Several new mutations in the NPC NPC and SMPD
Several new mutations in the NPC1, NPC2 and SMPD1 genes were found in this study. All these mutations are predicted to be disease causing (online program “mutation taster” Schwarz et al., 2014) except for the splice mutation IVS4+1G>A in NPC2, which is a known variant (rs140130028). Only heterozygote patients with this mutation have been described in the literature (Bauer et al., 2013), already presenting symptoms of NPC disease. However, while the frequency of this variant in the population was not mentioned in that paper, indeed it was similar to the frequency of the mutation in the NPC-patient group, and therefore heterozygosity for this mutation was most likely not causative for the phenotype. Patient 73 carries the IVS4+1G>A mutation in a homozygous state and shows symptoms typical for NPC (see Table S2). Further investigations on this patient and the splice mutation have been initiated. The most common NPC1 mutations among western Europeans, I1061T and P1007A, were found in 13/150 purchase guanidine hydrochloride (I1061T) and 23/150 alleles (P1007A) respectively (I1061T: 3/13 South America, 10/13 Europe; P1007A: 3/24 South America, 20/24 Europe).
In patients 84.1 and 84.2, one heterozygote mutation was found in the NPC1 gene. After unsuccessful extensive sequencing, the second disease causing mutation could not be found and NP-C1 has been excluded as suspected diagnosis. Due to the elevated c-triol concentration that was also found in NP-A/B patients, the SMPD1 gene was sequenced and two known heterozygous mutations have been found. The presence of one heterozygous mutation was puzzling and led to a diagnostic delay.
Other biomarkers are tested in parallel to the oxysterols, including bile acids in urine and plasma parameters such as lysosphingolipids or CCL18/PARC. In retrospective studies it has been shown that lysosphingolipids and CCL18/PARC are also elevated in NP-C patients (Welford et al., 2014; Chang et al., 2010). There are no prospective studies yet that show the clinical use of these promising parameters as potential biomarkers for NP-C.
Declaration of Interests
Introduction Posttraumatic stress disorder (PTSD) is a response to traumatic experiences characterized by four main symptom clusters: re-experiencing symptoms (e.g. flashback and nightmares), avoidance symptoms, negative cognitions and mood, and arousal symptoms (e.g. hypervigilance and exaggerated startle). Given its high lifetime prevalence of 6.8% in the American general population, and its significant morbidity (Kessler et al., 2005), there is an urgent need to better understand its neurobiology. A recent meta-analysis from our group showed that PTSD is associated with gray matter abnormalities (Li et al., 2014). Fewer studies have investigated white matter integrity (for a recent review (Daniels et al., 2013)). Results of these studies have been inconsistent, with reports of decreased fractional anisotropy (FA) in corpus callosum (Kitayama et al., 2007; Villarreal et al., 2004), prefrontal cortex (PFC) (Schuff et al., 2011), anterior cingulum (Kim et al., 2005; Schuff et al., 2011; Zhang et al., 2011) and posterior cingulum (Fani et al., 2012b), but also of increased FA in anterior cingulum (Abe et al., 2006) and superior frontal gyrus (Zhang et al., 2011). There are important methodological issues regarding imaging protocols and patient sample characteristics that may contribute to the variability in study findings. Most early white matter studies in PTSD used manual tracing analysis in predefined regions of interest (ROI) (Daniels et al., 2013). Although this method can be sensitive, results are highly reliant on anatomically specific prior hypotheses (Lee et al., 2009). This ROI-bias is avoided by whole-brain voxel-based analysis (Bandettini, 2009). Second, most previous voxel-based studies had small patient samples, and this might limit the reliability of results and sensitivity to illness effects (Abe et al., 2006; Fani et al., 2012b; Kim et al., 2005; Schuff et al., 2011; Zhang et al., 2012). Third, most studies have examined chronically ill patients treated with psychotropic medications, so that multiple secondary factors might differentially impact neuroanatomic measurements in the PTSD patients. Fourth, most prior studies compared PTSD patients to non-traumatized healthy controls, making it difficult to determine whether observed effects were related to PTSD per se or simply to traumatic stress exposure (Li et al., 2014). Only a few studies have compared PTSD patients to controls who experienced similar psychological trauma but did not develop PTSD (Abe et al., 2006; Schuff et al., 2011), and those studies often were complicated by psychotropic medication. Fifth, the nature, intensity and duration of trauma often varied widely among study participants. Studies using voxel based approaches with large samples of individuals with PTSD who experienced discrete stress compared to similarly stressed healthy individuals may better clarify PTSD neurobiology.