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T Sander

Publications and source records attributed to T Sander.

At least 73 records · Page 4Linked to original sources
PubMed1996

Common subtypes of idiopathic generalized epilepsies: lack of linkage to D20S19 close to candidate loci (EBN1, EEGV1) on chromosome 20.

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). A trait locus (EBN1) for a rare subtype of IGEs, the benign neonatal familial convulsions, and a susceptibility gene (EEGV1) for the common human low-voltage electroencephalogram have been mapped close together with D20S19 to the chromosomal region 20q13.2. Both loci are potential candidates for the susceptibility to IGE spectra with age-related onset beyond the neonatal period. The present study tested the hypothesis that a putative susceptibility locus linked to D20S19 predisposes to spectra of IGEs with age-related onset from childhood to adolescence. Linkage analyses were conducted in 60 families ascertained through IGE patients with juvenile myoclonic epilepsy, juvenile absence epilepsy or childhood absence epilepsy. Our results provide evidence against linkage of a putative susceptibility gene for four hierarchically broadened IGE spectra with D20S19 assuming tentative single-locus genetic models. The extent of an "exclusion region" (lod scores below-2) varied from 0.5 cM up to 22 cM on either side of D20S19 depending on the trait assumed. These results are contrary to the expectation that a susceptibility gene in vicinity to D20S19 confers a common major gene effect to the expression of IGE spectra with age-related onset from childhood to adolescence.

Chromosome Mapping↗
PubMed1996

Exclusion of linkage between idiopathic generalized epilepsies and the GABAA receptor alpha 1 and gamma 2 subunit gene cluster on chromosome 5.

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). The pivotal function of ionotropic gamma-aminobutyric acid type A receptors (GABRs) in inhibitory neurotransmission in the mammalian central nervous system suggests that they may be involved in epileptogenesis and genetic predisposition to IGEs. Dinucleotide repeat polymorphisms associated with the human GABAA receptor alpha 1 (GABRA1) and gamma 2 subunit (GABRG2) gene cluster on chromosome 5q32-q35 offer the opportunity to test whether these candidate genes confer susceptibility to IGEs. Our linkage analyses in 63 families ascertained through IGE patients with either juvenile myoclonic epilepsy, juvenile absence epilepsy or childhood absence epilepsy do not support the hypothesis that variants within the GABRA1 and GABRG2 gene cluster contribute a frequent major gene effect to the expression of the common familial IGEs.

Base Sequence↗
PubMed1996

Lack of linkage between idiopathic generalized epilepsies and the gene encoding the neural cell adhesion molecule.

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). The frequent neuropathological occurrence of microdysgeneses in the brain of IGE patients implies that genes regulating neural migration and cell adhesion might be involved in epileptogenesis of age-related generalized seizures. Our present linkage study tested the hypothesis that DNA sequence variants associated with the gene encoding the neural cell adhesion molecule (NCAM) confer genetic susceptibility to IGE traits in 57 families ascertained through patients with either juvenile myoclonic epilepsy, juvenile or childhood absence epilepsy. Our consistently negative results provide evidence against a common major effect of NCAM gene variants to the expression of IGEs with age-related onset from childhood to adolescence.

Adult↗
PubMed1996

The genetics of idiopathic generalized epilepsy: implications for the understanding of its aetiology.

Epilepsy is one of the most common neurological disorders. Both inherited and acquired factors contribute to its multifactorial pathogenesis. A genetic predisposition plays a major role in the aetiology of the common idiopathic generalized epilepsies. Susceptibility genes for two syndromes of idiopathic generalized epilepsies, the benign familial neonatal convulsions and juvenile myoclonic epilepsy, have been assigned to the chromosomal regions 20q13 (EBN1), 8q24 (EBN2) and 6p21 (EJM1). Positional cloning of the mutations causing these traits will help to elucidate the molecular pathways of epileptogenesis and will imply a classification on a neurobiological basis. Insights into the underlying impairment of neuronal excitability should provide new concepts for the development of rational treatment strategies.

