PubMed Health⌕ Search

Biomedical subjects

L Ozelius

Publications and source records attributed to L Ozelius.

At least 19 recordsLinked to original sources
PubMed2005

The North American Multiple System Atrophy Study Group.

The North American Multiple System Atrophy Study Group involves investigators in 12 US medical centers funded by a grant from the National Institutes of Health. The objectives are to examine the environmental and genetic risk factors for MSA; elucidate pathogenic mechanisms underlying the disorder; and refine evaluations used for assessment. During its first year, the group enrolled 87 patients, implemented four cores, and initiated four scientific projects. Most patients among the 87 had parkinsonian features, which frequently began asymmetrically and remained asymmetrical; one-third responded to levodopa and many developed levodopa complications; almost two-thirds of the patients had cerebellar dysfunction, of these 90% had ataxia; urinary incontinence occurred commonly, and sleep disorders affected most. The investigators studied the effects of oxidative and nitrative stress upon the formation of alpha-synuclein inclusions; generated transgenic models of alpha-synuclein accumulation that recapitulate several behavioral and neuropathological features of MSA; and compared the severity of the autonomic features of MSA, Parkinson's disease and dementia with Lewy bodies.

Animals↗
PubMed2004

Phenylalanine loading as a diagnostic test for DRD: interpreting the utility of the test.

Phenylalanine loading has been proposed as a diagnostic test for autosomal dominant DRD (dopa-responsive dystonia), and recently, a phenylalanine/tyrosine (phe/tyr) ratio of 7.5 after 4 h was reported as diagnostic of DRD. To test the utility of this test in another sample with DRD, we administered an oral challenge of phenylalanine (100 mg/kg) to 11 individuals with DRD and one non-manifesting gene carrier. Only 6/12 had a 4 h phe/tyr ratio of greater than 7.5, suggesting that additional parameters must be set to avoid missing the diagnosis of DRD, including the need for the plasma phenylalanine to reach a minimum level 600 in order for the test to be valid. We propose that in cases where this minimum plasma phenylalanine level is not reached, plasma tetrahydrobiopterin should be measured or alternatively other symptomatic family members should be screened.

Adolescent↗
PubMed2002

Diagnostic criteria for dystonia in DYT1 families.

Family studies of primary torsion dystonia have used the diagnostic categories of definite, probable, and possible dystonia for gene mapping and identification, but the validity of this hierarchical classification is not known. The authors assessed 147 DYT1 GAG deletion carriers and 113 blood-related noncarriers from 43 families. Only the category of definite dystonia was 100% specific. Probable dystonia, but not possible, was increased in carriers compared with noncarriers. The authors recommend that only those with definite signs of dystonia be considered affected in linkage and other genetic studies.

Adult↗
PubMed2002

Clinical findings of a myoclonus-dystonia family with two distinct mutations.

Myoclonus-dystonia has recently been associated with mutations in the epsilon-sarcoglycan gene (SCGE) on 7q21. Previously, the authors reported a patient with myoclonus-dystonia and an 18-bp deletion in the DYT1 gene on 9q34. The authors have now re-evaluated the patient harboring this deletion for mutations in the SGCE gene and identified a missense change. In the current study, the authors describe the clinical details of this family carrying mutations in two different dystonia genes. Further analysis of these mutations separately and together in cell culture and in animal models should clarify their functional consequences.

Adolescent↗
PubMed1999

Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of multiple hamartomas involving many organs. About two-thirds of the cases are sporadic and appear to represent new mutations. With the cloning of two causative genes, TSC1 and TSC2 it is now possible to analyze both genes in TSC patients and identify germline mutations. Here we report the mutational analysis of the entire coding region of both TSC1 and TSC2 genes in 126 unrelated TSC patients, including 40 familial and 86 sporadic cases, by single-stranded conformational polymorphism (SSCP) analysis followed by direct sequencing. Mutations were identified in a total of 74 (59%) cases, including 16 TSC1 mutations (5 sporadic and 11 familial cases) and 58 TSC2 mutations (42 sporadic and 16 familial cases). Overall, significantly more TSC2 mutations were found in our population, with a relatively equal distribution of mutations between TSC1 and TSC2 among the familial cases, but a marked underrepresentation of TSC1 mutations among the sporadic cases (P = 0.0035, Fisher's exact test). All TSC1 mutations were predicted to be protein truncating. However, in TSC2 13 missense mutations were found, five clustering in the GAP-related domain and three others occurring in exon 16. Upon comparison of clinical manifestations, including the incidence of intellectual disability, we could not find any observable differences between TSC1 and TSC2 patients. Our data help define the distribution and spectrum of mutations associated with the TSC loci and will be useful for both understanding the function of these genes as well as genetic counseling in patients with the disease.

Codon, Nonsense↗
PubMed1999

Report and abstracts of the Sixth International Workshop on chromosome 9.

