Dissecting genetic architecture of rare dystonia: genetic, molecular and clinical insights.

BACKGROUND: Dystonia is one of the most common movement disorders. To date, the genetic causes of dystonia in populations of European descent have been extensively studied. However, other populations, particularly those from the Middle East, have not been adequately studied. The purpose of this study is to discover the genetic basis of dystonia in a clinically and genetically well-characterised dystonia cohort from Turkey, which harbours poorly studied populations. METHODS: Exome sequencing analysis was performed in 42 Turkish dystonia families. Using co-expression network (CEN) analysis, identified candidate genes were interrogated for the networks including known dystonia-associated genes and genes further associated with the protein-protein interaction, animal model-based characteristics and clinical findings. RESULTS: We identified potentially disease-causing variants in the established dystonia genes (PRKRA, SGCE, KMT2B, SLC2A1, GCH1, THAP1, HPCA, TSPOAP1, AOPEP; n=11 families (26%)), in the uncommon forms of dystonia-associated genes (PCCB, CACNA1A, ALDH5A1, PRKN; n=4 families (10%)) and in the candidate genes prioritised based on the pathogenicity of the variants and CEN-based analyses (n=11 families (21%)). The diagnostic yield was found to be 36%. Several pathways and gene ontologies implicated in immune system, transcription, metabolic pathways, endosomal-lysosomal and neurodevelopmental mechanisms were over-represented in our CEN analysis. CONCLUSIONS: Here, using a structured approach, we have characterised a clinically and genetically well-defined dystonia cohort from Turkey, where dystonia has not been widely studied, and provided an uncovered genetic basis, which will facilitate diagnostic dystonia research.

The relationship between nurses' moral courage and whistleblowing approaches.

BACKGROUND: Whistleblowing is an action that particularly requires moral courage. Understanding the relationship between nurses' levels of moral courage and their whistleblowing approaches is important for reducing adverse situations in healthcare services. OBJECTIVES: This study aims to understand and analyze the relationship between nurses' levels of moral courage and their whistleblowing approaches. RESEARCH DESIGN: This is a descriptive and correlational study. METHODS: The study sample consists of 582 nurses actively working in a province in northwest Türkiye. Research data were collected using an Information Form, the Nurses' Moral Courage Scale, and the Whistleblowing Scale. ETHICAL CONSIDERATIONS: Ethical approval from the ethics committee, institutional permission, and informed consent from the participants were obtained for data collection. FINDINGS: Nurses were found to perceive their moral courage as high, and their whistleblowing levels were at a moderate level. There was a significant and moderate relationship between participants' levels of moral courage and whistleblowing levels (p < .05). CONCLUSIONS: The findings emphasize the importance of promoting moral courage and creating an appropriate environment for exposing ethical violations. This study can contribute to the development of strategies to enhance nurses' moral courage and foster a more ethical working environment in healthcare services.

Association of Intelectin 1 Gene rs2274907 A > T Polymorphism with Obesity, Type 2 Diabetes, Serum Intelectin-1 Levels and Lipid Profiles in Turkish Adults.

The anti-inflammatory adipokine intelectin-1, which is encoded by the ITLN1 gene, is hypothesized to be linked to the pathogenesis of type 2 diabetes (T2DM) and obesity. The purpose of this study was to examine the effect of the ITLN1 gene polymorphism rs2274907 on obesity and T2DM in Turkish adults. The impact of genotype on lipid profiles and serum intelectin levels in the obese and diabetes groups was also investigated. Randomly selected 2266 adults (mean age, 55.0 ± 11.7 years; 51.2% women) participating in the population-based Turkish adult risk factor study were cross-sectionally analyzed. The genotyping of rs2274907 A > T polymorphism was performed by using the hybridization probe based LightSNiP assay in real-time PCR. T2DM were defined using the criteria of the American Diabetes Association. Obesity was described as Body mass index ≥ 30 kg/m2. Statistical analyses were used to investigate the association of genotypes with clinical and biochemical measurements. According to findings, there was no vital connection between the rs2274907 polymorphism and obesity, T2DM, or serum intelectin-1 level. The TA+AA carriers had significantly higher triglyceride levels (p = 0.007) compared with the TT carriers in both obese and T2DM women when adjusted for relevant covariates. ITLN1 rs2274907 polymorphism is not correlated with the risk of obesity and T2DM and not affect serum ITLN1 levels in Turkish adults. However, this polymorphism appears to be important in regulating triglyceride levels in obese and diabetic women.

