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Nature Communications Apr 2023Haemoglobin E (HbE) β-thalassaemia causes approximately 50% of all severe thalassaemia worldwide; equating to around 30,000 births per year. HbE β-thalassaemia is due...
Haemoglobin E (HbE) β-thalassaemia causes approximately 50% of all severe thalassaemia worldwide; equating to around 30,000 births per year. HbE β-thalassaemia is due to a point mutation in codon 26 of the human HBB gene on one allele (GAG; glutamatic acid → AAG; lysine, E26K), and any mutation causing severe β-thalassaemia on the other. When inherited together in compound heterozygosity these mutations can cause a severe thalassaemic phenotype. However, if only one allele is mutated individuals are carriers for the respective mutation and have an asymptomatic phenotype (β-thalassaemia trait). Here we describe a base editing strategy which corrects the HbE mutation either to wildtype (WT) or a normal variant haemoglobin (E26G) known as Hb Aubenas and thereby recreates the asymptomatic trait phenotype. We have achieved editing efficiencies in excess of 90% in primary human CD34 + cells. We demonstrate editing of long-term repopulating haematopoietic stem cells (LT-HSCs) using serial xenotransplantation in NSG mice. We have profiled the off-target effects using a combination of circularization for in vitro reporting of cleavage effects by sequencing (CIRCLE-seq) and deep targeted capture and have developed machine-learning based methods to predict functional effects of candidate off-target mutations.
Topics: Humans; Animals; Mice; beta-Thalassemia; Hemoglobin E; Thalassemia; Mutation; Point Mutation
PubMed: 37076455
DOI: 10.1038/s41467-023-37604-8 -
The Cochrane Database of Systematic... Sep 2017Sickle cell disease comprises a group of genetic haemoglobin disorders. The predominant symptom associated with sickle cell disease is pain resulting from the occlusion... (Review)
Review
BACKGROUND
Sickle cell disease comprises a group of genetic haemoglobin disorders. The predominant symptom associated with sickle cell disease is pain resulting from the occlusion of small blood vessels by abnormally 'sickle-shaped' red blood cells. There are other complications, including chronic organ damage and prolonged painful erection of the penis, known as priapism. Severity of sickle cell disease is variable, and treatment is usually symptomatic. Priapism affects up to half of all men with sickle cell disease, however, there is no consistency in treatment. We therefore need to know the best way of treating this complication in order to offer an effective interventional approach to all affected individuals.
OBJECTIVES
To assess the benefits and risks of different treatments for stuttering (repeated short episodes) and fulminant (lasting for six hours or more) priapism in sickle cell disease.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 15 September 2017.Date of most recent search of trial registries and of Embase: 12 December 2016.
SELECTION CRITERIA
All randomised or quasi-randomised controlled trials comparing non-surgical or surgical treatment with placebo or no treatment, or with another intervention for stuttering or fulminant priapism.
DATA COLLECTION AND ANALYSIS
The authors independently extracted data and assessed the risk of bias of the trials.
MAIN RESULTS
Three trials with 102 participants were identified and met the criteria for inclusion in this review. These trials compared stilboestrol to placebo, sildenafil to placebo and ephedrine or etilefrine to placebo and ranged in duration from two weeks to six months. All of the trials were conducted in an outpatient setting in Jamaica, Nigeria and the UK. None of the trials measured our first primary outcome, detumescence but all three trials reported on the reduction in frequency of stuttering priapism, our second primary outcome. No significant effect of any of the treatments was seen compared to placebo. Immediate side effects were not found to be significantly different from placebo in the two trials where this information was reported. We considered the quality of evidence to be low to very low as all of the trials were at risk of bias and all had low participant numbers.
AUTHORS' CONCLUSIONS
There is a lack of evidence for the benefits or risks of the different treatments for both stuttering and fulminant priapism in sickle cell disease. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre randomised controlled trials assessing the effectiveness of specific interventions for priapism in sickle cell disease.
