TS Patients Research Articles

SUN-084 A Quantitative-PCR Based Rapid and Cost-Effective Diagnostic Method for Turner Syndrome and Its Variants

Turner’s syndrome (TS) is a common aneuploidy diagnosed by peripheral blood karyotyping in patients. Karyotyping involves manual labour, time and costs. Quantitative real-time PCR (qPCR) is a rapid molecular diagnostic test for TS that yields results of upto 48 samples within two hours at low cost with reasonable accuracy. To assess the sensitivity and specificity of qPCR in the rapid diagnosis of TS, genomic DNA was isolated and estimated from peripheral blood from 50 TS patients(45,XO-23, XO/XX mosaics - 10, Isochromosome Xq-12, XO/XY mosaics - 5), 25 normal females(46,XX) and 5 normal males(46,XY). qPCR was done using 96 well plates, fast real-time PCR. 4 primers were used - two on Xp [SHOX and ARSE] and two on Xq (VAMP7 and XIST). Autosomal gene HBB was used as housekeeping gene. The ΔΔ CT method was used for calculation of the ‘X gene dose’ with respect to the housekeeping gene and X genes from normal females. Differences of doses of the four X-chromosomal primers in different karyotypes were analysed. ROC curves were plotted to determine cut-offs to discriminate the different karyotypes of TS from normal females. qPCR could distinguish classical TS from normal females with >95% sensitivity and specificity. SHOX gene primer was the best to diagnose TS of all karyotypes combined and also classical TS(XO) from normal females. qPCR could also identify non-classical TS with >92% sensitivity and specificity,the best primer being ARSE, for detecting both mosaics and isochromosomes. The cut-offs determined from our study corroborates with past similar studies.1,2 qPCR using an appropriate panel of primers on the short and long arms of X chromosomes can be a rapid and cheaper alternative to karyotyping to diagnose TS of different karyotypes. The choice of primers should be guided by the need for a more sensitive or specific test depending on the clinical scenario. If used as a neonatal screening test, SHOX should be the best primer. For diagnostic purposes, when the pre-test probability is low, a more specific primer like SHOX would be more appropriate. However, when the pre-test probability is high, a sensitive primer for ruling out TS like VAMP7 is better. In case there is a high pre test probability of the patient having a non-classic TS rather than classic TS, ARSE should be used. This is the first study to show good sensitivity of qPCR in detecting non-classic TS of different karyotypes in addition to classic TS.

Natural History of Adult Patients with GM2 Gangliosidosis.

GM2 gangliosidoses are lysosomal diseases due to biallelic mutations in the HEXA (Tay-Sachs disease [TS]) or HEXB (Sandhoff disease [SD]) genes, with subsequent low hexosaminidase(s) activity. Most patients have childhood onset, but some experience the first symptoms during adolescence/adulthood. This study aims to clarify the natural history of adult patients with GM2 gangliosidosis. We retrospectively described 12 patients from a French cohort and 45 patients from the literature. We observed 4 typical presentations: (1) lower motoneuron disorder responsible for proximal lower limb weakness that subsequently expanded to the upper limbs, (2) cerebellar ataxia, (3) psychosis and/or severe mood disorder (only in the TS patients), and (4) a complex phenotype mixing the above 3 manifestations. The psoas was the first and most affected muscle in the lower limbs, whereas the triceps and interosseous were predominantly involved in the upper limbs. A longitudinal study of compound motor action potentials showed a progressive decrease in all nerves, with different kinetics. Sensory potentials were sometimes abnormally low, mainly in the SD patients. The main brain magnetic resonance imaging feature was cerebellar atrophy, even in patients without cerebellar symptoms. The prognosis was mainly related to gait disorder, as we showed that beyond 20 years of disease evolution, half of the patients were wheelchair users. Improved knowledge of GM2 gangliosidosis in adults will help clinicians achieve correct diagnoses and better inform patients on the evolution and prognosis. It may also contribute to defining proper outcome measures when testing emerging therapies. ANN NEUROL 2020;87:609-617.

