Frequency of Human T-Cell Leukemia Virus Type 1 in Patients with Rare Bleeding Disorders

Background and Objective: Human T-cell leukemia virus type 1 (HTLV-1) is a virus that is endemic in some parts of the world, and as a pathogen, it can lead to severe infections in humans. Since no antiviral treatment is currently available and the only way of confrontation is prevention and identification of infected blood, this study was performed to determine the frequency of antibodies against HTLV-1 in patients with rare bleeding disorders receiving blood in Zahedan. Methods: The study population included 180 patients with rare bleeding disorders referred to Ali Asghar Hospital in Zahedan selected by census method and 90 healthy individuals who referred to hospital lab selected by convenience sampling method in 2020. Age range was 1 to 39 years. Blood samples were collected from all participants and antibody test against HTLV-1 was confirmed using ELISA kit and positive ELISA test was confirmed using Real-time PCR. Findings: In the case group, there were 86 men (47.8%) and 94 women (52.2%) and in the control group there were 43 men (47.8%) and 47 women (52.2%). Antibodies against HTLV-1 were found in 2 patients (1.1%) with rare bleeding disorders and none in healthy individuals. The first was a 29-year-old man with Glanzmann's disease who had severe Glanzmann's thrombasthenia. The second case was a 23-year-old woman with severe forms of factor V and factor VIII deficiency whose family history of Rare Bleeding Disorders (RBD) was positive. Conclusion: The results of the study showed that the risk of HTLV-1 transmission through plasma-induced blood products and new types of coagulation factors seems negligible

LTBP2 null mutations in an autosomal recessive ocular syndrome with megalocornea, spherophakia, and secondary glaucoma

The latent TGFβ-binding proteins (LTBPs) and fibrillins are a superfamily of large, multidomain proteins with structural and TGFβ-signalling roles in the extracellular matrix. Their importance is underscored by fibrillin-1 mutations responsible for Marfan syndrome, but their respective roles are still incompletely understood. We report here on two families where children from healthy, consanguineous parents, presented with megalocornea and impaired vision associated with small, round, dislocated lenses (microspherophakia and ectopia lentis) and myopia, as well as a high-arched palate, and, in older children, tall stature with an abnormally large arm span over body height ratio, that is, associated features of Marfan syndrome. Glaucoma was not present at birth, but was diagnosed in older children. Whole genome homozygosity mapping followed by candidate gene analysis identified homozygous truncating mutations of LTBP2 gene in patients from both families. Fibroblast mRNA analysis was consistent with nonsense-mediated mRNA decay, with no evidence of mutated exon skipping. We conclude that biallelic null LTBP2 mutations cause the ocular phenotype in both families and could lead to Marfan-like features in older children. We suggest that intraocular pressures should be followed-up in young children with an ocular phenotype consisting of megalocornea, spherophakia and/or lens dislocation, and recommend LTBP2 gene analysis in these patients

SVEP1 as a Genetic Modifier of TEK-Related Primary Congenital Glaucoma.

Purpose: Affecting children by age 3, primary congenital glaucoma (PCG) can cause debilitating vision loss by the developmental impairment of aqueous drainage resulting in high intraocular pressure (IOP), globe enlargement, and optic neuropathy. TEK haploinsufficiency accounts for 5% of PCG in diverse populations, with low penetrance explained by variable dysgenesis of Schlemm's canal (SC) in mice. We report eight families with TEK-related PCG, and provide evidence for SVEP1 as a disease modifier in family 8 with a higher penetrance and severity. Methods: Exome sequencing identified coding/splice site variants with an allele frequency less than 0.0001 (gnomAD). TEK variant effects were assayed in construct-transfected HEK293 cells via detection of autophosphorylated (active) TEK protein. An enucleated eye from an affected member of family 8 was examined via histology. SVEP1 expression in developing outflow tissues was detected by immunofluorescent staining of 7-day mouse anterior segments. SVEP1 stimulation of TEK expression in human umbilical vascular endothelial cells (HUVECs) was measured by TaqMan quantitative PCR. Results: Heterozygous TEK loss-of-function alleles were identified in eight PCG families, with parent-child disease transmission observed in two pedigrees. Family 8 exhibited greater disease penetrance and severity, histology revealed absence of SC in one eye, and SVEP1:p.R997C was identified in four of the five affected individuals. During SC development, SVEP1 is secreted by surrounding tissues. SVEP1:p.R997C abrogates stimulation of TEK expression by HUVECs. Conclusions: We provide further evidence for PCG caused by TEK haploinsufficiency, affirm autosomal dominant inheritance in two pedigrees, and propose SVEP1 as a modifier of TEK expression during SC development, affecting disease penetrance and severity

