Effect of epilepsy on autism symptoms in Angelman syndrome.

Background: Autism spectrum disorder and epilepsy often co-occur; however, the extent to which the association between autism symptoms and epilepsy is due to shared aetiology or to the direct effects of seizures is a topic of ongoing debate. Angelman syndrome (AS) is presented as a suitable disease model to explore this association. Methods: Data from medical records and questionnaires were used to examine the association between age of epilepsy onset, autism symptoms, genetic aberration and communication level. Forty-eight participants had genetically verified AS (median age 14.5 years; range 1-57 years). A measure of autism symptoms (the Social Communication Questionnaire; SCQ) was completed for 38 individuals aged ≥ 4 years. Genetic cause was subgrouped into deletion and other genetic aberrations of the 15q11-q13 area. The number of signs used to communicate (< 20 sign and ≥ 20 signs) was used as a measure of nonverbal communication. Results: Mean age of epilepsy onset was 3.0 years (range 3 months-7.8 years). Mean SCQ score for individuals without epilepsy was 13.6 (SD = 6.7) and with epilepsy 17.0 (SD = 5.6; p = 0.17); 58% used fewer than 20 signs to communicate. There were no age differences between groups according to presence of epilepsy, level of nonverbal communication or type of genetic aberration. SCQ scores were higher in individuals with the deletion than in those with other genetic aberrations (18.7 vs 10.8 p = 0.008) and higher in the group who used < 20 signs to communicate (19.4 vs 14.1 p = 0.007). Age of epilepsy onset was correlated with SCQ (r = - 0.61, p < 0.001). Multiple regression showed that age of seizure onset was significantly related to SCQ score (ß = - 0.90; p = 0.006), even when the type of genetic abnormality was controlled (R2 = 0.53; F = 10.7; p = 0.001). Conclusions: The study provides support for the notion that seizures themselves contribute more to autism symptoms than expected from the underlying genetic pathology alone. The study demonstrates how a rare genetic syndrome such as Angelman syndrome may be used to study the relation between epilepsy and autism symptomatology.

Temple syndrome as a differential diagnosis to Prader-Willi syndrome: Identifying three new patients.

The two imprinting syndromes Temple syndrome (TS14) and Prader-Willi syndrome (PWS) share many features in infancy and childhood. TS14 is an important, yet often neglected, differential diagnosis to PWS. We wanted to assess the frequency of TS14 among patients tested for PWS. In all samples submitted to our lab for genetic PWS testing during 2014 and 2015, we consecutively conducted additional analyses for TS14. A total of 143 samples were included. The most frequent indications for testing were developmental delay, overweight, and hypotonia. For TS14 testing, we performed a methylation-sensitive MLPA-kit detecting deletions and methylation aberrations in chromosomal region 14q32. TS14 was confirmed in 3 out of 143 patients (2.1%). In comparison, PWS was also confirmed in three patients. Brief clinical descriptions of the TS14 patients are presented. Temple syndrome is presumably underdiagnosed, and should be considered when testing children for PWS.

Effects of Anthocyanins on CAG Repeat Instability and Behaviour in Huntington's Disease R6/1 Mice.

BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative disorder caused by CAG repeat expansions in the HTT gene. Somatic repeat expansion in the R6/1 mouse model of HD depends on mismatch repair and is worsened by base excision repair initiated by the 7,8-dihydroxy-8-oxoguanine-DNA glycosylase (Ogg1) or Nei-like 1 (Neil1). Ogg1 and Neil1 repairs common oxidative lesions. METHODS: We investigated whether anthocyanin antioxidants added daily to the drinking water could affect CAG repeat instability in several organs and behaviour in R6/1 HD mice. In addition, anthocyanin-treated and untreated R6/1 HD mice at 22 weeks of age were tested in the open field test and on the rotarod. RESULTS: Anthocyanin-treated R6/1 HD mice showed reduced instability index in the ears and in the cortex compared to untreated R6/1 mice, and no difference in liver and kidney. There were no significant differences in any of the parameters tested in the behavioural tests among anthocyanin-treated and untreated R6/1 HD mice. CONCLUSIONS: Our results indicate that continuous anthocyanin-treatment may have modest effects on CAG repeat instability in the ears and the cortex of R6/1 mice. More studies are required to investigate if anthocyanin-treatment could affect behaviour earlier in the disease course.

