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Biomedical subjects

L J Treiman

Publications and source records attributed to L J Treiman.

10 recordsLinked to original sources
PubMed1998

Childhood absence epilepsy with tonic-clonic seizures and electroencephalogram 3-4-Hz spike and multispike-slow wave complexes: linkage to chromosome 8q24.

Childhood absence epilepsy (CAE), a common form of idiopathic generalized epilepsy, accounts for 5%-15% of childhood epilepsies. To map the chromosomal locus of persisting CAE, we studied the clinical and electroencephalographic traits of 78 members of a five-generation family from Bombay, India. The model-free affected-pedigree member method was used during initial screening with chromosome 6p, 8q, and 1p microsatellites, and only individuals with absence seizures and/or electroencephalogram 3-4-Hz spike- and multispike-slow wave complexes were considered to be affected. Significant P values of .00000-.02 for several markers on 8q were obtained. Two-point linkage analysis, assuming autosomal dominant inheritance with 50% penetrance, yielded a maximum LOD score (Zmax) of 3.6 for D8S502. No other locus in the genome achieved a significant Zmax. For five smaller multiplex families, summed Zmax was 2.4 for D8S537 and 1.7 for D8S1761. Haplotypes composed of the same 8q24 microsatellites segregated with affected members of the large family from India and with all five smaller families. Recombinations positioned the CAE gene in a 3.2-cM interval.

California↗
PubMed1997

The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia.

The dominant cerebellar ataxias (ADCAs) represent a clinically and genetically heterogeneous group of disorders linked by progressive deterioration in balance and coordination. The utility of genetic classification of the ADCAs has been highlighted by the striking variability in clinical phenotype observed within families and the overlap in clinical phenotype observed between those with different genotypes. The recent demonstration that spinocerebellar ataxia type 2 (SCA2) is caused by a CAG repeat expansion within the ataxin-2 gene has allowed us to determine the frequency of SCA2 compared with SCA1, SCA3/Machado-Joseph disease (MJD), and dentatorubropallidoluysian atrophy (DRPLA) in patients with sporadic and inherited ataxia. SCA2 accounts for 13% of patients with ADCA (without retinal degeneration), intermediate between SCA1 and SCA3/MJD, which account for 6% and 23%, respectively. Together, SCA1, SCA2, and SCA3/MJD constitute >40% of the mutations leading to ADCA I in our population. No patient without a family history of ataxia, or with a pure cerebellar or spastic syndrome, tested positive for SCA1, SCA2, or SCA3. No overlap in ataxin-2 allele size between normal and disease chromosomes, or intermediate-sized alleles, were observed. Repeat length correlated inversely with age at onset, accounting for approximately 80% of the variability in onset age. Haplotype analysis provided no evidence for a single founder chromosome, and diverse ethnic origins were observed among SCA2 kindreds. In addition, a wide spectrum of clinical phenotypes was observed among SCA2 patients, including typical mild dominant ataxia, the MJD phenotype with facial fasciculations and lid retraction, and early-onset ataxia with a rapid course, chorea, and dementia.

Adolescent↗
PubMed1996

Juvenile myoclonic epilepsy in chromosome 6p12-p11: locus heterogeneity and recombinations.

We recently analyzed under homogeneity a large pedigree from Belize with classic juvenile myoclonic epilepsy (JME). After a genome wide search with 146 microsatellites, we obtained significant linkage between chromosome 6p markers, D6S257 and D6S272, and both convulsive and EEG traits of JME. Recombinations in two affected members defined a 40 cM JME region flanked by D6S313 and D6S258. In the present communication, we explored if the same chromosome 6p11 microsatellites also have a role in JME mixed with pyknoleptic absences. We allowed for heterogeneity during linkage analyses. We tested for heterogeneity by the admixture test and looked for more recombinations. D6S272, D6S466, D6S294, and D6S257 were significantly linked (Zmax > 3.5) to the clinical and EEG traits of 22 families, assuming autosomal dominant inheritance with 70% penetrance. Pairwise Zmax were 4.230 for D6S294 (theta m = f at 0.133) and 4.442 for D6S466 (theta m = f at 0.111). Admixture test (H2 vs. H1) was significant (P = 0.0234 for D6S294 and 0.0128 for D6S272) supporting the hypotheses of linkage with heterogeneity. Estimated proportion of linked families, alpha, was 0.50 (95% confidence interval 0.05-0.99) for D6S294 and D6S272. Multipoint analyses and recombinations in three new families narrowed the JME locus to a 7 cM interval flanked by D6S272 and D6S257.

