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Helmut Remschmidt

Publications and source records attributed to Helmut Remschmidt.

51 records · Page 3Linked to original sources
PubMed2004

Genetic risk factors in eating disorders.

Eating disorders such as anorexia nervosa and bulimia nervosa involve complex and interacting mechanisms. Formal genetic studies suggest that there is a substantial genetic influence for these disorders. Animal models of eating disorders are scarce. Candidate gene studies have initially focused on the serotonergic and other central neurotransmitter systems and on genes involved in body weight regulation. Most of the studies, including meta-analysis, have yielded negative results; only a single positive finding has been replicated independently. Recently, systematic genome-wide scans based on families with two or more individuals with an eating disorder (anorexia nervosa or bulimia nervosa) revealed initial linkage regions on chromosomes 1, 3, and 4 (anorexia nervosa) and 10p (bulimia nervosa). Fine mapping of one of these regions led to the identification of genes where an association with anorexia nervosa was detected. Currently treatment of patients with eating disorders can not rely on results of molecular genetic studies.

Animals↗
PubMed2003

Pharmacokinetics of clozapine and its metabolites in hippocampal HT22 cells.

Up to now, it is not yet clear whether and how clozapine and its metabolites are metabolized in neuronal cells. The interconversion of clozapine and its metabolites, clozapine-N-oxide and norclozapine, was studied in the hippocampal neuronal in vitro system of HT22 cells. Clinically relevant concentrations of clozapine (200+400 ng/ml) and its metabolites (100+200 ng/ml) were used for the examination of the metabolizing effects after short- (4 h) and long- (24 h) term incubation. Two-way analysis of variance revealed a significant decrease of clozapine (P<0.01) and norclozapine (P<0.01) levels in the supernatants of HT22 cells after the treatment procedures. Student-Newman-Keuls tests showed a significant decrease of clozapine 400 after 24 h of incubation (P=0.01) as well as of all concentrations of norclozapine. No significant treatment effects were found for the clozapine-N-oxide degradation. Using semi-quantification by reverse transcriptase-polymerase chain reaction methods, we could show a significant increase of cytochrome P450 (CYP) 1A2 mRNA levels (P<0.05) after clozapine treatment with 200 ng/ml. The results of the present study strongly suggest that clozapine and norclozapine are metabolized in hippocampal neuronal HT22 cells by CYP1A2, whereas the levels of clozapine-N-oxide were not affected. Moreover, CYP1A2 mRNA levels were significantly changed by incubation with clozapine 200.

Analysis of Variance↗
PubMed2003

HLA-DRB genotyping in Gilles de la Tourette patients and their parents.

Gilles de la Tourette syndrome (GTS) is a common neuropsychiatric disorder of unknown cause. There is, however, growing evidence that both autoimmune and genetic factors are involved in the pathogenesis of GTS. In classical autoimmune disorders such as diabetes mellitus or multiple sclerosis, genetic susceptibility is at least in part conferred by human leucocyte antigen (HLA-) subtypes, in particular by distinct HLA-DRB alleles. We undertook modern, PCR-based HLA-DRB typing in 83 trios (affected index child and both parents) to investigate whether GTS may be associated with a particular HLA-DRB allele. The extended transmission/disequilibrium test (ETDT) was applied to analyze transmission disequilibrium for any of the 13 alleles detected. The ETDT failed to detect transmission disequilibrium for any allele at the DRB1 locus (overall allele-wise chi(2) (12) = 12.741, Monte Carlo P = 0.4998). Our results imply that the HLA-DRB locus does not confer genetic susceptibility to GTS.

Family Health↗
PubMed2003

Lower serum leptin levels in female students of the nutritional sciences with eating disorders.