The association between tic medication therapy and psychiatric comorbidities among patients with Tourette syndrome: A national population-based study in Taiwan

BackgroundTourette syndrome (TS) is often comorbid with attention deficit hyperactivity disorder, obsessive–compulsive disorder, and depression. Medications are the main treatment for TS. Relationships between TS medication therapy and psychiatric comorbidities remain unclear. This study explored the impacts of TS medication on the risk of psychiatric comorbidities using a nationally representative sample of TS in Taiwan. MethodsData from National Health Insurance Research Database in Taiwan was used to identify 997,213 children and adolescents aged 6–18 years who had received a diagnosis of TS based on ICD-9-CM codes in 2000–2010. Cox’s proportional hazard regression analysis was conducted to estimate the risk of comorbidities among subjects with and without tic medication therapy. ResultsWe found that in TS patients, a lower risk of psychiatric comorbidities occurred in the tic medication therapy group (p = 0.012) and the crude hazard ratio (HR) was 0.6 (95% confidence interval (CI) = 0.4–0.8, p < 0.001). After adjusting for potential confounders of gender, age, income, level of care, department visited, brain injury, and the number of suicide attempts, the risk of comorbidities was still significantly lower in the tic medication therapy group (adjusted HR = 0.5, 95% CI = 0.3–0.6, p < 0.001). DiscussionOne limitation was that we did not include all mediations used to treat psychiatric comorbidities among TS patients. This study found the effectiveness of TS medications on improving psychiatric comorbidities. ConclusionsCompared to those without medication, medication therapy appears to have a benefit of decreasing the risk of psychiatric comorbidities. Strategies to improve medication regimens should be considered in clinical settings.

Family-Based Analysis Combined with Case-Controls Study Implicate Roles of PCNT in Tourette Syndrome.

ObjectiveTourette syndrome (TS) is a childhood-onset neuro-developmental disorder and the genetic factors play an important role in its etiology. As pericentrin (PCNT) binds to disruption-in-schizophrenia 1 (DISC1) and is a risk factor for many mental illnesses, we aimed to investigate the effect of PCNT on TS in the Chinese Han population.MethodsFive tag single nucleotide polymorphisms (SNPs) (rs17371795, rs2839227, rs2839228, rs6518291 and rs9983522) in PCNT were screened in 407 TS nuclear family trios and 506 healthy persons by the TaqMan assays real-time. A common case–control study was designed to recognize differences in the genetic distributions. Additionally, we conducted a family based association study including transmission disequilibrium test, haplotype relative risk, and haplotype-based haplotype relative risk for these SNPs.ResultsThe allele frequencies revealed a significant difference of rs17371795, rs2839227 and rs2839228 between TS patients and controls (for rs17371795: P=0.002, OR=0.691, 95% CI=0.547–0.874; for rs2839227: P=0.001, OR=0.682, 95% CI=0.540–0.860; for rs2839228: P=0.028, OR=0.775, 95% CI=0.618–0.973) and genotypic distributions showed a positive association only in rs17371795 and rs2839227 (for rs17371795: P=0.010; for rs2839227: P=0.008). Moreover, only rs2839227 remained significant after Bonferroni correction (P<0.01).ConclusionOur study suggested genetic variability at the PCNT locus may be associated with TS risk in the Chinese Han population.

Evaluation of the usefulness of antymüllerian hormone and inhibin B as markers of ovarian activity in patients with Turner syndrome - preliminary results.

Spontaneous puberty occurs in 30% of patients with Turner Syndrome. Its absence is an indication for hormone replacement therapy (HRT). No reliable markers of spontaneous puberty have been defined to date. To evaluate the usefulness of antymüllerian hormone (AMH) and inhibin B assessment in predicting ovarian function and spontaneous puberty in girls with TS. The study included 35 TS patients treated with human recombinant growth hormone (rhGH). Gonadal axis function parameters (LH, FSH and estradiol) were evaluated at the age of physiological puberty (10-12 years, mean 10.5 years), before introduction of HRT. Ad-ditionally AMH and inhibin B levels were assessed. In follow up patients were divided into 2 groups: with (SP) and without (WP) spontaneous puberty. Spontaneous puberty was defined as Tanner stage 2 or higher breast development. WP patients were observed until the mean age of 16y. SP occurred in 16 patients (mean age 10 years). Patients with SP presented with significantly lower mean FSH level (1.14-91.1 mIU/ml, mean mIU/ml 24.5 vs. 7.7-196.4 mIU/ml, mean 66.5 mIU/ml, p = 0.002), higher mean estradiol (10.5-68.8 pg/ml, mean 28.4 pg/ml vs. 6.1-26.0 pg/ml, mean 14.9 pg/ml, p = 0.005), AMH (0.0-3.11 ng/ml, mean 0.8 ng/ml vs. 0.0-0.002 ng/ml, mean 0.003 ng/ml, p = 0.001) and inhibin B (0.0-110.0 pg/ml, mean 29.1 pg/ml vs. 0.0-11.0 pg/ml, mean 1.06 pg/ml, p = 0.026) levels. In three SP patients without elevated FSH level (FSH < 35 mIU/ml) we found zero concen-tration levels of AMH and inhibin B. SP patients had mosaic (non 45,X) karyotype in 87.5% and WP patients only in 47%. AMH and inhibin B assessment may be a valuable complement to the diagnosis of ovarian function in patients with TS. Low levels of these parameters may indicate a risk of ovarian failure even in patients with spontaneous puberty and without hypergonadotropic hy-pogonadism.

