-
Journal of Thrombosis and Haemostasis :... Nov 2013GFI1B is a transcription factor important for erythropoiesis and megakaryocyte development but previously unknown to be associated with human disease.
BACKGROUND
GFI1B is a transcription factor important for erythropoiesis and megakaryocyte development but previously unknown to be associated with human disease.
METHODS
A family with a novel bleeding disorder was identified and characterized. Genetic linkage analysis and massively parallel sequencing were used to localize the mutation causing the disease phenotype on chromosome 9. Functional studies were then performed in megakaryocytic cell lines to determine the biological effects of the mutant transcript.
RESULTS
We have identified a family with an autosomal dominant bleeding disorder associated with macrothrombocytopenia, red cell anisopoikilocytosis, and platelet dysfunction. The severity of bleeding is variable with some affected individuals experiencing spontaneous bleeding while other family members exhibit only abnormal bleeding with surgery. A single nucleotide insertion was identified in GFI1B that predicts a frameshift mutation in the fifth zinc finger DNA-binding domain. This mutation alters the transcriptional activity of the protein, resulting in a reduction in platelet α-granule content and aberrant expression of key platelet proteins.
CONCLUSIONS
GFI1B mutation represents a novel human bleeding disorder, and the described phenotype identifies GFI1B as a critical regulator of platelet shape, number, and function.
Topics: Adult; Aged; Aged, 80 and over; Blood Platelet Disorders; Blood Platelets; Erythrocytes; Female; Frameshift Mutation; Genetic Linkage; Humans; Male; Megakaryocytes; Middle Aged; Mutation; Phenotype; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins; Repressor Proteins; Sequence Analysis, DNA; Transfection; Young Adult
PubMed: 23927492
DOI: 10.1111/jth.12368 -
BMC Pediatrics Jan 2024The administration of high-dose intravenous immunoglobulin (IVIG) is a standard treatment for the management of Kawasaki disease (KD). IVIG is known to be a highly...
BACKGROUND
The administration of high-dose intravenous immunoglobulin (IVIG) is a standard treatment for the management of Kawasaki disease (KD). IVIG is known to be a highly effective and safe treatment.
CASE PRESENTATION
We report the development of hemolytic anemia in seven children receiving repeated doses of IVIG. The children were aged 3-44 months and included 4 girls and 3 boys. All children received 10% IVIG and a second course of immunoglobulin because they did not respond to the first course of immunoglobulin. Two received high-dose aspirin (50 mg/kg), and five received low-dose aspirin (5 mg/kg). Two patients required additional methylprednisolone pulse therapy (30 mg/kg) after the second dose of immunoglobulin, and three patients received oral prednisolone therapy for defervescence. Three patients showed coronary artery dilation during hospitalization and normalized within two months. Pretreatment hemoglobin averaged 11.3-14.2 g/dL, and post-hemolytic anemia hemoglobin ranged from 7.4 to 9.6 g/dL, with a difference of 1.7-6.8 g/dL. Reticulocytes were increased to 3.3-13.2%. Peripheral blood smears showed normochromic normocytic anemia, and anisopoikilocytosis. All children were positive for warm-type antibodies with IgG+, C3d- in direct antiglobulin test, and the blood group was A + in five and B + in two. None of the patients received immunomodulatory therapy or red blood cell transfusions. They were followed for a year and all recovered.
CONCLUSION
Especially, in non-O blood group KD patients who are refractory to initial IVIG and require a second dose of IVIG or 10% formulation the possibility of immune hemolytic anemia should be carefully considered, and close follow-up should be maintained after therapy.
Topics: Child; Female; Humans; Male; Anemia, Hemolytic; Aspirin; Hemoglobins; Immunoglobulins, Intravenous; Mucocutaneous Lymph Node Syndrome; ABO Blood-Group System
PubMed: 38245705
DOI: 10.1186/s12887-024-04546-z -
Blood Jun 2021The tight regulation of intracellular nucleotides is critical for the self-renewal and lineage specification of hematopoietic stem cells (HSCs). Nucleosides are major...