A comprehensive analysis of copy number variation in a Turkish dementia cohort.

BACKGROUND: Copy number variants (CNVs) include deletions or multiplications spanning genomic regions. These regions vary in size and may span genes known to play a role in human diseases. As examples, duplications and triplications of SNCA have been shown to cause forms of Parkinson's disease, while duplications of APP cause early onset Alzheimer's disease (AD). RESULTS: Here, we performed a systematic analysis of CNVs in a Turkish dementia cohort in order to further characterize the genetic causes of dementia in this population. One hundred twenty-four Turkish individuals, either at risk of dementia due to family history, diagnosed with mild cognitive impairment, AD, or frontotemporal dementia, were whole-genome genotyped and CNVs were detected. We integrated family analysis with a comprehensive assessment of potentially disease-associated CNVs in this Turkish dementia cohort. We also utilized both dementia and non-dementia individuals from the UK Biobank in order to further elucidate the potential role of the identified CNVs in neurodegenerative diseases. We report CNVs overlapping the previously implicated genes ZNF804A, SNORA70B, USP34, XPO1, and a locus on chromosome 9 which includes a cluster of olfactory receptors and ABCA1. Additionally, we also describe novel CNVs potentially associated with dementia, overlapping the genes AFG1L, SNX3, VWDE, and BC039545. CONCLUSIONS: Genotyping data from understudied populations can be utilized to identify copy number variation which may contribute to dementia.

Genotype-Phenotype correlations of SCARB2 associated clinical presentation: a case report and in-depth literature review.

BACKGROUND: Biallelic pathogenic variants in the SCARB2 gene have been associated with action myoclonus-renal failure (AMRF) syndrome. Even though SCARB2 associated phenotype has been reported to include typical neurological characteristics, depending on the localization and the feature of the pathogenic variants, clinical course and the presentations have been shown to differ. CASE PRESENTATION: Whole exome sequencing (WES) analysis revealed a homozygous truncating variant (p.N45MfsX88) in SCARB2 gene in the index case, and subsequent sanger sequencing analysis validated the variant in all affected family members from a Turkish family with the clinical characteristics associated with AMRF and related disorders. Intrafamilial clinical heterogeneity with common features including dysarthria, tremor and proteinuria, and distinct features such as peripheral neuropathy (PNP), myoclonus and seizures between the affected cases, was observed in the family. In-depth literature review enabled the detailed investigation of the reported variants associated with AMRF and suggested that while the type of the variant did not have a major impact on the course of the clinical characteristics, only the C terminal localization of the pathogenic variant significantly affected the clinical presentation, particularly the age at onset (AO) of the disease. CONCLUSIONS: In this study we showed that biallelic SCARB2 pathogenic variants might cause a spectrum of common and distinct features associated with AMRF. Of those features while the common features include myoclonus (100%), ataxia (96%), tonic clonic seizures (82%), dysarthria (68%), tremor (65%), and renal impairment (62%), the uncommon features involve PNP (17%), hearing loss (6.8%), and cognitive impairment (13.7%). AO has been found to be significantly higher in the carriers of the p.G462DfsX34 pathogenic variant. SCARB2 pathogenic variants have not been only implicated in AMRF but also in the pathogenesis of Parkinson's disease (PD) and Gaucher disease (GD), suggesting the importance of genetic and functional studies in the clinical and the diagnostic settings. Given the proven role of SCARB2 gene in the pathogenesis of AMRF, PD and GD with a wide spectrum of clinical symptoms, investigation of the possible modifiers, such as progranulin and HSP7, has a great importance.

TREM2 variants as a possible cause of frontotemporal dementia with distinct neuroimaging features.

