Preimplantation exclusion of embryos at risk for prion diseases.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
V Meiner
Publications and source records attributed to V Meiner.
The discrete and combined effect of SREBP-2 and SCAP isoforms in the control of plasma lipids among familial hypercholesterolaemia patients.
BACKGROUND AND AIM: Hypercholesterolaemia is a major risk factor for atherosclerosis. Cholesterol is modulated by genetic and environmental factors. An important regulatory pathway is controlled by the sterol-regulatory element-binding proteins (SREBPs) and the SREBP cleavage-activating protein (SCAP). Both SREBP-2 and SCAP are candidates to contribute to the development of atherosclerosis. We investigated the possible effects of the variability of proteins involved in this regulatory pathway on plasma lipids among familial hypercholesterolaemia patients. METHODS AND RESULTS: Single nucleotide polymorphisms (SNPs) in the genes encoding SREBP-2 and SCAP causing amino acid changes at positions 595 (595G/A) and 796 (796I/V), respectively, were genotyped in 801 FH individuals originating from Israel, The Netherlands, and Switzerland. A linear regression model to examine the associations between SREBP-2 and SCAP isoforms and lipid and lipoprotein levels was used. In females, homozygosity either for the SREBP-2-595A or for the SCAP-796I isoform was associated with higher LDL-cholesterol plasma concentrations (14.7 mg/dl and 20.3 mg/dl, respectively). Surprisingly, heterozygosity for the combination SREBP-2-595A/SCAP-796I was associated with a decrease of 30.28 mg/dl in LDL-C (p-value for gene-gene interaction=0.09). No such effect was observed among FH males. Subgroup analysis considering the most frequent (N>/=24) LDL receptor mutations (del191-2, ins313+1-2, C660X, E207K, S285L) revealed further gene-dosage- and gender-dependent effects of the SCAP mutations on LDL-cholesterol concentrations (p=0.0345). These effects were, however, not present when less frequent LDL receptor mutations were investigated. CONCLUSIONS: These results suggest a possible gene-gene interaction between the genes encoding SREBP-2 and SCAP that modulate plasma lipids in a strictly gender-specific fashion. Further investigation is needed to confirm this effect. A study in a larger FH group or in non-FH hypercholesterolaemic subjects may further define the role of this regulatory mechanism in determining plasma lipid concentration.
Atherosclerosis↗
Mutational spectrum of the CHAC gene in patients with chorea-acanthocytosis.
Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. Mutations in the CHAC gene on 9q21 were recently found to cause chorea-acanthocytosis. CHAC encodes a large, novel protein with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in CHAC were screened for mutations by denaturing high-performance liquid chromatography in 43 probands with ChAc. We identified 57 different mutations, 54 of which have not previously been reported, in 39 probands. The novel mutations comprise 15 nonsense, 22 insertion/deletion, 15 splice-site and two missense mutations and are distributed throughout the CHAC gene. Three mutations were found in multiple families within this or our previous study. The preponderance of mutations that are predicted to cause absence of gene product is consistent with the recessive inheritance of this disease. The high proportion of splice-site mutations found is probably a reflection of the large number of exons that comprise the CHAC gene. The CHAC protein product, chorein, appears to have a certain tolerance to amino-acid substitutions since only two out of nine substitutions described here appear to be pathogenic.
Chorea↗
Kidney transplantation unraveling Wolfram syndrome: a case report.
BACKGROUND: In Wolfram syndrome insulin-dependent diabetes is associated with a multisystem neurodegenerative disorder. There are no prior reports of kidney transplantation in patients with Wolfram syndrome. METHODS: Kidney transplantation was undertaken in a child with dysplastic kidneys, sensorineural hearing impairment and bilateral optic atrophy-a combination of features insufficient to define Wolfram syndrome. RESULTS: After the procedure diabetes mellitus, diabetes insipidus and urinary bladder dysfunction emerged, thereby revealing Wolfram syndrome. CONCLUSIONS: We discuss the etiology of our patient's postoperative events, and conclude that kidney transplantation may expose dormant manifestations-or aggravate existing manifestations-of Wolfram syndrome.