BACKGROUND: Evidence has accumulated that in both acutely ill and recovered patients with either anorexia or bulimia nervosa circulating leptin levels (LL) are lower than in controls matched for body mass index (BMI; kg/m(2)). It is unknown if these lower leptin levels represent a state or trait marker. AIM OF THE STUDY: We aimed to confirm the lowered leptin levels in eating disordered females and to identify underlying mechanisms. METHODS: We screened 181 female students of the nutritional sciences for eating disorders with the respective module of the M-Composite International Diagnostic Interview and the Cognitive Restraint scale of the Three Factor Eating Questionnaire. The physical assessment included determinations of BMI, body composition and LL. Each case fulfilling lifetime DSM-IV criteria for an eating disorder was BMI matched to two controls. We used a multivariate mixed regression model to evaluate if the observed difference in lg(10)-leptin level between cases and controls is actually due to the influence of restrained eating and/or previous weight loss after adjustment for BMI and percent body fat. RESULTS: In accordance with our hypothesis the 32 (17.7 %) cases had a lower serum lg(10)-leptin level than the 64 BMI matched controls (one-sided p < 0.001). We were not able to detect an influence of restrained eating or previous weight loss. CONCLUSIONS: We confirm that females with a lifetime history of an eating disorder have lower LL. We were not able to identify an underlying mechanism. Similar to most previous studies we found a high rate of eating disorders among female students of nutritional sciences.

Adult↗
PubMed2003

Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity.

We initially performed a mutation screen of the coding region of the MC4R in 808 extremely obese children and adolescents and 327 underweight or normal-weight controls allowing for a case-control study. A total of 16 different missense, nonsense, and frameshift mutations were found in the obese study group; five of these have not been observed previously. In vitro assays revealed that nine [the haplotype (Y35X; D37V) was counted as one mutation] of the 16 mutations led to impaired cAMP responses, compared with wild-type receptor constructs. In contrast, only one novel missense mutation was detected in the controls, which did not alter receptor function. The association test based on functionally relevant mutations was positive (P = 0.006, Fisher's exact test, one-sided). We proceeded by screening a total of 1040 parents of 520 of the aforementioned obese young index patients to perform transmission disequilibrium tests. The 11 parental carriers of functionally relevant mutations transmitted the mutation in 81.8% (P = 0.033; exact one-sided McNemar test). These results support the hypothesis that these MC4R mutations represent major gene effects for obesity.

Adolescent↗
PubMed2003

Elevated physical activity and low leptin levels co-occur in patients with anorexia nervosa.

Low leptin levels are an endocrinological hallmark of acute anorexia nervosa (AN); a subthreshold leptin secretion in adipocytes as a consequence of a reduced energy intake is presumed to be the major trigger of the adaptation of an organism to semistarvation. The aim of the current study is to define symptoms of AN that are potentially linked to low leptin levels. For this purpose, quantitative somatic and psychopathological variables were obtained in 61 inpatients with acute AN (study group 1) upon referral for inpatient treatment, and they were concomitantly blood sampled to allow determination of serum leptin levels. Correlations between these variables and logarithmic transformed (lg10) leptin levels were descriptively assessed. Apart from the well-known correlations between leptin levels and anthropometric measurements, the strongest correlation was observed between lg10 serum leptin levels and expert ratings of motor restlessness (r = -0.476; nominal P = 0.003) upon use of visual analog scales. We thus generated the hypothesis that physical activity levels in AN patients are related to serum leptin levels. This hypothesis was tested in an independent study group of 27 adolescent inpatients (study group 2) who were also assessed upon referral. Physical activity levels, which, in this study group, were assessed with the activity module of the expert rating form of the Structured Inventory for Anorexic and Bulimic Syndromes, were significantly correlated with lg10 leptin levels (r = -0.51; one-sided P = 0.006). A regression model based on the independent variables body mass index and lg10 leptin levels explained 37% of the variance of physical activity (R(2) = 0.37; P = 0.003); only the lg10 leptin levels contributed significantly to the variance (P = 0.003). Our results suggest that, similar to semistarvation-induced hyperactivity in rats, hypoleptinemia in patients with AN may be one important factor underlying the excessive physical activity.

Acute Disease↗
PubMed2003

Genome scan for childhood and adolescent obesity in German families.

