RESUMEN
OBJECTIVE: Duchenne muscular dystrophy (DMD) is the most common single-gene lethal disorder. Substantial patient-patient variability in disease onset and progression and response to glucocorticoids is seen, suggesting genetic or environmental modifiers. METHODS: Two DMD cohorts were used as test and validation groups to define genetic modifiers: a Padova longitudinal cohort (n = 106) and the Cooperative International Neuromuscular Research Group (CINRG) cross-sectional natural history cohort (n = 156). Single nucleotide polymorphisms to be genotyped were selected from mRNA profiling in patients with severe vs mild DMD, and genome-wide association studies in metabolism and polymorphisms influencing muscle phenotypes in normal volunteers were studied. RESULTS: Effects on both disease progression and response to glucocorticoids were observed with polymorphism rs28357094 in the gene promoter of SPP1 (osteopontin). The G allele (dominant model; 35% of subjects) was associated with more rapid progression (Padova cohort log rank p = 0.003), and 12%-19% less grip strength (CINRG cohort p = 0.0003). CONCLUSIONS: Osteopontin genotype is a genetic modifier of disease severity in Duchenne dystrophy. Inclusion of genotype data as a covariate or in inclusion criteria in DMD clinical trials would reduce intersubject variance, and increase sensitivity of the trials, particularly in older subjects.
Asunto(s)
Distrofia Muscular de Duchenne/genética , Osteopontina/genética , Polimorfismo de Nucleótido Simple , Niño , Preescolar , Estudios Transversales , Progresión de la Enfermedad , Femenino , Genotipo , Glucocorticoides/administración & dosificación , Humanos , Cooperación Internacional , Italia , Estimación de Kaplan-Meier , Masculino , Distrofia Muscular de Duchenne/patología , Distrofia Muscular de Duchenne/fisiopatología , Oportunidad Relativa , Valor Predictivo de las Pruebas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Índice de Severidad de la EnfermedadRESUMEN
We have studied responses in thymoma patients to interferon-alpha and to the acetylcholine receptor (AChR) in early-onset myasthenia gravis (EOMG), seeking clues to autoimmunizing mechanisms. Our new evidence implicates a two-step process: (step 1) professional antigen-presenting cells and thymic epithelial cells prime AChR-specific T cells; then (step 2) thymic myoid cells subsequently provoke germinal center formation in EOMG. Our unifying hypothesis proposes that AChR epitopes expressed by neoplastic or hyperplastic thymic epithelial cells aberrantly prime helper T cells, whether generated locally or infiltrating from the circulation. These helper T cells then induce antibody responses against linear epitopes that cross-react with whole AChR and attack myoid cells in the EOMG thymus. The resulting antigen-antibody complexes and the recruitment of professional antigen-presenting cells increase the exposure of thymic cells to the infiltrates and provoke local germinal center formation and determinant spreading. Both these and the consequently enhanced heterogeneity and pathogenicity of the autoantibodies should be minimized by early thymectomy.
Asunto(s)
Autoinmunidad , Linfocitos B/inmunología , Miastenia Gravis/inmunología , Linfocitos T/inmunología , Edad de Inicio , Animales , Autoanticuerpos , Bungarotoxinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/fisiología , Epítopos/inmunología , Técnica del Anticuerpo Fluorescente , Centro Germinal , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Insulina/metabolismo , Interferón-alfa/inmunología , Interleucina-2/inmunología , Queratinas/metabolismo , Modelos Inmunológicos , Mutación , Miastenia Gravis/metabolismo , Receptores Colinérgicos/inmunología , Células del Estroma , Linfocitos T/clasificación , Timoma/inmunología , Timo/citología , Timo/fisiología , Neoplasias del Timo , Troponina I/metabolismoRESUMEN
We randomized 18 Duchenne muscular dystrophy (DMD) boys whose age ranged from 5.2 to 14.6 years (mean, 7.3 years) for treatment with either deflazacort (0.9 mg/kg/day) or prednisone (0.75 mg/kg/day) on the basis of age and functional score at the onset of treatment. We followed the patients every 3 months for 1 year, evaluating four limb muscles with the Medical Research Council scale and performance of four functions (walking, climbing stairs, Gowers' maneuver, and rising from a chair). Side effects were monitored by a questionnaire and by routine blood examination, and weight and height were recorded at each visit. At 12 months, the effect of both steroids was examined by comparing the status of the treated patients with another group of untreated DMD patients that served as natural history control. The two steroids were equally effective in improving motor function and functional performances. At 9 months, the average weight increase with respect to baseline value was 5% (2 kg) in the deflazacort group but 18% in the prednisone group (P < 0. 005), and the change remained significant after 12 months (P < 0.05). Other minor but nonsignificant side effects were observed. Steroid treatment with deflazacort appears to cause fewer side effects than with prednisone, particularly weight gain, which could be important to maximize motor performances.