BACKGROUND AND PURPOSE: Nasu-Hakola disease (NHD) is a rare, autosomal recessive disorder characterized by skeletal and neurological symptoms. Behavioral symptoms with cognitive impairment may mimic the behavioral variant of frontotemporal dementia (bvFTD) and other early-onset dementias. Our patients were analyzed and the literature was reviewed to delineate neurological and neuroimaging findings suggestive of NHD. METHOD: Fourteen patients carrying a pathogenic mutation in the TREM2 gene were found in our database. Demographic, clinical, laboratory and radiological data were retrieved and analyzed. RESULTS: The presenting clinical picture was behavioral changes with cognitive decline resembling bvFTD in all patients. The mean age was 37.1 ± 4.97 years and the mean duration of the disease was 8.9 ± 3.51 years. Only two patients had typical bone cysts. Seven patients had bilateral calcification of the basal ganglia in computed tomography of the brain. Magnetic resonance imaging of the brain revealed severe atrophy of the corpus callosum, enlargement of the ventricles, atrophy of the caudate nuclei and periventricular white matter changes in all patients. Symmetrical global atrophy of the brain mainly affecting frontoparietal and lateral temporal regions were observed in all cases, and 13 patients had atrophy of the hippocampus. Cerebrospinal fluid examination of 10 patients showed elevated protein levels in six and the presence of oligoclonal bands in four patients. CONCLUSION: A combination of white matter changes, enlarged ventricles, atrophy of the caudate nuclei and thinning of the corpus callosum in magnetic resonance imaging strongly suggests NHD in patients with FTD syndrome. Molecular genetic analysis should be performed in suspected cases, and families should receive genetic counseling.

A novel PSEN2 p.Ser175Phe variant in a family with Alzheimer's disease.

Alzheimer's disease (AD) can be either sporadic or familial, and familial forms of AD accounts for only 5% of the cases. So far, autosomal dominantly inherited mutations in "Presenilin 1" (PSEN1), "Presenilin 2" (PSEN2), and "Amyloid precursor protein" (APP) genes were associated with familial AD. Amid the others, pathogenic mutations in the PSEN2 gene are less common. In this study, we describe a novel heterozygous PSEN2 (c.524C>T, p.Ser175Phe) alteration identified in a 58-year-old Turkish patient from a family with multiple dementia cases. This variant was further present in the patient's clinically affected maternal cousin as well as in the asymptomatic mother and two maternal aunts who were carriers of the APOE ε2/ε3 genotype. The variant is located in the conserved residue of transmembrane domain III encoded by exon 6 of the major transcript. In silico protein structure analyses predicted that this variant might change the architecture of interaction between the two alpha helixes of PSEN2. We propose that p.Ser175Phe may have a pathogenic effect on protein function and may play a significant role in the molecular pathways leading to Alzheimer's disease in this family.

Peripheral TREM2 mRNA levels in early and late-onset Alzheimer disease's patients.

'Triggering receptor expressed on myeloid cells 2' (TREM2) gene is involved in Alzheimer's disease (AD) and TREM2 mRNA expression is known to be increased in the peripheral blood cells of AD patients. In this study, we examined the expression levels of TREM2 mRNA in peripheral leukocytes of early and late-onset AD patients. We have also investigated the effect of the presence of APOE ε4 allele on TREM2 expression. TREM2 mRNA expression was analyzed in 30 early-onset AD (EOAD) patients, 38 late-onset AD (LOAD) patients, and in their age-matched controls by using quantitative real-time polymerase chain reaction. TREM2 levels in LOAD patients were higher than EOAD. Also, in elderly controls significantly higher TREM2 levels were found compared with young controls. Moreover, APOE ε4 carriers in LOAD patients exhibited significantly higher TREM2 expression levels than APOE ε4 non-carriers and elderly controls. Also, correlation analysis showed that TREM2 mRNA expression was increased by age. The differential expression of TREM2 mRNA levels between EOAD and LOAD patients might be independent of the AD disease status and results from an age-related increase in TREM2 expression. In LOAD patients, increased age and the presence of APOE ε4 allele further increase TREM2 expression. Taken together, we can suggest that age is a factor that increases TREM2 expression, and TREM2 and APOE ε4 may interact together in the pathogenesis of LOAD.

Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy.

Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

Association between selected cholesterol-related gene polymorphisms and Alzheimer's disease in a Turkish cohort.

