ABSTRACT
BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is the most important cause of motor neuron disease in childhood, and continues to represent the leading genetic cause of infant death. Adulthood-onset SMA (SMA type 4) is rare, with few isolated cases reported. The objective of the present study was to describe a cohort of patients with SMA type 4. METHODS: A cross-sectional study was conducted to characterize clinical, genetic, radiological and neurophysiological features of patients with adulthood-onset SMA. Correlation analysis of functional assessment with genetic, radiological and neurophysiological data was performed. RESULTS: Twenty patients with SMA type 4 were identified in a Brazilian cohort of 227 patients with SMA. The most common clinical symptom was limb-girdle muscle weakness, observed in 15 patients (75%). The most frequent neurological findings were absent tendon reflexes in 18 (90%) and fasciculations in nine patients (45%). Sixteen patients (80%) had the homozygous deletion of exon 7 in the SMN1 gene, with 12 patients (60%) showing four copies of the SMN2 gene. The functional scales Hammersmith Functional Motor Scale Expanded, Amyotrophic Lateral Sclerosis Functional Rating Scale Revised, Revised Upper Limb Module and Spinal Muscular Atrophy Functional Rating Scale, as well as the six-minute walk and the Time Up and Go tests showed a correlation with duration of disease. Motor Unit Number Index was correlated both with duration of disease and with performance in functional assessment. Radiological studies exhibited a typical pattern, with involvement of biceps femoris short head and gluteus minimus in all patients. CONCLUSION: This study represents the largest cohort of patients with SMA type 4 and provides functional, genetic, radiological and neurophysiological features that can be used as potential biomarkers for the new specific genetic therapies for SMA.
Subject(s)
Muscular Atrophy, Spinal , Adult , Cross-Sectional Studies , Exons , Homozygote , Humans , Infant , Muscular Atrophy, Spinal/diagnostic imaging , Muscular Atrophy, Spinal/genetics , Sequence DeletionSubject(s)
Leukoencephalopathies/genetics , Motor Neuron Disease/genetics , Mutation, Missense , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Brazil , Demyelinating Diseases/complications , Demyelinating Diseases/diagnosis , Demyelinating Diseases/genetics , Humans , Leukoencephalopathies/complications , Leukoencephalopathies/diagnosis , Male , Motor Neuron Disease/complications , Motor Neuron Disease/diagnosis , Young AdultSubject(s)
Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/pathology , Mutation, Missense , Trans-Activators/genetics , Aged , Amyotrophic Lateral Sclerosis/diagnosis , Brazil , Bulbar Palsy, Progressive/diagnosis , Bulbar Palsy, Progressive/etiology , Bulbar Palsy, Progressive/genetics , Bulbar Palsy, Progressive/pathology , Disease Progression , Humans , Male , Time FactorsABSTRACT
Leigh syndrome represents a complex inherited neurometabolic and neurodegenerative disorder associated with different clinical, genetic and neuroimaging findings in the context of bilateral symmetrical lesions involving the brainstem and basal ganglia. Heterogeneous neurological manifestations such as spasticity, cerebellar ataxia, dystonia, choreoathetosis and parkinsonism are associated with multisystemic and ophthalmological abnormalities due to >75 different monogenic causes. Here, we describe the clinical and genetic features of a Brazilian cohort of patients with Leigh Syndrome in which muscle biopsy analysis showed mitochondrial DNA defects and determine the utility of whole exome sequencing for a final genetic diagnostic in this cohort.
