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Fulltext Growth hormone therapy for people with thalassaemia

Ngim CF, Lai NM, Hong JY, Tan SL, Ramadas A, Muthukumarasamy P, et al.

Cochrane Database Syst Rev, 2020 05 28;5:CD012284.
PMID: 32463488 DOI: 10.1002/14651858.CD012284.pub3

BACKGROUND: Thalassaemia is a recessively-inherited blood disorder that leads to anaemia of varying severity. In those affected by the more severe forms, regular blood transfusions are required which may lead to iron overload. Accumulated iron from blood transfusions may be deposited in vital organs including the heart, liver and endocrine organs such as the pituitary glands which can affect growth hormone production. Growth hormone deficiency is one of the factors that can lead to short stature, a common complication in people with thalassaemia. Growth hormone replacement therapy has been used in children with thalassaemia who have short stature and growth hormone deficiency. This review on the role of growth hormone was originally published in September 2017 and updated in April 2020.
OBJECTIVES: To assess the benefits and safety of growth hormone therapy in people with thalassaemia.
SEARCH METHODS: We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of latest search: 14 November 2019. We also searched the reference lists of relevant articles, reviews and clinical trial registries. Date of latest search: 06 January 2020.
SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing the use of growth hormone therapy to placebo or standard care in people with thalassaemia of any type or severity.
DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion. Data extraction and assessment of risk of bias were also conducted independently by two authors. The certainty of the evidence was assessed using GRADE criteria.
MAIN RESULTS: We included one parallel trial conducted in Turkey. The trial recruited 20 children with homozygous beta thalassaemia who had short stature; 10 children received growth hormone therapy administered subcutaneously on a daily basis at a dose of 0.7 IU/kg per week and 10 children received standard care. The overall risk of bias in this trial was low except for the selection criteria and attrition bias which were unclear. The certainty of the evidence for all major outcomes was moderate, the main concern was imprecision of the estimates due to the small sample size leading to wide confidence intervals. Final height (cm) (the review's pre-specified primary outcome) and change in height were not assessed in the included trial. The trial reported no clear difference between groups in height standard deviation (SD) score after one year, mean difference (MD) -0.09 (95% confidence interval (CI) -0.33 to 0.15 (moderate-certainty evidence). However, modest improvements appeared to be observed in the following key outcomes in children receiving growth hormone therapy compared to control (moderate-certainty evidence): change between baseline and final visit in height SD score, MD 0.26 (95% CI 0.13 to 0.39); height velocity, MD 2.28 cm/year (95% CI 1.76 to 2.80); height velocity SD score, MD 3.31 (95% CI 2.43 to 4.19); and change in height velocity SD score between baseline and final visit, MD 3.41 (95% CI 2.45 to 4.37). No adverse effects of treatment were reported in either group; however, while there was no clear difference between groups in the oral glucose tolerance test at one year, fasting blood glucose was significantly higher in the growth hormone therapy group compared to control, although both results were still within the normal range, MD 6.67 mg/dL (95% CI 2.66 to 10.68). There were no data beyond the one-year trial period.
AUTHORS' CONCLUSIONS: A small single trial contributed evidence of moderate certainty that the use of growth hormone for a year may improve height velocity of children with thalassaemia although height SD score in the treatment group was similar to the control group. There are no randomised controlled trials in adults or trials that address the use of growth hormone therapy over a longer period and assess its effect on final height and quality of life. The optimal dosage of growth hormone and the ideal time to start this therapy remain uncertain. Large well-designed randomised controlled trials over a longer period with sufficient duration of follow up are needed.

Matched MeSH terms: beta-Thalassemia/complications*; beta-Thalassemia/genetics
Hydroxyurea for reducing blood transfusion in non-transfusion dependent beta thalassaemias

