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T Gasser

Publications and source records attributed to T Gasser.

At least 109 records · Page 6Linked to original sources
PubMed1999

Somatic gene therapy in animal models of Parkinson's disease.

Gene therapy in Parkinson's disease (PD) emerged about 10 years ago but until now, no clinical trials are under way, because most approaches have failed to show long-term therapeutic effects in PD animal models and because safety concerns precluded the use in humans so far. This review tries to give an overview on the development of different strategies in gene therapy in PD animal models and point out new and possibly more successful directions, including the transplantation of neural precursor cells and pig tissue.

Animals↗
PubMed1999

[Genetic counseling and prenatal diagnosis in mitochondrial diseases].

Since mitochondrial diseases lead frequently to severe phenotypes and are often hereditary, there is a need for genetic counselling of the affected families. The specific features of mitochondrial genetics, however, hamper straightforward definition of recurrence risks as in Mendelian diseases. Empirical risks were recently provided for MELAS and MERRF syndromes and for Leber hereditary optic neuropathy. In MELAS and MERFF, higher levels of mutant mtDNA in the mothers' blood were associated with an increased frequency of affected offspring. Chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome are in general sporadic disorders without increased recurrence risks in the offspring. As Leigh syndrome is found with maternal, autosomal recessive or X chromosomal transmission, the definition of the molecular defect is crucial for genetic counselling. Prenatal diagnosis was reported only in one case of mitochondrial disease so far, and in our opinion it remains questionable because of the uncertain correlation of the proportion of mutant DNA in chorionic villi and in clinically relevant tissues such as brain.

Adolescent↗
PubMed1999

Markedly different course of Friedreich's ataxia in sib pairs with similar GAA repeat expansions in the frataxin gene.

Friedreich's ataxia (FA) is most frequently caused by intronic trinucleotide repeat expansions in the frataxin gene on chromosome 9. The broad clinical spectrum includes late-onset FA (LOFA) and FA with retained reflexes (FARR). The size of the GAA expansions accounts for most, but not all, of the clinical variability. We report the unusual occurrence of LOFA and FARR in two siblings of patients with classical early-onset FA in two families. In spite of the markedly different course of the disease, the respective siblings harboured GAA repeat expansions of similar size in leucocytes. Since haplotype-related variability is not likely among siblings, we suppose that this intrafamilial phenotype variability is due to somatic mosaicism, with the more severely affected siblings harbouring the larger expansions in spinal cord and other affected tissues. In view of these results, genetic counseling and predictions on the course of FA are particularly difficult, even if an expansion mutation is found.

Adult↗
PubMed1999

Muscle and skin biopsies are a sensitive diagnostic tool in the diagnosis of CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a microangiopathic syndrome. Although the defective gene has been identified, genetic analysis may be effort some due to its large size and various mutations. Providing a reliable diagnostic marker would therefore be helpful. Electron microscopy has revealed characteristic electron-dense granular deposits in the basal lamina of vessels of patients with CADASIL. We investigated the sensitivity of skin and muscle biopsies for diagnosing CADASIL. We examined 30 family members of three unrelated German families affected by CADASIL. In 14 of the 21 affected individuals we performed skin and muscle biopsies; two patients were clinically asymptomatic. Under electron microscopy all muscle and skin biopsy specimens showed patches of granular and electron-dense material in the basal layer of both arterioles and capillaries. These findings confirm that general microangiopathy is a typical feature of this syndrome and is present in the early phase of the disease with or without clinical manifestation. Thus, as electron microscopy of skin biopsy specimens can establish the diagnosis of CADASIL with high certainty, it may be considered the method of first choice.

Adult↗
PubMed1999

High-throughput tissue microarray analysis to evaluate genes uncovered by cDNA microarray screening in renal cell carcinoma.

Many genes and signaling pathways are involved in renal cell carcinoma (RCC) development. However, genetic tumor markers have not gained use in RCC diagnostics and prognosis prediction. Identification and evaluation of new molecular parameters are of utmost importance in cancer research and cancer treatment. Here we present a novel approach to rapidly identify clinically relevant molecular changes in cancer. To identify genes with relevance to RCC, a cDNA array analysis was first performed on 5184 cDNA clones on a filter to screen for genes with differential expression between the renal cancer cell line CRL-1933 and normal kidney tissue. There were 89 differentially expressed genes in the cancer cell line, one of them coding for vimentin, a cytoplasmic intermediate filament. In a second step, a renal cancer tissue microarray containing 532 RCC specimen was used to determine vimentin expression by immunohistochemistry. Vimentin expression was seen frequently in clear cell (51%) and papillary RCC (61%), but rarely in chromophobe RCC (4%) and oncocytomas (12%). Furthermore, vimentin expression was significantly associated with poor patient prognosis (P < 0.007) independent of grade and stage. These results obtained from minute arrayed tumor samples match well with previous findings on vimentin expression in renal tumors. It is concluded that the combination of tumor arrays and cDNA arrays is a powerful approach to rapidly identify and further evaluate genes that play a role in tumor biology.