Child↗
Recent origin and spread of a common Lithuanian mutation, G197del LDLR, causing familial hypercholesterolemia: positive selection is not always necessary to account for disease incidence among Ashkenazi Jews.
G197del is the most prevalent LDL receptor (LDLR) mutation causing familial hypercholesterolemia (FH) in Ashkenazi Jew (AJ) individuals. The purpose of this study was to determine the origin, age, and population distribution of G197del, as well as to explore environmental and genetic effects on disease expression. Index cases from Israel (n=46), South Africa (n=24), Russia (n=7), The Netherlands (n=1), and the United States (n=1) were enlisted. All trace their ancestry to Lithuania. A highly conserved haplotype (D19S221:104-D19S865:208-D19S413:74) was identified in G197del chromosomes, suggesting the occurrence of a common founder. When two methods were used for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the deletion was found to be 20 +/- 7 generations (the 95% confidence interval is 15-26 generations), so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 14th century. This corresponds with the founding of the Jewish community of Lithuania (1338 a.d.), as well as with the great demographic expansion of AJ individuals in eastern Europe, which followed this settlement. The penetrance of mutation-linked severe hypercholesterolemia is high (94% of heterozygotes have a baseline concentration of LDL cholesterol (LDL-C) that is >160 mg/dl), and no significant differences in the mean baseline lipid level of G197del carriers from different countries were found. Polymorphisms of apolipoprotein E and of scavenger-receptor class B type I were observed to have minor effects on the plasma lipid profile. With respect to determinative genetic influences on the biochemical phenotype, there is no evidence that could support the possibility of a selective evolutionary metabolic advantage. Therefore, the founder effect in a rapidly expanding population from a limited number of families remains a simple, parsimonious hypothesis explaining the spread of G197del-LDLR-linked FH in AJ individuals.
Adolescent↗
Prenatal diagnosis of sex chromosome aneuploidy: possible reasons for high rates of pregnancy termination.
Sex chromosome aneuploidy (SCA), when detected in amniocentesis, is usually an unexpected result of a test carried out for another purpose. For most SCAs, the prognosis is milder and less predictable than trisomy 21, and therefore parents are faced with a difficult decision regarding the option of pregnancy termination. While studies from Europe and the USA report a declining trend in termination rates for SCA, our local experience is different. During the period 1989-1998, we diagnosed 60 SCA (including mosaics) in 20 106 amniocenteses (0.29%) and 48 (80%) of these pregnancies were terminated, a significantly higher proportion than has been reported in Europe and the USA. The present study shows that the difference between our experience and others' may be related to differences in cultural norms and values. Thirty women were interviewed, of whom 23 terminated and seven continued the pregnancy. Interview analyses showed that the main reason behind the decision to terminate the pregnancy was associated with the parents' fear of non-specific abnormality of the child, and concerns about abnormal sexual development. Although genetic counseling practised in our center aims to be non-directive, 56% of the women reported that the counseling was either directive towards termination, or that they at least felt that the counselor's attitude was pro-termination. Most women (93%) reported themselves as having come to terms with their decision.
Abortion, Induced↗
Chorionic villus sampling prior to pregnancy termination, a tool for forensic paternity testing.
Chorionic villus sampling (CVS), prior to pregnancy termination (pre-termination CVS), is suggested as a tool for forensic paternity testing. Unlike the abortion material, which consists of ruptured tissues of fetal and maternal origin, extra-embryonic membranes obtained through CVS can provide an uncontaminated source of fetal tissue for genotyping. We discuss the possibility of confined placental mosaicism (CPM) and its implications on the polymerase chain reaction (PCR) based analyses of short tandem repeats (STRs) and the D1S80 loci.
Abortion, Legal↗
Immunolocalization of acyl-coenzyme A:cholesterol O-acyltransferase in macrophages.
