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European Journal of Haematology May 2023Thalassemias are common monogenic autosomal recessive hemoglobin disorders. The usually asymptomatic heterozygotes (β-thalassemia traits, βTT) may rarely develop...
INTRODUCTION
Thalassemias are common monogenic autosomal recessive hemoglobin disorders. The usually asymptomatic heterozygotes (β-thalassemia traits, βTT) may rarely develop non-transfusion-dependent-thalassemia (NTDT) due to co-inheritance of supernumerary α-globin genes. Literature on phenotypic/genotypic features of these rare combinations is limited.
MATERIALS AND METHODS
We studied the demographic, clinical, and laboratory data from 47 persons with co-inherited βTT + supernumerary α-globin genes. HBB mutations were tested for by ARMS-PCR and/or Sanger sequencing, ααα /ααα and deletional α-thalassemia testing by multiplex gap-PCRs, and Xmn1 γ genotyping by PCR-RFLP.
RESULTS
The 47 cases comprised 0.08% of 61 010 hemoglobinopathy screenings during the study period. Mean age was 31.9 ± 14.7 years (range 5.5-83 years), with 57.4% males. Thirty (63.8%) had NTDT-phenotype, 16 (34%) were asymptomatic/minimally symptomatic, and 1 became transfusion-dependent at the age of 20 years. Anemia/pallor and jaundice were the commonest complaints (76% each); 40% had required blood transfusions. Twenty-one had splenomegaly, 14 had hepatomegaly. Mean hemoglobin was 9.0 ± 1.9 g/dl (range 4.0-13.0). HbA2 was 5.1 ± 0.7% (3.4%-6.3%) and HbF% 4.2 ± 3.2% (0.5%-18.4%). Forty-four (93.6%) had ααα , while 3 (6.4%) had ααα triplications. HBB:c.92+5G>C (47%), HBB:c.27_28insG (14.9%), and HBB:c.47G>A (8.5%) were the commonest β-globin mutations. One case showed HBB:c.-138C>T (β ), while the rest had β or severe-β mutations. Symptomatic cases had significantly lower hemoglobins and higher HbF% than asymptomatic ones.
CONCLUSION
This largest Indian and globally second-largest study reports the βTT + ααα state for the first time in such genotypically-complex Indian cases. Supernumerary α-genes should be suspected in all βTT with disproportionate clinical symptoms, mild-to-moderately elevated HbF, and unexplained anisopoikilocytosis.
Topics: Male; Female; Humans; beta-Thalassemia; alpha-Globins; Genetic Profile; Hemoglobinopathies; Mutation; beta-Globins
PubMed: 36598439
DOI: 10.1111/ejh.13923 -
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 -
Cureus May 2022An immunocompetent 45-year-old Cuban-American man presented with worsening knee pain and swelling despite antibiotic therapy. On physical examination, the patient was...
An immunocompetent 45-year-old Cuban-American man presented with worsening knee pain and swelling despite antibiotic therapy. On physical examination, the patient was ill-appearing, cachectic, with a protuberant abdomen and massive splenomegaly. In addition, he had a 10 cm area of peripheral hyperemia with central necrosis in the medial left knee that was non-tender and non-fluctuant. Initial lab work demonstrated pancytopenia, hyponatremia, hypoalbuminemia, and anemia of chronic inflammation. Peripheral smear showed microcytic, hypochromic red blood cells with mild anisopoikilocytosis. and leukopenia with slight left shift and metamyelocytes. Bone marrow biopsy demonstrated amastigotes and kinetoplasts within white blood cells and extracellular space consistent with leishmaniasis. Centers for Disease Control and Prevention (CDC) testing with PCR returned positive for . The patient received two courses of amphotericin B lipid complex (ABLC) with a 28-day course of miltefosine, which resulted in clinical improvement. This case illustrates the unique pathology that can affect immigrants and highlights the need to increase health provider awareness of foreign pathologies in areas with large migrant populations.
PubMed: 35774655
DOI: 10.7759/cureus.25442 -
African Journal of Laboratory Medicine 2022Haemoglobinopathies are inherited haemoglobin disorders that result in anaemia characterised by erythrocyte anisopoikilocytosis. Red cell distribution width (RDW)...
