RESUMEN
Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research and therapeutics. We assembled and array genotyped sCJD cases diagnosed in life or at autopsy. Clinical duration (median:4, interquartile range (IQR):2.5-9 (months)) was available in 3,773 and age at onset (median:67, IQR:61-73 (years)) in 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved genome-wide significance for the clinical duration phenotype; all of which were located at chromosome 20 (top SNP rs1799990, pvalue = 3.45x10-36, beta = 0.34 for an additive model; rs1799990, pvalue = 9.92x10-67, beta = 0.84 for a heterozygous model). Fine mapping, conditional and expression analysis suggests that the well-known non-synonymous variant at codon 129 is the obvious outstanding genome-wide determinant of clinical duration. Pathway analysis and suggestive loci are described. No genome-wide significant SNP determinants of age at onset were found, but the HS6ST3 gene was significant (pvalue = 1.93 x 10-6) in a gene-based test. We found no evidence of genome-wide genetic correlation between case-control (disease risk factors) and case-only (determinants of phenotypes) studies. Relative to other common genetic variants, PRNP codon 129 is by far the outstanding modifier of CJD survival suggesting only modest or rare variant effects at other genetic loci.
Asunto(s)
Edad de Inicio , Síndrome de Creutzfeldt-Jakob , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Humanos , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/patología , Anciano , Persona de Mediana Edad , Femenino , Masculino , Fenotipo , GenotipoRESUMEN
Human T lymphotropic virus type I (HTLV-I) was isolated from peripheral blood- and cerebrospinal fluid-derived mononuclear cells of a 13-y-old boy and from the peripheral blood lymphocytes of both his parents. All three had IgG antibodies to HTLV-I and varying degrees of the clinical features of tropical spastic paraparesis (TSP). The son also had IgG antibodies specific for HTLV-I in his serum. Isolations were successfully made from peripheral blood lymphocytes and cerebrospinal fluid lymphocytes stimulated with interleukin-2 or cocultivated with umbilical cord blood mononuclear cells. Established cell lines contained HTLV-I antigen by immunfluorescence and cell-associated virus by electron microscopy; cells became transformed in vitro as determined by their continuous growth in the absence of exogenous interleukin-2. This boy is the youngest TSP patient known to be reported, and the isolation of HTLV-I from all three family members suggests the causative role of this virus in TSP. (AU)
Asunto(s)
Humanos , Adolescente , Adulto , Masculino , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Paraparesia Espástica TropicalRESUMEN
Viral-like particles morphologically identical to human T-lymphotropic virus type I or II, but distinct from human T-lymphotropic virus type III, have been seen by electron microscopy in spinal cord tissue from a Jamaican tropical spastic paraparesis patient who was known to be positive for human T-lymphotropic virus I antibody before death. This is the first electron microscopy report on a patient from an endemic tropical spastic paraparesis region. (AU)