scholarly journals Congenital Amegakaryocytic Thrombocytopenia: A Brief Review of the Literature

2010 ◽  
Vol 3 ◽  
pp. CPath.S4972 ◽  
Author(s):  
Fatma S. Al-Qahtani
Keyword(s):  
Bone Marrow ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disorder ◽  
Primary Treatment ◽  
Bleeding Complications ◽  
Type I ◽  
Cell Transplant ◽  
Missense Mutations ◽  
Severe Type ◽  
Marrow Stem Cell

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited autosomal recessive disorder that presents with thrombocytopenia and absence of megakaryocytes. It presents with bleeding recognized on day 1 of life or at least within the first month. The cause for this disorder appears to be a mutation in the gene for the thrombopoeitin (TPO) receptor, c-Mpl, despite high levels of serum TPO. Patients with severe Type I-CAMT carry nonsense Mpl mutations which causes a complete loss of the TPO receptor whereas those with Type II CAMT carry missense mutations in the Mpl gene affecting the extracellular domain of the TPO receptor. Differential diagnosis for severe CAMT includes thrombocytopenia with absent radii (TAR) and Wiskott-Aldrich syndrome (WAS). The primary treatment for CAMT is bone marrow transplantation. Bone Marrow/Stem Cell Transplant (HSCT) is the only thing that ultimately cures this genetic disease. Newer modalities are on the way, such as TPO-mimetics for binding towards partially functioning c-Mpl receptors and gene therapy. Prognosis of CAMT patients is poor, because all develop in childhood a tri-linear marrow aplasia that is always fatal when untreated. Thirty percent of patients with CAMT die due to bleeding complications and 20% -due to HSCT if it has been done.

scholarly journals Identification of Molecular Defects in ITGA2B and ITGB3 Genes and Phenotypic Correlation in Pakistani Patients with Glanzmann Thrombasthenia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4658-4658
Author(s):  
Yonus Jamal ◽  
Shariq Ahmed ◽  
Akbar Najmuddin ◽  
Ayisha Imran ◽  
Tehmina nafees sonia Khan ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Autosomal Recessive Disorder ◽  
Phenotypic Correlation ◽  
Type I ◽  
Missense Mutations ◽  
Wild Type ◽  
Glanzmann Thrombasthenia ◽  
Molecular Defects ◽  
Platelet Receptor ◽  
Severe Type

Abstract Background: Glanzmann thrombasthenia (GT) is most common inherited platelet functional defect. It is an autosomal recessive disorder, characterized by a bleeding diathesis. Incidence is increased in locations where consanguineous marriages are common. The defect is caused by mutations in the genes encoding ITGA2B or ITGB3. This results in qualitative or quantitative abnormalities of the platelet receptor, αIIb-β3 integrin. Objectives: The aim of this study was to identify and correlate the mutations in GT patients with phenotype of the patient. Subjects and methods: 20 patients with GT were enrolled in the study to identify the molecular defects and to correlate their phenotype with their genotype. CBC with peripheral film, PT, APTT and Fibrinogen levels were done initially. Platelet aggregation studies, flow cytometry, and mutation analysis was done by Sanger sequencing. Genomic DNA was extracted from peripheral blood by QIAamp DNA Blood mini kit (Qiagen) and Exon specific PCR was done for GT gene and Direct gene sequenced on automated ABI-3130 Genetic Analyzer (Applied Biosystems). For any variation wild type was matched on HGMD (Human Gene Mutation Database http://www.hgmd.cf.ac.uk/ac/index.php) and wild type color fasta sequence (http://pga.gs.washington.edu/). Pathogenecity score was evaluated by using software tools including : Polyphen-2(http://genetics.bwh.harvard.edu/pph2/) ,SNP&GO(http://snps.biofold.org/snps-and-go/index.html), MUpro (http://mupro.proteomics.ics.uci.edu/) ,SIFT (http://sift.jcvi.org), Provean (http://provean.jcvi.org/about.php) . All samples were sequenced at the Gene Sequencing Lab of NIBD (National Institute of Blood diseases and Bone Marrow Transplantation) Karachi. Results: Mutations were identified in all patients. Missense mutations were seen in most of the GT patients. The remaining mutations were heterogeneous and were distributed throughout the length of the gene. Conclusions: The severe type I GT was the most common subtype found in this study.Carrier detection and genetic counseling in these families is a potentially effective alternative for decreasing the burden of severe type of GT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Cardiovascular involvement in alpha-n-acetyl neuraminidase deficiency syndromes (sialidosis type I and II)