A meeting on chromosome 9 was held on Tuesday, 27 October 1998 in Denver, with 38 participants (see appendix). Since the last meeting several of the positional cloning efforts on chromosome 9q have come to fruition, and the most detailed discussion was on 9p. Dr Ian Dunham from the Sanger Centre explained the strategy to be used for sequencing chromosome 9, and encouraged collaboration in the preparatory mapping. He indicated that some priority could be given to those regions where people in the field had a strong interest and could identify relevant PAC clones. At this short meeting it was clearly not possible to construct a comprehensive map of chromosome 9, and it was decided that efforts should be made to maintain links to sources of information on the chromosome 9 web page (http:@www.gene.ucl.ac.uk/chr9/). The discussions at the meeting are summarized in four sections: 9p, 9cen-q31, 9q32-9q34 and comparative mapping. Many of the posters presented at the meeting were also presented at the ASHG meeting (28-31 October 1998). They are listed here and are published in The American Journal of Human Genetics, vol. 63 (supplement). Abstracts for posters presented only at this meeting are appended to this report.

Animals↗
PubMed1998

Exon scanning of the entire TSC2 gene for germline mutations in 40 unrelated patients with tuberous sclerosis.

Tuberous sclerosis complex (TSC) is a dominantly inherited multisystem disorder resulting in the development of hamartomatous growths in many organs. Genetic heterogeneity has been demonstrated linking the familial cases to either TSC1 at 9q34.3, or TSC2 at 16p13.3. About two-thirds of the TSC cases are sporadic and appear to represent new mutations. While both genes are thought to account for all familial cases, with each representing approximately 50% of the mutations, the proportion of sporadic cases with mutations in TSC1 and TSC2 is yet to be determined. We have examined the entire coding sequence of the TSC2 gene in 20 familial and 20 sporadic cases and identified a total of twenty-one mutations representing 50% and 55% of familial and sporadic cases respectively. Our rate of mutation detection is significantly higher than other published reports. Twenty out of 21 mutations are novel and include 6 missense, 6 nonsense, 5 frameshifts, 2 splice alterations, a 34 bp deletion resulting in abnormal splicing, and an 18 bp deletion which maintains the reading frame. The mutations are distributed throughout the coding sequence with no specific hot spots. There is no apparent correlation between mutation type and clinical severity of the disease. Our results document that at least 50% of sporadic cases arise from mutations in the TSC2 gene. The location of the mutations described here, particularly the missense events, should be valuable for further functional analysis of this tumor suppressor protein.

Adolescent↗
PubMed1997

Fine mapping of the nail-patella syndrome locus at 9q34.

Nail-patella syndrome (NPS), or onychoosteodysplasia, is an autosomal dominant, pleiotropic disorder characterized by nail dysplasia, absent or hypoplastic patellae, iliac horns, and nephropathy. Previous studies have demonstrated linkage of the nail-patella locus to the ABO and adenylate kinase loci on human chromosome 9q34. As a first step toward isolating the NPS gene, we present linkage analysis with 13 polymorphic markers in five families with a total of 69 affected persons. Two-point linkage analysis with the program MLINK showed tight linkage of NPS and the anonymous markers D9S112 (LOD = 27.0; theta = .00) and D9S315 (LOD = 22.0; theta = .00). Informative recombination events place the NPS locus within a 1-2-cM interval between D9S60 and the adenylate kinase gene (AK1).

Chromosome Mapping↗
PubMed1995

Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population.

We have examined data on six closely linked microsatellite loci on chromosome 9q34 from 59 Ashkenazi Jewish families with idiopathic torsion dystonia (ITD). Our data show that the vast majority (> 90%) of early-onset ITD cases in the Ashkenazi population are due to a single founder mutation, which we estimate first appeared approximately 350 years ago. We also show that carriers preferentially originate from the northern part of the historic Jewish Pale of settlement (Lithuania and Byelorussia). The recent origin of this dominant mutation and its current high frequency (between 1/6,000 and 1/2,000) suggest that the Ashkenazi population descends from a limited group of founders, and emphasize the importance of genetic drift in determining disease allele frequencies in this population.

Alleles↗
PubMed1995

Adult onset idiopathic torsion dystonia is excluded from the DYT 1 region (9q34) in a Swedish family.

A gene (DYT1) for early onset idiopathic torsion dystonia was mapped to chromosome 9q34 in non-Jewish and Jewish families. The DYT1 gene region has been excluded in other families with adult onset and cervical or cranial onset idiopathic torsion dystonia from the United States, Great Britain, and France. The role of DYT1 in a Swedish family with adult onset idiopathic torsion dystonia in four generations was examined. The disease seems to be inherited in an autosomal dominant mode with reduced penetrance in this family. There were 10 affected family members, with a mean age of onset of 27 (range 18 to 50) years. The disease showed variable expression, with focal, multifocal, and generalised forms of dystonia in different family members. Genetic analysis excluded the chromosomal region containing the DYT1 locus as being responsible for dystonia in this family.

Adolescent↗
PubMed1994

Genetic linkage studies in autosomal dominant parkinsonism: evaluation of seven candidate genes.