Macrophages in atherosclerotic lesions accumulate large amounts of cholesteryl-fatty acyl esters ("foam cell" formation) through the intracellular esterification of cholesterol by acyl-coenzyme A:cholesterol O-acyltransferase (ACAT). In this study, we sought to determine the subcellular localization of ACAT in macrophages. Using mouse peritoneal macrophages and immunofluorescence microscopy, we found that a major portion of ACAT was in a dense reticular cytoplasmic network and in the nuclear membrane that colocalized with the luminal endoplasmic reticulum marker protein-disulfide isomerase (PDI) and that was in a similar distribution as the membrane-bound endoplasmic reticulum marker ribophorin. Remarkably, another portion of the macrophage ACAT pattern did not overlap with PDI or ribophorin, but was found in as yet unidentified cytoplasmic structures that were juxtaposed to the nucleus. Compartments containing labeled beta-very low density lipoprotein, an atherogenic lipoprotein, did not overlap with the ACAT label, but rather were embedded in the dense reticular network of ACAT. Furthermore, cell-surface biotinylation experiments revealed that freshly harvested, non-attached macrophages, but not those attached to tissue culture dishes, contained approximately 10-15% of ACAT on the cell surface. In summary, ACAT was found in several sites in macrophages: a cytoplasmic reticular/nuclear membrane site that overlaps with PDI and ribophorin and has the characteristics of the endoplasmic reticulum, a perinuclear cytoplasmic site that does not overlap with PDI or ribophorin and may be another cytoplasmic structure or possibly a unique subcompartment of the endoplasmic reticulum, and a cell-surface site in non-attached macrophages. Understanding possible physiological differences of ACAT in these locations may reveal an important component of ACAT regulation and macrophage foam cell formation.
Animals↗
Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329Ser mutation in the glycogen-branching enzyme gene.
Adult polyglucosan body disease (APBD) is a late-onset, slowly progressive disorder of the nervous system caused by glycogen branching enzyme (GBE) deficiency in a subgroup of patients of Ashkenazi Jewish origin. Similar biochemical finding is shared by glycogen storage disease type IV (GSD IV) that, in contrast to APBD, is an early childhood disorder with primarily systemic manifestations. Recently, the GBE cDNA was cloned and several mutations were characterized in different clinical forms of GSD IV. To examine whether mutations in the GBE gene account for APBD, we studied 7 patients from five Jewish families of Ashkenazi ancestry. The diagnosis was based on the typical clinical and pathological findings, and supported by reduced GBE activity. We found that the clinical and biochemical APBD phenotype in all five families cosegregated with the Tyr329Ser mutation, not detected in 140 controls. As this mutation was previously identified in a nonprogressive form of GSD IV and was shown in expression studies to result in a significant residual GBE activity, present findings explain the late onset and slowly progressive course of APBD in our patients. We conclude that APBD represents an allelic variant of GSD IV, but the reason for the difference in primary tissue involvement must be established.
1,4-alpha-Glucan Branching Enzyme↗
Intrafamilial heterogeneity of movement disorders: report of three cases in one family.
We report three members of a single family with an apparently autosomal dominant, nonparoxysmal, hyperkinetic movement disorder with onset in adolescence. The proband, a 56-year-old woman, manifested dystonia, tremor and myoclonus; one of her daughters exhibited myoclonus with tremor, and the other demonstrated myoclonus with chorea later accompanied by tremor and dystonia. The slowly progressive but not debilitating symptoms were restricted to the head, arms and hands and were only moderately affected by alcohol. Laboratory investigations failed to identify any abnormality, and linkage analysis excluded the region containing the DYT1 locus, indicating that the gene responsible for idiopathic torsion dystonia was not implicated in this family. While this disorder shares manifestations with myoclonic dystonia, essential myoclonus and benign chorea, the marked intrafamilial heterogeneity and the sex-limited phenotype expressed only in females of two generations appear to be unique.
Adolescent↗
Tissue expression studies on the mouse acyl-CoA: cholesterol acyltransferase gene (Acact): findings supporting the existence of multiple cholesterol esterification enzymes in mice.