Topics: Anemia, Sickle Cell; Diethylstilbestrol; Estrogens, Non-Steroidal; Humans; Male; Priapism
PubMed: 28926088
DOI: 10.1002/14651858.CD004198.pub3 -
Hematology. American Society of... Dec 2017The pathophysiology, clinical presentation, and natural history of acute pain in sickle cell disease are unique and require a disease-centered approach that also applies... (Review)
Review
The pathophysiology, clinical presentation, and natural history of acute pain in sickle cell disease are unique and require a disease-centered approach that also applies general principles of acute and chronic pain management. The majority of acute pain episodes are managed at home without the need to access health care. The long-term consequences of poorly treated acute pain include chronic pain, adverse effects of chronic opioid usage, psychological maladjustment, poor quality of life, and excessive health care utilization. There is no standard protocol for management of an acute pain crisis in either the hospital or the community. The assumptions that severe acute pain must be managed in the hospital with parenteral opioids and that strong opioids are needed for home management of pain need to be questioned. Pain management in the emergency department often does not meet acceptable standards, while chronic use of strong opioids is likely to result in opioid-induced hyperalgesia, exacerbation of chronic pain symptoms, and opioid dependency. We suggest that an integrated approach is needed to control the underlying condition, modify psychological responses, optimize social support, and ensure that health care services provide safe, effective, and prompt treatment of acute pain and appropriate management of chronic pain. This integrated approach should begin at an early age and continue through the adolescent, transition, and adult phases of the care model.
Topics: Acute Pain; Adolescent; Adult; Analgesics, Opioid; Anemia, Sickle Cell; Humans; Pain Management; Psychosocial Support Systems
PubMed: 29222301
DOI: 10.1182/asheducation-2017.1.525 -
BMC Medical Genetics Aug 2020The frequency of the alpha thalassemia trait is approximately 40% in the Kuwaiti population, but there has been no comprehensive study of the prevalent alleles. This is...
BACKGROUND
The frequency of the alpha thalassemia trait is approximately 40% in the Kuwaiti population, but there has been no comprehensive study of the prevalent alleles. This is a report of patients who were referred for molecular diagnosis over a 20-year period.
METHODS
This is a retrospective study of the α-globin genotypes obtained in the Hemoglobin Research Laboratory of the Department of Pediatrics, Kuwait University from 1994 to 2015. Genotyping was performed by a combination of PCR, allele-specific oligonucleotide hybridization and reverse dot blot hybridization (Vienna Lab Strip Assay).
RESULTS
Four hundred samples were characterized and analyzed from individuals aged < 1 month to 80 years, with a median of 6 years from 283 unrelated families. Most (90.8%) were Kuwaiti nationals. The commonest genotype was homozygosity for the polyadenylation-1 mutation (αα/α α) in 33.3% of the samples, followed by heterozygosity (αα/α α) for the same mutation in 32.3%. PA-1 was therefore the most frequent allele (0.59). The frequency of the α (--) allele was 0.017. Rare alleles that were found in very low frequencies included α (--) in a Filipino child, Hb Constant Spring, Hb Adana, and Hb Icaria.
CONCLUSION
There is a wide variety of alpha thalassemia alleles among Kuwaitis, but nondeletional PA-1 is by far the most common cause of the moderate to severe HbH (β4 tetramer) disease phenotype. The α (-) allele is also encountered, which has implications for premarital counseling, especially for the possibility of having babies with alpha thalassemia major (Barts hydrops fetalis).
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Child; Child, Preschool; Female; Gene Frequency; Genotype; Humans; Infant; Infant, Newborn; Kuwait; Male; Middle Aged; Retrospective Studies; Young Adult; alpha-Globins; alpha-Thalassemia
PubMed: 32831051
DOI: 10.1186/s12881-020-01105-y -
The Cochrane Database of Systematic... Apr 2020Sickle cell disease comprises a group of genetic haemoglobin disorders. The predominant symptom associated with sickle cell disease is pain resulting from the occlusion... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Sickle cell disease comprises a group of genetic haemoglobin disorders. The predominant symptom associated with sickle cell disease is pain resulting from the occlusion of small blood vessels by abnormally 'sickle-shaped' red blood cells. There are other complications, including chronic organ damage and prolonged painful erection of the penis, known as priapism. Severity of sickle cell disease is variable, and treatment is usually symptomatic. Priapism affects up to half of all men with sickle cell disease, however, there is no consistency in treatment. We therefore need to know the best way of treating this complication in order to offer an effective interventional approach to all affected individuals. This is an update of a previously published review.
OBJECTIVES
To assess the benefits and risks of different treatments for stuttering (repeated short episodes) and fulminant (lasting for six hours or more) priapism in sickle cell disease.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries. Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 09 September 2019. Date of most recent search of trial registries and of Embase: 01 October 2019.
SELECTION CRITERIA
All randomised or quasi-randomised controlled trials comparing non-surgical or surgical treatment with placebo or no treatment, or with another intervention for stuttering or fulminant priapism.
DATA COLLECTION AND ANALYSIS
The authors independently extracted data and assessed the risk of bias of the trials.
