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Biomedical subjects

U Seligsohn

Publications and source records attributed to U Seligsohn.

At least 73 records · Page 4Linked to original sources
PubMed1997

Factor XIII deficiency due to a Leu660Pro mutation in the factor XIII subunit-a gene in three unrelated Palestinian Arab families.

In this report we describe the molecular basis of FXIII a-subunit deficiency in three unrelated Palestinian Arab families. In three patients representing each family two substitutions were identified in exon 14 on both alleles: C to G change resulting in a Gln651Glu substitution (a previously described polymorphism) and a T to C transition causing Leu660Pro substitution. The latter is a new mutation which creates a restriction site for FnuDII enzyme. Restriction analysis performed in members of the three families clearly distinguished between severely affected patients, obligate carriers and unaffected subjects. A population survey failed to detect the mutation among 250 Jewish individuals but did detect two heterozygotes among 300 Arabs suggesting a 0.0033 frequency for the Pro660 allele in this population. In two out of the three families the Pro660 allele was linked to allele 5 of the 5' short tandem repeat polymorphism within the FXIII a-subunit gene suggesting that the mutation might have occurred at least twice. cDNA obtained from mRNA isolated from patients' platelets and monocytes appeared similar in size to that of normal control indicating that the Leu660Pro mutation does not affect mRNA synthesis. Computer modeling based on cristallographic studies of the a-subunit of factor XIII predicted that the mutant protein is expected to misfold into a structure which is either unstable or susceptible to degradation.

Arabs↗
PubMed1997

Purpura fulminans induced by disseminated intravascular coagulation following infection in 2 unrelated children with double heterozygosity for factor V Leiden and protein S deficiency.

Purpura fulminans is associated with homozygous protein C and homozygous protein S deficiency or may follow bacterial or viral infections. We present 2 children from 2 unrelated Arab families with purpura fulminans who were double heterozygotes for factor V Leiden inherited from their fathers and protein S deficiency inherited from their mothers. No previous thrombotic events have occurred in either patient or their respective family members. In one patient sepsis accompanied by disseminated intravascular coagulation appeared to be the trigger of purpura fulminans. In the other patient varicella infection preceded purpura fulminans and was also associated with disseminated intravascular coagulation. This report emphasizes the need for evaluation of hereditary defects in the inhibitory mechanisms of blood coagulation in patients with purpura fulminans at any age.

Child, Preschool↗
PubMed1996

Venous thromboembolism associated with double heterozygosity for R506Q mutation of factor V and for T298M mutation of protein C in a large family of a previously described homozygous protein C-deficient newborn with massive thrombosis.

It is remarkable that certain patients with heterozygous protein C (PC) deficiency manifest venous thromboembolism (VTE), whereas others, particularly those belonging to families with homozygous PC deficiency, remain asymptomatic. The goals of the present study of a family, in which the proband had homozygous PC deficiency, were to identify members with and without VTE, to determine the mutation causing PC deficiency, and to search for the R506Q mutation of factor V (FV) causing activated PC resistance. Heterozygosity for a T298M mutation in exon 9 of the PC gene was found in the father of the homozygous proband who died of massive thrombosis. Based on analysis of a three-dimensional molecular model of PC, we speculate that this mutation causes type I deficiency due to disruption of packing of hydrophobic side chains and loss of an H-bond between Q184 and T298. Forty-six family members were examined for the T298M mutation by polymerase chain reaction (PCR) amplification of exon 9 and restriction analysis using Mae III and for the FV R506Q mutation by PCR amplification of exon 10 and restriction analysis using Mnl I. VTE was observed in five of 11 members who were heterozygous for both PC and FV mutations. In contrast, VTE was not observed for the PC mutation in 13 heterozygotes who had normal FV, including the parents of the deceased proband, 10 heterozygotes for the FV mutation who had normal PC, and 12 individuals bearing neither mutation. These observations extend recent evidence of an increased thrombotic risk conferred by the coexistence of heterozygous PC deficiency and heterozygous activated PC resistance and support the paradigm in which hereditary thrombophilia is often a multigenic disease.