OBJECTIVE: Several genome scans have been performed for adult obesity. Because single formal genetic studies suggest a higher heritability of body weight in adolescence and because genes that influence body weight in adulthood might not be the same as those that are relevant in childhood and adolescence, we performed a whole genome scan. METHODS: The genome scan was based on 89 families with 2 or more obese children (sample 1). The mean age of the index patients was 13.63 +/- 2.75 years. A total of 369 individuals were initially genotyped for 437 microsatellite markers. A second sample of 76 families was genotyped using microsatellite markers that localize to regions for which maximum likelihood binomial logarithm of the odd (MLB LOD) scores on use of the concordant sibling pair approach exceeded 0.7 in sample 1. RESULTS: The regions with MLB LOD scores >0.7 were on chromosomes 1p32.3-p33, 2q37.1-q37.3, 4q21, 8p22, 9p21.3, 10p11.23, 11q11-q13.1, 14q24-ter, and 19p13-q12 in sample 1; MLB LOD scores on chromosomes 8p and 19q exceeded 1.5. In sample 2, MLB LOD scores of 0.68 and 0.71 were observed for chromosomes 10p11.23 and 11q13, respectively. CONCLUSION: We consider that several of the peaks identified in other scans also gave a signal in this scan as promising for ongoing pursuits to identify relevant genes. The genetic basis of childhood and adolescent obesity might not differ that much from adult obesity.

Adolescent↗
PubMed2002

Serotonergic effects of clozapine and its metabolites in hippocampal HT22 cells.

In the hippocampal neuronal in vitro system of HT22 cells, we studied the effects of clozapine (Cloz) and its metabolites clozapine-N-oxide (Cloz-N-oxide) and norclozapine (Norcloz) on 5-HT transporter affinity (K(M)) and uptake (V(max)), MAO-B affinity (K(M)) and maximal velocity (V(max)), as well as on 5-HT(2) receptor affinity and density. Clinically relevant concentrations of Cloz (200 and 400 ng/ml) and its metabolites (100 and 200 ng/ml) were used for the examination of the effects after short-term (4 h) and long-term (24 h) incubation. Statistical evaluation revealed that a significantly lowered 5-HT transporter affinity (higher K(M)) was related to higher concentrations of Cloz and its metabolites. A significantly higher 5-HT transporter uptake was dependent on both high concentrations of drugs and an increased time of incubation. No significant influence of the investigated independent variables on MAO-B affinity could be demonstrated, whereas a significant drug-related increase of MAO-B velocity was detectable. Additionally, low and high concentrations of Cloz and its metabolites induced a higher 5-HT(2) receptor affinity (lower K(D)). No significant influences of the investigated independent variables on 5-HT(2) receptor density were detectable. The results of the present study show that Cloz and its metabolites induce significant alterations in serotoninergic parameters of hippocampal HT22 cells, validating the system of hippocampal HT22 cells for further examinations of the mechanisms of action of atypical neuroleptics.

Antipsychotic Agents↗
PubMed2002

No evidence for involvement of the calpain-10 gene 'high-risk' haplotype combination for non-insulin-dependent diabetes mellitus in early onset obesity.

In light of evidence of linkage of obesity to chromosome 2q31-q37, we hypothesized that the calpain-10 gene 'high-risk' haplotype combination for non-insulin-dependent diabetes mellitus (NIDDM) is involved in early onset obesity. We screened the NIDDM 'high-risk'-haplotype combination formed by the alleles 112 and 121 of the polymorphisms UCSNP-43, -19, and -63 in 166 families consisting of an extremely obese child or adolescent (mean BMI percentile: 99.3+/-1.38), one or more obese sibs (mean BMI percentile: 97.42+/-2.88), and both of their parents. Genotyping for three calpain-10 gene polymorphisms was performed by polymerase chain reaction (PCR) with (a) length polymorphism detection (UCSNP-19) or (b) allele-specific PCR (UCSNP-43 and -63). To allow for correct haplotype assignment all individuals were additionally genotyped for two microsatellite markers (D2S125 and D2S2338). We followed a hierarchical test procedure. As the first step, model-free linkage analysis was performed using maximum likelihood binomial statistics. The second stage consisted of a one-sided asymptotic pedigree disequilibrium test for the UCSNP-43 and on an exploratory level for the other SNP-markers and all haplotypes formed by the three SNPs. The final stage investigated the reported haplotype combination. We failed to detect an initial linkage of obesity to this region (LOD score <0.4). All subsequent exploratory analyses were negative. Our analysis of the relationship between the NIDDM 'high-risk' haplotype combination and extreme early onset obesity revealed no evidence for linkage and association.