Carcinoma, Renal Cell↗
PubMed1999

Search for the PARK3 founder haplotype in a large cohort of patients with Parkinson's disease from northern Germany.

A founder haplotype on chromosome 2p for autosomal dominant Parkinson's disease (PD) has been postulated for two families of Northern European descent, and a new mutation in the alpha-synuclein gene (Ala30Pro) has been found in a German PD family. We evaluated 85 German PD patients and 85 ethnically matched controls for shared markers on chromosome 2p and for the new alpha-synuclein mutation. We found no evidence for linkage disequilibrium, suggesting that the putative founder mutation on chromosome 2p is not a common cause of PD in the local population. Furthermore, no patient carried the Ala30Pro change, supporting earlier findings that mutations in the alpha-synuclein gene are extremely rare.

Aged↗
PubMed1999

A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease.

Autosomal recessive juvenile parkinsonism (AR-JP, PARK2; OMIM 602544), one of the monogenic forms of Parkinson's disease (PD), was initially described in Japan. It is characterized by early onset (before age 40), marked response to levodopa treatment and levodopa-induced dyskinesias. The gene responsible for AR-JP was recently identified and designated parkin. We have analysed the 12 coding exons of the parkin gene in 35 mostly European families with early onset autosomal recessive parkinsonism. In one family, a homozygous deletion of exon 4 could be demonstrated. By direct sequencing of the exons in the index patients of the remaining 34 families, eight previously undescribed point mutations (homozygous or heterozygous) were detected in eight families that included 20 patients. The mutations segregated with the disease in the families and were not detected on 110-166 control chromosomes. Four mutations caused truncation of the parkin protein. Three were frameshifts (202-203delAG, 255delA and 321-322insGT) and one a nonsense mutation (Trp453Stop). The other four were missense mutations (Lys161Asn, Arg256Cys, Arg275Trp and Thr415Asn) that probably affect amino acids that are important for the function of the parkin protein, since they result in the same phenotype as truncating mutations or homozygous exon deletions. Mean age at onset was 38 +/- 12 years, but onset up to age 58 was observed. Mutations in the parkin gene are therefore not invariably associated with early onset parkinsonism. In many patients, the phenotype is indistinguishable from that of idiopathic PD. This study has shown that a wide variety of different mutations in the parkin gene are a common cause of autosomal recessive parkinsonism in Europe and that different types of point mutations seem to be more frequently responsible for the disease phenotype than are deletions.

Binding Sites↗
PubMed1999

[Identification of prognostic parameters for renal cell carcinoma by cDNA arrays and cell chips].

We report here an example of how the combined application of cDNA and tumor array can lead to the identification of a novel prognostic marker within a very short time. A cDNA array analysis was performed on 5184 cDNA clones on a filter to screen for genes with differential expression between the renal cancer cell line CRL-1933 and normal kidney tissue to identify genes with relevance in RCC. There were 89 differentially expressed genes in the cancer cell line, one of them coding for vimentin, a cytoplasmic intermediate filament. To determine the in vivo prevalence and prognostic significance of vimentin expression, a renal cancer tissue micro array containing 532 RCC specimen was constructed and vimentin expression was determined by immunohistochemistry. Vimentin expression was frequently seen in clear-cell (51%) and papillary RCC (61%), but rarely in chromophobe RCC (4%) and oncocytomas (12%). These results obtained from minute arrayed tumor samples match with previous findings on vimentin expression in renal tumors. Furthermore, vimentin expression was significantly associated with poor patient prognosis (p < 0.007) independently of grade and stage. These results suggest that tissue microarray analysis provides a rapid and powerful method to determine the prevalence and prognostic significance of novel candidate genes discovered to be involved in cancer development with large-scale cDNA expression arrays. The tissue array can be adapted as a routine tool in research laboratories for analyses of large tumor series at the DNA, RNA or protein level. With such a tool, cancer researchers can study vast numbers of tumor samples in a short time and can generate a wealth of data on the application of tumor markers.

Biomarkers, Tumor↗
PubMed1998

Comparative genomic hybridization reveals frequent chromosome 13q and 4q losses in renal carcinomas with sarcomatoid transformation.

