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M Rietschel

Publications and source records attributed to M Rietschel.

At least 73 records · Page 4Linked to original sources
PubMed1998

Reliability and validity of the premorbid adjustment scale (PAS) in a German sample of schizophrenic and schizoaffective patients.

Premorbid functioning seems to be a phenomenological marker that possibly distinguishes a subtype of schizophrenia. The Premorbid Adjustment Scale (PAS) is an instrument for measuring premorbid functioning. It has gained international acceptance, although little is known about the reliability and validity of the test. Here data on the reliability and validity of the test derived from a German sample of schizoaffective and schizophrenic subjects (n = 86) and their healthy parents (n = 38) is presented. The DSM-IV diagnosis, PAS and Positive and Negative Syndrome Scale (PANSS) data were used as well as data on the course of the disorder. The estimation of the reliability per scale by internal consistency showed high positive values of Cronbach's alpha between 0.809 and 0.931. High scores in PAS representing a bad premorbid social adjustment correlated significantly with a low age of onset, high PANSS scores, an insidious onset and a long period of hospitalisation. The disorganised DSM-IV subtype of schizophrenia showed a trend towards higher mean PAS scores. In the presented sample, the threshold between schizophrenics and healthy individuals is at 0.23. The PAS values higher than 0.53 appeared in patients with an unfavourable course of the disorder. These findings correspond with previous reports in the literature.

Adolescent↗
PubMed1998

Analysis of a polymorphism in the tuberous sclerosis (TSC2) gene does not predispose to schizophrenia.

The tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of malformations in various organs including the brain. A polymorphism in the TSC2 gene has been found to be increased in gangliogliomas, a lesion which is associated with disturbed neuro-glial cell migration pattern. Since these pathomorphological changes are compatible with disturbed neuronal migration in schizophrenic brains, we investigated this polymorphism in 130 families with a schizophrenic index patient. A 222-bp fragment of genomic DNA containing the TSC2 variant was analyzed by SSCP. The analysis revealed that there is no association with schizophrenia.

Adult↗
PubMed1998

A gene for universal congenital alopecia maps to chromosome 8p21-22.

Complete or partial congenital absence of hair (congenital alopecia) may occur either in isolation or with associated defects. The majority of families with isolated congenital alopecia has been reported to follow an autosomal-recessive mode of inheritance (MIM 203655). As yet, no gene has been linked to isolated congenital alopecia, nor has linkage been established to a specific region of the genome. In an attempt to map the gene for the autosomal recessive form of the disorder, we have performed genetic linkage analysis on a large inbred Pakistani family in which affected persons show complete absence of hair development (universal congenital alopecia). We have analyzed individuals of this family, using >175 microsatellite polymorphic markers of the human genome. A maximum LOD score of 7.90 at a recombination fraction of 0 has been obtained with locus D8S258. Haplotype analysis of recombination events localized the disease to a 15-cM region between marker loci D8S261 and D8S1771. We have thus mapped the gene for this hereditary form of isolated congenital alopecia to a locus on chromosome 8p21-22 (ALUNC [alopecia universalis congenitalis]). This will aid future identification of the responsible gene, which will be extremely useful for the understanding of the biochemistry of hair development.

Alopecia↗
PubMed1998

Cloning, genomic organization, alternative transcripts and mutational analysis of the gene responsible for autosomal recessive universal congenital alopecia.

Complete or partial congenital absence of hair (congenital alopecia) may occur isolated or with associated defects. The majority of families with isolated congenital alopecia has been reported to follow an autosomal recessive mode of inheritance (MIM 203655). We have previously mapped the gene for autosomal recessive congenital alopecia in a large inbred Pakistani family in which affected persons show complete absence of hair development (universal congenital alopecia) to a 15 cM region on chromosome 8p21-22. Here we report the cloning and characterization of the human homologue of the mouse hairless gene and show that it is located in the critical region on chromosome 8p21-22. Determining the exon-intron structure allowed detailed mutational analysis of DNA samples of patients with universal congenital alopecia. We detected a homozygous missense mutation in the Pakistani family and a homozygous splice donor mutation in a family from Oman. In addition, we show that the human hairless gene undergoes alternative splicing and that at least two isoforms generated by alternative usage of exon 17 are found in human tissues. Interestingly, the isoform containing exon 17 is the predominantly expressed isoform in all tissues but skin, where exclusive expression of the shorter isoform was observed. We speculate that this tissue-specific difference in the proportion of hairless transcripts lacking exon 17 sequences could contribute to the tissue-specific disease phenotype observed in individuals with isolated congenital alopecia.

Adult↗
PubMed1997

Efficacy and side-effects of clozapine not associated with variation in the 5-HT2C receptor.

In the present study we tested the hypothesis that individual response to clozapine treatment and/or the occurrence of side-effects may be influenced by genetic variation in the serotonin 5-HT2C receptor. We investigated the frequency of a common Cys23Ser substitution, which is known to alter the pharmacological properties of the protein, in 152 patients treated with clozapine. Presence of the Ser23 variant was previously reported to predict a good response to clozapine. However, our results did not support an association between genetic variation of the 5-HT2C receptor and response to clozapine. This held true whether the patients were subgrouped for sex and length of treatment. Moreover, we found no consistent association with any of the observed side-effects.