Centromere↗
PubMed1994

Progress in mapping human epilepsy genes.

The chromosomal loci for seven epilepsy genes have been identified in chromosomes 1q, 6p, 8q, 16p, 20q, 21q, and 22q. In 1987, the first epilepsy locus was mapped in a common benign idiopathic generalized epilepsy syndrome, juvenile myoclonic epilepsy (JME). Properdin factor or Bf, human leukocyte antigen (HLA), and DNA markers in the HLA-DQ region were genetically linked to JME and the locus, named EJM1, was assigned to the short arm of chromosome 6. Our latest studies, as well as those by Whitehouse et al., show that not all families with JME have their genetic locus in chromosome 6p, and that childhood absence epilepsy does not map to the same EJM1 locus. Recent results, therefore, favor genetic heterogeneity for JME and for the common idiopathic generalized epilepsies. Heterogeneity also exists in benign familial neonatal convulsions, a rare form of idiopathic generalized epilepsy. Two loci are now recognized; one in chromosome 20q (EBN1) and another in chromosome 8q. Heterogeneity also exists for the broad group of debilitating and often fatal progressive myoclonus epilepsies (PME). The gene locus (EPM1) for both the Baltic and Mediterranean types of PME or Unverricht-Lundborg disease is the same and is located in the long arm of chromosome 21. Lafora type of PME does not map to the same EPM1 locus in chromosome 21. PME can be caused by the juvenile type of Gaucher's disease, which maps to chromosome 1q, by the juvenile type of neuronal ceroid lipofuscinoses (CLN3), which maps to chromosome 16p, and by the "cherry-red-spot-myoclonus" syndrome of Guazzi or sialidosis type I, which has been localized to chromosome 10. A point mutation in the mitochondrial tRNA(Lys) coding gene can also cause PME in children and adults (MERFF).

Chromosome Mapping↗
PubMed1993

Genetics of epilepsy: an overview.

Studies of the genetics of epilepsy have, until recently, involved epidemiologic or segregation analyses of phenotypic characteristics of a number of seizure disorders. Technical advances in molecular biology involving gene mapping and gene identification have made it possible to examine the heritability of various epilepsy syndromes. Using "reverse genetics" or positional cloning, it is possible to identify an abnormal protein through gene isolation and cloning. Genes are localized through analysis of linkage to phenotypic markers (proteins) or DNA markers such as restriction fragment length polymorphisms, variable number of tandem repeats, and dinucleotides. Methods used to obtain DNA of interest involve digestion of genomic DNA with specific restriction endonucleases or amplification of DNA by polymerase chain reaction technology. Gel electrophoresis is the basis for the separation of different sized DNA. Inherited disorders for which a gene has been cloned or localized have highly penetrant, well-defined clinical phenotypes with no remissions and abundant clinical material. Genetic epilepsies, however, are variably penetrant age-dependent disorders with heterogeneous clinical phenotypes. Despite these difficulties, three genetic epilepsies have been mapped to specific chromosomes: benign familial neonatal convulsions to 20q, juvenile myoclonic epilepsy to 6p, and Baltic progressive myoclonus epilepsy to 21q. Further progress in understanding genetic epilepsies will depend on better definition of syndrome phenotypes, isolation of the epilepsy gene(s), and identification of the abnormal protein(s).

Animals↗
PubMed1986

Looking for epilepsy genes: clinical and molecular genetic studies.

The complexity of the human genome creates special problems in understanding the genetic component of disease processes. An estimated 50,000 genes exist in the human genome, and it is reasonable to assume that mutation in any one of these genes may result in an inherited disorder. Because of the complex pattern of gene expression controlling the development and organization of the central nervous system (CNS), insights into the genetic component, if any, of diseases such as epilepsy are most accessible to analysis by genetic linkage studies. Advances in the manipulation of DNA have made possible more effective acquisition of genotypic information in humans by studying the inheritance of restriction fragment length polymorphisms (RFLPs) using cloned DNA probes. Two approaches exist to utilize this technology in studying inherited disorders. The first approach consists of genotypic determinations in affected families with cloned genes in which a mutation might result in the phenotype observed. Analysis of these data will show whether the inheritance of an allele of the candidate gene is linked to the disease. The second approach relies upon the construction with these probes of a linkage map for the human genome such that disease families can be screened in order to determine with which of these markers the phenotype is linked, indicating the map position of a gene associated with the inherited disorder. The use of these new approaches enables investigators to screen either specific biochemical defects in disease families or to identify the underlying genetic mechanisms in inherited disorders whose phenotype is expressed only in the intact human (84). The first step in localizing the chromosomal site of specific epilepsies is to define their pattern of inheritance. This determination is now being carried out for benign juvenile myoclonic epilepsy; 50 multigenerational families are being studied in three separate epilepsy programs in Los Angeles, Winston-Salem, North Carolina, and Berlin. Concurrent with these studies, investigators are combining the principles of classic linkage analysis, using 30 protein markers, with the use of RFLPs to determine the chromosomal location of juvenile myoclonic epilepsy. Two problems appear formidable, however. First, since the chromosomal location of specific epilepsies is unknown, the entire human genome must be screened.(ABSTRACT TRUNCATED AT 400 WORDS)