Foong WC, Ho JJ, Loh CK, Viprakasit V

Cochrane Database Syst Rev, 2016 Oct 18;10:CD011579.
PMID: 27755646

BACKGROUND: Non-transfusion dependent beta thalassaemia is a subset of inherited haemoglobin disorders characterised by reduced production of the beta globin chain of the haemoglobin molecule leading to anaemia of varying severity. Although blood transfusion is not a necessity for survival, it is required when episodes of chronic anaemia occur. This chronic anaemia can impair growth and affect quality of life. People with non-transfusion dependent beta thalassaemia suffer from iron overload due to their body's increased capability of absorbing iron from food sources. Iron overload becomes more pronounced in those requiring blood transfusion. People with a higher foetal haemoglobin level have been found to require fewer blood transfusions. Hydroxyurea has been used to increase foetal haemoglobin level; however, its efficacy in reducing transfusion, chronic anaemia complications and its safety need to be established.
OBJECTIVES: To assess the effectiveness, safety and appropriate dose regimen of hydroxyurea in people with non-transfusion dependent beta thalassaemia (haemoglobin E combined with beta thalassaemia and beta thalassaemia intermedia).
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of relevant journals. We also searched ongoing trials registries and the reference lists of relevant articles and reviews.Date of last search: 30 April 2016.
SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of hydroxyurea in people with non-transfusion dependent beta thalassaemia comparing hydroxyurea with placebo or standard treatment or comparing different doses of hydroxyurea.
DATA COLLECTION AND ANALYSIS: Two authors independently applied the inclusion criteria in order to select trials for inclusion. Both authors assessed the risk of bias of trials and extracted the data. A third author verified these assessments.
MAIN RESULTS: No trials comparing hydroxyurea with placebo or standard care were found. However, we included one randomised controlled trial (n = 61) comparing 20 mg/kg/day with 10 mg/kg/day of hydroxyurea for 24 weeks.Both haemoglobin and foetal haemoglobin levels were lower at 24 weeks in the 20 mg group compared with the 10 mg group, mean difference -2.39 (95% confidence interval - 2.8 to -1.98) and mean difference -1.5 (95% confidence interval -1.83 to -1.17), respectively. Major adverse effects were significantly more common in the 20 mg group, for neutropenia risk ratio 9.93 (95% confidence interval 1.34 to 73.97) and for thrombocytopenia risk ratio 3.68 (95% confidence interval 1.13 to 12.07). No difference was reported for minor adverse effects (gastrointestinal disturbances and raised liver enzymes). The effect of hydroxyurea on transfusion frequency was not reported.The overall quality for the outcomes reported was graded as very low mainly because the outcomes were derived from only one small study with an unclear method of allocation concealment.
AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials to show whether hydroxyurea has any effect compared with controls on the need for blood transfusion. Administration of 10 mg/kg/day compared to 20 mg/kg/day of hydroxyurea resulted in higher haemoglobin levels and seems safer with fewer adverse effects. It has not been reported whether hydroxyurea is capable of reducing the need for blood transfusion. Large well-designed randomised controlled trials with sufficient duration of follow up are recommended.

Matched MeSH terms: beta-Thalassemia/blood; beta-Thalassemia/drug therapy*
Fulltext Growth hormone therapy for people with thalassaemia

Ngim CF, Lai NM, Hong JY, Tan SL, Ramadas A, Muthukumarasamy P, et al.

Cochrane Database Syst Rev, 2017 09 18;9:CD012284.
PMID: 28921500 DOI: 10.1002/14651858.CD012284.pub2

BACKGROUND: Thalassaemia is a recessively-inherited blood disorder that leads to anaemia of varying severity. In those affected by the more severe forms, regular blood transfusions are required which may lead to iron overload. Accumulated iron from blood transfusions may be deposited in vital organs including the heart, liver and endocrine organs such as the pituitary glands which can affect growth hormone production. Growth hormone deficiency is one of the factors that can lead to short stature, a common complication in people with thalassaemia. Growth hormone replacement therapy has been used in children with thalassaemia who have short stature and growth hormone deficiency.
OBJECTIVES: To assess the benefits and safety of growth hormone therapy in people with thalassaemia.
SEARCH METHODS: We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles, reviews and clinical trial registries. Our database and trial registry searches are current to 10 August 2017 and 08 August 2017, respectively.
SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing the use of growth hormone therapy to placebo or standard care in people with thalassaemia of any type or severity.
DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion. Data extraction and assessment of risk of bias were also conducted independently by two authors. The quality of the evidence was assessed using GRADE criteria.
MAIN RESULTS: One parallel trial conducted in Turkey was included. The trial recruited 20 children with homozygous beta thalassaemia who had short stature; 10 children received growth hormone therapy administered subcutaneously on a daily basis at a dose of 0.7 IU/kg per week and 10 children received standard care. The overall risk of bias in this trial was low except for the selection criteria and attrition bias which were unclear. The quality of the evidence for all major outcomes was moderate, the main concern was imprecision of the estimates due to the small sample size leading to wide confidence intervals. Final height (cm) (the review's pre-specified primary outcome) and change in height were not assessed in the included trial. The trial reported no clear difference between groups in height standard deviation (SD) score after one year, mean difference (MD) -0.09 (95% confidence interval (CI) -0.33 to 0.15 (moderate quality evidence). However, modest improvements appeared to be observed in the following key outcomes in children receiving growth hormone therapy compared to control (moderate quality evidence): change between baseline and final visit in height SD score, MD 0.26 (95% CI 0.13 to 0.39); height velocity, MD 2.28 cm/year (95% CI 1.76 to 2.80); height velocity SD score, MD 3.31 (95% CI 2.43 to 4.19); and change in height velocity SD score between baseline and final visit, MD 3.41 (95% CI 2.45 to 4.37). No adverse effects of treatment were reported in either group; however, while there was no clear difference between groups in the oral glucose tolerance test at one year, fasting blood glucose was significantly higher in the growth hormone therapy group compared to control, although both results were still within the normal range, MD 6.67 mg/dL (95% CI 2.66 to 10.68). There were no data beyond the one-year trial period.
AUTHORS' CONCLUSIONS: A small single trial contributed evidence of moderate quality that the use of growth hormone for a year may improve height velocity of children with thalassaemia although height SD score in the treatment group was similar to the control group. There are no randomised controlled trials in adults or trials that address the use of growth hormone therapy over a longer period and assess its effect on final height and quality of life. The optimal dosage of growth hormone and the ideal time to start this therapy remain uncertain. Large well-designed randomised controlled trials over a longer period with sufficient duration of follow up are needed.