Animals↗
PubMed1996

No association of the structural dopamine D2 receptor (DRD2) variant 311Cys with alcoholism.

The human dopamine D2 receptor (DRD2) has been implied in the vulnerability for alcoholism and/or the modification of its severity. This is supported through animal experimental and pharmacological data. We analyzed the DRD2 311Ser/Cys polymorphism in 312 German alcoholics and 131 ethnically matched controls to investigate the association of genetic DRD2 variants with alcoholism or clinical characteristics of homogeneous subgroups of alcoholics. We observed no association between the 311Cys variant and alcoholism, and none of the clinical characteristics evaluated was significantly associated with 311Cys. The allele frequencies of the 311Cys variant were 0.026 and 0.031 in the alcoholics and controls, respectively. These are the highest reported 311Cys frequencies in Caucasians. The DRD2 TaqI A1/A2 restriction fragment length polymorphism was analyzed simultaneously in our samples. In most cases, the 311Cys allele is associated with the TaqI A2-allele. Data do not suggest a clinical relevance of the 311Cys variant in alcoholism. However, the relevance of this variant in other diseases or the existence of other DRD2 variants with altered receptor function or expression cannot be excluded.

Adult↗
PubMed1996

Lack of allelic association of dopamine D1 and D2 (TaqIA) receptor gene polymorphisms with reduced dopaminergic sensitivity to alcoholism.

Our study tested the hypothesis of whether the sensitivity of central dopamine receptors corresponds to the genotypic constitution of DNA-polymorphisms of the dopamine D1 and D2 receptor (DRD1, DRD2) genes and is associated with poor treatment outcome. Therefore, 97 alcohol-dependent patients were assessed according to their sensitivity of central dopamine receptors (apomorphine-induced secretion of growth hormone), clinical outcome during a 6-month observation period, and genotypic constitution of the TaqIA restriction fragment length polymorphism (RFLP) at the DRD2 locus and of the Bsp1286I RFLP at the DRD1 locus. On the 1st day of detoxification, dopamine receptor hyposensitivity was found in treatment nonresponders, but not in responders. Apomorphine-induced growth hormone release did not differ significantly in alcoholics with different genotypes of the DRD1 and DRD2 RFLPs. Neither did we find a significant allelic association with treatment response. Thus, we did not find evidence for a genetic determination of dopamine receptor hyposensitivity in alcoholics with poor treatment outcome.

Adult↗
PubMed1995

The phenotypic spectrum related to the human epilepsy susceptibility gene "EJM1".

Linkage studies of families ascertained through patients with juvenile myoclonic epilepsy (JME) suggest that an HLA-linked susceptibility gene on chromosome 6, designated "EJM1," predisposes to a group of idiopathic generalized epilepsies (IGEs) comprising JME, juvenile absence epilepsy (JAE), childhood absence epilepsies (CAE), and epilepsies with generalized tonic-clonic seizures (GTCS). To explore the EJM1-related phenotypic spectrum, we conducted linkage studies with HLA-DQ alpha restriction fragment length polymorphisms in 44 families ascertained through patients with CAE or JAE. Our results for the entire group of families provide evidence against a major susceptibility locus for idiopathic absence epilepsies and broader spectra of IGEs in the HLA region. Lod scores less than -2 were obtained for a region from 10 cM up to 23 cM on either side of the HLA-DQ alpha locus, depending on the assumed trait model. Suggestive evidence for linkage was found only for a subgroup of families with JME patients assuming an autosomal dominant mode of inheritance with 70% penetrance. A maximum lod score was obtained when family members with JME, JAE, CAE, and idiopathic GTCS were included into the affection status. Our results demonstrate that (1) the genetic susceptibility to idiopathic absence epilepsies and broader spectra of IGEs is heterogeneous, (2) the gene effect of EJM1 depends on the familial genetic background, and (3) EJM1 confers genetic susceptibility to idiopathic absence epilepsies and broader spectra of IGEs in the presence of family members with JME.