2021 ◽  
pp. 1-3
Author(s):  
Priyanka Prasanna ◽  
Chenni S. Sriram ◽  
Sarah H. Rodriguez ◽  
Utkarsh Kohli
Keyword(s):  
Autosomal Recessive ◽  
Ventricular Dysfunction ◽  
Clinical Presentation ◽  
Clinical Course ◽  
Rare Condition ◽  
Autosomal Recessive Disorder ◽  
Left Ventricular ◽  
Type I ◽  
Neonatal Onset ◽  
Cardiovascular Involvement

Abstract Sialidosis, a rare autosomal recessive disorder, is caused by a deficiency of NEU1 encoded enzyme alpha-N-acetyl neuraminidase. We report a premature male with neonatal-onset type II sialidosis which was associated with left ventricular dysfunction. The clinical presentation and subsequent progression which culminated in his untimely death at 16 months of age are succinctly described. Early-onset cardiovascular involvement as noted in this patient is not well characterised. The case report is supplemented by a comprehensive review of the determinants, characteristics, and the clinical course of cardiovascular involvement in this rare condition.

scholarly journals Mutational Analysis of Oculocutaneous Albinism: A Compact Review

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Balu Kamaraj ◽  
Rituraj Purohit
Keyword(s):  
Autosomal Recessive ◽  
Mutational Analysis ◽  
Autosomal Recessive Disorder ◽  
Oculocutaneous Albinism ◽  
Melanin Production ◽  
Melanin Biosynthesis ◽  
Molecular Features ◽  
New Genes ◽  
Pigment Accumulation ◽  
Severe Type

Oculocutaneous albinism (OCA) is an autosomal recessive disorder caused by either complete lack of or a reduction of melanin biosynthesis in the melanocytes. The OCA1A is the most severe type with a complete lack of melanin production throughout life, while the milder forms OCA1B, OCA2, OCA3, and OCA4 show some pigment accumulation over time. Mutations in TYR, OCA2, TYRP1, and SLC45A2 are mainly responsible for causing oculocutaneous albinism. Recently, two new genes SLC24A5 and C10orf11 are identified that are responsible to cause OCA6 and OCA7, respectively. Also a locus has been mapped to the human chromosome 4q24 region which is responsible for genetic cause of OCA5. In this paper, we summarized the clinical and molecular features of OCA genes. Further, we reviewed the screening of pathological mutations of OCA genes and its molecular mechanism of the protein upon mutation byin silicoapproach. We also reviewed TYR (T373K, N371Y, M370T, and P313R), OCA2 (R305W), TYRP1 (R326H and R356Q) mutations and their structural consequences at molecular level. It is observed that the pathological genetic mutations and their structural and functional significance of OCA genes will aid in development of personalized medicine for albinism patients.

scholarly journals Malignant infantile osteopetrosis with rickets presenting with bicytopenia in septic shock: case report

2021 ◽  
Vol 8 (7) ◽  
pp. 1268
Author(s):  
Varun Govindarajan ◽  
Thanzir Mohammed ◽  
Meghana Jagadish ◽  
Mallesh Kariyappa
Keyword(s):  
Septic Shock ◽  
Autosomal Recessive ◽  
Hematopoietic Stem Cell Transplant ◽  
Married Couple ◽  
Delayed Diagnosis ◽  
Failure To Thrive ◽  
Autosomal Recessive Disorder ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Subarachnoid Cyst

Malignant infantile osteopetrosis is a rare, fatal autosomal recessive disorder due to abnormal osteoclast activity. We report a 1-year-old infant, born to consanguineously married couple, who presented to our ER with acute respiratory distress and bicytopenia. He had tender hepatomegaly, splenomegaly, failure to thrive and features of rickets. He was evaluated previously for possible hydrocephalus secondary to his abnormal shape of head with proptosis, MRI revealed a subarachnoid cyst, but possibility of osteopetrosis was missed. Skeletal radiographs done later detected dense, sclerotic bone with sandwich vertebra, provided a delayed diagnosis of MIOP. Rickets, a paradoxical association, was also seen in our case, with low serum calcium and vitamin D3 levels. He succumbed due to severe bronchopneumonia with septic shock. Early diagnosis and timely hematopoietic stem cell transplant are the only curative approach for MIOP, which is otherwise fatal.