Deficient knowledge in adult Turner syndrome care as an incentive to found Turner centers in Germany.

ObjectiveTurner syndrome (TS) is characterized by the complete or partial loss of the second sex chromosome and associated with a wide range of clinical manifestations. We aimed to assess the medical care of adult patients with TS in Germany.DesignRetrospective multicenter observational study.MethodsData were collected from medical records of 258 women with TS treated between 2001 and 2017 in five non-university endocrinologic centers in Germany.ResultsMean age was 29.8 ± 11.6 years, mean height 152 ± 7.7 cm, and mean BMI 26.6 ± 6.3 kg/m2. The karyotype was known in 50% of patients. Information on cholesterol state, liver enzymes, and thyroid status was available in 81–98% of women with TS; autoimmune thyroiditis was diagnosed in 37%. Echocardiography was performed in 42% and cardiac MRI in 8.5%, resulting in a diagnosis of cardiovascular disorder in 28%. Data on growth hormone therapy were available for 40 patients (15%) and data concerning menarche in 157 patients (61%).ConclusionIn 258 women with TS, retrospective analysis of healthcare data indicated that medical management was focused on endocrine manifestations. Further significant clinical features including cardiovascular disease, renal malformation, liver involvement, autoimmune diseases, hearing loss, and osteoporosis were only marginally if at all considered. Based on this evaluation and in accordance with recent guidelines, we compiled a documentation form facilitating the transition from pediatric to adult care and further medical management of TS patients. The foundation of Turner Centers in March 2019 will improve the treatment of TS women in Germany.

Autoimmunity Predisposition in Girls With Turner Syndrome.

Background: Turner Syndrome is associated with an increased risk of autoimmune diseases, such as autoimmune thyroiditis, coeliac disease, type 1 diabetes mellitus, inflammatory bowel disease, alopecia areata, or vitiligo. The presence of isochromosome iXq and exposure to estradiol may contribute to the development of the autoimmune process. The aim of this study was to determine the prevalence of autoimmune diseases in a group of TS patients and to assess the impact of karyotype and puberty on the development of autoimmune diseases.Patients and Methods: The analysis encompassed clinical and biochemical data of 134 patients treated between 2001 and 2018. All the patients were examined for autoimmune disease symptoms and tested for the presence of antithyroperoxidase (anti-TPO) and antithyreoglobulin (anti-TG) antibodies. In 73 of the patients, anti-transglutaminase (anti-tTG) antibodies were measured. Thyroid function was assessed by measuring TSH and fT4 levels.Results: The mean follow-up was 5.7 ± 3 years. An autoimmune disease was diagnosed in 46 (34.3%) patients: 39 (29.1%) had only one disorder, whilst 7 (5.2%) presented two disorders. The most common disorder, observed in 40 (29.9%) patients, was thyroid autoimmunity. Hashimoto disease was diagnosed in 20 (14.9%) patients. Of the 73 patients tested for coeliac disease, 4 (5.5%) had anti-tTG and 2 (2.7%) presented overt coeliac disease. Vitiligo was diagnosed in 3 (2.2%) patients, type 1 diabetes mellitus or psoriasis were diagnosed in 2 (1.5%) patients, whilst alopecia areata or lichen sclerosus were diagnosed in 1 (0.7%) patient. The impact of karyotype or estradiol exposure on developing autoimmune diseases were not statistically significant.Conclusions: Our study showed a higher incidence of autoimmune diseases in TS, which is in line with the literature; however, the impact of iXq, or spontaneous/inducted puberty was not confirmed.