Adult↗
PubMed1997

5-HT2A receptor and bipolar affective disorder: association studies in affected patients.

The aim of this study was to investigate the possible involvement of genetic variation in serotonin receptors in the aetiology of bipolar affective disorder. The 5-HT2A receptor gene was systematically screened for genetic variants by single strand conformation polymorphism (SSCP) methods in subjects with bipolar affective disorder. Four polymorphisms (two structural changes, Thr25Asn and His4 M52Tyr, and two silent polymorphisms, 102-T/C and 516-C/T) which had previously been found in patients with schizophrenia and control subjects were detected. No novel polymorphisms were found in patients with bipolar affective disorder. These polymorphisms were genotyped in a sample of 129 patients and 252 controls of German origin and 176 patients and 182 controls of British origin. No strong associations were found between any of these polymorphisms and bipolar affective disorder. Genetic variation at the 5-HT2A receptor gene does not play a major role in the pathogenesis of the disorder.

Alleles↗
PubMed1997

Association study of schizophrenia and the histidase gene.

Previous findings of increased heterozygosity for histidinemia among schizophrenic patients make the histidase gene a plausible candidate for genetic studies in schizophrenia. In the present study, we used a tetranucleotide repeat polymorphism in intron 8 of the histidase gene to examine the possibility that the histidase gene contributes to the genetic component of schizophrenia. In a first sample of 161 patients and 128 controls, we found the 4 repeat allele to be in excess in the patients. In contrast, the 3 repeat allele was less frequent in patients. A second sample of 95 patients and 93 controls was utilized to test these hypotheses. However, both observations were not replicated. We therefore concluded that our results do not support an involvement of the histidase gene in the development of schizophrenia.

Alleles↗
PubMed1996

Systematic screening for mutations in the 5'-regulatory region of the human dopamine D1 receptor (DRD1) gene in patients with schizophrenia and bipolar affective disorder.

A possible dysregulation of dopaminergic neurotransmission has been implicated in a variety of neuropsychiatric diseases. In the present study we systematically searched for the presence of mutations in the 5'-flanking region of the dopamine D1 receptor (DRD1) gene. This region has previously been shown to contain a functional promoter [Minowa et al., 1992: Proc Natl Acad Sci 89:3045-3049; Minowa et al., 1993: J Biol Chem 268:23544-23551]. We investigated 119 unrelated individuals (including 36 schizophrenic patients, 38 bipolar affective patients, and 45 healthy controls) using single-strand conformation analysis (SSCA). Eleven overlapping PCR fragments covered 2,189 bp of DNA sequence. We identified six single base substitutions: -2218T/C, -2102C/A, -2030T/C, -1992G/A, -1251G/C, and -800T/C. None of the mutations was found to be located in regions which have important influence on the level of transcriptional activity. Allele frequencies were similar in patients and controls, indicating that genetic variation in the 5'-regulatory region of the DRD1 gene is unlikely to play a frequent, major role in the genetic predisposition to either schizophrenia or bipolar affective disorder.

Alleles↗
PubMed1996

Systematic screening for mutations in the human serotonin 1F receptor gene in patients with bipolar affective disorder and schizophrenia.

Using single strand conformational analysis we screened the complete coding sequence of the serotonin 1F (5-HT1F) receptor gene for the presence of DNA sequence variation in a sample of 137 unrelated individuals including 45 schizophrenic patients, 46 bipolar patients, as well as 46 healthy controls. We detected only three rare sequence variants which are characterized by single base pair substitutions, namely a silent T-->A transversion in the third position of codon 261 (encoding isoleucine), a silent C-->T transition in the third position of codon 176 (encoding histidine), and an C-->T transition in position -78 upstream from the start codon. The lack of significant mutations in patients suffering from schizophrenia and bipolar affective disorder indicates that the 5-HT1F receptor is not commonly involved in the etiology of these diseases.

Base Sequence↗
PubMed1996

Human adenosine A2a receptor (A2aAR) gene: systematic mutation screening in patients with schizophrenia.

Several lines of evidence suggest an involvement of adenosine A2a receptor (A2aAR) mediated adenosinergic neuromodulation in the etiopathogenesis of schizophrenia. We therefore performed a systematic mutation scan of the complete coding region of the human A2aAR gene in a sample of 42 schizophrenic patients. We detected one rare naturally occurring receptor variant (Gly-340-Ser) and two silent mutations (405C/T and 1083C/T). To our knowledge the Gly-340-Ser substitution is the first naturally occurring molecular variant of the A2aAR identified. Determining the frequency of the three variants in 42 unrelated healthy controls, we observed a significant trend towards an overrepresentation of the 1083T variant in patients when compared to controls (p = 0.041). This trend was followed up in a large independent replication sample. However, we were not able to confirm the original trend in the second sample (p = 0.367). The Ser-340 variant was found in a single schizophrenic individual. Investigation of the patient's family revealed independent segregation between the Ser-340 variant and psychiatric illness. Our data suggest that genetically determined structural variation of the A2aAR does not play a major role in the development of schizophrenia.