First Report of Transheterozygosity in a Patient with An Inherited Platelet Bleeding Disorder Due to Mutations in the Thromboxane A2 Receptor (TBXA2R) and cyclooxygenase1 (PTGS1),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3260-3260
Author(s):  
Kathleen Freson ◽  
Chantal Thys ◽  
Christel Van Geet
Keyword(s):  
Platelet Aggregation ◽  
Autosomal Recessive ◽  
Conflicts Of Interest ◽  
Autosomal Recessive Disorder ◽  
Bleeding Disorder ◽  
Bleeding Complications ◽  
Normal Platelet ◽  
First Case ◽  
Functional Defect ◽  
Sequencing Platforms

Abstract Abstract 3260 Platelet aggregation by thromboxane (TBXA2) stimulation of its G protein-coupled receptor TXA2R is initiated after conversion of arachidonic acid (AA) into prostaglandin H2 (PGH2) by cyclooxygenase1 (PTGS1) and subsequently by conversion of PGH2 into TXA2 by thromboxane synthase (TBXAS1). Hirata et al (JCI, 1994) reported the first TBXA2R mutation that resulted in reduced platelet responses to U46619 and low AA concentrations in subjects with a heterozygous R60L mutation. This functional defect in combination with mild clinical bleeding problems was only described for the one patient that was homozygous for this mutation. A second TBXA2 patient with an obvious bleeding diathesis carried a heterozygous D304N mutation but it was reported that this variant by itself could not explain the bleeding phenotype as other family members heterozygous for D304N presented with abnormal aggregation responses but no bleeding problems (Mumford, Blood, 2010). Functional SNPs in PTGS1 were described in pharmacogenetic studies including the L237M variant with 50% reduced COX1 metabolic activity but its effect on platelet function was not studied (Lee CR, Pharmacogenet Genomics, 2007). We here describe a 6-year old patient with ecchymosis, easy bruising and important post-traumatic bleeding complications after adenotonsillectomy and circumcision. The boy presents with normal coagulation parameters, normal platelet count and MPV, structurally normal platelets, normal ATP secretion by collagen, and the PFA100 closure time was normal for Col/Epi and mildly prolonged for Col/ADP. Platelet aggregation studies further showed an absent response to 1 mM AA as determined on different occasions, a reduced but not absent response to U46619 and a normal activation with ADP, ristocetin and Horm collagen. His parents and sister presented with increased sensitivity for ecchymoses but none had severe clinical bleeding problems and their platelets showed normal aggregation responses except for the father and sister with a reduced though not absent response to AA. Thromboxane B2 formation was determined and found to be normal in basal (plasma) and maximal stimulated (serum) conditions. In contrast, TXB2 levels were decreased after activation with U46619 for the patient but also for the father and sister compared to the control or mother. Activation with AA also resulted in reduced TXB2 levels for the patient and mildly reduced levels for all other family member compared to controls. This strongly suggests the presence of an autosomal recessive disorder. The TBXAS1, PTGS1 and TBXA2R genes were sequenced for the patient and we identified two heterozygous mutations in separate genes being R60H in TXBA2R and the functional L237M variant in PTGS1. Interestingly, his mother carried the L237M variant while R60H was present in father and sister with similar functional platelet defects as earlier described for the other heterogenous TBXA2R mutations but no clinical bleeding symptoms. To our knowledge, this is the first case of transheterozygosity for mutations explaining an autosomal recessive bleeding disorder. We hypothesize that this pattern of inheritance might be more common than expected and therefore this possibility should be taken into account when analyzing patients in the future using exome or genome wide sequencing platforms. Disclosures: No relevant conflicts of interest to declare.

