KCNN2 mutation in autosomal-dominant tremulous myoclonus-dystonia.

BACKGROUND AND PURPOSE: Despite recent advances in neurogenetics that have facilitated the identification of a number of dystonia genes, many familial dystonia syndromes remain without known cause. The aim of the study was to identify the cause of autosomal dominant tremulous myoclonus-dystonia in a UK kindred with affected individuals in three generations. METHODS: Known genetic causes of myoclonus-dystonia were excluded. We combined clinical and electrophysiological phenotyping with whole-exome sequencing and Sanger sequencing to identify candidate causal variants in a family with tremulous myoclonus-dystonia. RESULTS: The core phenotype consisted of childhood-onset dystonia predominantly affecting hands and neck, with a fast tremor with superimposed myoclonus and, in some individuals, subtle cerebellar signs. We identified a novel missense variant in potassium calcium-activated channel subfamily N member 2 (KCNN2) [NM_021614:c.1112G>A:p.(Gly371Glu)], which was the only variant that we were able to identify as segregating with the phenotype over three generations. This variant, which is absent from the most recent version of gnomAD, was predicted to be deleterious by SIFT and PolyPhen-2 and had an overall CADD score of 29.7. CONCLUSIONS: KCNN2, a member of the KCNN family of potassium channel genes, is highly conserved across species and in humans is highly expressed in the brain, particularly the cerebellum. KCNN2 mutations have never been described as pathological in human disease, but are recognized abnormalities in two rodent models of fast, jerky tremor. Segregation, absence of the variant in the normal population and in-silico prediction of a deleterious effect together with animal models compatible with the clinical phenotype are all in line with KCNN2 mutations being a plausible cause underlying myoclonus-dystonia.

Comparison of microclimate measurements and perceptions as part of a global evaluation of environmental quality at neighbourhood scale.

The EUREQUA project raises the issue of the definition and evaluation of the environmental quality of neighbourhoods. The approach consists of integrating and cross-referencing observable data characterising the physical environment and people's perception of their quality of life. The study area is a neighbourhood in Toulouse (France) with high social and typo-morphological diversity, subject to noise and air pollution nuisances. Three 3-day field campaigns were organised in January, April, and June 2014. Instrumented and commented walks took place three times per day. For each one, measurements of physical environmental parameters and surveys were performed simultaneously at six locations in the neighbourhood. The study focuses on microclimate and thermal comfort issues. It aims to compare in situ meteorological data of air temperature, humidity, wind speed, and mean radiant temperature, with quantitative results rating human perception of heat, humidity, wind, and thermal comfort. The variability in perception and measurements is mainly driven by seasonal effects, especially for heat and humidity, and, to a lesser extent, for wind. Wind perception and measurement also vary spatially, thus highlighting site effects. Linear models indicate a positive link between heat perception and mean radiant temperature, as well as between wind perception and mean and standard deviation of wind speed (with a higher sensitivity of people to wind under winter climate conditions). Finally, it is found that perception of thermal comfort is only slightly linked to the different microclimate dimensions, and is rather driven by other appreciation factors and emotional criteria related to the general environmental quality of the study area.

Correction to: Cardiovascular causes of sudden unexpected death in children and adolescents (0-17 years) : A nationwide autopsy study in the Netherlands.

Correction to:Neth Heart J 2018 https://doi.org/10.1007/s12471-018-1152-y In the version of the article originally published online, there was an error in the 'Methods and results' section of the Abstract. It is stated that 'In the 10-14 year group, hypertrophic cardiomyopathy (n = 1) and ruptured ….

Whole-exome sequencing of the BDR cohort: evidence to support the role of the PILRA gene in Alzheimer's disease.