Clinical Impact of Atrial Fibrillation on Short-Term Outcomes and In-Hospital Mortality in Patients with Takotsubo Syndrome: A Propensity-Matched National Study

IntroductionTakotsubo Syndrome (TS) patients are at high risk of developing atrial fibrillation. We sought to investigate the outcomes and economic impact of atrial fibrillation on TS patients utilizing the National Inpatient Sample. MethodsPatients with TS were identified in the National Inpatient Sample (NIS) database between 2010 and 2014 using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM), and subsequently were divided into two groups, those with and without atrial fibrillation. The primary outcome was all-cause in-hospital mortality in the two groups. Secondary outcomes were in-hospital complications. We also evaluated the length of hospital stay and the cost of hospitalization. Propensity score-matched analysis was performed to address potential confounding factors. ResultsAmong the study population, the prevalence of atrial fibrillation was 17.57%. After matching, the atrial fibrillation group had no significant increase of in-hospital mortality (OR: 1.13; 95% CI: 0.94–1.35, p = 0.211). However, atrial fibrillation patients were more likely to develop cardiac arrest and ventricular arrhythmias (OR: 1.51, 95% CI: 1.26–1.80, p < 0.0001), have higher rate of major cardiac complications when combined as a single endpoint in-hospital complication (OR: 1.16, 95% CI: 1.04–1.29, p: 0.006), also they were more likely to stay longer in hospital (OR: 1.13, 95% CI: 1.08–1.19, p < 0.0001), and have increased cost of hospitalization (OR: 1.13, 95% CI 1.07–1.20, p < 0.0001). ConclusionAtrial fibrillation does not increase in-hospital mortality in patients presenting with TS. However atrial fibrillation is associated with an increased risk of ventricular arrhythmias, length of stay, non-routine discharges and cost of hospitalization.

The cardioprotective effects of icariin on the isoprenaline-induced takotsubo-like rat model: Involvement of reactive oxygen species and the TLR4/NF-κB signaling pathway

IntroductionTakotsubo syndrome (TS) is an acute cardiac syndrome that mimics acute coronary syndrome (ACS) but lacks coronary obstruction and is associated with sudden physical or psychiatric episodes. Several hypotheses have been proposed for the TS mechanism, but the precise cause of this syndrome remains poorly known. Recent studies noted TS patients with acute endogenous catecholamine discharge, which could trigger an oxidative stress response and inflammatory action. MethodsA single dose of the selective β-adrenergic agonist isoprenaline (ISO) was used to induce a takotsubo-like (TS-like) model. Different icariin or metoprolol doses were supplied as cardioprotective agents by intragastric administration (IG), and lipopolysaccharides (LPS) were assessed to investigate the possible mechanism of action of icariin. Transthoracic echocardiography was used to study cardiac function and morphology. The amounts of intracellular lipids and myocardial fibrosis, which represent the degree of cardiac impairment, were assessed by histological analysis. Real-time polymerase chain reaction (RT-PCR) was performed to analyze a variety of anti-oxidant elements and inflammatory factors, and Western blotting was conducted to analyze the expression of signaling pathway proteins involved in the development of TS. ResultsThe TS-like incidence in rats was lowest with icariin precondition at 2-h post-ISO administration, and both the left ventricular ejection fraction (LVEF) and ejection volume per minute were higher than those of the other groups. However, LPS administration increased the incidence of TS and aggravated cardiac impairment. Moreover, ISO significantly increased the levels of both reactive oxygen species (ROS) and TLR4/NF-κB signaling pathway proteins compared to those of the Sha-group, whereas icariin remarkably decreased the ROS levels and increased anti-oxidant element expression while reducing pro-inflammatory factor secretion and suppressing TLR4/NF-κB signaling pathway protein expression. However, the cardioprotective effect of icariin was significantly weakened by combining treatment with LPS. ConclusionIcariin prevented ISO-induced TS-like cardiac dysfunction in rats. The effects were induced mainly through maintenance of the dynamic balance of the ROS system, promotion of anti-oxidant element activity, and suppression of TLR4/NF-κB signaling pathway protein expression. Furthermore, the ability of icariin to increase anti-inflammatory and reduce pro-inflammatory factor secretion may be involved in the protective process.

Nipple-Areolar Complex Position in Female-to-Male Transsexuals After Non-skin-excisional Mastectomy: A Case-Control Study in Japan.