Adolescent↗
PubMed2002

Ghrelin gene: identification of missense variants and a frameshift mutation in extremely obese children and adolescents and healthy normal weight students.

Ghrelin induces obesity via central and peripheral mechanisms. Administration of ghrelin leads to increased food intake and decreased fat utilisation in rodents. Ghrelin levels are decreased in obese individuals. Recently, a polymorphism (Arg-51-Gln) within the ghrelin gene (GHRL) was described to be associated with obesity. We screened the GHRL coding region in 215 extremely obese German Children and adolescents (study group 1) and 93 normal weight students (study group 2) by single strand conformation polymorphism analysis (SSCP). We found the two previously described single nucleotide polymorphisms (SNP: Arg-51-Gln and Leu-72-Met) in similar frequencies in study groups 1 and 2 (allele frequencies were: 0.019 and 0.016 for the 51-Gln allele and 0.091 and 0.086 for the 72-Met allele, respectively). Hence, we could not confirm the previous finding. Additionally, two novel variants were identified within the coding region: (1) We detected one healthy normal weight individual with a frameshift mutation (2bp deletion at codon 34). This frameshift mutation affects the coding region of the mature ghrelin. Hence, it is highly likely that the normal weight student is haplo-insufficient for ghrelin. (2) An A to T transversion leads to an amino acid exchange from Gln to Leu at amino acid position 90. The frequency of the 90-Leu allele was significantly higher in the extremely obese children and adolescents (0.063) than in the normal weight students (0.016; nominal p = 0.011). Additionally, we genotyped 134 underweight students and 44 normal weight adults for this SNP. Genotype frequencies were similar in extremely obese children and adolescents, underweight students and normal weight adults (p > 0.8). In conclusion, we identified four sequence variants in the coding region of the ghrelin gene in individuals belonging to different weight extremes. A frameshift mutation was detected in a normal weight individual. None of the variants seem to influence weight regulation.

Adolescent↗
PubMedDate not supplied

Induced delusional disorder. a review of the concept and an unusual case of folie à famille.

Induced delusional disorder (or shared paranoid disorder), also known as folie à deux, is a fairly uncommon disturbance characterized by the presence of similar psychotic symptoms in two or more individuals. Most often the symptoms are delusional. Usually the 'primary' case, i.e. the individual who first develops psychotic symptoms, can be distinguished from one or more 'secondary' cases, in whom the symptoms are induced. We discuss the concept of shared paranoid disorder and consider various aetiological, clinical and diagnostic issues related to the disturbance. We also describe a case of folie à famille, this condition being a type of shared paranoid disorder. The case involves a couple and their 12-year-old son. The boy's father is the 'primary' case, whilst the boy and his mother are both 'secondary' cases. The boy was admitted to our child and adolescent psychiatric unit for in-patient treatment. Treatment success was moderate in terms of improving the features of folie à famille in the three individuals involved.

Child↗
PubMedDate not supplied

[Diagnosis and etiology of Asperger syndrome in children and adolescents].

The Asperger-Syndrom is a pervasive developmental disorder, characterized by impairments in primarily social and communicative competence, empathy, associated with motor awkwardness and/or clumsiness and highly circumscribed interests. The diagnostic criteria and the diagnostic methods are in detail exemplified. While the validity of autism (Kanner-syndrom) has been shown through multiple different levels of evidence, the validity of Asperger-Syndrom is still unestablished. The few literature is extremely difficult to summarize (Volkmar u. Klin 2000), given that a range of important methodological issues render comparability of findings across studies virtually impossible: these include differences in definition and circularity in definition relative to validating measures. In terms of causes of Asperger-Syndrom the following factors are discussed: genetic reasons, neurobiological disturbances and neuropsychological deficits.

Adolescent↗