Matched MeSH terms: beta-Thalassemia/complications*
Fulltext The spectrum of beta-globin gene mutations in children with beta-thalassaemia major from Kota Kinabalu, Sabah, Malaysia

Thong MK, Soo TL

Singapore Med J, 2005 Jul;46(7):340-3.
PMID: 15968446

Beta-thalassaemia major is one of the commonest genetic disorders in South East Asia. The strategy for the community control of beta-thalassaemia major requires the characterisation of the spectrum of beta-globin gene mutations in any multi-ethnic population. There is only a single report of mutation analyses of the beta-globin gene in an isolated Kadazandusun community in Kota Belud, Sabah, Malaysia, which showed the presence of a common 45 kb deletion.

Matched MeSH terms: beta-Thalassemia/ethnology*; beta-Thalassemia/genetics*
Fulltext Detection of beta-globin gene mutations among Kelantan Malay thalassaemia patients by polymerase chain reaction restriction fragment length polymorphism

Rozitah R, Nizam MZ, Nur Shafawati AR, Nor Atifah MA, Dewi M, Kannan TP, et al.

Singapore Med J, 2008 Dec;49(12):1046-9.
PMID: 19122960

Beta-thalassaemia major is an autosomal recessive disorder that results in severe microcytic, hypochromic, haemolytic anaemia among affected patients. Beta-thalassaemia has emerged as one of the most common public health problems in Malaysia, particularly among Malaysian Chinese and Malays. This study aimed to observe the spectrum of mutations found in Kelantan Malay beta-thalassaemia major patients who attended the Paediatrics Daycare Unit, Hospital Universiti Sains Malaysia, Kelantan, Malaysia, the data of which was being used in establishing the prenatal diagnosis in this Human Genome Centre.

Matched MeSH terms: beta-Thalassemia/ethnology; beta-Thalassemia/genetics*
Fulltext Serum ferritin concentrations in transfusion dependent beta-thalassaemia

George E, Wong HB, George R, Ariffin WA

Singapore Med J, 1994 Feb;35(1):62-4.
PMID: 8009283

Patients on a moderate red cell transfusion programme have iron overload where the concentrations of the serum ferritin were inappropriate to increases in the transfusion load as a result of limitations of apoferritin synthesis and conversion of ferritin into haemosiderin. This study confirms the limitations for the use of estimations of the serum ferritin to evaluate the iron status in patients with expected high overload as would be seen in patients on many years of maintenance red cell transfusions in the absence of iron chelation therapy. Poor compliance, inadequate dosage of Desferal (deferoxamine), and the late initiation of iron chelation therapy were factors that were considered in the patients with failure of response to iron chelation.