Mastectomy is performed in female-to-male transsexual (FTM TS) patients as a surgical treatment to make a female thorax resemble a male thorax; however, no studies have examined the nipple-areolar complex (NAC) position in FTM TS patients after mastectomy. The NAC position in 41 FTM TS patients before and after non-skin-excisional mastectomy was examined and compared with that in 50 age- and BMI-matched biologically male subjects as controls. The factors affecting the NAC position after the operation were also examined and verified by multiple regression analysis. After non-skin-excisional mastectomy, the NAC in the FTM TS patients was positioned significantly more medially (horizontal NAC position ratio {('internipple distance'/'width of thorax') × 100} [HNPR]: preoperatively, 70.07% ± 4.19%; postoperatively, 63.28% ± 3.79%) and cranially (vertical NAC position ratio {('distance from sternal notch to nipple height'/'distance from sternal notch to umbilicus') × 100} [VNPR]: preoperatively, 43.87% ± 3.68%; postoperatively, 41.37% ± 3.15%). Postoperatively, the NAC in the FTM TS patients was located significantly more medially than that in the control subjects (HNPR: 63.28% ± 3.79% to 66.79% ± 4.82%), although the height of the NAC was the same. Multiple regression analysis revealed that the NAC position on breasts characterized by ptosis, a high projection, and lateral leaning (low skin elasticity and a substantial amount of skin between the nipples) tended to be positioned more medially after non-skin-excisional mastectomy. Laterally deviated eccentric circulartype mastectomy may be a good option for FTM TS patients who have moderately sized breasts with such features. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Rare copy number variants in the genome of Chinese female children and adolescents with Turner syndrome.

Turner syndrome (TS) is a congenital disease caused by complete or partial loss of one X chromosome. Low bone mineral status is a major phenotypic characteristic of TS that can not be fully explained by X chromosome loss, suggesting other autosomal-linked mutations may also exist. Therefore, the present study aimed to detect potential genetic mutations in TS through examination of copy number variation (CNV). Seventeen patients with TS and 15 healthy volunteer girls were recruited. Array-based comparative genomic hybridization (a-CGH) was performed on whole blood genomic DNA (gDMA) from the 17 TS patients and 15 healthy volunteer girls to identify potential CNVs. The abnormal CNV of one identified gene (CARD11) was verified by quantitative PCR. All cases diagnosed had TS based on genotype examination and physical characteristics, including short stature and premature ovarian failure. Three rare CNVs, located individually at 7p22.3, 7p22.2, and Xp22.33, where six genes (TTYH3, AMZ1, GNA12, BC038729, CARD11, and SHOX (stature homeobox)) are located, were found in TS patients. Quantitative PCR confirmed the CNV of CARD11 in the genome of TS patients. Our results indicate that CARD11 gene is one of the mutated genes involved in TS disease. However, this CNV is rare and its contribution to TS phenotype requires further study.

Insulin resistance linked to subtle myocardial dysfunction in normotensive Turner syndrome young patients without structural heart diseases.

Background Turner syndrome (TS) patients have increased cardiovascular risk. This cardiovascular risk is famously attributed to structural abnormalities of the left side of the heart such as aortic stenosis and aortic coarctation. However, due to insulin resistance and subsequent pathogenic mechanisms, normotensive TS patients without structural abnormalities may develop varying degrees of myocardial dysfunction. The aim of this research was to examine the role of speckle tracking echocardiography in early detection of Turner cardiomyopathy and to correlate this myocardial dysfunction with measures of insulin resistance. Methods This cross-sectional case control study included 30 children with TS and 30 age-matched healthy controls. TS patients were excluded if: hypertensive, with major structural abnormalities of the heart or other systemic diseases that may affect myocardial function. Conventional speckle tracking echocardiography and glucose-insulin ratio were performed for all study subjects. Results Routine echocardiographic parameters of left ventricular systolic function were similar in cases and controls while global longitudinal and circumferential strain (GLS and GCS) were lower in patients with TS than controls: (-13.2±1.1 vs. -18.3±2.4, p-value<0.000) and (-11.3±1.1 vs. -16.3±2.1, p-value<0.000), respectively. Fasting glucose:insulin ratio (FGIR) proved to be the best predictor of myocardial dysfunction in TS patients by multivariate analysis. Conclusions This study points towards the potential role of two-dimensional (2D) speckle tracking echocardiography in early detection of subtle systolic myocardial dysfunction in TS patients. It also points towards the implication of insulin resistance in precipitation of the observed dysfunction in TS patients.

