RESUMO
AIMS: Pompe disease is caused by pathogenic mutations in the alpha 1,4-glucosidase (GAA) gene and in patients with late onset Pome disease (LOPD), genotype-phenotype correlations are unpredictable. Skeletal muscle pathology includes glycogen accumulation and altered autophagy of various degrees. A correlation of the muscle morphology with clinical features and the genetic background in GAA may contribute to the understanding of the phenotypic variability. METHODS: Muscle biopsies taken before enzyme replacement therapy were analysed from 53 patients with LOPD. On resin sections, glycogen accumulation, fibrosis, autophagic vacuoles and the degree of muscle damage (morphology-score) were analysed and the results were compared with clinical findings. Additional autophagy markers microtubule-associated protein 1A/1B-light chain 3, p62 and Bcl2-associated athanogene 3 were analysed on cryosections from 22 LOPD biopsies. RESULTS: The myopathology showed a high variability with, in most patients, a moderate glycogen accumulation and a low morphology-score. High morphology-scores were associated with increased fibrosis and autophagy highlighting the role of autophagy in severe stages of skeletal muscle damage. The morphology-score did not correlate with the patient's age at biopsy, disease duration, nor with the residual GAA enzyme activity or creatine-kinase levels. In 37 patients with LOPD, genetic analysis identified the most frequent mutation, c.-32-13T>G, in 95%, most commonly in combination with c.525delT (19%). No significant correlation was found between the different GAA genotypes and muscle morphology type. CONCLUSIONS: Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology. Increased pathology is associated with more fibrosis and autophagy.
Assuntos
Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/patologia , Músculo Esquelético/patologia , Adolescente , Adulto , Idoso , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/ultraestrutura , Fenótipo , Adulto JovemRESUMO
The term amyotrophic lateral sclerosis (ALS) comprises a group of motor neuron diseases which are characterized by rapid disease progression and poor prognosis which is mostly due to severe respiratory muscle weakness and its sequelae. Since causative treatment options are limited it is crucial to offer comprehensive symptomatic therapies to affect patients. Symptoms of respiratory muscle weakness, sleep-disordered breathing and, subsequently, chronic hypercapnic respiratory failure are known to severely affect health-related quality of life and social functioning of patients with ALS. This review article delineates the clinical presentation of respiratory muscle weakness, diagnostic procedures to assess diaphragmatic function, and practical aspects of both mechanical ventilation and cough assistance, respectively. Various technical and electrophysiological methods allow for detection of diaphragmatic weakness and nocturnal hypoventilation. These include spiro-manometric tests of respiratory muscle strength, cardiorespiratory polygraphy and polysomnography, transcutaneous capnography, and blood gas analysis. Once the diagnosis of respiratory muscle weakness is established, non-invasive ventilation, tracheostomy-invasive ventilation (if the patient agrees to it), and management of secretions all become increasingly important in the course of the disease.
Assuntos
Esclerose Lateral Amiotrófica/terapia , Respiração Artificial/métodos , Esclerose Lateral Amiotrófica/complicações , Humanos , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Músculos Respiratórios/fisiopatologiaRESUMO
BACKGROUND AND PURPOSE: Respiratory muscle weakness is the major cause of early death in patients with adult Pompe disease. It first manifests as nocturnal hypercapnia, eventually leading to sleep disruption. Sleep-related symptoms along with motor performance, forced vital capacity (FVC) and respiratory symptoms were investigated in 65 adult patients with Pompe disease. METHODS: Patients answered the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale, the Fatigue Severity Scale, the Rotterdam Nine-item Handicap Scale, the SF-36 health-related quality of life questionnaire, and a respiratory symptom questionnaire. In all patients, the 6-min walk test was performed and FVC was obtained. Polysomnography and oxycapnometry results were available in 31 patients. RESULTS: Sixty patients received enzyme replacement therapy, and 32 individuals were on home ventilatory support. Reduced sleep quality was highly prevalent (PSQI > 5; 43.1%) and correlated with both excessive daytime sleepiness (Epworth Sleepiness Scale > 10; 24.6%) and fatigue (Fatigue Severity Scale > 4; 72.3%). The SF-36 health-related quality of life questionnaire was reduced in the physical domains, and was inversely correlated with sleep quality, FVC and motor performance. In 11 out of 17 non-ventilated patients with polysomnography records, sleep-disordered breathing was present, and duration of nocturnal oxygen desaturation (SaO2 < 90%) was significantly correlated to the PSQI global score. CONCLUSIONS: In adult Pompe disease, sleep disturbances are a common cause of excessive daytime sleepiness and fatigue. Sleep-related symptoms may be indicative of respiratory muscle weakness and should give rise to further work-up of sleep-disordered breathing.
Assuntos
Doença de Depósito de Glicogênio Tipo II/complicações , Músculos Respiratórios/fisiopatologia , Síndromes da Apneia do Sono/etiologia , Transtornos do Sono-Vigília/etiologia , Adolescente , Adulto , Idoso , Fadiga/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Gene therapy in the central nervous system (CNS) is hindered by the presence of the blood-brain barrier, which restricts access of serum constituents and peripheral cells to the brain parenchyma. Expression of exogenously administered genes in the CNS has been achieved in vivo using highly invasive routes, or ex vivo relying on the direct implantation of genetically modified cells into the brain. Here we provide evidence for a novel, noninvasive approach for targeting potential therapeutic factors to the CNS. Genetically-modified hematopoietic cells enter the CNS and differentiate into microglia after bone-marrow transplantation. Up to a quarter of the regional microglial population is donor-derived by four months after transplantation. Microglial engraftment is enhanced by neuropathology, and gene-modified myeloid cells are specifically attracted to the sites of neuronal damage. Thus, microglia may serve as vehicles for gene delivery to the nervous system.
Assuntos
Transplante de Medula Óssea , Marcação de Genes , Terapia Genética/métodos , Microglia/transplante , Animais , Barreira Hematoencefálica , Células da Medula Óssea/citologia , Isquemia Encefálica/terapia , Diferenciação Celular , Vetores Genéticos , Proteínas de Fluorescência Verde , Proteínas Luminescentes/isolamento & purificação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Proteínas Recombinantes/isolamento & purificação , Retroviridae/genéticaRESUMO
BACKGROUND: The first ever diagnosis of multiple sclerosis (MS) requires consideration of both diagnostic criteria and differential diagnosis. Clinicians are particularly challenged by rare conditions which may mimic MS symptoms and relapses. CASE REPORT: We report the case of a young female patient who presented with relapsing left hemispheric symptoms that were highly suspicious of MS but were caused by an idiopathic occlusive angiopathy of the circle of Willis. CONCLUSION: Occlusive disease of the great cerebral arteries in young patients is a rare but important differential diagnosis of MS. It has to be considered in patients presenting with the first symptoms suspicious of MS as substantial treatment consequences will arise.