Mild phenotype in an adult male with X-linked adrenoleukodystrophy - case report.

X-linked adrenoleukodystrophy may present with a deceptively mild phenotype, even in adult males. Tight collaboration between clinicians, geneticists, biochemists, and other specialists is increasingly required for clarification of diagnosis in cases with atypical presentation.

De novo 19p13.2 microdeletion encompassing the insulin receptor and resistin genes in a patient with obesity and learning disability.

Genetic studies have provided novel insights of appetite regulation and pathophysiology of obesity. The adipose tissue is an active endocrine organ secreting several hormones contributing to insulin resistance and the development of the comorbidities of obesity, such as type 2 diabetes and cardiovascular disease. Herein, we report on a patient with severe obesity and mild learning disability with a 750 kb de novo deletion of chromosome 19. The deletion encompasses several genes, including resistin and the first part of the insulin receptor, genes that are relevant for obesity. This novel deletion may therefore represent a region for obesity research. Plasma analyses and gene expression demonstrated that the deletion resulted in haploinsufficiency for resistin and insulin receptor in the patient compared to controls. We then studied the biochemical and adipocytokine profile in these subjects. We observed no differences in glucose and lipid parameters between the patient and the controls. Thus, haploinsufficiency of insulin receptor and resistin does not appear to influence glucose and lipid metabolism. However, the patient had considerably higher values of adiponectin and TNFα than controls. In conclusion, we identified a 19p13.2 microdeletion encompassing the insulin receptor and resistin genes resulting in haploinsufficiency in an obese, but otherwise healthy patient. No firm conclusions could be drawn regarding the potential effect of the microdeletion on adipokine profile.

Adrenoleukodystrophy in Norway: high rate of de novo mutations and age-dependent penetrance.

To investigate X-linked adrenoleukodystrophy in an unselected population, we performed a population based, cross-sectional prevalence study, supplemented by a retrospective study of deceased subjects. Sixty-three subjects (34 males, 29 females) belonging to 22 kindreds were included. Thirty-nine subjects (13 males, 26 females) were alive, and 24 (21 males, 3 females) were deceased on the prevalence day. The point prevalence of X-linked adrenoleukodystrophy in Norway on July 1, 2011, was 0.8 per 100,000 inhabitants. The incidence at birth in the period 1956-1995 was 1.6 per 100,000 inhabitants. An age-dependent penetrance was observed among males and females, with more severe phenotypes appearing with rising age. Only 5% of deceased males had not developed cerebral leukodystrophy. No female older than 50 years was neurologically intact. Sixteen mutations in the ABCD1 gene were identified. De novo mutations were found in 19% of probands. The frequency of X-linked adrenoleukodystrophy was lower in Norway than reported in the literature. A more severe natural course than previously reported was observed, indicating a need for better follow-up of both male and female patients. Given the high rate of de novo mutations, identification programs such as newborn screening may be required to offer timely treatment to all patients.

A common haplotype in NAPEPLD is associated with severe obesity in a Norwegian population-based cohort (the HUNT study).

Obesity has a strong genetic etiology involving numerous identified metabolic pathways and others not yet examined. We investigated the association between severe obesity and genetic variation in selected candidate genes, including three drug-related genes: cannabinoid receptor 1 (CNR1), N-acyl phosphatidylethanolamine phospholipase D (NAPEPLD), and gastric lipase (LIPF); and three genes related to inflammation: nicotinamide phosphoribosyltransferase, six-transmembrane epithelial antigen of the prostate 4 (STEAP4) and interleukin 18 (IL-18). Subjects were 1,632 individuals with severe obesity (BMI ≥ 35 kg/m²) and 3,379 controls (BMI 20-24.9 kg/m²) that took part in a Norwegian population based cohort study. Tagging single-nucleotide polymorphisms (SNPs) of the coding region of these genes were analyzed. SNP-haplotypes for each gene were constructed in order to analyze allelic, genotypic, and haplotypic association to obesity. A single SNPs rs17605251 in NAPEPLD was nominally associated with BMI ≥ 35 kg/m² (P = 0.035). A common haplotype in NAPEPLD was associated with BMI ≥ 35 kg/m² after correction for multiple testing. The allele frequency was 56.8% in cases and 60.3% in controls, giving an odds ratio (OR) of 0.87 (95% confidence interval (CI) 0.79, 0.95; P = 0.0016). Homozygosity for this haplotype was protective against obesity (OR 0.79 (CI 0.70-0.91); P = 0.00059). The SNP rs7913071 in LIPF was associated with obesity, but the association lost statistical significance after correction for multiple testing. The CNR1, IL-18, STEAP4, and nicotinamide phosphoribosyltransferase genes were not associated with obesity. In conclusion a common haplotype in NAPEPLD, an enzyme involved in endocannabinoid synthesis, was protective against obesity.