Matched MeSH terms: beta-Thalassemia/blood*; beta-Thalassemia/genetics; beta-Thalassemia/surgery
Fulltext Hb E beta +-thalassaemia in west Malaysia: clinical features in the most common beta-thalassaemia mutation of the Malays [IVS 1-5 (G-->C)]

George E, Wong HB

Singapore Med J, 1993 Dec;34(6):500-3.
PMID: 8153710

Patients with the Hb beta + [IVS 1-5 (G-->C)] clinically presented as beta-thalassaemia intermedia and remained asymptomatic in the absence of blood transfusions. With or without blood transfusions the patients were short and had moderate to marked thalassaemia facies. Children who received blood transfusions showed progressive iron loading with age. The serum ferritin and serum alanine transaminase levels were significantly raised in the patients who were given blood transfusions. In the presence of blood transfusions, and absence of adequate iron chelation therapy, splenectomy became an inevitable event at some stage of the disease because of increasing transfusing requirements.

Matched MeSH terms: beta-Thalassemia/blood; beta-Thalassemia/drug therapy; beta-Thalassemia/genetics*; beta-Thalassemia/surgery; beta-Thalassemia/therapy*
Fulltext A prospective study on the use of leucocyte-filters in reducing blood transfusion reactions in multi-transfused thalassemic children

Tan KK, Lee WS, Liaw LC, Oh A

Singapore Med J, 1993 Apr;34(2):109-11.
PMID: 8266145

Two hundred and eleven blood transfusions were administered to 26 multi-transfused thalassemic children (aged 9 months-13 years) over a 6-month period. Eighteen children were receiving buffy coat-poor packed red cells (PRC) prepared by centrifuge while 8 children received filtered blood through a leucocyte-filter (Sepacell R-500A). Transfusion reactions occurred in 8.5% (n = 18) of transfusions and in 42.3% (n = 11) of patients. 11.9% (n = 16) and 2.6% (n = 2) of reactions occurred in 50% (n = 9) and 25% (n = 2) of patients receiving buffy coat-poor PRC and filtered blood respectively. Transfusion reactions in toto were significantly reduced in the group receiving filtered blood (p < 0.05). However, febrile reaction alone was not significantly reduced (p > 0.1). The median onset and duration of reaction were 2 hours (range 10 minutes-18 hours) and 4 hours (range 1/2-24 hours) respectively. 72.2% (n = 13) of the reactions occurred occurred during transfusion. 88.8% (n = 16) of the reactions caused only one symptom. 19.2% (n = 5) of all patients had recurrent reactions, all of them receiving buffy coat-poor PRC. The commonest clinical manifestation was fever (n = 7), followed by urticaria (n = 5) and petechial rash (n = 2). The outcome was good, with no patient experiencing symptoms exceeding 24 hours. Only 0.9% (n = 2) of the transfusions were discontinued.

Matched MeSH terms: beta-Thalassemia/therapy*
Fulltext High throughput molecular confirmation of β-thalassemia mutations using novel TaqMan probes

Kho SL, Chua KH, George E, Tan JA

Sensors (Basel), 2013;13(2):2506-14.
PMID: 23429513 DOI: 10.3390/s130202506

β-Thalassemia is a public health problem where 4.5% of Malaysians are β-thalassemia carriers. The genetic disorder is caused by defects in the β-globin gene complex which lead to reduced or complete absence of β-globin chain synthesis. Five TaqMan genotyping assays were designed and developed to detect the common β-thalassemia mutations in Malaysian Malays. The assays were evaluated with 219 "blinded" DNA samples and the results showed 100% sensitivity and specificity. The in-house designed TaqMan genotyping assays were found to be cost- and time-effective for characterization of β-thalassemia mutations in the Malaysian population.

Matched MeSH terms: beta-Thalassemia/genetics*
Fulltext A novel gap-PCR with high resolution melting analysis for the detection of α-thalassaemia Southeast Asian and Filipino β°-thalassaemia deletion