AIM: Late-onset Alzheimer's disease (LOAD) accounts for 95% of all Alzheimer's cases and is genetically complex in nature. Overlapping clinical and neuropathological features between AD, FTD and Parkinson's disease highlight the potential role of genetic pleiotropy across diseases. Recent genome-wide association studies (GWASs) have uncovered 20 new loci for AD risk; however, these exhibit small effect sizes. Using NGS, here we perform association analyses using exome-wide and candidate-gene-driven approaches. METHODS: Whole-exome sequencing was performed on 132 AD cases and 53 control samples. Exome-wide single-variant association and gene burden tests were performed for 76 640 nonsingleton variants. Samples were also screened for known causative mutations in familial genes in AD and other dementias. Single-variant association and burden analysis was also carried out on variants in known AD and other neurological dementia genes. RESULTS: Tentative single-variant and burden associations were seen in several genes with kinase and protease activity. Exome-wide burden analysis also revealed significant burden of variants in PILRA (P = 3.4 × 10-5 ), which has previously been linked to AD via GWAS, hit ZCWPW1. Screening for causative mutations in familial AD and other dementia genes revealed no pathogenic variants. Variants identified in ABCA7, SLC24A4, CD33 and LRRK2 were nominally associated with disease (P < 0.05) but did not withstand correction for multiple testing. APOE (P = 0.02) and CLU (P = 0.04) variants showed significant burden on AD. CONCLUSIONS: In addition, polygenic risk scores (PRS) were able to distinguish between cases and controls with 83.8% accuracy using 3268 variants, sex, age at death and APOE ε4 and ε2 status as predictors.

Cardiovascular causes of sudden unexpected death in children and adolescents (0-17 years) : A nationwide autopsy study in the Netherlands.

BACKGROUND: Little is known about the causes of unexpected death in minors (0-17 years). In young adults an important cause is cardiovascular disease, with primary arrhythmogenic disorders, atherosclerotic events, cardiomyopathies and myocarditis as main contributors. The aim of this autopsy study was to determine the contribution of cardiovascular disease to unexpected death in minors. METHODS AND RESULTS: In the Netherlands, systematic investigation of all cases of unexplained death in minors was compulsory in a nationwide governmental project during a 15-month period. Autopsies were performed according to a standardised protocol (autopsy rate 85%). A cardiovascular cause of death was found in 13/56 cases (23%). In the group <1 year, the main cardiovascular causes were various congenital defects (n = 3) and myocarditis (n = 2). In the 1-9 year group, no cardiovascular causes were found. In the 10-14 year group, coronary anomalies (n = 2) and arrhythmogenic cardiomyopathy (n = 1) were observed. In the 15­17 year group, hypertrophic cardiomyopathy (n = 1) and ruptured ascending aortic aneurysm (n = 1) were among the observed cardiovascular causes [corrected]. In 14/56 (25%) cases autopsy revealed no structural abnormalities that could explain the sudden death, mostly in the group <1 year. CONCLUSION: This national cohort with a high autopsy rate reveals a high incidence (23%) of cardiovascular diseases as the pathological substrate of sudden unexpected death in children. Another high percentage of minors (25%) showed no structural abnormalities, with the possibility of a genetic arrhythmia. These findings underline the importance of systematic autopsy in sudden death in minors, with implications for cardiogenetic screening of relatives.

Primary familial brain calcification linked to deletion of 5' noncoding region of SLC20A2.

OBJECTIVES: Primary familial brain calcification (PFBC) is a rare neurological disease often inherited as a dominant trait. Mutations in four genes (SLC20A2, PDGFB, PDGFRB, and XPR1) have been reported in patients with PFBC. Of these, point mutations or small deletions in SLC20A2 are most common. Thus far, only one large deletion covering entire SLC20A2 and several smaller, exonic deletions of SLC20A2 have been reported. The aim of this study was to identify the causative gene defect in a Finnish PFBC family with three affected patients. MATERIALS AND METHODS: A Finnish family with three PFBC patients and five unaffected subjects was studied. Sanger sequencing was used to exclude mutations in the coding and splice site regions of SLC20A2, PDGFRB, and PDGFB. Whole-exome (WES) and whole-genome sequencing (WGS) were performed to identify the causative mutation. A SNP array was used in segregation analysis. RESULTS: Copy number analysis of the WGS data revealed a heterozygous deletion of ~578 kb on chromosome 8. The deletion removes the 5' UTR region, the noncoding exon 1 and the putative promoter region of SLC20A2 as well as the coding regions of six other genes. CONCLUSIONS: Our results support haploinsufficiency of SLC20A2 as a pathogenetic mechanism in PFBC. Analysis of copy number variations (CNVs) is emerging as a crucial step in the molecular genetic diagnostics of PFBC, and it should not be limited to coding regions, as causative variants may reside in the noncoding parts of known disease-associated genes.

Functional and structural characterization of family 6 carbohydrate-binding module (CtCBM6A) of Clostridium thermocellum α-L-Arabinofuranosidase.