Adult↗
PubMed1996

Coexistence of hereditary homocystinuria and factor V Leiden--effect on thrombosis.

BACKGROUND: Venous and arterial thromboembolism occurs in only about one third of patients homozygous for homocystinuria, which suggests that other, contributory factors are necessary for the development of thrombosis in these patients. Factor V Leiden, an R506Q mutation in the gene coding for factor V, is the most common cause of familial thrombosis and could be a potentiating factor. METHODS: We determined activated partial-thromboplastin times in the presence and absence of activated protein C and tested for the factor V Leiden mutation in 45 members of seven unrelated consanguineous kindreds in which at least 1 member was homozygous for homocystinuria. RESULT: Thrombosis (venous, arterial, or both) occurred in 6 of 11 patients with homocystinuria (age, 0.2 to 8 years). All six also had the factor V Leiden mutation. One patient with prenatally diagnosed homocystinuria who was also heterozygous for factor V Leiden has received warfarin therapy since birth and has not had thrombosis (age, 18 months). Of four patients with homocystinuria who did not have factor V Leiden, none had thrombosis (ages at this writing, 1 to 17 years). Three women who were heterozygous for both homocystinuria and factor V Leiden had recurrent fetal loss and placental infarctions. CONCLUSIONS: Patients with concurrent homocystinuria and factor V Leiden can have an increased risk of thrombosis. Screening for factor V Leiden may be indicated in patient with homocystinuria and their family members.

Adolescent↗
PubMed1996

ETRO Working Party on Factor XIII questionnaire on congenital factor XIII deficiency in Europe: status and perspectives. Study Group.

A questionnaire was sent out in 1993 to more than 350 European institutions caring for patients with hemorrhagic disorders with the request to provide data of patients with congenital factor XIII deficiency, to pursue the following aims: (1) establish a registry of congenital factor XIII deficiency patients, (2) promote exchange between clinicians and basic researchers, (3) improve diagnostic and therapeutic approaches, and (4) stimulate research on gene defects and their impact on factor XIII function. So far, 72 patient questionnaires from 60 families have been collected. Their bleeding pattern is typical, with frequent involvement of the umbilical cord and the central nervous system. Forty-nine patients receive regular factor XIII replacement, but obviously some patients with mild symptoms do not require prophylactic substitution, despite low factor XIII levels. On the other hand, 18 patients had factor XIII activities of > or = 5% of normal, but only 3 of those patients were reported to have no bleeding symptoms. Furthermore, 17 symptomatic, apparently heterozygous relatives in eight families were observed. Seven out of 30 females aged over 18 years had experienced spontaneous abortions; wound healing problems were seen in 26 patients. Currently, a second questionnaire is being distributed to obtain more detailed information on bleeding and other symptoms, diagnostic approaches, and exclusion of concurrent other bleeding diatheses. Future activities will be validation and standardization of assays, and study of gene defects and their impact on the structure of factor XIII and symptoms of patients. We intend to expand the survey to countries outside Europe.

Abortion, Habitual↗
PubMed1996

Ala244Val is a common, probably ancient mutation causing factor VII deficiency in Moroccan and Iranian Jews.

We investigated the molecular basis for factor VII (FVII) deficiency in Israel and found that 13 patients were homozygous and 10 heterozygous for a C to T substitution at nucleotide 10648 of the FVII gene. This predicted an Ala244Val change and was associated with decreased FVII activity and antigen level. Of the 36 Ala244Val positive alleles, 20 were observed in patients of Moroccan origin, 10 in Iranian-Jewish patients and 6 in patients of other origins. A computer model of the serine protease domain of FVII suggested that the Ala244Val substitution may cause distortion of the entire protein structure. Intragenic polymorphic sites analyses disclosed a founder effect for the Moroccan and Iranian-Jewish patients. A survey of the Ala244Val mutation revealed an allele frequency of 1:42.5 in Moroccan Jews and 1:40 in Iranian Jews. As Moroccan Jews have been separated from Iranian Jews for more than two millennia, the data suggest that the Ala244Val mutation occurred in ancient times.