Disease Susceptibility↗
PubMed1995

Dopamine D1, D2 and D3 receptor genes in alcohol dependence.

Hereditary factors play a substantial role in the etiology of alcohol dependence. Alcohol mediates its reinforcing effects by an activation of the mesolimbic dopamine system. These findings suggest that the genes encoding the dopamine receptor (DR) subtypes represent high-ranking candidates for susceptibility genes to addictive disorders. Our present population-based association study investigated whether sequence variants of the dopamine D1, D2 and D3 receptor genes confer susceptibility to alcohol dependence in 278 alcoholics, and clinically more homogeneous subgroups ascertained through positive family history, early age at onset, delirium, withdrawal seizures and antisocial tendencies. No evidence for an allelic association was found for the PCR-based TaqA RFLP fo the DRD2 gene and a Bsp1286I RFLP of the DRD1 gene. Without correction for multiple testing, we found a significantly increased allele frequency of a common DRD3 gene variant expressing a serine at position 9 in the extracellular N-terminal part of the receptor protein in 55 alcohol-dependent individuals with delirium (chi 2 = 4.1, df = 1, p = 0.042). Further studies have to examine whether this amino acid substitution or a nearby mutation confers genetic susceptibility to at least a subgroup of alcohol-dependent individuals with delirium.

Adult↗
PubMed1995

Refinement of map position of the human GluR6 kainate receptor gene (GRIK2) and lack of association and linkage with idiopathic generalized epilepsies.

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). The pivotal function of glutamate receptors (GluRs) in excitatory neurotransmission implicates their involvement in epileptogenesis and genetic susceptibility to IGEs. A trinucleotide repeat polymorphism detected in the 3' untranslated region of the kainate-selective GluR6 receptor gene (GRIK2) on chromosome 6 makes it possible to perform linkage and association studies with this high-ranking candidate gene. The present study tested the hypothesis that allelic variants of GRIK2 contribute to the genetic susceptibility to the common IGEs. Linkage and association analyses were conducted in 63 families ascertained through IGE patients with juvenile myoclonic epilepsy, juvenile absence epilepsy, or childhood absence epilepsy. Our linkage and association results suggest that allelic variants of GRIK2 are not involved in the expression of the common familial IGEs, and radiation hybrid mapping assigns GRIK2 to the chromosomal region 6q16.3-q21. This localization excludes GRIK2 as a candidate for the putative IGE susceptibility locus "EJM1" on the short arm of chromosome 6.

Chromosome Mapping↗
PubMed1994

Molecular biological perspectives in treating neuropsychiatric disorders with dopaminergic drugs.

This review aims to present perspectives of molecular neuropharmacology in the development of more targeted drugs that modulate dopaminergic functions in various neuropsychiatric disorders. Recent advances in molecular neurobiology have revealed five distinct dopamine receptor (DR) genes and multiple allelic variations encoding DR subtypes with functional diversity. Depending on the different biophysical and pharmacological properties and the various cerebral distributions of the DR subtypes, the action profile of subtype-specific dopaminergic drugs can be predicted. In vitro expression of DR gene variants in mammalian cell lines will facilitate the screening and pharmacological characterization of dopaminergic ligands. Molecular modeling of the DR subtypes by three-dimensional computer models will be useful for establishing structure-function relationships between ligands and the DRs, and could provide a template for the design of receptor-specific drugs. In the near future, drugs modulating dopamine turnover and transport or involving the successive effector systems will increase the current therapeutical spectrum.

Dopamine↗
PubMed1992

[The long-term toxicity of polychemotherapy in successfully treated testicular carcinoma].