The gene encoding the family 6 carbohydrate-binding module (CtCBM6A) from Clostridium thermocellum, cloned in pET-21a(+) expression vector, was overexpressed using Escherichia coli BL-21(DE3) cells and purified by immobilized metal-ion affinity chromatography. SDS-PAGE analysis of the recombinant CtCBM6A showed molecular size of approximately 15 kDa. Ligand-binding analysis of CtCBM6A with rye arabinoxylan and oat spelt xylan by affinity gel electrophoresis showed low affinity for these ligands (Ka of 40 and 26 liter/g, respectively), and analysis by fluorescence spectroscopy (Ka of 33 and 15 liter/g, respectively) corroborated lower binding affinity with the above soluble ligands. However, CtCBM6A displayed significantly higher ligand-binding affinity with insoluble wheat arabinoxylan with equilibrium association constant Ka of 230 M(-1) and binding capacity (N0) of 11 µmole/g. The protein melting curve of CtCBM6A displayed a peak shift from 53 to 58°C in the presence of Ca2+, indicating that Ca2+ imparts thermal stability to the CtCBM6A structure. Homology modeling of CtCBM6A revealed a characteristic ß-sandwich core structure. The Ramachandran plot of CtCBM6A showed 89% of the residues in the most favorable region, 10% in additionally favored region, and 1% in generously allowed region, indicating that CtCBM6A has a stable conformation.

Allelic loss of chromosome 1p36 in neuroblastoma is of preferential maternal origin and correlates with N-myc amplification.

Neuroblastomas frequently have deletions of chromosome 1p and amplification of the N-myc oncogene. We analysed 53 neuroblastomas for the N-myc copy number, loss of heterozygosity (LOH) of chromosome 1p36 and the parental origin of the lost alleles. Allelic loss of 1p36 was found in 15 tumours. All N-myc amplified tumours belonged to this subset. In 13/15 tumours with LOH of 1p36 the lost allele was of maternal origin. This non-random distribution implies that the two alleles of the putative neuroblastoma suppressor gene on chromosome 1p36 are functionally different, depending on their parental origin. This is the first evidence as far as we know for genomic imprinting on chromosome 1p.

Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease.

BACKGROUND: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. METHODS: Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. RESULTS: All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. CONCLUSIONS: Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.

Predictive factors of severe disease secondary to falciparum malaria among travelers.

OBJECTIVES: To identify independent risk factors of severe falciparum malaria among travelers to endemic regions. MATERIALS AND METHODS: A retrospective study on imported malaria into metropolitan France. The World's Health Organization severity criteria were used to classify malarial episodes. RESULTS: Nine hundred and twenty-one malarial cases were studied; 81 were severe. Independent risk factors of severe malaria were aged above 40 years, high level of parasitized erythrocytes (more than 4%), parasite acquisition in the south-eastern asian region, infection with a chloroquine resistant Plasmodium falciparum (P. falciparum) phenotype and a self administered antimalarial treatment. CONCLUSION: This study points out two particularly interesting results: severe malaria is significantly associated with the infection by a chloroquine resistant P. falciparum phenotype and with the parasite's acquisition in the south-eastern asian region.

Gastric adenocarcinoma in a 13-year-old boy: a diagnosis not often seen in this age group.

Gastric adenocarcinoma is not uncommon in the adult population, but in the pediatric population it is an extremely rare entity. A 13-year-old boy was referred to a pediatric oncology unit for evaluation of a tumor in the upper abdomen. Further investigation revealed an advanced stage gastric carcinoma with metastases suggestive for a hereditary cause. Awareness for uncommon diagnoses is a key issue in regard of accurate treatment and overall prognosis.

Natural acidic deep eutectic solvent to obtain cellulose nanocrystals using the design of experience approach.

In this study, a new approach to optimize the cellulose nanocrystals (CNCs) extraction using acidic natural deep eutectic solvents (NADES) was introduced using, for the first time, design of experiment method. Choline chloride:oxalic acid dihydrate with a molar ratio of 1:1 was used to extract CNCs. Then, three most important parameters were varied to design the experiment: (i) cotton fibre concentrations, (ii) temperature and (iii) treatment time. Two outcomes were studied: the CNC yield and the crystallinity. The mathematical model for crystallinity perfectly described the experiments, while the model for CNC yield provided only a tendency. For a reaction time of 6 h at 95 °C with a fibre concentration of 2 %, the expected optimum CNC yield was approximately 35.5 ±â€¯2.7 % with a crystallinity index of 80 ±â€¯1 %. The obtained experimental results confirmed the models with 43.6 ±â€¯1.9 % and 81 ±â€¯1 % for the CNC yield and the crystallinity index, respectively. This study shows that it is possible to predict the CNC yield CNC and their crystallinity thanks to predictive mathematical models, which gives a great advantage to consider in the near future a scale up of the extraction of cellulose nanocrystals using this original family of green solvents.