Alanine↗
PubMed1996

Cyclosporine therapy for acquired factor VIII inhibitor in a patient with systemic lupus erythematosus.

The case of a 27-year-old woman with systemic lupus erythematosus and development of an autoantibody against factor VIII during an exacerbation of her underlying disorder is described. Attempts to eliminate the antibody with high dose gammaglobulin and repeated courses of cyclophosphamide failed, whereafter she received cyclosporine in increasing doses. When therapeutic serum levels of cyclosporine were achieved (150-350 ng/ml) the inhibitor rapidly decreased and disappeared with a concomitant normalization of the factor VIII levels. Treatment with cyclosporine was subsequently reduced and discontinued after one year, and at present no inhibitor is detectable. In view of the successful results with cyclosporine treatment in 4 of 6 previous cases and in all 3 previous cases with autoimmune disorders, this regimen should be evaluated in a systematic manner as a potential first line drug in patients with acquired hemophilia and an underlying autoimmune disorder.

Adult↗
PubMed1995

Carrier frequency of the IVS4 + 4 A-->T mutation of the Fanconi anemia gene FAC in the Ashkenazi Jewish population.

Fanconi anemia (FA) is a genetically and phenotypically heterogeneous autosomal recessive disorder defined by a cellular hypersensitivity to DNA cross-linking agents. One of the FA genes, FAC, has been cloned and the genomic structure of the coding region has been characterized. We have developed amplification refractory mutation system (ARMS) assays for five known mutations in FAC, and have applied these assays to determine the carrier frequency of the IVS4 + 4 A-->T (IVS4) mutation in an Ashkenazi Jewish population. We tested 3,104 Jewish individuals, primarily of Ashkenazi descent, for the two most common FAC mutations, IVS4 and 322delG. Thirty-five IVS4 carriers were identified, for a carrier frequency of 1 in 89 (1.1%; 95% confidence interval 0.79% to 1.56%); no 322delG carriers were found. To determine if the IVS4 mutation was confined to the Ashkenazi Jewish population, we tested 563 Iraqi Jews for IVS4, and no carriers were found. Because the IVS4 mutation has only been found on chromosomes of Ashkenazi Jewish origin and is the only FAC mutation found on these chromosomes, we suggest that a founder effect is responsible for the high frequency of this mutation. With a carrier frequency greater than 1% and simple testing available, the IVS4 mutation merits inclusion in the battery of tests routinely provided to the Jewish population.

Base Sequence↗
PubMed1995

Glanzmann's thrombasthenia associated with deletion-insertion and alternative splicing in the glycoprotein IIb gene.

Glanzmann's thrombasthenia is a bleeding disorder characterized by a decrease or absence of the functional platelet membrane glycoprotein (GP) complex, GPIIb/IIIa (alpha IIb beta 3). We describe a new deletion-insertion mutation in the GPIIb gene causing type I Glanzmann's thrombasthenia in two siblings of a consanguineous Iranian-Jewish family. The proband's platelets bound more antibodies against the vitronectin receptor-alpha V beta 3 than normal platelets, suggesting a normal GPIIIa (beta 3) gene and a defect in the GPIIb gene. Sequencing of amplified cDNA and genomic DNA fragments showed a 6-bp deletion and 31-bp insertion in exon 25 of the GPIIb gene. The predominant platelet GPIIb mRNA of the proband was a product of the splicing of exon 24 to a cryptic AG acceptor site in the insertion and encoded for deletion of amino acids Leu817-Asn826 and insertion of eight different amino acids. Cotransfection of COS-7 cells with expression vectors containing wild-type GPIIIa cDNA and the mutated GPIIb cDNA failed to produce detectable amounts of GPIIb/IIIa on the surface of the cells. Allele-specific restriction analysis of genomic DNA of family members showed homozygosity for the mutation in the affected siblings, heterozygosity in the parents, and homozygosity for the normal allele in an unaffected sibling. The observed mutation is in a region that is conserved from rodents to humans and has been suggested to be involved in the interaction between GPIIb and GPIIIa when these GPs are complexed in solution.