Alleles↗
PubMed1996

Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor gene: identification of two naturally occurring receptor variants and association analysis in schizophrenia.

A statistically significant association between a silent mutation (102T/C) in the serotonin-2A (5-HT2A) receptor gene and schizophrenia has recently been reported in a sample of Japanese patients and healthy controls. This finding suggests that genetic predisposition to schizophrenia may be affected by a functional 5-HT2A receptor variant that is in linkage disequilibrium with 102T/C. In the present study, we have sought to identify genetic variation in the 5-HT2A receptor gene by screening genomic DNA samples from 91 unrelated subjects comprising 45 patients with schizophrenia and 46 healthy controls by using single-strand conformation analysis. We have identified four nucleotide sequence variants. Two sequence changes would result in protein alterations: a substitution of threonine by asparagine at position 25 (Thr25Asn), and a substitution of histidine by tyrosine at position 452 (His452Tyr). In order to test for a possible contribution to the development of schizophrenia, we have determined allele frequencies in extended samples of unrelated patients and healthy controls. The two amino acid substitutions are found with similar frequencies in patients and controls, indicating that the presence of these variants is not causally related to the development of schizophrenia. However, the reported association of the non-coding polymorphism 102T/C with the disease has also been detected in our sample (P=0.041, odds ratio=1.28, 95% confidence interval 1.012-1.623).

Alleles↗
PubMed1996

Assessing the statistical power to detect linkage in a sample of 51 bipolar affective disorder pedigrees.

We used computer simulation method to address the question of power in an initial collaborative sample of 51 bipolar affective disorder pedigrees. Simulations were performed for all possible combinations using (1) two levels of diagnostic stringency, (2) three transmission models, (3) locus heterogeneity, and (4) different assumed phenocopy rates. Some of the factors affect the power to detect linkage are (1) the specification of the correct genetic model, (2) the degree of locus heterogeneity, and (3) the frequency of phenocopies. The first two assertions were supported by our simulation results, but varying the rates of phenocopy did not substantially alter the power of the sample until a critical point. However, it is important to point out that these results are dependent on the genetic models under study and on the use of the "correct" model (i.e., the one used to simulate the data). If we assume a dominant mode of inheritance and locus homogeneity, the power to detect linkage is 97.5% at a theta of .01. However, the power declines dramatically, to 60.5% and 14.7%, if only 75 and 50% of the families are linked, respectively. Locus heterogeneity has a similar effect on the power of the sample to exclude linkage. The relative lack of power in our data, in the presence of significant locus heterogeneity, and for an intermediate mode of inheritance, underscores the need for multicenter collaboration.

Adolescent↗
PubMed1996

Dopamine D3 receptor Gly9/Ser9 polymorphism and schizophrenia: no increased frequency of homozygosity in German familial cases.

Disturbances in the dopaminergic transmission have been implicated in the etiology of schizophrenia. Recently, an association of schizophrenia with increased homozygosity of a Gly9/Ser9 polymorphism in the dopamine D3 receptor gene (DRD3) has been reported (Crocq et al., 1992; Mant et al., 1994). This finding reflected a departure from the Hardy-Weinberg equilibrium in the genotype distribution observed in schizophrenic patients. The effect was found to be at its strongest in patients with a high familial loading. In the present study, we tried to replicate this finding in a sample of 146 German patients with a DSM-III-R diagnosis of schizophrenia. All patients had a positive family history of major psychiatric disorder including 70 patients with a family history of schizophrenia. Given our sample size, we have a power of 99.8% to detect 2. deviation from the Hardy-Weinberg equilibrium of the reported magnitude. However, we found no evidence of an excess of homozygosity in our schizophrenic patients. This seems to indicate that homozygosity for the Gly9/Ser9 polymorphism at the DRD3 locus is unlikely to confer susceptibility to schizophrenia in the German population. This held true whether the psychiatric diagnoses in the affected relatives of the patient samples was established by the family history or family interview method.

Adult↗
PubMed1996

Efficacy and side-effects of clozapine: testing for association with allelic variation in the dopamine D4 receptor gene.

Genetic factors are supposed to play a major role not only in the etiology of psychiatric disorders but also in individual response to medications. To test the hypothesis that inter-individual differences in response to clozapine and the occurrence of side-effects might be influenced by variations in the dopamine D4 receptor gene, we examined frequencies of four known polymorphic sites affecting protein structure in the dopamine D4 receptor gene in 149 patients with schizophrenia or schizoaffective disorder treated with clozapine. The D4 polymorphisms included a 13-base pair deletion, which through a frameshift leads to a truncated nonfunctional receptor protein. There were, however, no significant differences in genotype counts between responders and nonresponders. Furthermore, no side-effect was found to be associated with genetic variants of the dopamine D4 receptor.

Adult↗