Kho SL, Chua KH, George E, Tan JA

Sci Rep, 2015;5:13937.
PMID: 26365497 DOI: 10.1038/srep13937

Homozygosity for the α-thalassaemia Southeast Asian (α-SEA) and Filipino β°-thalassaemia (β-FIL) deletions can cause serious complications leading to foetal death or life-long blood transfusions. A rapid and accurate molecular detection assay is essential in populations where the deletions are common. In this study, gap-polymerase chain reaction (PCR) with high resolution melting (HRM) analysis was developed to detect both the large deletions. Melting curves at 86.9 ± 0.1 °C were generated by normal individuals without the α-SEA deletion, 84.7 ± 0.1 °C by homozygous α-SEA deletion individuals and two melting curves at 84.7 ± 0.1 °C and 86.9 ± 0.1 °C by α-SEA deletion carriers. Normal individuals without the β-FIL deletion produce amplicons with a melting temperature (Tm) at 74.6 ± 0.1 °C, homozygous β-FIL individuals produce amplicons with Tm at 73.6 ± 0.1 °C and heterozygous β-FIL individuals generate two amplicons with Tm at 73.6 ± 0.1 °C and 74.6 ± 0.1 °C. Evaluation using blinded tests on 220 DNA samples showed 100% sensitivity and specificity. The developed assays are sensitive and specific for rapid molecular and prenatal diagnosis for the α-SEA and β-FIL deletions.

Matched MeSH terms: beta-Thalassemia
Fulltext Predictive SNPs for β0-thalassemia/HbE disease severity

Munkongdee T, Tongsima S, Ngamphiw C, Wangkumhang P, Peerapittayamongkol C, Hashim HB, et al.

Sci Rep, 2021 05 14;11(1):10352.
PMID: 33990643 DOI: 10.1038/s41598-021-89641-2

β-Thalassemia/HbE disease has a wide spectrum of clinical phenotypes ranging from asymptomatic to dependent on regular blood transfusions. Ability to predict disease severity is helpful for clinical management and treatment decision making. A thalassemia severity score has been developed from Mediterranean β-thalassemia patients. However, different ethnic groups may have different allele frequency and linkage disequilibrium structures. Here, Thai β0-thalassemia/HbE disease genome-wild association studies (GWAS) data of 487 patients were analyzed by SNP interaction prioritization algorithm, interacting Loci (iLoci), to find predictive SNPs for disease severity. Three SNPs from two SNP interaction pairs associated with disease severity were identifies. The three-SNP disease severity risk score composed of rs766432 in BCL11A, rs9399137 in HBS1L-MYB and rs72872548 in HBE1 showed more than 85% specificity and 75% accuracy. The three-SNP predictive score was then validated in two independent cohorts of Thai and Malaysian β0-thalassemia/HbE patients with comparable specificity and accuracy. The SNP risk score could be used for prediction of clinical severity for Southeast Asia β0-thalassemia/HbE population.

Matched MeSH terms: beta-Thalassemia/blood; beta-Thalassemia/diagnosis*; beta-Thalassemia/genetics
[Simple and rapid analysis of beta-thalassemia mutation by sequence-specific amplification]

Harano K, Harano T

Rinsho Byori, 2013 Mar;61(3):217-23.
PMID: 23785790

This study was done to detect and diagnose beta-thalassemia (beta-Thal) gene quickly. We applied sequence specific Amplification (SSA) method to the analysis. 13 kinds of beta-Thal and two kinds of hemoglobin variants were able to detect under the same PCR condition. These mutations were found frequently in ten countries of Asian region (the southern part of China, Vietnam, Cambodia, Thailand, Myanmar, Malaysia, Singapore, Indonesia, Pakistan, India), and 15 kinds in total (-28CapA-->G, CD5-CT, CD8/9+-G, CD15G-->A, CD17A-->T, IVSI-1G-->T, CD41/42-4del, CD16-C, CD26G-->A(betaE), IVSI-5G-->C, CD35C-->A, CD71/72 +A, CD6A-->T (betaS), -619del, IVSII-654C-->T). More than 80% of patients are included in these mutations. To make the reagents a kit, the procedure became simple and rapid. DNA was extracted by salting out method. The PCR product was detected by polyacrylamide gel electrophoresis and silver staining. The confirmation of the variant was done by the PCR-direct sequencing method. It took approximately six hours for PCR reaction, electrophoresis and staining. This method made us to detect and diagnose beta-Thal in one day.

Matched MeSH terms: beta-Thalassemia/diagnosis*; beta-Thalassemia/genetics
[Case of deletion type beta(0)-thalassemia found in an Asian (Malaysian) family living in Japan]