Adult↗
PubMed1995

One of the two common mutations causing factor XI deficiency in Ashkenazi Jews (type II) is also prevalent in Iraqi Jews, who represent the ancient gene pool of Jews.

In recent years four mutations causing factor XI deficiency have been identified in Jews of Ashkenazi (European) origin. Two of them, type II (a nonsense mutation) and type III (a missense mutation), were found to prevail among 125 unrelated Ashkenazi Jews with severe factor XI deficiency. A finding of type II mutation in four unrelated Iraqi-Jewish families raised the possibility that this mutation is also common in Iraqi Jews, who represent the ancient gene pool of the Jews. A molecular-based analysis performed in 1,040 consecutively hospitalized patients disclosed the following results: Among 531 Ashkenazi-Jewish patients, the type II allele frequency was 0.0217 and among 509 Iraqi-Jewish patients, 0.0167 (P = .50). The type III allele frequency in the Ashkenazi-Jewish patients was 0.0254, whereas none of 502 Iraqi-Jewish patients examined had this mutation. These data suggest that the type II mutation was present in Jews already 2.5 millenia ago. The data also indicate that the estimated risk for severe factor XI deficiency in Ashkenazi Jews (due to either genotype) is 0.22% and in Iraqi Jews, 0.03%, and that the estimated risk of heterozygosity in Ashkenazi Jews is 9.0% and in Iraqi Jews, 3.3%. As patients with severe factor XI deficiency are prone to bleeding after injury and patients with partial deficiency may have similar bleeding complications when an additional hemostatic derangement is present, the observed high frequencies should be borne in mind when surgery is planned for individuals belonging to these populations.

Aged↗
PubMed1995

[Resistance to activated protein C--a novel cause of thrombophilia].

A point mutation in coagulation factor V which causes resistance to cleavage of factor Va by activated protein C (APC), was recently found to underlie thrombotic events. We examined 20 consecutive patients, under the age of 40, who suffered from idiopathic venous or arterial thrombosis. In 8 (40%) there was resistance to APC manifested by absence of the expected prolongation of activated partial thromboplastin time (aPTT). In 3, the addition of normal plasma corrected the anomaly in the patient's plasma, although the addition of factor V- deficient plasma caused no change. In a family of a 17-year-old boy with idiopathic deep venous thrombosis we found a mutation in factor V which was responsible for APC resistance. The patient and 4 family members showed a single G to A transition in position 1691 in their cDNA, resulting in substitution of arginine (506) for glutamine. The mutation in this area, which is the cleavage site for APC, is associated with thrombotic episodes and is frequently observed in patients with familial thrombophilia.

Adolescent↗
PubMed1995

[International postgraduate training program in medicine: survey of 13 training courses, 1988-1994].

In 1988 an International Postgraduate Training Program in Medicine was established as a joint venture of the Tel Aviv University School of Continuing Medical Education and the Ministry for Foreign Affairs, Division of International Cooperation. During 1988-1994, 359 physicians participated. A survey of 271 graduates was carried out within 1-5 years following the completion of training, and 57% responded to our questionnaire. The program fulfilled the academic expectations of 78% of the trainees, and the practical clinical expectations of 80%. 95% graded the program as good-to-excellent from the sociocultural aspect. 75% and 67.5% of the trainees graded the program as good-to-excellent with regard to improvement in their theoretical and practical skills, respectively. Regretfully, only 45% have continued their ties with the host departments and only 11% have carried out joint research projects. These results imply that further attention should be paid to the trainees' real-time input, in order to increase satisfaction. Personal tutors should be nominated in each department, and should be adequately compensated. More emphasis should be given to initiation of bilateral research projects and maintenance of professional ties between the trainees and their host departments.

Attitude of Health Personnel↗