Renal cell carcinomas (RCCs) with sarcomatoid transformation show the most malignant behaviour of all renal carcinoma types. In this study, comparative genomic hybridization was used to screen for losses and gains of DNA sequences along all chromosome arms in 12 sarcomatoid (S) RCCs. On average, there were 8.6 aberrations per tumour. DNA sequence losses (5.2 +/- 4.4) were slightly more frequent than gains (3.4 +/- 2.6). DNA gains most often involved chromosomes 17 (33 per cent), 7, and 8q (25 per cent each). High-level co-amplification involving 11q22-23 and 7p21-22 in one SRCC was not present in adjacent non-sarcomatous tumour areas, raising the possibility of oncogene involvement at these loci for sarcomatoid transformation. DNA losses were most prevalent at 13q (75 per cent) and 4q (50 per cent), suggesting that inactivation of tumour suppressor genes at chromosomes 13q and 4q may be linked to sarcomatoid growth of RCC. It is concluded that SRCCs are genetically highly complex. Chromosomes 13q, 4q, 7p21-22, and 11q22-23 may carry genes with relevance for sarcomatoid growth in RCC.

Adult↗
PubMed1998

Phenotypic expression of the DYT1 mutation: a family with writer's cramp of juvenile onset.

Recently, the mutation causing early-onset generalized torsion dystonia has been identified as a GAG deletion in the gene for an adenosine triphosphate-binding protein named torsinA. We describe a German family with 5 clinically affected individuals carrying this mutation. In at least 4 of the 5 patients, the disease presented as a dystonic writer's cramp during late childhood or adolescence, which affected sequentially both sides but did not progress to a generalized form of dystonia. We conclude that familial writer's cramp may be a manifestation of the DYT1 mutation.

Adolescent↗
PubMed1998

The alpha-synuclein Ala53Thr mutation is not a common cause of familial Parkinson's disease: a study of 230 European cases. European Consortium on Genetic Susceptibility in Parkinson's Disease.

We report the results of a screen of 230 European familial index cases of Parkinson's disease for the recently described Ala53Thr mutation in the alpha-synuclein gene in an autosomal dominant Parkinson's disease kindred. No mutations were found from this broad white population, and we therefore conclude that although of great interest, this mutation is a very rare cause of familial Parkinson's disease.

Adult↗
PubMed1998

The phenotypic spectrum of CADASIL: clinical findings in 102 cases.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an increasingly recognized autosomal dominant disorder that leads to cerebrovascular manifestations in early adulthood. This study delineates the phenotypic spectrum and the natural history of the disease in 102 affected individuals from 29 families with biopsy-proven CADASIL. Recurrent ischemic episodes (transient ischemic attack [TIA] or stroke) were the most frequent presentation found in 71% of the cases (mean age at onset, 46.1 years; range, 30-66 years; SD, 9.0 years). Forty-eight percent of the cases had developed cognitive deficits. Dementia (28%) was frequently accompanied by gait disturbance (90%), urinary incontinence (86%), and pseudobulbar palsy (52%). Thirty-nine patients (38%) had a history of migraine (mean age at onset, 26.0 years; SD, 8.2 years), which was classified as migraine with aura in 87% of the cases. Psychiatric disturbances were present in 30% of the cases, with adjustment disorder (24%) being the most frequent diagnosis. Ten patients (10%) had a history of epileptic seizures. To delineate the functional consequences of ischemic deficits, we studied the extent of disability in different age groups. The full spectrum of disability was seen in all groups older than age 45. Fifty-five percent of the patients older than age 60 were unable to walk without assistance. However, 14% in this age group exhibited no disability at all. Kaplan-Meier analysis disclosed median survival times of 64 years (males) and 69 years (females). An investigation of the 18 multiplex families revealed marked intrafamilial variations.

Adult↗
PubMed1998

Genetics of Parkinson's disease.

A genetic contribution to the etiology of Lewy body Parkinson's disease (PD) is now well established, based on the demonstration of a familial aggregation of the disease by case-control and twin studies and on the description of large multigenerational families in whom clinically and pathologically typical PD is inherited in an autosomal dominant fashion. In the largest of these families, a gene locus has been mapped to the long arm of chromosome 4 and a putative disease-causing mutation has been identified in the gene for alpha-synuclein. However, analysis of a large number of individuals with sporadic and familial PD suggests that a mutation in this gene is a very rare cause of the disorder, either familial or sporadic. Another locus for autosomal dominantly inherited Lewy body PD has recently been mapped to chromosome 2p13. Possible strategies for the identification of further PD genes are discussed.

Chromosome Mapping↗