Dysautonomia in a six-year-old mule in the United States.

Equine dysautonomia, also known as equine grass sickness (EGS), is a well documented disease in several countries. To the authors' knowledge, EGS has not been reported previously in North America. This report describes EGS in a 6-year-old female mule in the USA. Failure initially to consider EGS resulted in a delayed diagnosis. EGS should be considered as a differential diagnosis and appropriate diagnostic tests performed in similar cases in North America.

Extended tracts of homozygosity identify novel candidate genes associated with late-onset Alzheimer's disease.

Large tracts of extended homozygosity are more prevalent in outbred populations than previously thought. With the advent of high-density genotyping platforms, regions of extended homozygosity can be accurately located allowing for the identification of rare recessive risk variants contributing to disease. We compared measures of extended homozygosity (greater than 1 Mb in length) in a population of 837 late-onset Alzheimer's disease (LOAD) cases and 550 controls. In our analyses, we identify one homozygous region on chromosome 8 that is significantly associated with LOAD after adjusting for multiple testing. This region contains seven genes from which the most biologically plausible candidates are STAR, EIF4EBP1, and ADRB3. We also compared the total numbers of homozygous runs and the total length of these runs between cases and controls, showing a suggestive difference in these measures (p-values 0.052-0.062). This research suggests a recessive component to the etiology of LOAD.

Peripheral Biomarkers of Inflammation in Depression: Evidence from Animal Models and Clinical Studies.

Depression is a highly prevalent psychiatric condition, with over 300 million sufferers, and is an important comorbidity for other conditions, like cardiovascular disorders or diabetes. Therapy is largely based on psychotherapy and/or pharmacological intervention, particularly aimed at altering neurotransmitter levels in the central nervous system, but inadequate response to treatment remains a significant clinical problem. Herein, evidence supporting a molecular link between inflammation and depression will be discussed, particularly the increased prevalence of depression in chronic inflammatory diseases and the evidence on the use of anti-inflammatory drugs to treat depression. Moreover, the potential for the levels of peripheral inflammatory molecules to act as depression biomarkers, in the diagnosis and monitoring of depression will be examined, considering clinical- and animal model-based evidence.

Influence of pasture intake on the fatty acid composition, and cholesterol, tocopherols, and tocotrienols content in meat from free-range broilers.

Over the last centuries, Western diets acquired a dramatic imbalance in the ratio of polyunsaturated fatty acids (PUFA) to saturated fatty acids (SFA) with a concomitant reduction in the dietary proportion of n-3 PUFA. Pastures are a good source of n-3 fatty acids, although the effect of forage intake in the fatty acid profile of meat from free-range chicken remains to be evaluated. In addition, it is unknown if consumer interest in specialty poultry products derived from free-range or organic production systems is accompanied by a greater nutritional quality of these products. In this study, broilers of the RedBro Cou Nu x RedBro M genotype were fed on a cereal-based diet in portable floorless pens located either on subterranean clover (Trifolium subterraneum) or white clover (Trifolium repens) pastures. Control birds were maintained at the same site in identical pens but had no access to pasture. The capacity of ingested forage to modulate broiler meat fatty acid profiles and the meat content of total cholesterol, tocopherols, and tocotrienols was investigated in broiler chicks slaughtered at d 56. The results suggested that pasture intake (<5% DM) had a low impact on the fatty acid and vitamin E homologue profiles of meat from free-range broilers. However, breast meat from birds with free access to pasture presented lower levels of the n-6 and n-3 fatty acid precursors linoleic acid (18:2n-6) and alpha-linolenic acid (18:3n-3), respectively. In spring the levels of eicosapentaenoic acid (20:5n-3) in breast meat were significantly greater in birds consuming pastures, which suggests greater conversion of alpha-linolenic acid into eicosapentaenoic acid in these birds. Finally, when compared with meat from slower-growing genotypes obtained under the conventional European free-range production systems with slaughtering at d 81, meat from birds of the Ross genotype raised intensively and slaughtered at d 35 seemed to have greater nutritional quality.

Pasture intake improves the performance and meat sensory attributes of free-range broilers.