BACKGROUND
Haemoglobinopathies are inherited haemoglobin disorders that result in anaemia characterised by erythrocyte anisopoikilocytosis. Red cell distribution width (RDW) measures anisopoikiloytosis and is readily reported by haematology analysers as a complete blood count parameter. The utility of RDW as a diagnostic marker of haemoglobinopathies in Kenya remains undetermined and undocumented.
OBJECTIVE
This study aimed to determine the diagnostic efficacy of RDW in discriminating haemoglobinopathy and haemoglobinopathy-free cases in Kenya.
METHODS
The case-control study used randomly selected haematology analyser outputs for haemoglobinopathy-free (241, 49.4%) and haemoglobinopathy cases (247, 50.1%) aged 1 month to 66 years old tested in the Aga Khan Hospital, Kisumu, and its satellite centres in western Kenya from 01 January 2015 to 31 December 2020. Results were verified using high performance liquid chromatography. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic power of RDW as a biomarker for sickle cell disease (SCD) and sickle cell trait phenotypes and β-thalassaemia.
RESULTS
The RDW showed diagnostic significance in SCD phenotypes at 21.1 ROC curve coordinate with 67.7% sensitivity, 90.0% specificity, 0.789 accuracy, 70.5% positive predictive validity, 88.8% negative predictive validity, 6.77 positive likelihood ratio, 0.36 negative likelihood ratio and 18.94 (11.4-31.4) odds ratio.
CONCLUSION
An RDW of 21.1% is potentially a predictor of SCD haemoglobin phenotypes and should be included in the haematology screening algorithm as a critical value, above which suspected cases qualify to be investigated for SCD.
PubMed: 35547332
DOI: 10.4102/ajlm.v11i1.1644 -
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 -
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 -
British Journal of Haematology Sep 2020
Topics: Aged; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Erythrocytes; Female; Hemolysis; Humans; Lung Neoplasms; Male; Piperidines; Protein Kinase Inhibitors
PubMed: 32537738
DOI: 10.1111/bjh.16813 -
European Journal of Case Reports in... 2020Isolated congenital asplenia is a rare condition that mostly manifests in the early years, usually due to fatal systemic infections. In this paper, however, we present a...
UNLABELLED
Isolated congenital asplenia is a rare condition that mostly manifests in the early years, usually due to fatal systemic infections. In this paper, however, we present a case of a 36-year-old asymptomatic patient who was referred for suspected hyposplenism, with no history of splenectomy. There were no significant changes on physical examination. Blood analysis revealed leukocytosis and thrombocytosis as well as moderate anisopoikilocytosis and red blood cells with Howell-Jolly bodies. No spleen or other malformations were identified on imaging. Individuals with isolated congenital asplenia have an increased susceptibility to invasive infections and sepsis, with rapid clinical decline and a high mortality rate despite treatment.
LEARNING POINTS
Isolated congenital asplenia is underdiagnosed in adults and should be excluded in patients with Howell-Jolly bodies in a peripheral blood smear, leukocytosis or/and thrombocytosis.Febrile episodes may present initially in these patients with mild symptoms; however, rapid progress to septic shock can occur. As a result, a delay in initiating broad-spectrum antibiotics may compromise their survival.Prevention with an individual vaccination plan and patient education is paramount.
PubMed: 32309250
DOI: 10.12890/2020_001429 -
Indian Journal of Public Health 2020We report the case of a 22-year-old primigravida detected as having sickle cell disease (SCD), initially presenting in the third trimester (30 week) of pregnancy. The...
We report the case of a 22-year-old primigravida detected as having sickle cell disease (SCD), initially presenting in the third trimester (30 week) of pregnancy. The patient came to our center with a complaint of severe lower limb pain. The peripheral smear showed marked anisopoikilocytosis, numerous leptocytes, sickle cells, and target cells. High-performance liquid chromatography corroborated the diagnosis of SCD, showing a significant peak in the sickle window. The patient was conservatively managed and delivered a healthy baby through normal vaginal delivery. Delayed presentation of SCD in the third trimester of pregnancy is unusual. This report aims to bring attention to the possible causes of such a lag in detection. We also suggest measures to refine the antenatal healthcare screening at multiple levels, with regard to the detection of sickle cell hemoglobinopathy.
Topics: Anemia, Sickle Cell; Female; Humans; India; Pregnancy; Pregnancy Trimester, Third; Young Adult
PubMed: 32189693
DOI: 10.4103/ijph.IJPH_223_19