No abstract

Aspirin non-responder status may contribute to failure of aspirin therapy in the secondary prevention of cerebrovascular incidents in as much as 30-40 % of patients. Quantitative assessment of platelet functions may provide a means to predict aspirin treatment failure in individual patients and to re-direct therapeutic strategies.

No abstract

The sequence change described here may be a novel pathogenic mutation of TOR1A in DYT1.

Our data underline the wide range of phenotypic variability of the DYT1 mutation. A priori prediction of the mutation carrier status in dystonic patients and genetic counseling of affected families with respect to the clinical manifestation may prove difficult.

Primary dystonias are a clinically and genetically heterogeneous group of movement disorders, but only for two of them, i.e., dystonia 1 and dystonia 6, the disease causing gene has been identified. Dystonia 1 is characterized by an early onset and is caused by a mutation in the TOR1A gene. Only recently, mutations in THAP1 have been shown to be the cause of DYT6 dystonia. We analyzed 610 patients with various forms of dystonia for sequence variants in the THAP1 gene by means of high resolution melting to delineate the prevalence of sequence variants and phenotypic variability. We identified seven sequence variants in patients and one sequence variant in a control. The sequence variants were not detected in 537 healthy controls. Four patients present with generalized dystonia with speech involvement of early onset, another three patients suffered exclusively from cervical dystonia of adult onset. These findings suggest that THAP1 sequence variations seem to be associated with different ages of onset and distribution of symptoms. Consequently, the phenotypic spectrum might be broader than previously assumed.

Multi-gene panels are used to identify genetic causes of hereditary breast and ovarian cancer (HBOC) in large patient cohorts. This study compares the diagnostic workflow in two centers and gives valuable insights into different next-generation sequencing (NGS) strategies. Moreover, we present data from 620 patients sequenced at both centers. Both sequencing centers are part of the German consortium for hereditary breast and ovarian cancer (GC-HBOC). All 620 patients included in this study were selected following standard BRCA1/2 testing guidelines. A set of 10 sequenced genes was analyzed per patient. Twelve samples were exchanged and sequenced at both centers. NGS results were highly concordant in 12 exchanged samples (205/206 variants = 99.51 %). One non-pathogenic variant was missed at center B due to a sequencing gap (no technical coverage). The custom enrichment at center B was optimized during this study; for example, the average number of missing bases was reduced by a factor of four (vers. 1: 1939.41, vers. 4: 506.01 bp). There were no sequencing gaps at center A, but four CCDS exons were not included in the enrichment. Pathogenic mutations were found in 12.10 % (75/620) of all patients: 4.84 % (30/620) in BRCA1, 4.35 % in BRCA2 (27/620), 0.97 % in CHEK2 (6/620), 0.65 % in ATM (4/620), 0.48 % in CDH1 (3/620), 0.32 % in PALB2 (2/620), 0.32 % in NBN (2/620), and 0.16 % in TP53 (1/620). NGS diagnostics for HBOC-related genes is robust, cost effective, and the method of choice for genetic testing in large cohorts. Adding 8 genes to standard BRCA1- and BRCA2-testing increased the mutation detection rate by one-third.

Primary dystonia is a poorly understood but common movement disorder. Recently, several new primary dystonia genes were identified that provide new insight into dystonia pathogenesis. The GNAL dystonia gene is central for striatal responses to dopamine (DA) and is a component of a molecular pathway already implicated in DOPA-responsive dystonia (DRD). Furthermore, this pathway is also dysfunctional and pathogenically linked to mTOR signaling in L-DOPA-induced dyskinesias (LID). These new data suggest that striatal DA responses are central to primary dystonia, even when symptoms do not benefit from DA therapies. Here we integrate these new findings with current understanding of striatal microcircuitry and other dystonia-causing insults to develop new ideas on the pathophysiology of this incapacitating movement disorder.