Cognitive and motor event-related potentials in Tourette syndrome and tic disorders: A systematic review

ObjectivesTourette syndrome (TS) patients face various cognitive and motor impairments. Event-related potentials (ERP) constitute an effective way to investigate the neural correlates of those functional impairments. Various components have been assessed among TS patients, with a wide variety of paradigms. This systematic review aimed to evaluate the portrait of ERP components in TS patients, and to understand the factors leading to discrepancies across studies. MethodsA literature search was performed in Embase, PsycINFO, Pubmed, and Web of Science, to identify studies that conducted ERP experiments among TS patients. Of the 372 unique records identified, 47 met inclusion criteria and were included in our systematic review. ResultsVarious ERP particularities were reported among included studies. Many discrepancies exist, but impairments in motor-related potentials and contingent negative variation seem constant across studies. Divergent findings point toward a possibly reduced P3b during oddball tasks. ConclusionsERPs offer an insightful investigation into the cognitive and motor functions of TS patients. Future studies should always control for confounding factors such as comorbidity, age, or medication status. SignificanceThis is the first systematic review of ERP in TS patients. Motor-related and slow cortical potentials could constitute electrophysiological markers of TS.

21-hydroxylase autoantibodies are more prevalent in Turner syndrome but without an association to the autoimmune polyendocrine syndrome type I.

Turner syndrome (TS) is associated with an increased frequency of autoimmunity. Frequently observed autoimmune diseases in TS are also seen in the autoimmune polyendocrine syndrome type I (APS I), of which Addison disease is a key component. An overlapping antibody profile between TS and APS I could be considered. The aim of this work was to study women with TS regarding 21-hydroxylase (21-OH) antibodies and interferon omega (IFN-ω) antibodies, a highly specific marker for APS I, to determine if there are immunological overlaps between TS and APS I. Blood samples from 141 TS were assayed for 21-OH antibodies and IFN-ω antibodies using in-vitro-transcribed and translated autoantigen. Indices with a cut-off point of 57 and 200 for 21-OH antibody and IFN-ω antibody were used as reference. The median age of TS was 31·6years (range=11·2-62·2). Positive indices of 21-OH antibodies were present in six TS (4%), with a mean of 144·8 (range=60-535). None had apparent adrenal insufficiency. There was no age difference comparing 21-OH antibody-positive TS (median age=33·9years, range=17·7-44·7) and 21-OH antibody-negative TS (median age=31·6years, range=11·2-62·2) (P=0·8). No TS was positive for IFN-ω antibodies (mean=42·4, range=-435-191). No overlapping autoimmune profile between TS and APS I was found. Autoimmunity against 21-OH among TS patients was more prevalent than previously identified, suggesting an increased risk of adrenal failure in TS. However, whether adrenal impairment will develop remains unknown.

Ethics of Deep Brain Stimulation in Adolescent Patients with Refractory Tourette Syndrome: a Systematic Review and Two Case Discussions

IntroductionTourette Syndrome (TS) is a childhood onset disorder characterized by vocal and motor tics and often remits spontaneously during adolescence. For treatment refractory patients, Deep Brain Stimulation (DBS) may be considered.Methods and ResultsWe discuss ethical problems encountered in two adolescent TS patients treated with DBS and systematically review the literature on the topic. Following surgery one patient experienced side effects without sufficient therapeutic effects and the stimulator was turned off. After a second series of behavioural treatment, he experienced a tic reduction of more than 50%. The second patient went through a period of behavioural disturbances that interfered with optimal programming, but eventually experienced a 70% tic reduction. Sixteen DBS surgeries in adolescent TS patients have been reported, none of which pays attention to ethical aspects.DiscussionSpecific ethical issues arise in adolescent TS patients undergoing DBS relating both to clinical practice as well as to research. Attention should be paid to selecting patients fairly, thorough examination and weighing of risks and benefits, protecting the health of children and adolescents receiving DBS, special issues concerning patient’s autonomy, and the normative impact of quality of life. In research, registration of all TS cases in a central database covering a range of standardized information will facilitate further development of DBS for this indication.ConclusionClinical practice should be accompanied by ongoing ethical reflection, preferably covering not only theoretical thought but providing also insights in the views and perspectives of those concerned, that is patients, family members and professionals.