A double blind evaluation of cognitive decline in a Norwegian cohort of asymptomatic carriers of Huntington's disease.

Previous studies investigating subclinical signs of cognitive decline in presymptomatic carriers of Huntington's disease (HD) have shown conflicting results. The current study examines cognition in 105 at-risk individuals, using a broad neuropsychological test battery and adopting strict inclusion criteria for attaining a homogeneous sample. Results obtained by analyses of variance and effect size calculations indicate no clinical evidence of significant cognitive decline in asymptomatic HD carriers very far from onset of illness compared to noncarriers. Closeness to disease onset amongst gene carriers influenced cognition negatively whereas cytosine-adenine-guanine (CAG) repeat size did not. The findings call for longitudinal follow-up studies using a combination of clinical instruments and experimental paradigms to pinpoint when subtle cognitive deficits occur and within which of the cognitive domains.

The effect of red wine on plasma leptin levels and vasoactive factors from adipose tissue: a randomized crossover trial.

AIMS: It has been reported that alcohol has multiple effects on appetite. To elucidate potential mechanisms we measured the levels of plasma leptin and the vasoactive factors after red wine intake. METHODS: We conducted a randomized crossover trial to study the effect of red wine on the levels of leptin, TNF-alpha, TGF- beta(1), IL-6, ICAM-1, and VCAM-1 in healthy, non-smoking individuals. The subjects were randomized to drinking one glass of red wine (150 ml, 15 g alcohol) every day ('wine period') or to undergo a period of total abstention from alcohol ('abstention period'). After 3 weeks they switched the intervention group. Eighty-seven volunteers completed the study (mean age 50 years). RESULTS: After 3 weeks' daily intake of red wine, plasma leptin was significantly increased (from 6308 pg/ml to 7402 pg/ml, P = 0.05). There was a marked gender difference, as leptin levels increased only in females (P = 0.012). When calculated as leptin/body mass index (BMI) ratio, the trend and results were similar. Red wine consumption had no significant effect on other vasoactive factors measured in this study. CONCLUSION: Red wine increases levels of the appetite-regulating hormone leptin in females, but not in males. Whether red wine has an effect on appetite-regulation in its own right, remains to be solved.

Anthocyanins inhibit nuclear factor-kappaB activation in monocytes and reduce plasma concentrations of pro-inflammatory mediators in healthy adults.

The transcription factor nuclear factor-kappaB (NF-kappaB) is activated by oxidative stress and pro-inflammatory stimuli and controls the expression of numerous genes involved in the inflammatory response. Dampening NF-kappaB activation and thereby limiting the inflammatory response have been suggested as a potential strategy to prevent chronic inflammatory diseases. In cultured monocytes, anthocyanins isolated from bilberries and black currants (Medox) efficiently suppressed LPS-induced activation of NF-kappaB. Furthermore, we studied the effect of anthocyanin supplementation (Medox, 300 mg/d for 3 wk) in a parallel-designed, placebo-controlled clinical trial (n = 120 men and women aged 40-74 y). Differences were observed in several NF-kappaB related inflammatory mediators in the Medox group compared to placebo. The changes in the NF-kappaB-controlled pro-inflammatory chemokines IL-8, "regulated upon activation, normal T cell expressed and secreted," (RANTES) and IFNalpha (an inducer of NF-kappaB activation) in the Medox group (45, 15, and 40% decreases from baseline, respectively) differed from those in the placebo group (20, 0, and 15% decreases from baseline, respectively) (P < 0.050). Similarly, changes in IL-4 and IL-13, 2 cytokines that mediate pro-inflammatory responses and induce NF-kappaB activation, in the Medox group (60 and 38% decreases from baseline, respectively) tended to differ from those in the placebo group (4 and 6% decreases) (P = 0.056 and, P = 0.089, respectively). These data suggest that anthocyanin supplementation may have a role in the prevention or treatment of chronic inflammatory diseases by inhibition of NF-kappaB transactivation and deceased plasma concentrations of pro-inflammatory chemokines, cytokines, and inflammatory mediators.

Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor.

BACKGROUND: A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined. METHODS: We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives. RESULTS: Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations--7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency. CONCLUSIONS: The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism.

A daily glass of red wine induces a prolonged reduction in plasma viscosity: a randomized controlled trial.

Moderate red wine consumption has been associated with decreased risk of coronary heart disease. Reduced plasma viscosity and fibrinogen levels have been launched as possible contributors to this risk reduction. The effect of moderate red wine consumption on plasma viscosity, however, has not been investigated in a prospective, randomized trial. We wanted to evaluate the effect of moderate red wine consumption on plasma viscosity, fibrinogen concentration and fibrinogen subfractions. Healthy, nonsmoking volunteers were assigned to consume one glass of red wine daily for 3 weeks in a prospective, randomized cross-over study. In the second 3-week period the volunteers abstained from alcohol use. The plasma viscosity, fibrinogen concentration and the distribution of the main fibrinogen subfractions were determined at inclusion, after wine drinking and after abstention. Plasma viscosity was reduced by 0.026 and 0.024 mPa.s in the two groups following wine intake (95% confidence interval, 0.009-0.043, P = 0.004; 95% confidence interval, 0.0083-0.039, P = 0.003). The decrease in plasma viscosity was maintained following 3 weeks of abstention. The fibrinogen concentration was reduced by 0.17 g/l following wine drinking in the group starting with abstention (95% confidence interval, 0.04-0.29, P = 0.01). The distribution of the fibrinogen subfractions remained unaltered. We conclude that a daily glass of red wine for 3 weeks significantly reduces plasma viscosity. Fibrinogen concentrations are also significantly reduced, when preceded by an abstention period. The decreased viscosity levels are maintained after 3 weeks of abstention, suggesting a sustained viscosity lowering effect of red wine.

A twin study of nitric oxide levels measured by serum nitrite/nitrate.

Nitrite and nitrate are the stable end products of the L-arginine-NO pathway, and the sum of nitrite and nitrate (NOx) is a common way to measure nitric oxide (NO) production or secretion. To uncover any genetic influence on NO, we measured NOx in serum samples from monozygotic twin pairs after an overnight fast. Heritability was estimated as intraclass correlation coefficient. We arrived at a heritability estimate of .32 (95% confidence interval 0.17-0.45) for NOx. The numerical heritability estimate was higher for females than for males (0.38 vs. 0.21), and higher for nonsmokers than for smokers (0.36 vs. 0.22). The heritability estimate of NOx was lower than the heritability estimate for other cardiovascular risk factors. This study suggests a low degree of heredity for NOx levels.

[Genetic causes of obesity]. / Genetiske årsaker til fedme.

BACKGROUND: Overweight and obesity represent an increasing health problem. Both genetic and environmental factors contribute to the development of obesity. This article summarises the genetic aspects of these conditions. MATERIAL AND METHODS: A literature search was conducted using PubMed and OMIM. Both original and review articles were included. RESULTS AND INTERPRETATION: The genetic influence on body weight is shown by twin and family studies. Environmental changes in recent decades have promoted the development of obesity in individuals at risk because of their genetic composition. Our understanding of the molecular pathways underlying common obesity is limited. During the last decade a handful of monogenic disorders leading to early, severe obesity in humans have been identified. All affect the central regulation of appetite. These conditions are rare, except for mutations in the melanocortin 4 receptor that account for about 5% of morbidly obese patients (BMI > 40 kg/m). The identification of monogenic forms of obesity has contributed valuable insight into the regulation of appetite and development of obesity, although causal treatment only exists for leptin deficiency. In addition, several well defined Mendelian syndromes are associated with overweight and obesity. The molecular genetic cause is known for some of these syndromes, but how appetite and energy balance are affected is still unclear.

A daily glass of red wine: does it affect markers of inflammation?