Missense mutations in the human β fibrinogen gene cause congenital afibrinogenemia by impairing fibrinogen secretion

Blood ◽  
2000 ◽  
Vol 95 (4) ◽  
pp. 1336-1341 ◽  
Author(s):  
Stefano Duga ◽  
Rosanna Asselta ◽  
Elena Santagostino ◽  
Sirous Zeinali ◽  
Tatjana Simonic ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Recessive Disorder ◽  
Chain Gene ◽  
Missense Mutations ◽  
Wild Type ◽  
Large Deletions ◽  
Congenital Afibrinogenemia ◽  
Low Levels ◽  
A Chain ◽  
Mutation Mechanisms

Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by bleeding that varies from mild to severe and by complete absence or extremely low levels of plasma and platelet fibrinogen. Although several mutations in the fibrinogen genes associated with dysfibrinogenemia and hypofibrinogenemia have been described, the genetic defects of congenital afibrinogenemia are largely unknown, except for a recently reported 11-kb deletion of the fibrinogen A-chain gene. Nevertheless, mutation mechanisms other than the deletion of a fibrinogen gene are likely to exist because patients with afibrinogenemia showing no gross alteration within the fibrinogen cluster have been reported. We tested this hypothesis by studying the affected members of two families, one Italian and one Iranian, who had no evidence of large deletions in the fibrinogen genes. Sequencing of the fibrinogen genes in the 2 probands detected 2 different homozygous missense mutations in exons 7 and 8 of the Bβ-chain gene, leading to amino acid substitutions Leu353Arg and Gly400Asp, respectively. Transient transfection experiments with plasmids expressing wild-type and mutant fibrinogens demonstrated that the presence of either mutation was sufficient to abolish fibrinogen secretion. These findings demonstrated that missense mutations in the Bβ fibrinogen gene could cause congenital afibrinogenemia by impairing fibrinogen secretion.

scholarly journals Human Disease Phenotypes Associated with Loss and Gain of Function Mutations in STAT2: Viral Susceptibility and Type I Interferonopathy

2021 ◽  
Vol 41 (7) ◽  
pp. 1446-1456
Author(s):  
Christopher James Arthur Duncan ◽  
Sophie Hambleton
Keyword(s):  
Autosomal Recessive ◽  
Clinical Presentation ◽  
Viral Disease ◽  
Negative Regulator ◽  
Type I ◽  
Viral Susceptibility ◽  
Disease Phenotypes ◽  
Monogenic Diseases ◽  
Severe Type ◽  
Missense Substitution

AbstractSTAT2 is distinguished from other STAT family members by its exclusive involvement in type I and III interferon (IFN-I/III) signaling pathways, and its unique behavior as both positive and negative regulator of IFN-I signaling. The clinical relevance of these opposing STAT2 functions is exemplified by monogenic diseases of STAT2. Autosomal recessive STAT2 deficiency results in heightened susceptibility to severe and/or recurrent viral disease, whereas homozygous missense substitution of the STAT2-R148 residue is associated with severe type I interferonopathy due to loss of STAT2 negative regulation. Here we review the clinical presentation, pathogenesis, and management of these disorders of STAT2.

scholarly journals The Analysis of Variants in the General Population Reveals That PMM2 Is Extremely Tolerant to Missense Mutations and That Diagnosis of PMM2-CDG Can Benefit from the Identification of Modifiers

2018 ◽  
Vol 19 (8) ◽  
pp. 2218 ◽  
Author(s):  
Valentina Citro ◽  
Chiara Cimmaruta ◽  
Maria Monticelli ◽  
Guglielmo Riccio ◽  
Bruno Hay Mele ◽  
...  
Keyword(s):  
General Population ◽  
Autosomal Recessive ◽  
Biochemical Analysis ◽  
Autosomal Recessive Disease ◽  
Type I ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Phenotype Correlation ◽  
Phenotypic Spectrum ◽  
Partial Deficiency

Type I disorders of glycosylation (CDG), the most frequent of which is phosphomannomutase 2 (PMM2-CDG), are a group of diseases causing the incomplete N-glycosylation of proteins. PMM2-CDG is an autosomal recessive disease with a large phenotypic spectrum, and is associated with mutations in the PMM2 gene. The biochemical analysis of mutants does not allow a precise genotype–phenotype correlation for PMM2-CDG. PMM2 is very tolerant to missense and loss of function mutations, suggesting that a partial deficiency of activity might be beneficial under certain circumstances. The patient phenotype might be influenced by variants in other genes associated with the type I disorders of glycosylation in the general population.

Sign in / Sign up

Export Citation Format

Share Document