MAIN RESULTS
Three trials with 102 participants were identified and met the criteria for inclusion in this review. These trials compared stilboestrol to placebo, sildenafil to placebo and a four-arm trial which compared ephedrine or etilefrine to placebo and ranged in duration from two weeks to six months. All of the trials were conducted in an outpatient setting in Jamaica, Nigeria and the UK. None of the trials measured our first primary outcome, detumescence. However, all three trials reported on the reduction in frequency of stuttering priapism, our second primary outcome; and from the evidence included in this review, we are uncertain whether stilboestrol, etilefrine or ephedrine reduce the frequency of stuttering priapism as the certainty of the evidence has been assessed as very low. Additionally, we conclude that sildenafil may make little or no difference (low-certainty evidence). Two trials reported on immediate side effects and we are uncertain whether etilefrine or ephedrine reduce the occurrence of these (very low-certainty of evidence) and also conclude that sildenafil may make little or no difference in side effects (low-quality evidence). Given that all of the trials were at risk of bias and all had low participant numbers, we considered the certainty of the evidence to be low to very low.
AUTHORS' CONCLUSIONS
There is a lack of evidence for the benefits or risks of the different treatments for both stuttering and fulminant priapism in sickle cell disease. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre randomised controlled trials assessing the effectiveness of specific interventions for priapism in sickle cell disease.
Topics: Adrenergic Agents; Anemia, Sickle Cell; Diethylstilbestrol; Ephedrine; Estrogens, Non-Steroidal; Etilefrine; Humans; Male; Priapism; Randomized Controlled Trials as Topic; Sildenafil Citrate; Tachycardia; Vasoconstrictor Agents; Young Adult
PubMed: 32251534
DOI: 10.1002/14651858.CD004198.pub4 -
Balkan Medical Journal Jul 2023Hemoglobinopathies are the most common inherited diseases in humans resulting from impaired globin chain synthesis of hemoglobin. The progression of thalassemia rates is...
BACKGROUND
Hemoglobinopathies are the most common inherited diseases in humans resulting from impaired globin chain synthesis of hemoglobin. The progression of thalassemia rates is prevented with prenatal screening methods.
AIMS
To evaluate the hematological parameters of α- and β-thalassemia and normal fetuses aged 17-25 weeks of gestation.
STUDY DESIGN
A cross-sectional study.
METHODS
Pregnant women who underwent cordocentesis in the second trimester because of the risk of having a baby with thalassemia were included in the study. Hematological indices and molecular DNA methods were analyzed from the cord blood samples of 129 women who were 17-25 weeks into pregnancy. The HPLC method was used for Hb fraction analysis. Amplification refractory mutation system, restriction enzyme analysis, multiplex polymerase chain reaction, and sequencing methods were used for the molecular analysis. Maternal contamination was eliminated by the short tandem repeat method.
RESULTS
In total, 112 of the fetuses carry α- and β-thalassemia heterozygous or homozygous (α: 37, β: 58, mixed: 17) and 17 fetuses had a normal genotype for thalassemia. Significant differences in adult hemoglobin (HbA), fetal hemoglobin (HbF), Hb Barts, MCV, MCH, and RDW were detected in three groups compared with the normal group (p < 0.001, except for RBC, Hb, HCT, and MCHC). Differences in HbF, Hb Barts, MCV, MCH, and RDW were observed in the α-thalassemia groups compared with the normal group (p < 0.001). Among the five β-thalassemia subgroups, only HbA and RDW were different from the normal group (p < 0.001).
CONCLUSION
This study could be a good reference for future studies and prenatal diagnostic applications in emphasizing the importance of changes in the blood parameters of fetuses before molecular genotyping. These hematological data give valuable information to clinicians about the fetus to enlighten families in making appropriate decisions during prenatal diagnosis.
Topics: Female; Pregnancy; Humans; beta-Thalassemia; Pregnancy Trimester, Second; Fetal Blood; Cross-Sectional Studies; alpha-Thalassemia; Genotype; Fetus
PubMed: 37154826
DOI: 10.4274/balkanmedj.galenos.2023.2023-1-86 -
British Journal of Haematology Jul 2014Management of the acute painful crisis (APC) of sickle cell disease (SCD) remains unsatisfactory despite advances in the understanding and management of acute pain in... (Review)
Review
Management of the acute painful crisis (APC) of sickle cell disease (SCD) remains unsatisfactory despite advances in the understanding and management of acute pain in other clinical settings. One reason for this is an unsophisticated approach to the use of opioid analgesics for pain management. This applies to haematologists who are responsible for developing acute sickle pain management protocols for their patients, and to health care staff in the acute care setting. The objective of this article is to evaluate the evidence for use of opioids in APC management. We have highlighted the possibilities for improving management by using alternatives to morphine, and intranasal (IN) or transmucosal routes of administration for rapid onset of analgesia in the emergency department (ED). We suggest how experience gained in managing acute sickle pain in children could be extrapolated to adolescents and young adults. We have also questioned whether patients given strong opioids in the acute setting are being safely monitored and what resources are required to ensure efficacy, safety and patient satisfaction. We also identify aspects of care where there are significant differences of opinion, which require further study by randomized controlled trial.
