genética , Atrofia/patología , Atrofia/fisiopatología , Ataxia Cerebelosa/metabolismo , Ataxia Cerebelosa/fisiopatología , Cerebelo/patología , Cerebelo/fisiopatología , Consanguinidad , Análisis Mutacional de ADN , Electroencefalografía , Femenino , Pruebas Genéticas , Genotipo , Humanos , Imagen por Resonancia Magnética , Mutación Missense/genética , Trastornos de la Motilidad Ocular/metabolismo , Trastornos de la Motilidad Ocular/fisiopatología , Linaje , Fenotipo , Tomografía de Emisión de PositronesRESUMEN
BACKGROUND: Limb ataxia is classically attributed to cerebellar hemispheric lesions, although isolated lesions of the inferior cerebellar peduncle (ICP) in the medulla may also cause this sign. It is still unclear why only some patients with acute cerebellar infarcts in the posterior inferior cerebellar artery (PICA) territory present with limb ataxia. The proximal intracranial posterior circulation (P-PC) territory includes structures fed by the intracranial vertebral arteries (ICVAs): the medulla, supplied by small ICVAs branches, and posterior inferior portion of the cerebellum, fed by PICA. ICP and PICA territory cerebellar infarcts most often occur independently but occasionally occur together. OBJECTIVE: To identify structures responsible for limb ataxia in acute P-PC brain infarcts, correlating clinical and topographical findings. METHODS: Sixteen patients (8 women) were included, aged 30-82 years (mean 62 years), with isolated acute strokes in the P-PC territory. RESULTS: The cases reported here indicate that limb ataxia in acute P-PC territory infarcts may be associated with damage to the ICP in the dorsolateral medulla, regardless of a hemispheric cerebellar lesion. In fact, among the nine patients with PICA stroke, limb ataxia was observed only in the two patients who also presented damage to the dorsolateral medulla involving the ICP. Of the seven patients with isolated dorsolateral medullary infarct, only five patients with ICP damage had limb ataxia. CONCLUSIONS: When correlating limb ataxia and acute P-PC infarcts, it is important to take into account the entire ICVA territory.
Asunto(s)
Ataxia/etiología , Cerebelo/patología , Infarto Cerebral/complicaciones , Infarto Cerebral/patología , Adulto , Anciano , Anciano de 80 o más Años , Cerebelo/irrigación sanguínea , Femenino , Humanos , Masculino , Persona de Mediana Edad , Accidente Cerebrovascular/complicaciones , Arteria Vertebral/patologíaRESUMEN
The neurofilament light chain (NF-L) is a major constituent of intermediate filaments and plays a pivotal function in the assembly and maintenance of axonal cytoskeleton. Mutations in the NF-L gene (NEFL) cause autosomal dominant neuropathies that are classified either as axonal Charcot-Marie-Tooth (CMT) type 2E (CMT2E) or demyelinating CMT type 1F (CMT1F). The pathophysiological bases of the disorder(s) are elusive. We performed a mutational analysis of NEFL in a series of 177 index cases with CMT and without mutations in the genes for peripheral myelin protein zero (MPZ), peripheral myelin protein 22 (PMP22) and connexin 32 (GJB1); the motor nerve conduction velocity (MNCV) at the median nerve was below 38 m/s in 76 cases and above 38 m/s in 101. We identified five new pedigrees with four mutations in the head and rod domains of NF-L, including a novel Leu268Pro substitution and a novel del322Cys_326Asn deletion. Several examined affected members exhibited marked variability in the severity of disease and age at onset. Nerve conduction alterations were consistent with an axonal neuropathy often associated with demyelinating features, such as prolonged distal latencies (DL). Pathological examination of sural nerve biopsies in the probands detected in four cases a chronic axonal neuropathy dominated by focal accumulations of NF with axonal swellings (giant axons) and significant secondary demyelination; in the fifth case no NFs accumulations were evident but many myelinated fibres consisted exclusively of microtubules with few or absent NF. The pathological phenotype correlated with the pattern of nerve conduction alterations and indicated that NEFL mutations cause a profound alteration of the cytoskeleton possibly related to defective targeting of NF.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Citoesqueleto/ultraestructura , Proteínas de Neurofilamentos/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Axones/ultraestructura , Enfermedad de Charcot-Marie-Tooth/metabolismo , Niño , Análisis Mutacional de ADN/métodos , Femenino , Genotipo , Haplotipos , Humanos , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Conducción Nerviosa , Proteínas de Neurofilamentos/metabolismo , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple , Nervio Sural/metabolismo , Nervio Sural/ultraestructuraRESUMEN
Some evidence suggests that endothelial dysfunction, including altered expression of cell adhesion molecules contributes to pathophysiology of nervous system disorders in the course of HIV infection. In this immunohistochemical study we investigated and compared the expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), platelet endothelial cell adhesion molecule-1 (PECAM-1) in peripheral nerve blood vessels from patients with distal sensory polyneuropathy (DSP) and control patients with other axonal neuropathies. Similar quantitative pattern of immunoreactivity was found in patients with DSP and controls. E-selectin and PECAM-1 immunostained vessels tended to increase in number only in patients with major CD4 cell depletion. The vascular endothelium of the peripheral nerve in HIV-infected subjects with DSP shows no changes facilitating the migration of infected or activated monocytes/macrophages into the nerve. These phenomena probably do not play a critical role in the development of axonal damage in DSP.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Moléculas de Adhesión Celular/biosíntesis , Células Endoteliales/metabolismo , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/metabolismo , Nervio Sural/irrigación sanguínea , Adulto , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Nervio Sural/metabolismo , Nervio Sural/patologíaRESUMEN
We describe four patients, from four different families, affected by a mild myopathy or asymptomatic elevated serum creatine kinase levels, in whom toluidine blue-stained semithin sections of muscle specimens revealed inclusions of different size and shape. The inclusions did not stain by routine histochemical studies. The sarcoplasmic or endoplasmic reticulum calcium 1 (SERCA1) ATPase and/or calsequestrin reactivity of inclusions, by immunohistochemistry, and the SERCA1- and calsequestrin-increased expression, by immunoblot, suggested that inclusions were constituted by an excess of proteins normally present in the terminal cisternae of sarcoplasmic reticulum. Our cases, both sporadic and familial, represent a new type of surplus protein myopathy.
