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.

[Diagnostic value of the SHAPE questionnaire in recognition of the hyperventilation syndrome in children: a pilot study]. / Valeur diagnostique du questionnaire SHAPE pour le syndrome d'hyperventilation de l'enfant : étude pilote.

OBJECTIVE: Determination of a diagnostic scoring method for hyperventilation syndrome (HVS) in children and proposal of a simplified questionnaire. METHOD: We used the main clinical signs of HVS in children and adolescents identified in a previous study and classified them according to their odds ratios (OR). The intensity of each sign, measured using a visual analogic scale in the previous study, led us to analyze several scoring methods, with a breakdown between major and minor signs according to their OR. Building receiver operating characteristics (ROC) curves allowed us to choose the best diagnostic combination. RESULTS: A sample of 85 children and adolescents aged from 7 to 20 years (mean age, 11.9 years) was tested. This sample comprised 45 children with isolated HVS or HVS associated with asthma and 40 controls, with asthma but without HVS or attending our emergency unit after trauma. Seven respiratory signs and 10 nonrespiratory signs were selected. For each scoring method, a significant difference was observed between HVS and non-HVS patients. The most suitable area under the curve (0.934) and the best combination between specificity and sensitivity (Sp=0.90 and Se=0.82) were obtained when the scoring method was 0,3,6 for major signs, and 0,1,2 for minor signs, according to perceived intensity of each sign ("never or almost never", "sometimes" or "often or very often"). CONCLUSION: Since no gold standard is available to confirm the diagnosis of HVS in children, we propose using a simplified questionnaire composed of 17 items to compute a diagnostic score. The questionnaire will be validated shortly in a new prospective study.

[A diagnostic questionnaire for the hyperventilation syndrome in children]. / Elaboration d'un questionnaire diagnostique du syndrome d'hyperventilation chez l'enfant.

INTRODUCTION: Intensive efforts should be made to diagnose the hyperventilation syndrome (HVS) at an early stage as this will prevent stigmatisation and reinforcement of symptoms. It will also prevent children from undergoing unnecessary medical examinations and treatment. A diagnostic questionnaire should be useful for this purpose. METHODS: We administered a questionnaire with 16 respiratory symptoms and 23 non respiratory symptoms to 25 children with HVS alone, 20 with asthma and HVS, and two control groups: 20 children with asthma without HVS and 20 presenting with trauma. For each symptom a visual analogue scale (VAS) was completed. The symptoms for which the mean VAS values were significantly different between the children with HVS and the controls were subject to principal component analysis after varimax rotation with Kaiser normalisation. RESULTS: There was no significant difference in symptoms between HVS children with or without asthma. The five major respiratory symptoms were: throat-clearing, sniffing, difficulty in breathing in, sighing and yawning. The combined sensitivity of those symptoms was 99%, the combined specificity 24%. The five major non-respiratory symptoms were: anxiety, difficulty in going to sleep, general fatigue, abdominal pain, and joint pains. The combined sensitivity of those symptoms was 99%, the combined specificity 36%. CONCLUSIONS: We performed a simplified diagnostic questionnaire for HVS in healthy and asthmatic children and found 5 respiratory and 5 non-respiratory symptoms of significance.

Genetic variants of microsomal epoxide hydrolase and glutamate-cysteine ligase in COPD.

The genetic factors that contribute to the development of chronic obstructive pulmonary disease (COPD) are poorly understood. Many candidate genes have been proposed, including enzymes that protect the lung against oxidative stress, such as microsomal epoxide hydrolase (EPHX1) and glutamate-cysteine ligase (GCL). To date, most reported findings have been for EPHX1, particularly in relation to functional variants associated with fast and slow metabolism of epoxide intermediates. The present study aimed to identify any association of variation in these genes with COPD susceptibility or severity. In total, 1,017 white COPD patients and 912 nondiseased age and sex matched smoking controls were genotyped for six single nucleotide polymorphisms (SNPs) in EPHX1 (including the fast and slow variants and associated haplotypes), and eight SNPs in the two genes encoding GCL. GCL is a rate-limiting enzyme in the synthesis of glutathione, a major contributor to anti-oxidant protection in the lung. No association of variation was found in EPHX1 or GCL with susceptibility to COPD or disease severity. This is the largest reported study to date and is well powered to detect associations that have been previously suggested. The current data indicate that these genetic variants are unlikely to be related to susceptibility or disease severity in white chronic obstructive pulmonary disease patients.

[Food hypersensibility: inhalation reactions are different from ingestion reactions]. / Allergie alimentaire : les réactions à l'inhalation sont différentes des réactions à l'ingestion.

Eight children, aged from 3 to 9 years, presented to inhaled peanut an immediate allergic reaction. All were sensitized to peanut but none had already ingested it overtly. A strict avoidance diet was prescribed concerning this food allergen. An oral provocation challenge was realized to determine the eliciting dose (ED) to ingestion. The ED was high enough to allow all the children a less restrictive diet. Inhaled allergic reaction to peanut does not always justify a strict avoidance diet.

[Hyperventilation syndrome in children]. / Le syndrome d'hyperventilation pulmonaire chez l'enfant, revue de la litterature.

Hyperventilation syndrome is frequent in adults. There are only very few and very ancient publications in children. Diagnosis is sometimes difficult, because the symptoms often mimic those of organic diseases. Hyperventilation syndrome and organic diseases, especially asthma, often coincide. Intensive efforts should be made to diagnose hyperventilation syndrome at an early stage because this will prevent stigmatization and fixation of symptoms and disease, and also prevent children from undergoing unnecessary medical examinations and therapies. The authors review the literature about hyperventilation syndrome in children.