The tight regulation of intracellular nucleotides is critical for the self-renewal and lineage specification of hematopoietic stem cells (HSCs). Nucleosides are major metabolite precursors for nucleotide biosynthesis and their availability in HSCs is dependent on their transport through specific membrane transporters. However, the role of nucleoside transporters in the differentiation of HSCs to the erythroid lineage and in red cell biology remains to be fully defined. Here, we show that the absence of the equilibrative nucleoside transporter (ENT1) in human red blood cells with a rare Augustine-null blood type is associated with macrocytosis, anisopoikilocytosis, an abnormal nucleotide metabolome, and deregulated protein phosphorylation. A specific role for ENT1 in human erythropoiesis was demonstrated by a defective erythropoiesis of human CD34+ progenitors following short hairpin RNA-mediated knockdown of ENT1. Furthermore, genetic deletion of ENT1 in mice was associated with reduced erythroid progenitors in the bone marrow, anemia, and macrocytosis. Mechanistically, we found that ENT1-mediated adenosine transport is critical for cyclic adenosine monophosphate homeostasis and the regulation of erythroid transcription factors. Notably, genetic investigation of 2 ENT1null individuals demonstrated a compensation by a loss-of-function variant in the ABCC4 cyclic nucleotide exporter. Indeed, pharmacological inhibition of ABCC4 in Ent1-/- mice rescued erythropoiesis. Overall, our results highlight the importance of ENT1-mediated nucleotide metabolism in erythropoiesis.
Topics: Adenosine Monophosphate; Animals; Equilibrative Nucleoside Transporter 1; Erythropoiesis; Hematopoietic Stem Cells; Homeostasis; Humans; Mice; Mice, Knockout
PubMed: 33690842
DOI: 10.1182/blood.2020007281 -
Frontiers in Pharmacology 2020We present two unrelated Chinese patients with CAD deficiency manifesting with a triad of infantile-onset psychomotor developmental delay with regression,...
We present two unrelated Chinese patients with CAD deficiency manifesting with a triad of infantile-onset psychomotor developmental delay with regression, drug-refractory epilepsy, and anaemia with anisopoikilocytosis. Timely translation into uridine supplementation, within 2-months of disease onset, allowed us to stop conventional anti-epileptic drugs and led to dramatic improvement in the clinical symptoms, with prompt cessation of seizures, resolution of anaemia, developmental progress, and prevention of development of severe and non-reversible manifestations. The remarkable recovery and prevention of advanced disease with prompt treatment, highlights the need to act immediately upon genetic diagnosis of a treatable disease. This further reinforces CAD deficiency as a treatable neurometabolic disorder and emphasises the need for a biomarker or genetic new born screening for early identification.
PubMed: 33364968
DOI: 10.3389/fphar.2020.608737 -
Annales de Biologie Clinique Feb 2020Hemoglobin D-Punjab is a common hemoglobin variant in India but very rare in Morocco. Often, its presence has minimal or no clinical impact. Its heterozygous association...
UNLABELLED
Hemoglobin D-Punjab is a common hemoglobin variant in India but very rare in Morocco. Often, its presence has minimal or no clinical impact. Its heterozygous association with β-thalassemia is exceptional. The purpose of the study is to describe the epidemiological, diagnostic and prophylactic aspects of hemoglobinosis D-Punjab from a family case study.
MATERIAL AND METHODS
Case study of hemoglobinosis D-Punjab in a Moroccan family, diagnosed at the Laboratory of Biochemistry-Toxicology of the Mohammed V Military Teaching Hospital. The biological study was based on iron and hemolysis checkups, hemogram and study of hemoglobin (electrophoresis in alkaline and acid medium, high performance liquid chromatography). The index patient also benefited from sequencing by molecular biology.
RESULTS
The index patient was heterozygous D-Punjab/β-thalassemia, confirmed by molecular biology. Two of her sisters had the same hemoglobin profile. At electrophoresis, all three had hemoglobin D-Punjab higher than 90%, hemoglobin A less than 1% and hemoglobin A higher than 6%. The results of the three hemograms showed similar abnormalities (pseudo-polycythemia, hypochromia, microcytosis, anisopoikilocytosis). Six other members of the family had a thalassemic trait and another three had heterozygous hemoglobinosis D-Punjab.