Harano K, Harano T

Rinsho Byori, 2010 Apr;58(4):325-31.
PMID: 20496759

Hb and gene analyses of a Malaysian mother and her two daughters with microcytic anemia living in Japan were performed. Hb analyses of their hemolysates by IEF and DEAE-HPLC revealed high values of Hb A2 and HbF, but abnormal Hbs such as Hb E and Hb Constant Spring, which cause beta- and alpha-thalassemia traits, were not detected. From these data, they were suspected to be beta-thalassemia carriers. The thalassemic mutations commonly found in the Asian area by ARMS and nucleotide sequencing methods were not detected, and the frameworks of the beta-globin gene and the haplotypes of the beta-like globin gene cluster between the mother and daughters were not identical. These results led us to conclude that there was a beta(0)-thalassemia mutation with a large deletion from the beta-globin gene beyond the 3'beta/BamHI polymorphic site 3' downstream to the beta-globin gene. However, the range of the deletion from the beta-like globin gene cluster has not yet been completed in detail. Recently, there have been many foreigners mainly from Asian countries in Japan. We may encounter people with the rare type thalassemic mutation described in the text besides the mutations frequently found in Asian countries.

Matched MeSH terms: beta-Thalassemia/genetics*
Counseling for prenatal diagnosis and termination of pregnancy due to thalassemia major: a survey of health care workers' practices in Malaysia

Ngim CF, Lai NM, Ibrahim H

Prenat Diagn, 2013 Dec;33(13):1226-32.
PMID: 24014379 DOI: 10.1002/pd.4233

OBJECTIVE: Genetic counseling for thalassemia carriers is conducted by nongeneticist health care workers (HCWs) in many countries. The aim of the study was to assess Malaysian HCWs' genetic counseling practices with regards to discussing prenatal diagnosis (PND) and termination of pregnancy (TOP) when counseling thalassemia carriers.
METHOD: A total of 118 Malaysian HCWs (52 doctors and 66 nurses) completed a structured questionnaire that enquired if they would discuss PND and TOP when counseling couples with thalassemia traits, and reasons for their responses were explored.
RESULTS: All the nurses and 50 (96.1%) doctors were in favor of discussing PND. Only 29 (58%) doctors and 33 (50%) nurses were agreeable to discuss about the option of TOP. Main reasons given for declining to discuss TOP were views that "the condition was not serious enough" (54.9%), TOP is not permissible by their religion (17.6%) and abortion for this indication was illegal (13.7%).
CONCLUSION: The results showed that HCWs in Malaysia lacked the comprehensive information and necessary skills required when counseling thalassemia carriers. When nongeneticist HCWs are tasked with such responsibilities, their practices and attitudes should be regularly evaluated so that areas of deficiencies could be identified and addressed.

Matched MeSH terms: beta-Thalassemia/diagnosis*; beta-Thalassemia/genetics; beta-Thalassemia/psychology
Fulltext Homozygous deletion of six olfactory receptor genes in a subset of individuals with Beta-thalassemia

Van Ziffle J, Yang W, Chehab FF

PLoS One, 2011;6(2):e17327.
PMID: 21390308 DOI: 10.1371/journal.pone.0017327

Progress in the functional studies of human olfactory receptors has been largely hampered by the lack of a reliable experimental model system. Although transgenic approaches in mice could characterize the function of individual olfactory receptors, the presence of over 300 functional genes in the human genome becomes a daunting task. Thus, the characterization of individuals with a genetic susceptibility to altered olfaction coupled with the absence of particular olfactory receptor genes will allow phenotype/genotype correlations and vindicate the function of specific olfactory receptors with their cognate ligands. We characterized a 118 kb β-globin deletion and found that its 3' end breakpoint extends to the neighboring olfactory receptor region downstream of the β-globin gene cluster. This deletion encompasses six contiguous olfactory receptor genes (OR51V1, OR52Z1, OR51A1P, OR52A1, OR52A5, and OR52A4) all of which are expressed in the brain. Topology analysis of the encoded proteins from these olfactory receptor genes revealed that OR52Z1, OR52A1, OR52A5, and OR52A4 are predicted to be functional receptors as they display integral characteristics of G-proteins coupled receptors. Individuals homozygous for the 118 kb β-globin deletion are afflicted with β-thalassemia due to a homozygous deletion of the β-globin gene and have no alleles for the above mentioned olfactory receptors genes. This is the first example of a homozygous deletion of olfactory receptor genes in human. Although altered olfaction remains to be ascertained in these individuals, such a study can be carried out in β-thalassemia patients from Malaysia, Indonesia and the Philippines where this mutation is common. Furthermore, OR52A1 contains a γ-globin enhancer, which was previously shown to confer continuous expression of the fetal γ-globin genes. Thus, the hypothesis that β-thalassemia individuals, who are homozygous for the 118 kb deletion, may also have an exacerbation of their anemia due to the deletion of two copies of the γ-globin enhancer element is worthy of consideration.