Numerous genetic evidence has pointed out that variations in cholesterol-related genes may be associated with an Alzheimer's disease (AD) risk. We aimed to investigate the association between polymorphisms in several cholesterol-related genes [APOA5 (rs662799), APOC1 (rs11568822), APOD (rs1568565), CH25H (rs13500), LDLR (rs5930), SORL1 (rs2282649)] and AD in a cohort of Turkish patients. The study group consisted of 257 AD patients (mean age: 75.9 years ± 10.4) and 414 controls (mean age: 62.2 years ± 13.1). Genotyping was performed by quantitative real-time polymerase chain reaction using hydrolysis probes. Our results showed that the 'TT' genotype of CH25H rs13500 polymorphism was significantly more frequent in the AD group (p < 0.001) and individuals carrying the CH25H 'T' allele had an increased risk for AD (OR 3.07, 95% CI 2.13-4.44, p = 2.20e-09) independently from age, gender and APOE ε4 allele. Moreover, this risk was excessively increased (OR 14.04, 95% CI 6.99-28.23, p = 9.78e-14) in the presence of APOE ε4 allele. The 'ins/ins' genotype of APOC1 rs11568822 was significantly more frequent in the AD group compared to controls (p = 1.95e-08). However, this increased AD risk in 'ins/ins' carriers was found to be dependent on their APOE ε4 carrier status. No significant associations were found in allele and genotype distributions of APOA5, APOD, LDLR and SORL1 gene polymorphisms. Our results suggest that the association between APOC1 'ins/ins' genotype and AD risk can be explained by linkage disequilibrium with the APOE locus. CH25H rs13500 polymorphism is associated with an AD risk in the Turkish population and CH25H might have a role in the pathogenesis of AD together with, and independently from APOE.

HPCA confirmed as a genetic cause of DYT2-like dystonia phenotype.

BACKGROUND: HPCA (hippocalcin) is one of the underlying genetic causes of autosomal-recessively inherited forms of dystonia. Here, we describe two consanguineous Turkish DYT-HPCA families carrying the novel HPCA mutations. METHODS: After detailed clinical and neurological examination, whole-exome sequencing was performed. RESULTS: Whole-exome sequencing analysis revealed two homozygous novel truncating mutations (p.W103* and p.P10PfsTer80) in the HPCA gene in two unrelated Turkish dystonia families presenting with complex dystonia. CONCLUSIONS: After identification of HPCA as a genetic cause of DYT-HPCA-like dystonia by Charlesworth et al, this is the second report in the scientific literature that describes dystonia families harboring HPCA mutations. Our findings confirm that HPCA leads to recessively inherited dystonia. © 2018 International Parkinson and Movement Disorder Society.

Histologic and Histomorphometric Comparison of Bone Regeneration Between Bone Morphogenetic Protein-2 and Platelet-Derived Growth Factor-BB in Experimental Groups.

Efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2) and recombinant human platelet-derived growth factor-BB (rhPDGF-BB) delivered via absorbable collagen sponge (ACS) on bone formation was evaluated in guinea pig tibias. Three-millimeter-circular bone tibia defects were created in 24 guinea pigs assigned randomly to 4 groups according to the following defect filling materials: ACS only, rhBMP-2+ACS, rhPDGF-BB+ACS, or empty. New bone formation was evaluated histologically and histomorphometrically at 15 (early healing) and 45 days (late healing). Mean new bone per total defect area ratio was 0.73, 0.57, 0.43, and 0.42 in rhBMP-2+ACS, rhPDGF-BB+ACS, ACS only, and empty groups at early healing, respectively. During early healing, significantly more new bone formation was observed in rhBMP-2+ACS and rhPDGF-BB+ACS groups than in the control groups. New bone formation was significantly higher with rhBMP-2+ACS than with rhPDGF-BB+ACS. Mean new bone per total defect area ratio was 0.81, 0.86, 0.74, and 0.75 in the rhBMP-2+ACS, rhPDGF-BB+ACS, ACS only, and empty groups at late healing, respectively. During late healing, new bone formation was significantly higher in the rhPDGF-BB+ACS group relative to both control groups, but the results did not differ significantly from those in the rhBMP-2+ACS group. New bone formation in the rhBMP-2+ACS group did not change significantly between the healing periods. In the rhPDGF-BB+ACS group, however, new bone formation was significantly higher in the late healing period. Both growth factors accelerated new bone formation in the early healing period. Although rhBMP-2 was more effective in the early healing period, the effects of rhPDGF-BB were longer lasting.

A new F-box protein 7 gene mutation causing typical Parkinson's disease.