Cholesterol esterification is involved in the regulation of cellular cholesterol content and has been hypothesized to play a role in important physiologic processes including intestinal cholesterol absorption, hepatic lipoprotein production, and macrophage foam cell formation in atherosclerotic lesions. Although initial studies of the mouse acyl CoA:cholesterol acyltransferase gene (Acact) suggested that its gene product was responsible for cholesterol esterification in most tissues, we observed recently that Acact-/- mice have only tissue-specific reductions in cholesterol esterification. To better understand the role of Acact in cholesterol esterification, we used in situ hybridization and immunoblotting to perform tissue expression studies in wild-type mice. We found high levels of Acact expression in steroidogenic tissues, sebaceous glands, and atherosclerotic lesions, but not in the liver or the small intestine. These data support the hypothesis that multiple cholesterol esterification enzymes exist in mammals and that another enzyme is likely to be responsible for cholesterol esterification activity in mouse liver and intestine.
Adrenal Cortex↗
Localization of two X-linked mental retardation (XLMR) genes to Xp: MRX37 gene at Xp22.31-p22.32 and a putative MRX gene on Xp22.11-p22.2.
MRX genes of 2 families with X-linked mental retardation (XLMR) were localized by linkage analysis. In family A, the gene was mapped to Xp22.31-p22.32, with significant LOD scores to various Xp22 markers within a distance of 6 Mb between DXS1223 and DXS1224. The MRX gene of this family was designated MRX37. In a mentally retarded female who is a carrier of the MRX37 gene, a random pattern of X inactivation was demonstrated. In family B, a positive LOD score, although not significant (< + 2), was found with the marker DXS1202 at Xp22.11-p22.2.
Chromosome Mapping↗
Familial pheochromocytoma associated with a novel mutation in the von Hippel-Lindau gene.
We report a three generation, 25 member kindred with familial pheochromocytoma. Seven subjects of generations I and II had pheochromocytoma, in five of the seven, the tumors were bilateral, and in two of the seven, the tumors were both adrenal and extraadrenal. One patient also had a carotid body chemodectoma, and one patient had a malignant adrenal tumor and abdominal paraganglioma. In the patient with the chemodectoma, a cerebellar hemangioblastoma became manifest 25 yr after his initial diagnosis with pheochromocytoma, leading only then to a clinical diagnosis of von Hippel-Lindau disease (VHL). A mutational analysis of the VHL gene revealed a novel nucleotide 709 G-->T transversion present in all affected subjects and in four presymptomatic children. In familial pheochromocytoma the diagnosis of VHL should be considered, even when the formal criteria for diagnosis of the syndrome are lacking.
Adrenal Gland Neoplasms↗
Simultaneous formation of inv dup(15) and dup(15q) in a girl with developmental delay: origin of the abnormal chromosomes.
Two de novo abnormal derivatives of chromosome 15, inv dup(15) and dup(15q) were found in a girl with developmental delay and mild dysmorphological signs. Fluorescence in situ hybridization, using DNA probes of the Prader-Willi/Angelman syndromes (PWS/AS) critical region and chromosome-15-specific alpha-satellite, combined with molecular analysis using dinucleotide repeat polymorphisms within the PWS/AS region and the parent-of-origin specific methylation sites at the locus D15S63, shed light on how the abnormal karyotype was formed. We suggest that a translocation between the two homologues of maternal chromosomes 15 resulted in the formation of dup(15q) and two reciprocal products: an acentric fragment of 15q that was lost and a centric fragment that underwent U-type reunion to form inv dup(15).
Angelman Syndrome↗
Molecular diagnosis of Prader-Willi syndrome: parent-of-origin dependent methylation sites and non-isotopic detection of (CA)n dinucleotide repeat polymorphisms.
We describe our experience in the molecular diagnosis of 22 patients suspected of Prader-Willi syndrome (PWS) using a DNA probe PW71 (D15S63) which detects a parent-of-origin specific methylated site in the PWS critical region. The cause of the syndrome was determined as deletion or uniparental disomy according to the segregation of (CA)n dinucleotide repeat polymorphisms of the PWS/AS region and more distal markers of chromosome 15. In 10 patients the clinical diagnosis was confirmed by this approach, 6 with paternal deletion and 4 with maternal disomy. In one patient, the aberrant methylation pattern that was detected by PW71 could not be confirmed by the segregation of (CA)n, probably due to paternal microdeletion in the PWS critical region which did not include the loci D15S97, D15S113, GABRB3, and GABRA5. This case demonstrates the advantage of the DNA probe PW71 in the diagnosis of PWS.