Subject(s)
DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , Exome Sequencing , Leigh Disease/genetics , Leigh Disease/metabolism , Adolescent , Adult , Aged , Brazil , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Leigh Disease/diagnosis , Male , Middle AgedSubject(s)
Spastic Paraplegia, Hereditary/diagnosis , Brazil , Calpain/genetics , Chronic Disease , Depression/complications , Depression/diagnosis , Depression/genetics , Female , Gait Disorders, Neurologic/diagnosis , Gait Disorders, Neurologic/etiology , Humans , Magnetic Resonance Imaging , Middle Aged , Mutation, Missense , Phenotype , Spastic Paraplegia, Hereditary/genetics , Spastic Paraplegia, Hereditary/pathology , Urinary Incontinence/complications , Urinary Incontinence/diagnosis , Urinary Incontinence/geneticsABSTRACT
OBJECTIVE: The expression of Bcl-x(L) has been shown to be regulated during the maturation process of different hematopoietic cell lineages (i.e., erythroid cells, neutrophils, monocytes/macrophages). In the present study, we examined the expression of Bcl-x(L) in megakaryocytes derived from CD34(+) progenitors and in the megakaryoblastic cell line UT7. MATERIALS AND METHODS: Expression of Bcl-x(L) was analyzed in CD41(+) cells cultured in the presence of thrombopoietin and in UT7 cells treated with phorbol diester by Western blot, flow cytometry, and immunocytochemistry analysis. Apoptosis was determined at different culture times by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling and propidium iodide uptake. RESULTS: Bcl-x(L) but not Bcl-2 was up-regulated in the megakaryocytic population (CD41(+)) during the first 15 days of culture, which was consistent with the pattern of Bcl-x(L) expression in UT7 cells differentiated to megakaryocytes by incubation with phorbol diester. However, by day 20 of culture, the levels of Bcl-x(L) in CD41(+) cells were greatly reduced, and this expression pattern was accompanied by an increase in the number of apoptotic cells. At this culture time, we detected the presence of cytoplasmic fragments resembling proplatelets with prominent Bcl-x immunostaining, most likely due to the Bcl-x(L) isoform, in close proximity to Bcl-x(-) senescent megakaryocytes. The presence of Bcl-x(L) but not of Bcl-2 in platelets was confirmed by Western blot analysis. CONCLUSION: Although little is known regarding the functional significance of survival proteins within the megakaryocytic compartment, the changes in the Bcl-x(L) expression pattern observed in UT7 and CD41(+) cells may play a role in the survival of developing megakaryocytes and the lifespan of mature platelets.
Subject(s)
Apoptosis/physiology , Cellular Senescence/physiology , Hematopoietic Stem Cells/physiology , Megakaryocytes/physiology , Proto-Oncogene Proteins c-bcl-2/genetics , Antigens, CD/analysis , Antigens, CD34/analysis , Blood Platelets/cytology , Blood Platelets/physiology , Blotting, Western , Carrier Proteins/analysis , Cell Adhesion Molecules, Neuronal/analysis , Cell Line , Cells, Cultured , Contactins , Fetal Blood/cytology , Fetal Blood/immunology , Flow Cytometry , Hematopoietic Stem Cells/cytology , Humans , Infant, Newborn , Megakaryocytes/cytology , Megakaryocytes/drug effects , Platelet Glycoprotein GPIIb-IIIa Complex/analysis , Protein Isoforms/analysis , Protein Isoforms/genetics , Proto-Oncogene Proteins/analysis , Proto-Oncogene Proteins c-bcl-2/analysis , Recombinant Proteins/pharmacology , Tetradecanoylphorbol Acetate/pharmacology , Thrombopoietin/pharmacology , Time Factors , bcl-2-Associated X Protein , bcl-Associated Death Protein , bcl-X ProteinABSTRACT
The aim of this study was to determine whether the detection of CTC in the apheresis product contribute significantly to treatment failure of patients with high-risk breast carcinoma treated with high-dose chemotherapy (HDC) and stem cell transplantation (SCT). Patients were with stage II and III adenocarcinoma of the breast with > or = 10 axillary lymph nodes affected after primary surgery (> or = 10 N+) who had received HDC with SCT. We analyzed retrospectively the presence of CTC as assessed by immunocytochemistry (ICC) in the apheresis products obtained after standard adjuvant chemotherapy. We compared the clinical outcome of patients who received HDC and SCT with or without CTC-positive apheresis. One hundred and twenty-seven apheresis products samples were obtained from 51 patients. Fourteen (27.4%) of these samples were CTC positive. After a median follow-up of 4.6 years, 20 patients have relapsed, 14 died from progression of their disease and 30 patients remain alive and free of progression. For the whole group of patients the 5 year probabilities of DFS and OS were 60% (IC 95%, 47-75%) and 71% (IC 95%, 55-83%), respectively. However, the 5 year probabilities of DFS were 23% (IC 95%, 0-46) and 75% (IC 95%, 60-89) for patients with CTC positive and negative, respectively. The 5 year probabilities of OS were 42% (IC 95%, 15-68) and 83% (IC 95%, 70-95) for patients with CTC positive and negative, respectively. Both univariate and multivariate analysis showed that the presence of CTC in the apheresis product was the only prognostic factor associated with a higher incidence of clinically overt disease relapse (P = 0.002) and shorter survival (P = 0.003). The presence of cytokeratin-positive metastatic cells in the apheresis product increases the risk of relapse after HDC and SCT in patients with stage II and III adenocarcinoma of the breast with > or = 10 N+.
Subject(s)
Blood Component Removal/standards , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/standards , Neoplastic Stem Cells/pathology , Adult , Analysis of Variance , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Blood Component Removal/mortality , Breast Neoplasms/chemistry , Cell Separation , Combined Modality Therapy , Female , Humans , Immunohistochemistry/methods , Middle Aged , Prognosis , Recurrence , Retrospective Studies , Risk Factors , Survival Rate , Treatment FailureABSTRACT
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