Variants in chondroitin sulfate metabolism genes in thrombotic storm

IntroductionThrombotic storm (TS) presents as a severe, acute thrombotic phenotype, characterized by multiple clotting events and frequently affecting younger adults. Understanding the extensive hypercoagulation of an extreme phenotype as TS will also provide insight into the pathogenesis of a wider spectrum of thrombotic disorders. Material and methodsWe completed whole exome sequencing on 26 TS patients, including 1 multiplex family, 13 trios and 12 isolated TS patients. We examined both dominant and recessive inheritance models for known thrombotic factors as well as performed a genome-wide screen. Identified genes of interest in the family and trios were screened in the remaining TS patients. Variants were filtered on frequency (<5% in 1000 genomes), conservation and function in gene and were annotated for effect on protein and overall functionality. ResultsWe observed an accumulation of variants in genes linked to chondroitin sulfate (CS), but not heparan sulfate metabolism. Sixteen conserved, rare missense and nonsense variants in genes involved in CS metabolism (CHPF, CHPF2, CHST3, CHST12, CHST15, SLC26A2, PAPSS2, STAB2) were identified in over one-third of the TS patients. In contrast, we identified only seven variants in known thrombosis genes (including FV Leiden). ConclusionsAs CS has multiple functions in the glycocalyx protecting the endothelial cells, reduced availability of CS could diminish the normal control mechanisms for blood coagulation, making these CS metabolism genes strong potential risk factors for TS. Overall, no single gene was identified with strong evidence for TS causality; however, our data suggest TS is mediated by an accumulation of rare pro-thrombotic risk factors.

Comparison of the Accuracy and Reproducibility of the Femoral Tunnel Location Between Anterior and Posterior Viewing During Outside-In Anterior Cruciate Ligament Reconstruction

Accuracy and reproducibility of the femoral tunnel location could be improved with a TS portal viewing using a 30° arthroscope. During outside-in anterior cruciate ligament (ACL) reconstruction, anteromedial (AM) or anterolateral (AL) portals are usually used for the viewing of the femoral foot print. However, observing the posterior portion of the ACL femoral foot print (AM bundle footprint) using an AM or AL portal could be difficult due to blocking by remnant ACL or ridge on the medial wall of the lateral femoral condyle. In this view point, using a 70° arthroscope through posterolateral (PL) portal, posterior part of the ACL footprint could be seen directly. However, this view could be a little distorted because the wall of the ACL insertion should be seen from posterior to anterior direction. The posterior trans-septal portal (TS) could allow direct visual access to the posterior part of the ACL femoral footprint through the posteromedial (PM) portal. The purpose of this study was to compare the accuracy and reproducibility of the femoral tunnel location between three different viewing techniques (observed through an AL or AM portal using a 30° arthroscope (A group) vs. PL portal using a 70° arthroscope (PL group) vs. TS portal using a 30° arthroscope (TS group) by 3D CT in outside-in ACL reconstruction. The hypothesis of this study was that femoral tunnel locations would be more accurate and reproducible in the posterior viewing group (PL and TS), and the TS viewing technique would be the best because it offers the most direct view of the medial wall of the lateral femoral condyle. One-hundred and six outside-in ACL constructions patients were recruited. Patients were divided into three groups according to the viewing techniques (36 A vs. 35 PL vs. 35 TS patients). Femoral tunnel locations were evaluated with a quadrant method and anatomic coordinate axes measurement (ACAM) method in the medial wall of the lateral femoral condyle using 3D reconstructed CT. The accuracy and reproducibility of the femoral tunnel locations were compared between three techniques. The accuracy of the tunnel location was higher in the TS group by the quadrant method (A group vs. TS group: p<0.001, PL group vs. TS group: p<0.001) as well as the ACAM (A group vs. TS group: p<0.001, PL group vs. TS group: p=0.02). The reproducibility of the femoral tunnel position in the TS group was the highest and femoral tunnel locations of the TS group were more compactly distributed compared with those of the A and PL group (standard deviation: A group [4.68%], PL group [3.75%], and TS group [1.34%] by the quadrant method; A group [5.18%], PL group [3.85%], and TS group [1.92%] by the ACAM method). Accuracy and reproducibility of the femoral tunnel location could be improved with a TS portal viewing using a 30° arthroscope and anterior and PL portal viewing using a 70° arthroscope showed no difference.