Of 55 patients with testicular cancer, treated by combination chemotherapy including cisplatin, 21 (mean age 35 [21-51] years) were reexamined for late sequelae of the chemotherapy 1-9 years later. No patient had a recurrence or second malignancy. They all had normal renal function (renal sequence scintigraphy; creatinine clearance). Seven of 20 patients had a polyneuropathy, nine of 18 had high-tone hearing loss. Two patients became fathers after treatment. In nine of 20 patients the serum concentration of follicle-stimulating hormone was raised to above 20 mU/ml, evidence of germ-cell damage. Six of 13 patients had an abnormal ejaculation following retroperitoneal lymphadenectomy or excision of a residual tumour. There was no evidence of any life-limiting toxicity of the chemotherapy.

Adult↗
PubMed1992

Confirmation of the localization of the human GABAA receptor alpha 1-subunit gene (GABRA1) to distal 5q by linkage analysis.

The GABAA receptor is the major inhibitory neurotransmitter receptor in the mammalian brain. To date, 14 genes that encode subunits of this receptor have been identified; these appear to be scattered throughout the human genome and are under investigation as candidate loci for a number of neurological and psychiatric disorders. We report here a highly polymorphic (dC-dA)n repeat within the human alpha 1-subunit gene (GABRA1). Typing of this marker in the Centre d'Etude du Polymorphisme Humain (CEPH) panel of families confirms the previous assignment of the GABRA1 locus to the distal portion of chromosome 5q by demonstrating linkage to the markers CRI-L45 (D5S61) (Zmax = 11.00, theta max = 0.15), CRI-V1022 (D5S54) (Zmax = 7.25, theta max = 0.20), and CRI-P148 (D5S72) (Zmax = 5.71, theta max = 0.24).

Base Sequence↗
PubMed1992

Do idiopathic generalized epilepsies share a common susceptibility gene?

Molecular genetic research in epilepsy is most promising in the homogeneous, genetically determined forms of the disease. The phenotype-genotype strategy used makes some epileptic syndromes more suitable for such study than others. Unequivocal clinical presentation, mendelian transmission with similar clinical expression in close relatives, and sufficiently large numbers of affected families are requisites. This makes idiopathic generalized epilepsies (IGEs), particularly absence and juvenile myoclonic epilepsies (JMEs), suitable subtypes for genetic analysis. Results of family studies to date show that five IGE syndromes have a common genetic origin. Linkage studies have localized a gene defect on chromosome 6p that predisposes to a group of IGEs: JME, absence epilepsy, and generalized tonic-clonic seizures in epilepsy families with JME probands. Environmental and additional genetic factors are other areas requiring further study to elucidate the discriminant factors associated with different varieties of IGE.

Chromosomes, Human, Pair 6↗
PubMed1991

Localization of idiopathic generalized epilepsy on chromosome 6p in families of juvenile myoclonic epilepsy patients.

Juvenile myoclonic epilepsy (JME) is a distinct subform of idiopathic generalized epilepsy of adolescence. Linkage studies with Bf and serologic HLA markers in families of JME patients have shown a tight linkage on chromosome 6. We present a linkage analysis with HLA-DQ restriction fragment length polymorphisms on more extended families, paying particular attention to the epilepsy type of the affected family members. We studied 21 families of JME patients with a total of 143 family members and obtained a highest logarithm of the odds (lod) score of 3.9 (theta m = 0.01, theta f = 0.01) assuming a dominant mode of inheritance and 70% penetrance when family members with JME, absence epilepsy, or epilepsy with generalized tonic-clonic seizures (GTCS) were considered as affected. When we also classified clinically normal family members with generalized spike-wave discharges in the EEG as "affected," the maximum lod score was 4.1 (theta m = 0.01, theta f = 0.3) under a dominant mode of inheritance and 90% penetrance. These findings support the conclusion that a gene locus for a group of idiopathic generalized epilepsies (JME, epilepsy with absences, and epilepsy with GTCS) maps to chromosome 6p.

Chromosomes, Human, Pair 6↗