BACKGROUND: Recessive mutations in the F-box protein 7 gene (FBXO7; PARK15) have been identified as a cause of the parkinsonian-pyramidal syndrome. Here, we report clinical and genetic findings in a Turkish family with novel FBXO7 mutations. METHODS: Whole exome and targeted Sanger sequencing were performed for genetic analysis in a family with two members affected by Parkinson's disease (PD). All family members underwent detailed clinical, mental, and neurological examination. RESULTS: The new p.L34R (c.101 T>G) FBXO7 mutation was detected in a homozygous state in two Turkish sibs with typical levodopa-responsive PD. CONCLUSION: This is the first time a FBXO7 mutation has been identified that causes a phenotype compatible with typical idiopathic PD and presents with some of its common nonmotor features, such as rapid eye movement sleep behavior disorder, depression, and anxiety.

Determining medical students' anxiety and readiness levels about artificial intelligence.

The aim of this study is to determine the levels of anxiety and readiness among medical students regarding artificial intelligence (AI) and examine the relationship between these factors. The research was conducted on medical students, and the data was collected through face-to-face and online surveys between April and June 2022. The study utilized a socio-demographic information form, an AI anxiety scale, and a medical AI readiness scale. The data collected from a total of 542 students were analyzed using the Statistical Program for Social Sciences (SPSS) version 25. Cronbach's α coefficient was used for reliability analysis. A path diagram was created using AMOS 24, and structural equation modelling (SEM) analysis was applied. The findings of the study indicate that medical students have a moderate level of readiness and a high level of anxiety regarding AI. Furthermore, an inverse relationship was found between AI readiness and AI anxiety. These results highlight the importance of increasing the preparedness of medical students for AI applications and reducing their anxieties. The study suggests the inclusion of AI in the medical curriculum and the development of a standardized curriculum to facilitate its teaching.

Evaluation of Turkish Academic and Student Attitudes on Plagiarism: Validity and Reliability of the Plagiarism Attitudes Scale.

The main purpose of this study was to translate the Plagiarism Attitude Scale into Turkish and validate it for use in Turkish settings, in order to better understand research integrity attitudes and awareness of the Turkish academic and student community, while also contributing an instrument for research in this area. The research was designed and conducted with 483 participants. In the process of adapting the scale to Turkish, language, content, and construct validity analyses were performed. Following the completion of the validity phase, the reliability of the scale was examined using Cronbach's alpha coefficient and the split-half method. The results indicate that the scale's language and content validity are deemed sufficient. According to the findings of the research, the Plagiarism Attitude Scale, in its adapted Turkish version, is considered a valid and reliable tool. The use of this Turkish scale will assist local researchers in sharing their unique perspectives and help the international community better understand research ethics concerns in Türkiye. Additionally, this scale will serve as a valuable resource for planning educational programs.

TREX1 p.A129fs and p.Y305C variants in a large multi-ethnic cohort of CADASIL-like unrelated patients.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and retinal vasculopathy with cerebral leukodystrophy and systemic manifestations (RVCL-S) are the most common forms of rare monogenic early-onset cerebral small vessel disease and share clinical, and, to different extents, neuroradiological and neuropathological features. However, whether CADASIL and RVCL-S overlapping phenotype may be explained by shared genetic risk or causative factors such as TREX1 coding variants remains poorly understood. To investigate this intriguing hypothesis, we used exome sequencing to screen TREX1 protein-coding variability in a large multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic CADASIL-like Caucasian patients from the USA, Portugal, Finland, Serbia and Turkey. We report 2 very rare and likely pathogenic TREX1 mutations: a loss of function mutation (p.Ala129fs) clustering in the catalytic domain, in an apparently sporadic 46-year-old patient from the USA and a missense mutation (p.Tyr305Cys) in the well conserved C-terminal region, in a 57-year-old patient with positive family history from Serbia. In concert with recent findings, our study expands the clinical spectrum of diseases associated with TREX1 mutations.

Effect of Euthanasia Education on the Views of Nursing Students.

