We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility genes that involves converging data from several unbiased genetic and genomic tools. We tested the association between IS and genes differentially expressed between cases and controls, then determined which data mapped to previously reported linkage peaks and were nominally associated with stroke in published genome-wide association studies. We first performed gene expression profiling in peripheral blood mononuclear cells of 20 IS cases and 20 controls. Sixteen differentially expressed genes mapped to reported whole-genome linkage peaks, including the TTC7B gene, which has been associated with major cardiovascular disease. At the TTC7B locus, 46 tagging polymorphisms were tested for association in 565 Portuguese IS cases and 520 controls. Markers nominally associated in at least one test and defining associated haplotypes were then examined in 570 IS Spanish cases and 390 controls. Several polymorphisms and haplotypes in the intron 5-intron 6 region of TTC7B were also associated with IS risk in the Spanish and combined data sets. Multiple independent lines of evidence therefore support the role of TTC7B in stroke susceptibility, but further work is warranted to identify the exact risk variant and its pathogenic potential.

Background and Purpose— Fabry disease is an X-linked monogenic disorder caused by mutations in the GLA gene. Recent data suggest that stroke in young adults may be associated with Fabry disease. We aimed to ascertain the prevalence of this disorder among young adult patients with stroke in Portugal by GLA genotyping. Methods— During 1 year, all patients aged 18 to 55 years with first-ever stroke, who were admitted into any of 12 neurology hospital departments in Portugal, were prospectively enrolled (n=625). Ischemic stroke was classified according to Trial of Org 10172 in Acute Stroke Treatment criteria. Alpha-galactosidase activity was further assayed in all patients with GLA mutations. Results— Four hundred ninety-three patients (mean age, 45.4 years; 61% male) underwent genetic analyses: 364 with ischemic stroke, 89 with intracerebral hemorrhage, 26 with subarachnoid hemorrhage, and 14 with cerebral venous thrombosis. Twelve patients had missense GLA mutations: 9 with ischemic stroke (p.R118C: n=4; p.D313Y: n=5), including 5 patients with an identified cause of stroke (cardiac embolism: n=2; small vessel disease: n=2; other cause: n=1), 2 with intracerebral hemorrhage (p.R118C: n=1; p.D313Y: n=1), and one with cerebral venous thrombosis (p.R118C: n=1). Leukocyte α-galactosidase activity was subnormal in the hemizygous males and subnormal or low-normal in the heterozygous females. Estimated prevalence of missense GLA mutations was 2.4% (95% CI, 1.3% to 4.1%). Conclusions— Despite a low diagnostic yield, screening for GLA mutations should probably be considered in different types of stroke. Restricting investigation to patients with cryptogenic stroke may underestimate the true prevalence of Fabry disease in young patients with stroke.

BackgroundThe genetic contribution to stroke is well established but it has proven difficult to identify the genes and the disease-associated alleles mediating this effect, possibly because only nuclear genes have been intensely investigated so far. Mitochondrial DNA (mtDNA) has been implicated in several disorders having stroke as one of its clinical manifestations. The aim of this case-control study was to assess the contribution of mtDNA polymorphisms and haplogroups to ischemic stroke risk.MethodsWe genotyped 19 mtDNA single nucleotide polymorphisms (SNPs) defining the major European haplogroups in 534 ischemic stroke patients and 499 controls collected in Portugal, and tested their allelic and haplogroup association with ischemic stroke risk.ResultsHaplogroup H1 was found to be significantly less frequent in stroke patients than in controls (OR = 0.61, 95% CI = 0.45–0.83, p = 0.001), when comparing each clade against all other haplogroups pooled together. Conversely, the pre-HV/HV and U mtDNA lineages emerge as potential genetic factors conferring risk for stroke (OR = 3.14, 95% CI = 1.41–7.01, p = 0.003, and OR = 2.87, 95% CI = 1.13–7.28, p = 0.021, respectively). SNPs m.3010G>A, m.7028C>T and m.11719G>A strongly influence ischemic stroke risk, their allelic state in haplogroup H1 corroborating its protective effect.ConclusionOur data suggests that mitochondrial haplogroup H1 has an impact on ischemic stroke risk in a Portuguese sample.

Cerebrovascular and cardiovascular diseases are the leading causes of death and disability worldwide. They are complex disorders resulting from the interplay of genetic and environmental factors, and may share several susceptibility genes. Several recent studies have implicated variants of the Kalirin (KALRN) gene with susceptibility to cardiovascular and metabolic phenotypes, but no studies have yet been performed in stroke patients. KALRN is involved, among others, in the inhibition of inducible nitric oxide synthase, in the regulation of ischemic signal transduction, and in neuronal morphogenesis, plasticity, and stability. The goal of the present study was to determine whether SNPs in the KALRN region on 3q13, which includes the Ropporin gene (ROPN1), predispose to ischemic stroke (IS) in a cohort of Portuguese patients and controls. We genotyped 34 tagging SNPs in the KALRN and ROPN1 chromosomal region on 565 IS patients and 517 unrelated controls, and performed genotype imputation for 405 markers on chromosome 3. We tested the singlemarker association of these SNPs with IS. One SNP (rs4499545) in the ROPN1-KALRN intergenic region and two SNPs in KALRN (rs17286604 and rs11712619) showed signiWcant (P < 0.05) allelic and genotypic (unadjusted and adjusted for hypertension, diabetes, and ever smoking) association with IS risk. Thirty-two imputed SNPs also showed an association at P < 0.05, and actual genotyping of Electronic supplementary material The online version of this article

Staphylococcus lugdunensis has been recognized to be a microorganism potentially more virulent than other coagulase-negative staphylococci. We report the case of a patient who presented with a single, large, right, frontoparietal abscess that evolved despite conventional antibiotic treatment. Bacteremia and endocarditis were excluded. After surgical treatment, S. lugdunensis sensible to trimethoprim-sulfamethoxazole was isolated, and the patient responded favorably to treatment. Although the ability of S. lugdunensis to produce brain abscesses has been recognized, we report a case of a brain abscess in the absence of bacteremia or endocarditis.

A 79-year-old diabetic and hypertensive woman with no history of underlying systemic diseases or immunosuppressive therapy presented in our neurology department with complaints of mild cognitive dysfunction that had developed in the past 6 months. Examination showed mild cognitive impairment without other neurologic defi cits. The patient was afebrile, and her vital signs were stable. However, signs of periorbital infl ammation affecting her right eye were found.A computed tomography (CT) scan of the patient's brain revealed a large, isoattenuated right frontal mass with central hypoattenuated areas of necrosis ( Figure A). Brain magnetic resonance imaging (MRI) images showed that the mass had a complex appearance and extended to the roof and soft tissues of the orbita ( Figure B).No abnormalities were detected in the laboratory studies. Immunological test results were normal, and the patient's serum was negative for human immunodefi ciency virus (HIV) and tumor markers. A computed tomography scan of her chest, abdomen, and pelvis showed unremarkable results.A craniotomy and sub-total resection of the mass were performed. Histopathological fi ndings revealed an infl ammatory, granulomatous lesion with septate hyphae (Figure C). The cultures from the brain specimen yielded a positive result for Aspergillus sp.Concerning the probable route of infection, a pulmonary source and hematogenous route were excluded, but a contiguous spread by maxillary sinusitis could not be ruled out.Postoperatively, the patient was treated by systemic administration of voriconazole (4mg/kg intravenously, twice daily) and caspofungin (50mg intravenously, daily) to which she showed only a minimal response. The disease progressed, and the patient eventually died 2 months after the diagnosis.

No abstract

No abstract