SVEP1 as a Genetic Modifier of TEK-Related Primary Congenital Glaucoma

PURPOSE. Affecting children by age 3, primary congenital glaucoma (PCG) can cause debilitating vision loss by the developmental impairment of aqueous drainage resulting in high intraocular pressure (IOP), globe enlargement, and optic neuropathy. TEK haploinsufficiency accounts for 5% of PCG in diverse populations, with low penetrance explained by variable dysgenesis of Schlemm’s canal (SC) in mice. We report eight families with TEK-related PCG, and provide evidence for SVEP1 as a disease modifier in family 8 with a higher penetrance and severity. METHODS. Exome sequencing identified coding/splice site variants with an allele frequency less than 0.0001 (gnomAD). TEK variant effects were assayed in constructtransfected HEK293 cells via detection of autophosphorylated (active) TEK protein. An enucleated eye from an affected member of family 8 was examined via histology. SVEP1 expression in developing outflow tissues was detected by immunofluorescent staining of 7-day mouse anterior segments. SVEP1 stimulation of TEK expression in human umbilical vascular endothelial cells (HUVECs) was measured by TaqMan quantitative PCR. RESULTS. Heterozygous TEK loss-of-function alleles were identified in eight PCG families, with parent–child disease transmission observed in two pedigrees. Family 8 exhibited greater disease penetrance and severity, histology revealed absence of SC in one eye, and SVEP1:p.R997C was identified in four of the five affected individuals. During SC development, SVEP1 is secreted by surrounding tissues. SVEP1:p.R997C abrogates stimulation of TEK expression by HUVECs. CONCLUSIONS. We provide further evidence for PCG caused by TEK haploinsufficiency, affirm autosomal dominant inheritance in two pedigrees, and propose SVEP1 as a modifier of TEK expression during SC development, affecting disease penetrance and severity.Supported by the National Institutes of Health [R01EY014685 to T.Y., R01HL124120, T32DK108738, R01EY025799, and P30DK114857 to S.Q.]; the Research to Prevent Blindness Inc. [Lew R. Wasserman Award to T.Y.]; a University of Wisconsin Centennial Scholars Award [to T.Y.]; the Flinders Foundation and the National Health and Medical Research Council of Australia [APP1116360, APP1107098, and fellowship APP1154824 to J.C.]; the Foundation for Science and Technology, Human Potential Operational Program/European Social Fund [fellowship SFRH/BD/90445/2012 to S.C.]; the Agency for Science Technology and Research, under the Industry Alignment Fund - Pre-Positioning Programme, as part of the Innovations in Food & Chemical Safety Programme [H18/01/a0/b14 to V.L.]; the Ophthalmic Research Center of Shahid Beheshti University of Medical Sciences and the Iran National Science Foundation [940012 to E.E.]; a Core Grant for Vision Research from the National Eye Institute/National Institutes of Health to the University of Wisconsin-Madison [P30EY016665]; and an Unrestricted Grant from Research to Prevent Blindness, Inc. to the UW-Madison Department of Ophthalmology and Visual Sciences. The authors are grateful to the Vanderbilt clinical site of the Undiagnosed Diseases Network for contribution of one individual for this manuscript: John A Phillips III, John H. Newman, Joy Cogan, and Rizwan Hamid; supported in part by the National Institutes of Health Common Fund [UO1HG007674]