Matched MeSH terms: beta-Thalassemia/classification; beta-Thalassemia/genetics*; beta-Thalassemia/metabolism
HbA2 levels in β-thalassaemia carriers with the Filipino β0-deletion: are the levels higher than what is found with non-deletional forms of β0-thalassaemia?

George E, Teh LK, Tan J, Lai MI, Wong L

Pathology, 2013 01;45(1):62-5.
PMID: 23222244 DOI: 10.1097/PAT.0b013e32835af7c1

AIMS: Classical carriers of β-thalassaemia are identified by a raised HbA2 level. Earlier studies indicated that the Filipino β-deletion has high raised HbA2 levels. The introduction of automated high performance liquid chromatography (HPLC) for thalassaemia screening is an important advance in technology for haematology laboratories. The BioRad Variant II Hb analyser is a common instrument used to quantify HbA2 levels in thalassaemia screening. This study aimed to determine HbA2 levels in carriers of Filipino β-mutation using the BioRad Variant II Hb analyser.
METHODS: The Filipino β-deletion was identified using gap-polymerase chain reaction (PCR) in the parents of transfusion dependent β-thalassaemia patients who were homozygous for the Filipino β-deletion in the indigenous population of Sabah, Malaysia. Hb subtypes were quantified on the BioRad Variant II Hb analyser. Concurrent α-thalassaemia was identified by multiplex gap-PCR for deletions and amplification refractory mutation system (ARMS)-PCR for non-deletional mutations.
RESULTS: The mean HbA2 level for Filipino β-thalassaemia trait was 5.9 ± 0.47 and with coinheritance of α-thalassaemia was 6.3 ± 0.44 (-α heterozygous) and 6.7 ± 0.36 (-α homozygous). The HbA2 levels were all >4% in keeping with the findings of classical β-thalassaemia trait and significantly higher than levels seen in non-deletional forms of β-thalassaemia.
CONCLUSION: The HbA2 level measured on the BioRad Variant II Hb analyser was lower than the level in the first description of the Filipino β-thalassaemia. β-thalassaemia trait with coinheritance of α-thalassaemia (-α) is associated with significantly higher HbA2 level.

Matched MeSH terms: beta-Thalassemia/blood*; beta-Thalassemia/diagnosis; beta-Thalassemia/genetics
Characterisation and confirmation of rare beta-thalassaemia mutations in the Malay, Chinese and Indian ethnic groups in Malaysia

Tan JA, Chin PS, Wong YC, Tan KL, Chan LL, George E

Pathology, 2006 Oct;38(5):437-41.
PMID: 17008283

In Malaysia, about 4.5% of the Malay and Chinese populations are heterozygous carriers of beta-thalassaemia. The initial identification of rare beta-globin gene mutations by genomic sequencing will allow the development of simpler and cost-effective PCR-based techniques to complement the existing amplification refractory mutation system (ARMS) and gap-PCR used for the identification of beta-thalassaemia mutations.

Matched MeSH terms: beta-Thalassemia/ethnology*; beta-Thalassemia/genetics*; beta-Thalassemia/pathology
Fulltext Thalassaemia screening among healthy blood donors in Hospital Tengku Ampuan Rahimah, Klang

Irmi Elfina, R., Ezalia, E., Elizabeth, G., Wan Hayati, M.Y, Norhanim, A., Wahidah, A., et al.

Medicine & Health, 2014;9(1):44-52.
MyJurnal

Thalassaemia screening programme has been conducted in Malaysia since 2004. The aim of the programme was to reduce the burden of the disease by identifying thalassaemia carriers. However, the response towards the screening activities was unsatisfactory as there was lack of public awareness against the importance of thalassaemia screening. An alternative approach is to screen blood donors. The purpose of this study was to observe the prevalence of thalassaemia carriers among healthy blood donors. Seven hundred and thirty eight healthy blood donors were screened in Hospital Tengku Ampuan Rahimah, Klang from July to September 2010 using cation-exchange high performance liquid chromatography (HPLC). Cases with haemoglobin variants were further analyzed by gel electrophoresis at alkaline pH. Result shows that the blood donors consisted of 413 Malays (56%), 162 Indians (22%), 148 Chinese (20%) and 15 others (2%). There were 19 (2.6%) individuals with haemoglobin E trait, six (0.8%) with co-inheritance of haemoglobin E and αα- thalassaemia and five (0.7%) with β-thalassaemia trait. Haemoglobin Constant Spring and haemoglobin A2 prime were observed in two (0.3%); and Haemoglobin Lepore and alpha chain variant in one (0.2%). αα-thalassaemia and normal haemoglobin A2 β-thalassaemia could not be excluded in 190 cases (26%), as they required deoxyribonucleic acid (DNA) studies for identification. Thalassaemia screening in blood donors is more feasible and effective. Therefore, a wider scale population screening including blood donors could benefit the existing thalassaemia screening programme in Malaysia.