CONCLUSION
Hemoglobin D-Punjab remains extremely rare in Morocco and very poorly documented in the literature. The number of reported cases is expected to raise due to increasing migration. Biologist advisory services require a precise diagnosis in order to give correct genetic counseling.
Topics: Adolescent; Adult; Child; Family; Female; Genetic Association Studies; Hemoglobins, Abnormal; Humans; Male; Middle Aged; Morocco; Pedigree; beta-Thalassemia
PubMed: 32108581
DOI: 10.1684/abc.2020.1523 -
Journal of Medical Case Reports Apr 2022Unstable hemoglobinopathies are rare inherited disorders of hemoglobin causing a reduction of hemoglobin molecule solubility. This results in an unstable hemoglobin...
BACKGROUND
Unstable hemoglobinopathies are rare inherited disorders of hemoglobin causing a reduction of hemoglobin molecule solubility. This results in an unstable hemoglobin tetramer/globin polypeptide, which precipitates within the red blood cell. Affected red blood cells have a reduced lifespan due to oxidative stress and cellular rigidity, and tend to be phagocytized by spleen macrophages more rapidly. Unstable hemoglobin is frequently under- or misdiagnosed, because its clinical presentation varies broadly. Therefore, testing for unstable hemoglobinopathies is indicated in cases of unexplained hemolytic anemia. However, this approach is not systematically followed in clinical practice.
CASE REPORT
A 25-year-old Caucasian man with a recent history of a presumed viral upper respiratory infection was referred to the hematology outpatient clinic because of hemolytic anemia. The patient had scleral icterus, moderate splenomegaly, and mild macrocytic anemia with high reticulocyte count. Unconjugated bilirubin and lactate dehydrogenase were elevated. Haptoglobin was undetectable. Direct antiglobulin test was negative. Blood smear examination revealed anisopoikilocytosis, polychromasia, bite cells, and basophilic stippling, but no Heinz bodies. High-performance liquid chromatography and capillary electrophoresis showed slightly increased hemoglobin A2, normal fetal hemoglobin, and a variant hemoglobin. Deoxyribonucleic Acid sequencing revealed the heterozygous mutation c430delC in the beta-globin gene hallmark of hemoglobin Montreal II and the heterozygous mutation c287C>T in the alpha-globin gene corresponding to hemoglobin G-Georgia, indicative of the not yet described combination of double-heterozygous hemoglobin Montreal II and hemoglobin G-Georgia variants. Hemoglobinopathy Montreal II was here not associated with β-thalassemia syndrome, and carriers did not show ineffective erythropoiesis. In addition to the case report, we provide information about the largest pedigree with hemoglobinopathy Montreal II identified to date.
CONCLUSION
We emphasize that a transitory acute condition may uncover an underlying inherited red blood cell disorder. In this regard, awareness should be raised among hematologists caring for adult patients that unstable hemoglobinopathies should be considered in the differential diagnosis of unexplained hemolytic anemias.
Topics: Adult; Anemia, Hemolytic; Hemoglobinopathies; Hemoglobins, Abnormal; Hemolysis; Humans; Male; Virus Diseases
PubMed: 35397565
DOI: 10.1186/s13256-022-03374-y -
Stem Cell Research Dec 2022Mutations in CAD gene, encoding a multifunctional enzyme involved in de novo pyrimidine biosynthesis, has been reported to be associated with early-onset epileptic...
Mutations in CAD gene, encoding a multifunctional enzyme involved in de novo pyrimidine biosynthesis, has been reported to be associated with early-onset epileptic encephalopathy (EOEE). Herein, we generated an induced pluripotent stem cell (iPSC) line from the skin fibroblasts of a five-year-old boy with CAD deficiency, presented with developmental delay, refractory epilepsy, anemia with anisopoikilocytosis, and dramatic responsive to supplementation with oral uridine, carrying biallelic mutations, c.108delC (p.Tyr36Tyrfs*15) and c.3775G>A (p.Val1259Met) in CAD. These iPSCs exhibited stable amplification, expressed pluripotent markers, and differentiated spontaneously into three germ layers in vitro.
