Biomedical subjects

L Grunebaum

Publications and source records attributed to L Grunebaum.

42 records · Page 3Linked to original sources

PubMed1986

A de novo intragenic deletion of the potential EGF domain of the factor IX gene in a family with severe hemophilia B.

We have studied a family of three patients who were severely afflicted with hemophilia B without inhibitor for their factor IX genes through the use of factor IX cDNA and genomic DNA probes. The patients had detectable (30% of normal) factor IX antigen. DNA hybridization analysis demonstrated that these patients had a partial intragenic deletion in their factor IX gene. This 2.8-kb deletion included exon d and the surrounding sequences. This exon codes for the amino acid sequence from No. 47 through 84 of the factor IX protein and contains its first potential EGF domain; the de novo occurrence of the mutation in the grandfather's germ cells was established by linkage analysis. This specific gene has been named F IXStrasbourg.

Chromosome Deletion↗

PubMed1985

Genetic screening for hemophilia A (classic hemophilia) with a polymorphic DNA probe.

We have developed a new method of screening for hemophilia A in families at risk for the disease. A DNA probe (St14) that detects a very polymorphic region on the human X chromosome has been shown to be closely linked to hemophilia A. We observed no recombination between the St14 locus and hemophilia A in 12 families studied. The odds in favor of linkage are 4.4 X 10(9) to 1 (lod score, 9.65). The 95 per cent confidence interval for the probability of a recombination between St14 and hemophilia A is 0 to 6.5 per cent. This DNA probe, which is informative in more than 90 per cent of families at risk of hemophilia A, can be used in conjunction with classic biologic assays to identify carriers with an accuracy of 96 per cent or more. If a small risk of misclassification due to crossover between the test and the disease loci is accepted, this DNA marker should allow first-trimester prenatal diagnosis of hemophilia A. Segregation analysis with St14 may thus represent a major improvement in genetic counseling for hemophilia A.

Alleles↗

PubMed1984

Carrier detection of Hemophilia B by using a restriction site polymorphism associated with the coagulation Factor IX gene.

The cloned complementary DNA for coagulation Factor IX (FIX) detects a frequent restriction fragment length polymorphism (RFLP) in human genomic DNAs digested with the restriction endonuclease Taq I. This genetic marker was used, in parallel with coagulation and immunological assays, to follow the segregation of an abnormal FIX gene in a large Hemophilia B family. Among the six potential female carriers, functional assays showed that four had a high probability, and two a low probability of being carriers. Analysis at the DNA level with the cDNA probe was informative in five of the six cases, and in all these five the diagnosis of carrier state was definitively confirmed. This demonstrates the feasibility of using linkage analysis at the DNA level for the genetic screening of Hemophilia B. This method has the advantages over conventional assays of giving a diagnosis of certainty, and of being applicable to early prenatal diagnosis using biopsies of trophoblast villi. At present, the single known polymorphism associated with the FIX gene restricts the application of linkage analysis to informative cases (40%), but findings of additional RFLPs in this region should improve this figure.

Adolescent↗

PubMedDate not supplied

[Antiphospholipid antibodies (aPL): detection and clinical significance].

Phospholipid-binding antibodies are heterogeneous immunoglobulins of G and/or M and/or A class which can be detected in association with a variety of pathologies. However they can also occur in the absence of any clinical manifestations. Despite their paradoxical in vitro anticoagulant activity, phospholipid-binding antibodies, either primary or secondary, are frequently associated with venous and/or arterial thrombotic events. Hence, their detection has to be performed in several major clinical situations, cerebral attack, myocardial infarction, recurrent fetal loss, deep vein thrombosis ... Their course has to be controlled at least every six months. Since the incidence of phospholipid-binding antibodies in auto-immune pathologies is high, immunological disorders should also be considered. As yet there is no standardized assay of phospholipid-binding antibodies, either functional with respect to their anticoagulant activity, or immunological (ELISA). It is not established whether they possess an own pathogenic potential or appear as a secondary response following cellular alterations known to be thrombogenic. However it has been suggested that they could participate in the disruption of the hemostatic balance towards procoagulant tendency resulting in thrombosis.

Antibodies, Anticardiolipin↗

PubMedDate not supplied

[Congenital deficiencies of natural anticoagulant systems responsible for recurrent thromboembolism].

The main characteristics of the blood coagulation system is its high potential of autoamplification. Cascade reactions consisting of successive activations of zymogens into their respective serine-proteinase active form culminate in the generation of thrombin, the central enzyme of the system. Blood coagulation is under control of two major natural regulatory mechanisms limiting the extension of the thrombus. The first one with antithrombin III as the central element, directly inhibits thrombin and other activated clotting factors in cooperation with heparans synthetized by the vascular wall. The second one, the protein C pathway, limits thrombin generation, through its ability to block the amplification potential of feedback reactions. The physiological significance of these regulatory mechanisms is clearly emphasized by the frequency of recurrent thrombotic episodes affecting subjects presenting an inherited deficiency of one of these components, estimated between 50 and 70%. Patients with protein S deficiency, the essential cofactor of activated protein C, exhibit a surprisingly high tendency to arterial thrombosis. The biological investigation of thromboembolic disease must be focused on antithrombin III, protein C and protein S deficiency using functional assays when available or feasible in order to detect both qualitative and quantitative defects.

Antithrombins↗

PubMedDate not supplied

[Gray platelet syndrome].

BACKGROUND: Gray platelet syndrome is a rare (about 40 cases published), inherited disorder characterized by a marked decrease or absence of platelet alpha-granules and platelet specific alpha-granule proteins. CASE REPORT: A boy, aged 4 years, presented with frequent ecchymoses. Acute idiopathic thrombocytopenia purpura was diagnosed because of his reduced platelet count (36,000/mm3) and recent viral infection. Intravenous gammaglobulin infusion was followed by a small rise in the platelet count (125,000/mm3). The patient was reinvestigated a few months later because of persistent thrombocytopenia and the failure of the immunologic treatment. The bleeding time was long and the platelets on blood smears appeared gray. Electron microscopy revealed numerous vacuoles and very few or no alpha-granules. Platelet aggregation and adhesion were normal, but stimulated platelets failed to liberate factor 4 and beta-thromboglobulin, while the plasma levels of beta-thromboglobulin were elevated. CONCLUSION: The frequency of gray platelet syndrome is probably underestimated in those diseases resulting in thrombocytopenia and this will continue until blood smears are thoroughly examined. Synthesis of platelet specific alpha-granule proteins seems normal; but these proteins cannot be stored as there are very few, or no alpha-granules. This abnormality could lead to increased levels of such proteins in the plasma.

Blood Platelet Disorders↗