Free-range chickens are assumed to consume low to moderate levels of pasture, although the effects of forage intake in broiler performance and poultry meat quality remain to be established. In addition, despite cellulases and hemicellulases being widely used as feed supplements to improve the nutritive value of cereal-based diets for fast-growing broilers, the potential interest of these biocatalysts in the production of free-range chicken is yet to be established. In this study, broilers of the RedBro Cou Nu x RedBro M genotype were fed a cereal-based diet in portable floorless pens located either on a rainfed subterranean clover (Trifolium subterraneum) pasture or on an irrigated white clover (Trifolium repens) pasture. Control birds were maintained at the same site in identical pens but with no access to pastures. The importance of pasture intake and enzyme supplementation in the performance and meat sensory properties of the free-range chicken from d 28 to 56 was investigated. The results revealed that although cellulase and hemicellulase supplementation had no impact on broiler performance (P > 0.05), birds foraging on legume-based pastures reached significantly greater final BW. The data suggest that the improvement in broiler performance results from increased intake of the cereal-based feed rather than from an improvement in the efficiency of nutrient utilization per se. Interestingly, although the intake of the subterranean clover pasture had no impact on the tenderness, juiciness, and flavor of broiler meat, members of a 30-person consumer panel classified the meat from grazing broilers with greater scores for overall appreciation. Together, the results suggest that pasture intake promotes bird performance while contributing to the production of broiler meat with preferred sensory attributes.

Cytoadherence characteristics to endothelial receptors ICAM-1 and CD36 of Plasmodium falciparum populations from severe and uncomplicated malaria cases.

The adhesion of infected red blood cells (IRBCs) to the cell lining of microvasculature is thought to play a central role in the pathogenesis of severe malaria. Individual IRBC can bind to more than one host receptor and parasites with multiple binding phenotypes may cause severe disease more frequently. However, as most clinical isolates are multiclonal, previous studies were hampered by the difficulty to distinguish whether a multiadherent phenotype was due to one or more parasite population(s). We have developed a tool, based on cytoadhesion assay and GeneScan genotyping technology, which enabled us to assess on fresh isolates the capacity of adherence of individual P. falciparum genotypes to human receptors expressed on CHO transfected cells. The cytoadhesion to ICAM-1 and CD36 of IRBCs from uncomplicated and severe malaria attacks was evaluated using this methodology. In this preliminary series conducted in non immune travelers, IRBCs from severe malaria appeared to adhere more frequently and/or strongly to ICAM-1 and CD36 in comparison with uncomplicated cases. In addition, a majority genotype able to strongly adhere to CD36 was found more frequently in isolates from severe malaria cases. Further investigations are needed to confirm the clinical relevance of these data.

[Tolerance and efficacy of atovaquone-proguanil for the treatment of paediatric imported Plasmodium falciparum malaria in France: clinical practice in a university hospital in Paris]. / Tolérance et efficacité de l'atovaquone-proguanil dans le traitement du paludisme d'importation àPlasmodium falciparum de l'enfant en France métropolitaine: expérience d'un centre hospitalier parisien.

UNLABELLED: Only few drugs for uncomplicated Plasmodium falciparum malaria are available in children. Atovaquone-proguanil is a recent antimalarial drug licensed in France for the uncomplicated P. falciparum malaria in adults. Few paediatric studies have evaluated atovaquone-proguanil in children for uncomplicated malaria in endemic area, but no study have evaluated this treatment for imported malaria. OBJECTIVE: To evaluate treatment by atovaquone-proguanil for uncomplicated and imported P. falciparum malaria in children. METHODS: We retrospectively evaluated the tolerance and the efficacy of atovaquone-proguanil in the children admitted in Robert-Debré Hospital (Paris) for a P. falciparum malaria. From January 2004 to December 2005, 48 children with a median age of 7,5 years (IQR 4-11) were treated with atovaquone-proguanil for a uncomplicated P. falciparum malaria, except for 5 children who had an isolated hyperparasitemia greater or equal to 5%. RESULTS: Atovaquone-proguanil was stopped for 3/48 children because of vomiting. Fever resolved in all the children between Day 3 and 7, following the beginning of the treatment. One child, with a favourable outcome, had a positive parasitemia at Day 4 equal to the initial parasitemia (0,1%). No late therapeutic failure was observed among the 24 children evaluated up to one month after starting treatment. CONCLUSION: Atovaquone-proguanil is an efficient and well-tolerated antimalarial treatment for uncomplicated P. falciparum malaria in children. The risk of vomiting should lead to a systematic initial hospitalisation of children treated with atovaquone-proguanil.