Topics: Humans; Child, Preschool; Induced Pluripotent Stem Cells; Uridine; Brain Diseases
PubMed: 36283272
DOI: 10.1016/j.scr.2022.102947 -
Journal of Clinical Pathology Nov 1967Nineteen patients with morphological abnormalities of the red blood cells are described, and these formed approximately 3% of the total cases of cardiac valvular...
Nineteen patients with morphological abnormalities of the red blood cells are described, and these formed approximately 3% of the total cases of cardiac valvular disease. In two patients the abnormal blood film developed after the insertion of an aortic and mitral valve prosthesis respectively, but in another two patients the abnormal blood film was corrected by aortic valve surgery. Anisopoikilocytosis may have been associated with microangiopathic haemolytic anaemia in one patient, but in the others the cardiac valvular disease was severe and other mechanical factors were not present. The mitral valve was involved in 16 patients and the aortic valve in eight. Elliptocytosis was the only abnormality in 11 blood films, schistocytes and burr cells were present in seven, and in three there were a few microspherocytes. Family studies in seven patients produced evidence of hereditary elliptocytosis in three. Anaemia was present in only two patients. One of these had infective endocarditis, and the other developed overt haemolytic anaemia following the replacement of a diseased mitral valve by a Starr-Edwards prosthesis. In this latter case there was a transiently positive direct antiglobulin test, and the anaemia and abnormal blood picture were corrected without further surgical treatment. Haemolytic anaemia did not develop in 23 patients after the insertion of an aortic valve prosthesis or homograft. Indirect evidence of haemolysis was obtained in some patients who were not anaemic. There was a reticulocytosis in one third and serum haptoglobins were decreased or absent in over half of the patients tested.
Topics: Adult; Aged; Anemia, Hemolytic; Blood Cell Count; Coombs Test; Elliptocytosis, Hereditary; Endocarditis, Bacterial; Erythrocytes, Abnormal; Female; Heart Valve Diseases; Heart Valve Prosthesis; Hemolysis; Humans; Male; Middle Aged; Mitral Valve; Postoperative Complications; Reticulocytes
PubMed: 5614071
DOI: 10.1136/jcp.20.6.848 -
Indian Pediatrics Mar 2009A 14 year male adolescent born of 2nd degree consanguineous marriage presented with asymptomatic proteinuria and severe anemia. He had leucopenia, anisopoikilocytosis,...
A 14 year male adolescent born of 2nd degree consanguineous marriage presented with asymptomatic proteinuria and severe anemia. He had leucopenia, anisopoikilocytosis, megaloblastic erythropoiesis, megakaryocytes with low serum B12 level. His younger sibling was similarly affected. This combination suggested Imerslund-Grasbeck syndrome. The hemoglobin levels improved with injection of vitamin B12 but proteinuria persisted. During follow-up, he developed ketoacidosis due to insulin dependent diabetes mellitus. This rare combination has not been reported in the Indian literature.
Topics: Adolescent; Anemia, Megaloblastic; Child; Diabetes Mellitus, Type 1; Failure to Thrive; Humans; Hyperpigmentation; Intestinal Absorption; Malabsorption Syndromes; Male; Mutation, Missense; Prevalence; Risk Factors; Syndrome; Vitamin B 12; Vitamin B 12 Deficiency
PubMed: 19346573
DOI: No ID Found -
Cureus Oct 2017Congenital dyserythropoietic anaemias (CDAs) are very rare, heterogeneous hereditary red blood cell disorders characterized by ineffective erythropoiesis, erythroblast...
Congenital dyserythropoietic anaemias (CDAs) are very rare, heterogeneous hereditary red blood cell disorders characterized by ineffective erythropoiesis, erythroblast morphological abnormalities, haemolysis, and hypoglycosylation of red-blood-cell membrane proteins and lipids. There are four types (I-IV) of the disease identified, and all of them are associated with abnormal maturation and division of erythroid precursors. We report the management of a rare case of CDA type II diagnosed in a 26-year-old pregnant woman.
PubMed: 29308339
DOI: 10.7759/cureus.1811