Asunto(s)
ATPasas Transportadoras de Calcio/metabolismo , Calsecuestrina/metabolismo , Enfermedades Musculares/metabolismo , Adulto , Anciano , Femenino , Humanos , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestructura , Enfermedades Musculares/patología , Retículo Sarcoplasmático/metabolismo , Retículo Sarcoplasmático/ultraestructura , ATPasas Transportadoras de Calcio del Retículo SarcoplásmicoRESUMEN
Peripheral neuropathy has emerged as the most common neurologic complication of human immunodeficiency virus (HIV) infection. It will continue to play an Important role in HIV Infection given the fact that HIV-infected Individuals are living longer, are at risk of long-term metabolic complications, and face an Increasing exposure to potentially neurotoxic antiretroviral drugs. We review the various types of peripheral neuropathy that have been associated with HIV infection, including distal symmetrical polyneuropathy, toxic neuropathy from antiretroviral drugs, diffuse infiltrative lymphocytosis syndrome, inflammatory demyelinating polyneuropathies, multifocal mononeuropathies, and progressive polyradiculopathy.
Asunto(s)
Terapia Antirretroviral Altamente Activa/efectos adversos , Infecciones por VIH/complicaciones , Enfermedades del Sistema Nervioso Periférico/etiología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Humanos , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/terapiaRESUMEN
Autosomal dominant Charcot-Marie-Tooth disease type 1B (CMT1B) is caused by heterozygous mutations in the extracellular domain of P0. Here, we investigated clinically, electrophysiologically and pathologically a pedigree with a novel mutation in the intracellular domain of P0 (P0ic). The mutational analysis included denaturing high performance liquid chromatography (DHPLC) and nucleotide sequencing. Two patients from subsequent generations were homozygous for an Asp195Tyr mutation in the intracellular domain of P0 (P0ic), whereas two healthy individuals with minimal electrophysiological changes were heterozygous for the same mutation. The authors conclude that mutations of P0ic may undergo a gene dosage effect manifesting semidominant inheritance.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Dosificación de Gen , Mutación , Proteína P0 de la Mielina/genética , Adulto , Anciano , Ácido Aspártico/genética , Enfermedad de Charcot-Marie-Tooth/patología , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Cromatografía Líquida de Alta Presión/métodos , Análisis Mutacional de ADN/métodos , Exones , Salud de la Familia , Femenino , Humanos , Masculino , Microscopía Electrónica de Transmisión/métodos , Datos de Secuencia Molecular , Fibras Nerviosas Mielínicas/patología , Fibras Nerviosas Mielínicas/ultraestructura , Linaje , Estructura Terciaria de Proteína/genética , Tirosina/genéticaRESUMEN
Axon-derived neuregulins (NRGs) are a family of growth factors whose binding to ErbB tyrosine kinase receptors promotes the maturation, proliferation and survival of Schwann cells (SCs). Correct NRG/ErbB signaling is essential for the homeostasis of axonal-glial complexes and seems to play a role in peripheral nerve repair. The potential involvement of ErbB receptors in human peripheral neuropathies has not been clarified. Therefore, we assessed the immunoreactivity for EGFR (ErbB1), ErbB2, and ErbB3 in nerve biopsies from patients with different forms of Charcot-Marie-Tooth disease, type 1, (CMT1), as compared to others with inflammatory neuropathies and controls. The most notable changes consisted in the overexpression of ErbB2 and ErbB3 by SCs of nerves from CMT1A patients. These findings are consistent with an impairment of SC differentiation and expand the molecular phenotype of CMT1A. The upregulation of these receptors may play a role in the inhibition of myelination or in the promotion of recurrent demyelination and axonal damage.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/metabolismo , Genes erbB-2/genética , Receptor ErbB-3/genética , Células de Schwann/metabolismo , Animales , Axotomía , Enfermedad de Charcot-Marie-Tooth/patología , Conexinas/biosíntesis , Conexinas/genética , Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Ratas , Ratas Wistar , Receptor ErbB-3/biosíntesis , Nervio Ciático/fisiología , Nervio Sural/patología , Degeneración Walleriana/fisiopatología , Proteína beta1 de Unión ComunicanteRESUMEN
Familial amyloidotic polyneuropathy is a rare autosomal dominant disease, with clinical symptoms beginning in most kindreds within the third to seventh decades of life. The primary defect results from one of a number of mutations in the transthyretin (TTR) gene. Over 80 mutations in the TTR gene have been described. Most mutations give rise to adult onset progressive peripheral and autonomic neuropathy, due to amyloid deposition within the nerves, and often subclinical cardiac amyloid and vitreous deposits. We report here the clinical and molecular characterization of a rare TTR missense mutation discovered in a young woman from Macedonia, showing severe axonal sensory-motor polyneuropathy, restrictive cardiomyopathy and bilateral vitreous deposits. The transthyretin gene, analyzed by direct nucleotide sequencing, demonstrated a T to G transversion at nucleotide 183 in the exon 2 which is predicted to cause a heterozygous valine for phenylalanine substitution at codon 33 (TTR Phe33Val). This mutation has been previously reported only twice, without complete clinical descriptions.