RESUMEN
Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.
Asunto(s)
Variación Genética , Inmunoglobulina G/líquido cefalorraquídeo , Complejo Mayor de Histocompatibilidad/genética , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Europa (Continente) , Femenino , Estudios de Asociación Genética , Humanos , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Bandas Oligoclonales/sangre , Bandas Oligoclonales/líquido cefalorraquídeo , Índice de Severidad de la Enfermedad , Proteína Smad4/genética , Proteínas Supresoras de Tumor/genética , Adulto JovenRESUMEN
A 55-year-old woman was admitted with a 3 days history of increasing lethargy with bradyphrenia and apathy. She progressively developed severe somnolence with marked abulia, right hemiparesis, right hemianopsia, and pseudobulbar palsy. Brain magnetic resonance imaging showed the rare image of bilateral acute anterior choroidal artery infarction. Pseudobulbar mutism and in rare cases abulia have been described in acute anterior choroidal artery infarction contralateral to an older lesion in mirror position. Although neurologic deterioration is not infrequent in anterior choroidal artery territory infarcts, the absence of focal neurologic signs on admission is rare and did not raise suspicion of acute stroke.