Topics: Acute Pain; Adolescent; Adult; Analgesics, Opioid; Anemia, Sickle Cell; England; Evidence-Based Medicine; Humans; Pain Management; Patient Satisfaction; Transition to Adult Care
PubMed: 24750050
DOI: 10.1111/bjh.12879 -
Journal of Clinical Laboratory Analysis Oct 2018Capillary isoelectric focusing is a type of capillary electrophoresis method newly used for thalassemia screening in China. Although the good performance has been proved...
BACKGROUND
Capillary isoelectric focusing is a type of capillary electrophoresis method newly used for thalassemia screening in China. Although the good performance has been proved by several studies, whether it can best suit the special needs of Chinese patients still requires further investigations.
METHODS
Comparisons were made between capillary zone electrophoresis method applied on Sebia Minicap and capillary isoelectric focusing method applied on Helena V8 platform E-class on identifying Hb E, Hb CS, Hb H, and Hb Barts for patients from southern China. And mixing studies were used to evaluate the lowest detection limits of these 2 kinds of capillary electrophoresis system.
RESULTS
Helena V8 could not make a distinction between peaks of Hb E and peaks of Hb A2 as Sebia Minicap did. All chosen patients with Hb H and/or Hb Barts could be screened out by both 2 systems, but when analyzed by Helena V8, it was hard to distinguish Hb H from Hb Barts sometimes, while Sebia Minicap could make a clear distinction between peaks of Hb H and Hb Barts. Only a part of patients (3 of 8, 37.5%) with Hb CS could be screened out by Helena V8, while all patients could be identified by Sebia Minicap. Sebia Minicap had a lower detection limit for trace peaks than Helena V8 (near to 0.2% vs near to 0.6%).
CONCLUSIONS
Compared with capillary zone electrophoresis, capillary isoelectric focusing applied on Helena V8 maybe is not the first choice for hemoglobinopathy testing in southern China.
Topics: Adult; Child, Preschool; Electrophoresis, Capillary; Female; Hemoglobins, Abnormal; Humans; Infant; Isoelectric Focusing; Limit of Detection; Linear Models; Male; Reproducibility of Results; Thalassemia
PubMed: 29761562
DOI: 10.1002/jcla.22567 -
International Journal of Laboratory... Oct 2015Automated high performance liquid chromatography and Capillary electrophoresis are used to quantitate the proportion of Hemoglobin A2 (HbA2 ) in blood samples order to... (Review)
Review
Automated high performance liquid chromatography and Capillary electrophoresis are used to quantitate the proportion of Hemoglobin A2 (HbA2 ) in blood samples order to enable screening and diagnosis of carriers of β-thalassemia. Since there is only a very small difference in HbA2 levels between people who are carriers and people who are not carriers such analyses need to be both precise and accurate. This paper examines the different parameters of such equipment and discusses how they should be assessed.
Topics: Automation, Laboratory; Chromatography, High Pressure Liquid; Electrophoresis, Capillary; Hemoglobin A2; Humans; Reproducibility of Results; Sensitivity and Specificity; beta-Thalassemia
PubMed: 26372049
DOI: 10.1111/ijlh.12413 -
BMJ Case Reports Jun 2017A 39-year-old man with a history of sickle cell disease (SCD) presented with left leg weakness. He had a normal CT head and CT angiogram, but MRI head showed multiple...
A 39-year-old man with a history of sickle cell disease (SCD) presented with left leg weakness. He had a normal CT head and CT angiogram, but MRI head showed multiple acute bilateral cortical infarcts including in the right precentral gyrus. The MRI findings were more in keeping with an embolic source rather than stroke related to SCD, although it could not be ruled out. He also had an echocardiogram which revealed a patent foramen ovale. He was treated with antiplatelet therapy and also had red blood cell exchange transfusion. His symptoms improved significantly and he was discharged with follow-up as an outpatient and a cardiology review.
Topics: Adult; Anemia, Sickle Cell; Echocardiography; Embolism; Erythrocyte Transfusion; Foramen Ovale, Patent; Frontal Lobe; Humans; Magnetic Resonance Imaging; Male; Platelet Aggregation Inhibitors; Stroke; Uncertainty
PubMed: 28645902
DOI: 10.1136/bcr-2016-218358