Background: Nurses play an important role in the healthcare team and are closely involved in the daily care of patients. Sometimes, they are involved in the care of terminal patients, who may thus be confronted with difficult end-of-life decisions such as euthanasia. Therefore, it is important to determine the views on euthanasia of nursing students who will work in health care and prepare them for such situations in their professional life. This study aimed to evaluate the effect of euthanasia education on nursing students' opinions. Methods: Pretest-posttest single group semi-experimental method was used in the study. Data were obtained with two surveys carried out both before and after education. Descriptive statistics, Chi-square test, or Fisher's exact tests were used to analyze. Results: Euthanasia education provided students with a different perspective. The results indicated that 56.4% of the students that they knew about euthanasia partially enough before education. After the training, 65.5% of them indicated that they had enough knowledge. Rate of those who are undecided on many questions before education decreased. Conclusions: Education can significantly change nursing students' approach to euthanasia and provides ethical awareness. Euthanasia and related topics should be added to the curriculum. Students should be encouraged to express their opinions and questions about euthanasia. Students should receive ethics education to prepare them to deal with euthanasia-related issues in their professional lives.

A novel homozygous COL11A2 deletion causes a C-terminal protein truncation with incomplete mRNA decay in a Turkish patient.

Recessive mutations in COL11A2 (collagen, type XI, alpha 2), are responsible for otospondylomegaepiphyseal dysplasia (OSMED) and non-syndromic hearing loss while dominant mutations are associated with Stickler type III, isolated cleft palate, Robin sequence, non-ophthalmic Stickler syndrome, early onset osteoarthritis and autosomal dominant hearing loss. We describe here the clinical findings of two Turkish cousins with OSMED carrying a novel homozygous truncating mutation in exon 38 of COL11A2 gene, c.2763delT, identified on cDNA and confirmed at gDNA. This mutation is located on triple helix repeat domain of the collagen alpha-2(XI) chain, where the majority of the previously identified mutations are located. Real-time RT-PCR experiment provided that mutated transcript does not decay completely. Although our analysis displays the partial survival of the mutant transcript from blood tissue, not from cartilage, we propose that this mechanism may play an important role on the variable expressivity of the heterozygous COL11A2 gene mutations.

PHACTR1 genetic variability is not critical in small vessel ischemic disease patients and PcomA recruitment in C57BL/6J mice.

Recently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical artery dissection and hypertension. Although these represent significant risk factors or comorbidities for ischemic stroke, PHACTR1 role in brain small vessel ischemic disease and ischemic stroke most important survival mechanism, such as the recruitment of brain collateral arteries like posterior communicating arteries (PcomAs), remains unknown. Therefore, we applied exome and genome sequencing in a multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic brain small vessel ischemic disease and CADASIL-like Caucasian patients from US, Portugal, Finland, Serbia and Turkey and in 2 C57BL/6J stroke mouse models (bilateral common carotid artery stenosis [BCCAS] and middle cerebral artery occlusion [MCAO]), characterized by different degrees of PcomAs patency. We report 3 very rare coding variants in the small vessel ischemic disease-CADASIL-like cohort (p.Glu198Gln, p.Arg204Gly, p.Val251Leu) and a stop-gain mutation (p.Gln273*) in one MCAO mouse. These coding variants do not cluster in PHACTR1 known pathogenic domains and are not likely to play a critical role in small vessel ischemic disease or brain collateral circulation. We also exclude the possibility that copy number variants (CNVs) or a variant enrichment in Phactr1 may be associated with PcomA recruitment in BCCAS mice or linked to diverse vascular traits (cerebral blood flow pre-surgery, PcomA size, leptomeningeal microcollateral length and junction density during brain hypoperfusion) in C57BL/6J mice, respectively. Genetic variability in PHACTR1 is not likely to be a common susceptibility factor influencing small vessel ischemic disease in patients and PcomA recruitment in C57BL/6J mice. Nonetheless, rare variants in PHACTR1 RPEL domains may influence the stroke outcome and are worth investigating in a larger cohort of small vessel ischemic disease patients, different ischemic stroke subtypes and with functional studies.

A patient with early-onset Alzheimer's disease with a novel PSEN1 p.Leu424Pro mutation.

"Presenilin 1" (PSEN1) gene mutations are the major known genetic cause of early-onset Alzheimer's disease. Herein, we report a novel heterozygous PSEN1 mutation (p.Leu424Pro) in a Turkish patient presenting with deterioration of short-term memory and visuospatial skills starting at the age of 47 years. This novel mutation is located in the conserved residue of transmembrane domain 8 coded by exon 12. At the protein level, this mutation caused a disruption in the alpha helix structure of PSEN1. The structural and possible functional consequences of the mutation suggest that it has probably a pathogenic effect, which in turns had a potential role in the development of Alzheimer's disease in our patient.