Linkage studies were performed in three families (A, B, and C) with autosomal dominantly inherited parkinsonism affecting multiple members in three generations. Affected individuals exhibited the cardinal signs and symptoms of Parkinson's disease, with a mean age of onset of 51, 62, and 61 years in Families A, B, and C, respectively. Parkinsonian symptoms responded to L-dopa treatment, and an [18F]6-fluoro-L-dopa positron emission tomography scan in 1 affected member of Family B showed decreased striatal uptake typical of Parkinson's disease. Ancestors of all three families were traced to a small region in northern Germany and southern Denmark, suggesting the possibility of a common mutation. Linkage studies were performed with polymorphic markers associated with the following candidate genes: the genes for glutathione peroxidase (GPX1, 3q11), tyrosine hydroxylase (TH, 11p15.5), brain-derived neurotrophic factor (BDNF, 11p14), catalase (CAT, 11p13), amyloid precursor protein (APP, 21q21), copper-zinc superoxide dismutase (SOD1, 21q21), and debrisoquin 4-hydroxylase (CYP2D6, 22q13.1). Summed lod scores for all families excluded linkage to the genes GPX1, TH, APP, SOD1, and CYP2D6, as well as to the chromosomal region containing the genes CAT and BDNF. If families were analyzed individually, exclusion was possible for two (Family A), six (Family B), and five (Family C) of the seven candidate genes. There was strong evidence against linkage for the remaining loci in all families analyzed individually, except for TH, which was uninformative in Families A and B, and CYP2D6, which gave slightly positive pairwise lod scores in Family A. Our results indicate that the candidate genes investigated are not involved in the etiology of parkinsonism in these families.

Adult↗
PubMed1994

The gene for familial dystonia with myoclonic jerks responsive to alcohol is not located on the distal end of 9q.

A gene (DYT1) for susceptibility to early-onset torsion dystonia in Ashkenazi Jewish and Gentile kindreds is situated on chromosome 9q32-q34 in a 6-7 cM span between markers AK1 and ASS. To determine whether transmission of familial dystonia with myoclonic jerks responsive to alcohol was consistent with a gene in this region, we studied the 37 members of a Swedish family, of whom 20 were so affected. A lod score of < -2.00 from a two-point linkage analysis with six DNA markers covering a 30 cM span from D9S26 to D9S10 that included the region of the DYT gene indicated that this gene is not located in this region, and that two or more autosomal loci are responsible for hereditary dystonia in humans.

Alcohols↗
PubMed1993

A high-resolution linkage map of human 9q34.1.

A map comprising 16 distinct markers with heterozygosities of 0.61-0.92 for a 10-cM region of human 9q34.1 is presented. The map incorporates four genes and has a maximum intermarker interval of 2.1 cM. Markers were analyzed in the Venezuelan reference pedigrees and all were placed uniquely in the map with a minimum likelihood of 676:1. The map should prove useful in analysis of families segregating dystonia and tuberous sclerosis, as the DYT1 and TSC1 loci map within this region.

ABO Blood-Group System↗
PubMed1993

Localization of juvenile, but not late-infantile, neuronal ceroid lipofuscinosis on chromosome 16.

The neuronal ceroid lipofuscinoses (NCL) are a group of progressive neurodegenerative disorders characterized by the deposition of autofluorescent proteinaceous fingerprint or curvilinear bodies. We have found that CLN3, the gene underlying the juvenile form of NCL, is very tightly linked to the dinucleotide repeat marker D16S285 on chromosome 16. Integration of D16S285 into the genetic map of chromosome 16 by using the Centre d'Etude du Polymorphisme Humain panel of reference pedigrees yielded a favored marker order in the CLN3 region of qtel-D16S150-.08-D16S285-.04-D16S148-.02-D16S 67-ptel. The most likely location of the disease gene, near D16S285 in the D16S150-D16S148 interval, was favored by odds of greater than 10(4):1 over the adjacent D16S148-D16S67 interval, which was recently reported as the minimum candidate region. Analysis of D16S285 in pedigrees with late-infantile NCL virtually excluded the CLN3 region, suggesting that these two forms of NCL are genetically distinct.

Adolescent↗
PubMed1992

A radiation-reduced hybrid cell line containing 5 Mb/17 cM of human DNA from 9q34.

Disease gene loci for tuberous sclerosis (TSC1), idiopathic torsion dystonia (DYT1), and nail-patella syndrome (NPS1) have been mapped by genetic linkage analysis to human chromosome 9q band 34. To create a resource for physical mapping and manipulation of this region of the genome, we have created a radiation-reduced hybrid cell line containing DNA from human 9q34 as its only human component. This cell line, E6B, has been characterized by Southern blot and PCR analysis using a panel of 9q markers and fluorescent in situ hybridization. We estimate that it contains 5 Mb of human DNA, equal to 17 cM of genetic distance, extending from AK1 to ABO on 9q34.

Cell Line↗