Genome-wide association study in takotsubo syndrome — Preliminary results and future directions

BackgroundTakotsubo syndrome (TS) is an acute non-ischemic cardiomyopathy characterized by transient regional systolic dysfunction of the left and/or right ventricle with still unknown etiology. The aim of the current study was to conduct for the first time a genome-wide association study (GWAS) in a cohort of TS patients to identify potential genetic risk variants. MethodsThis single-center study was conducted at the University Heart Center Lübeck from 2008 to 2016. DNA isolation was done according to standard protocols. Imputation of genotypes were performed at the Michigan Imputation Server (https://imputationserver.sph.umich.edu) using the 1000G Phase 3 v5 reference panel. ResultsThe study population consisted of 96 TS patients (91 females, 5 males) with a mean age of 71.9±10.4years and 475 healthy controls (268 males, 207 females). The results of GWAS analysis showed several promising candidate loci (68 loci after applying threshold of p<5∗10−4 and MAF>5%). Of these 68 loci, 18 loci contained top single nucleotide polymorphisms (SNPs) that were supported by SNPs in high Linkage Disequilibrium (r2>0.8) with p<10−3. Two out of the 18 loci contained SNP with hits in the GWAS catalog (traits: blood pressure, thyroid stimulating hormone). ConclusionThis first GWAS analysis in a larger cohort of patients with TS showed promising preliminary results. Further intensive research efforts of international collaborators are now necessary to enable deep-phenotyping of TS patients to ultimately assess a potential genetic cause of TS.

Specific executive control impairments in Tourette syndrome: The role of response inhibition

BackgroundTourette syndrome (TS) is a childhood-onset disorder characterized by motor and vocal tics. While cognitive features of common comorbid conditions such as attention deficit hyperactive disorder and obsessive compulsive disorder have been widely investigated, the cognitive profile of TS patients remains to be precisely defined. In this regard, the executive functions system (EF) is of especial interest. AimsThe aim of the study was to delineate the various components of executive processes in adult TS patients. MethodsA sample of 19 adults diagnosed with TS and 19 age-matched control subjects underwent computerized battery of executive tasks, as well as block design and memory tests. All patients received a thorough clinical assessment with an emphasis on illness severity. ResultsThere was a marked impairment in response inhibition ability regardless of comorbid conditions, In addition, there was decreased accuracy in set shifting, but not in response time. These results imply that impaired response inhibition in the EF system is the primary cognitive impairment in TS and that many of the previously reported impaired executive functions in TS are secondary to this impairment. ConclusionsThis finding of impaired response inhibition in TS may imply that rehabilitation of this inhibition component could prove to be an important therapeutic strategy in adults with TS.

Diagnosing pyogenic, brucella and tuberculous spondylitis using histopathology and MRI: A retrospective study

The present study examined the histopathological and magnetic resonance imaging (MRI) features of pyogenic, brucella and tuberculous spondylitis (PS, BS and TS, respectively). A total of 22 PS, 20 BS and 20 TS patients were included in the study. Histopathological examination was used to assess the lesion structure and composition, and the MRI observation identified the lesion location and signal features. The following histopathological and MRI features were identified significantly more in patients with PS than in patients with BS and TS: Predominant neutrophil infiltration, abnormal intervertebral disk signal, lesions on the ventral and lateral sides of the vertebral bodies, and thick and irregular abscess walls. The following histopathological and MRI features were identified significantly more in patients with BS than in patients with PS and TS: Predominant lymphocyte infiltration, new bone formation, epithelioid granuloma, lesions on the ventral sides of the vertebral bodies, no, or very mild, vertebral body deformation, no abnormal paraspinal soft tissue signal, no intraosseous or paraspinal abscesses, and thin and irregular abscess walls. The following histopathological and MRI features were identified significantly more in patients with TS than in patients with BS and PS: Sequestrum, Langerhans giant cells, caseous necrosis, lesions primarily in the thoracic region and on the lateral sides of the vertebral bodies, no obvious intervertebral disk damage, obvious vertebral body deformation, abnormal paraspinal soft tissue signal, intraosseous or paraspinal abscesses, and thin and smooth abscess walls. In conclusion, it can be suggested that these significant differences in histopathological and MRI features between the three different types of spondylitis may contribute towards the differential diagnosis of the diseases.