AIMS: Epidemiological studies have shown that moderate consumption of alcohol is associated with a decreased risk of developing cardiovascular disease, but the causal mechanisms are only partly understood. As inflammation is an important process in the progression of atherosclerosis, we hypothesized that the protective effect of red wine is partly mediated through a reduction in inflammation. METHODS: We conducted a randomized controlled crossover trial to study the effect of red wine on the levels of the inflammatory markers serum C-reactive protein (CRP) and plasma fibrinogen in healthy, non-smoking individuals. The subjects were randomized to drink one glass of red wine (150 ml, 15 g alcohol) every day ('wine period') or to undergo a period of total abstention from alcohol ('abstention period'). After 3 weeks they switched intervention group. Eighty-seven volunteers completed the study (mean age 50 years). RESULTS: Red wine did not reduce CRP levels and only marginally reduced fibrinogen levels compared with a similar period without alcohol. CONCLUSIONS: Consumption of 150 ml of red wine slightly reduced fibrinogen levels but did not reduce CRP levels.

A twin study of C-Reactive Protein compared to other risk factors for coronary heart disease.

Coronary heart disease (CHD) tends to cluster in families, and several established risk factors for the disease are to some extent inherited. Inflammation plays a key role in the development of atherosclerosis and CHD. A low-grade inflammation may be detected by highly sensitive C-Reactive Protein (CRP) determination, which is strongly associated to CHD. In order to uncover any role of genetics in low-grade inflammation, we measured CRP in healthy monozygotic twins. The within-pair correlation coefficient of CRP was 0.40, suggesting an important genetic contribution to the control of CRP level. CRP correlated significantly to other CHD risk factors like body mass index (BMI), systolic blood pressure, diastolic blood pressure, plasma fibrinogen, serum high-density lipoprotein cholesterol, plasma homocysteine, and serum triglycerides. Of these variables, BMI was most significantly associated to CRP in a linear multiple regression analysis. We conclude that CRP level (reflecting a low-grade inflammation) exhibits a moderate, but significant degree of heritability. The association between CRP and BMI, which has a larger degree of heritability, could partly explain the heritability of serum CRP level.

Induced changes in the consumption of coffee alter ad libitum dietary intake and physical activity level.

Dietary trials with subjects on a freely selected diet may be affected by unwanted behavioural changes. Few studies, if any, have examined changes in coffee consumption and possible concomitant changes in diet and health-related habits. The aim of the present study was to examine whether induced changes in coffee consumption lead to changes in food habits and leisure-time physical activity. Healthy, non-smoking coffee-drinkers (n 214) were asked to change their coffee habits in a controlled clinical trial on the metabolic effects of coffee. The participants were asked to maintain their usual dietary habits. Self-perceived changes in diet and physical activity during the 6-week intervention period were assessed at the end. In the analyses, the participants were rearranged into groups reflecting the difference in coffee intake during the trial as compared with habitual intake. Associations with changes in food intake or physical activity were analysed by Spearman rank correlation. Changes in intake of 'chocolate, sweets' (r 0.179, P<0.05), 'cakes, sweet biscuits, pastry' (r 0.306, P<0.001), and 'jam' r 0.198, P<0.05) showed positive associations with change in coffee intake during the trial. Negative associations were found for 'dishes with fish' (r -0.204, P<0.01) and many of the drinks as well as with physical activity (r -0.164, P<0.05). Induced changes in coffee intake seem to alter ad libitum intake of several foods. The recognized associations between health behaviours may have physiological explanations.

C-reactive protein predicts death in patients with previous premature myocardial infarction--a 10 year follow-up study.

Atherosclerosis is an inflammatory disease. C-reactive protein (CRP), a marker of inflammation, is associated with coronary heart disease (CHD). We measured CRP in a cohort of 247 patients (193 males and 54 females) who had had their first myocardial infarction (MI) at age < or = 55 (males) or < or = 60 (females). The cut-off values of the 25th, 50th and 75th centiles of CRP were 1.20, 2.37 and 4.20 mg/l. After 10 years, a total of 44 patients (17.8%) had died, 36 (81.8%) of cardiac causes. Unadjusted and adjusted (i.e. for age, ejection fraction (EF), serum total cholesterol (TC), fibrinogen, smoking and hypertension) relative risks (RRs) for total and cardiac mortality were generated. CRP was a strong predictor of death of all causes due to its strength as predictor of cardiac death. The RR of cardiac death was doubled with increasing CRP quartiles, and patients in the top quartile had six times as high risk of cardiac death as patients in the lowest quartile. The RRs were moderately attenuated after adjustment, but still significant. We conclude that CRP is a strong predictor of mortality in patients with premature MI. Thus, inflammation appears to be a critical prognostic factor in patients with previous premature MI.