Adolescent↗
Efficacy and safety of a combination fluvastatin-bezafibrate treatment for familial hypercholesterolemia: comparative analysis with a fluvastatin-cholestyramine combination.
PURPOSE: Familial hypercholesterolemia (FH) carries a markedly increased risk for coronary artery disease (CAD). Reduction of plasma low-density lipoprotein cholesterol (LDL-C) levels to the normal range may prevent premature atherosclerosis and usually requires a combination of cholesterol-lowering drugs. The major objective of this study is to compare two different drug combinations for the treatment of heterozygous FH. PATIENTS AND METHODS: The current investigation is a short-term, double-blind study comparing the efficacy and safety of fluvastatin when combined with cholestyramine (group 1) or with bezafibrate (group 2) in 38 patients with heterozygous FH. RESULTS: After 6 weeks of combination treatment, in comparison to a drug-free baseline (patients receiving single-blind placebo during the lead-in period of an earlier study, ie, before ever receiving fluvastatin), the combination of 40 mg/d of fluvastatin with 400 mg/d of bezafibrate in group 2 reduced plasma LDL-C levels by 35% as compared with 32% in group 1, and reduced the LDL-C/high-density cholesterol (HDL-C) ratio by 46%, compared to 37% in group 1 (a non-significant difference for both comparisons). When compared to an intermittent 6-week open-label administration of 40 mg fluvastatin monotherapy, the addition of cholestyramine or bezafibrate each reduced LDL-C by an additional 13% (P < 0.01 for both regimens). CONCLUSIONS: Fluvastatin-bezafibrate is superior to a fluvastatin-cholestyramine combination for lowering serum triglycerides and elevating HDL-C serum levels in patients in conjunction with a significant lowering of LDL-C/HDL-C ratios, and may be an effective synergistic therapy for heterozygous FH. No episodes of myositis were seen in this short-term study, a finding that is in agreement with most of the reported studies on statin-fibrate combinations reviewed here.
Adult↗
Premature termination codon at the sterol 27-hydroxylase gene causes cerebrotendinous xanthomatosis in an Afrikaner family.
Explore the source record for details and available documents.
Adult↗
Pacemaker endocarditis. Report of 44 cases and review of the literature.
We conducted a retrospective study to characterize the clinical course, microbiologic spectrum, and risk factors for endocarditis and for associated mortality in a large series of patients with documented pacemaker endocarditis. Using a computerized search through the medical records of 10 major hospitals in Israel from 1982 to 1992, and carefully reviewing the charts, we identified 44 patients with pacemaker endocarditis. The cases were categorized as definite (n = 25), probable (n = 12), or possible (n = 7) infective endocarditis based on strict case definition. Fever and chills were the most common symptoms. Increased ESR, leukocytosis, microscopic hematuria, and anemia were the most common laboratory findings. A relatively high proportion of the patients were diabetic. The most common source of endocarditis was infection acquired by the placement procedure or infection of the pacemaker pouch. Demographic, clinical, and laboratory features were similar to those of endocarditis patients of a similar age range without pacemakers, although the frequency of fever and chills was higher in our patients than in those patients and splenomegaly, vascular embolic phenomena, and new or changing murmurs were rare in our patients. The major pathogens were Staphylococcus aureus and Staphylococcus epidermidis, similar to other series of pacemaker-associated bacteremia and similar to the microbiologic findings of early prosthetic-valve endocarditis. However, this microbiologic profile is different from that of native-valve endocarditis. Although the present series did not show a statistically significant advantage to electrode removal over conservative treatment, when analyzed together with pooled data from other studies, it suggests that the surgical approach is preferable.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