Chromosome Mapping↗
PubMed1984

Long-term cultures of murine fetal liver retain very early B lymphoid phenotype.

Long-term cultures of murine fetal liver have been successfully established using a modification of our in vitro bone marrow culture system (14, 15). Fetal liver cells from midgestation BALB/c embryos were plated onto BAB-14 bone marrow stromal cell-adherent layers. After a 3-5 wk period, cell growth began to increase and these cells were expanded in number on fresh feeder layers. The cultured fetal liver cells were lymphoid in morphology, 5-20% cytoplasmic Ig-positive, but less than 1% surface Ig-positive. Southern blot analysis of the cultured fetal liver cells, as well as cultured bone marrow-derived B cells, demonstrated a population with germline Ig heavy chain loci, possibly representing very early B cell precursors. Abelson murine leukemia virus (A-MuLV) clonal transformants of such cultured fetal liver cells had a phenotypic distribution similar to that seen with fresh fetal liver transformants but distinct from those obtained with the transformation of either cultured or fresh bone marrow. All A-MuLV transformants isolated had rearrangements at the mu heavy chain locus of both chromosomes, irrespective of Ig production. In addition, most mu heavy chain producers had at least one rearranged kappa gene locus. These long-term fetal liver cultures provide large numbers of cells for studying events early in the B lymphocyte lineage. The cultured fetal liver cells retained phenotypic traits similar to fresh fetal liver B cells and distinctive from bone marrow cells cultured under similar conditions.

Abelson murine leukemia virus↗
PubMed1984

kappa gene diversity among the clonal progeny of pre-B lymphocytes.

Some clonal pre-B cell lines, when transformed by Abelson murine leukemia virus, are able to rearrange and express kappa light chain genes. We have analyzed the light chains expressed in sets of early B-cell subclones derived from two pre-B cell clones. Each subclone makes an indistinguishable mu heavy chain, while the kappa gene rearrangements and proteins synthesized were distinct. All members of one set of subclones expressed a V kappa 21 kappa light chain. Only one of the members of the other two sets of subclones expressed V kappa 21. Thus, a single pre-B-cell clone can select a kappa variable region from more than one family. In each subclone of the set that expressed V kappa 21 light chain the same member appears to be used. The differences detected in the expressed proteins can best be explained by primary sequence alterations in the rearranged V kappa 21 segment. These sequence alterations have resulted in a restriction site polymorphism in the expressed V kappa 21 gene and charge and size differences in the expressed proteins. These data suggest that diversification of kappa light chains can occur at the pre-B- to early B-cell stage of development.

Abelson murine leukemia virus↗
PubMed1983

Differentiation of cloned populations of immature B cells after transformation with Abelson murine leukemia virus.

The nature of the target cell for Abelson virus transformation and the effect of transformation on B cell differentiation were studied with six cloned lines of nontransformed immature B lymphocytes. Three clones were at the pre-B cell stage of maturation prior to A-MuLV infection; two were at the B cell stage, and one appeared to represent a stage prior to rearrangement of the mu heavy chain gene. All six cloned lines could be transformed by Abelson virus. Many of the transformants of the pre-B cell clones underwent kappa light chain gene rearrangement and expression following viral infection. Distinct light chain gene rearrangements were segregated by further subcloning these transformed lines. Abelson virus infection of one cloned cell line believed to represent a stage of maturation prior to the pre-B cell stage produced pre-B cell transformants with a variety of heavy chain gene rearrangements. Thus B lymphoid target cells for Abelson virus are not restricted to a single developmental stage, and some transformed subclones can undergo extensive immunoglobulin gene rearrangements shortly after viral infection.

Abelson murine leukemia virus↗