Matched MeSH terms: beta-Thalassemia
Fulltext Genotype-phenotype association of Hbe/β thalassemia disease and the role of genetic modifiers

HanafI S, Abdullah WZ, Adnan RA, Bahar R, Johan MF, Azman NF, et al.

Malaysian Journal of Paediatrics and Child Health, 2016;22(1):1-16.
MyJurnal

HbE/β-thalassemia is the most common severe form of thalassemia particularly in SEA region including Malaysia and globally, it comprised of a significant severe form of β-thalassemia disorder. It has various clinical manifestations ranging from very mild anemia to severe manifestation similar to beta thalassemia major. Many different syndromes are observed in HbE/β-thalassemia. Several genetic modifiers have been reported to play important role in contributing to phenotypic variability. The true reasons underlying this phenotypic variability remain unknown. The most reliable predictive factor of the disease phenotype is the nature of the beta globin gene mutation itself. However, the degree of severity is also believed to be affected by other genetic modifiers. For instance, high HbF level ameliorates the clinical severity of β thalassemia patients. Therefore, identification of these genetic modifiers is very important. The association of severe clinical manifestation and the specific β-globin gene mutation has been known. But the wide scope and other potential predictors have been only recently appreciated. This review therefore aimed to reveal the potential genetic modifiers of HbE/βthalassemia patients based on the previous reported studies. A better understanding on the mechanisms underlying the variety of phenotypes of this disease may lead to the direction for a better future management plans. This also promotes “personalized medicine” in patient care.

Matched MeSH terms: beta-Thalassemia*
Fulltext Melioidosis transfusion transmitted infection in beta thalassemia patient’s

Sahrol Nizam Bin Abu Bakar, Al-Afiq Alias, Masrah Tata

Malaysian Journal of Medicine and Health Sciences, 2019;15(106):100-100.
MyJurnal

Introduction:Transfusion Transmitted Infections is occurring worldwide. The common organisms related reported in literature were Human Immunodefiency Virus, Hepatitis B and C Virus, bacterial contamination and Malaria par-asites. Meanwhile, Melioidosis is endemic disease in Malaysia and especially Sabah. Mortality due to Melioidosis septicaemia was also high. It ranges between 60%-80%. In Sabah, 74% of Thalassemia children were diagnosed with Bacteraemia Melioidosis and 50% had died due to the organisms. The incidence of Melioidosis Transfusion Transmitted Infection is rarely reported in the literature. Case Description: A 17-year-old girl was diagnosed having Beta thalassemia major since 5 years old and splenectomised 8 years ago. Currently on prophylaxis Penicillin and Ex-jade. She was admitted into hospital for monthly blood transfusion. Two days prior to admission, patient complained of having sore throat and cough but no fever and other complained. On examination, the tonsil enlarged and was treated as exudative tonsillitis. She was transfused with 2 pint packed cells within 2 days. No transfusion reaction noted. Day seven admission, she had high grade fever and redness of the right hand cannulation site and was treated as right hand cellulitis with intravenous Cloxacillin. Full blood count shows Total White Cell count was 24.9 x109 /L, Haemoglobin level was 9.3 g/dl and Platelets was 462x109/L. Blood for culture and sensitivity was taken and Chest X-ray noted haziness over the left mid and lower zone of the lung and was treated as Hospital Acquired Pneumonia. She was referred to tertiary hospital for further management. Her conditioned deteriorated and died at the casualty unit in the tertiary hospital. Blood culture was positive for Burkholderia pseudomallei. The case was reported to Dis-trict health office for further investigation. Blood donor tracing was done and was positive for Melioidosis through Elisa Antibody titre IgM for Melioidosis (1:320). The patient’s house and school were visited and investigated. All environmental samples were negative for Burkholderia pseudomallei. Conclusion: Its shows a relationship between blood donations infected with Burkholderia pseudomallei causing mortality of Beta Thalassemia patients. It is highly recommended to screen all blood products for communicable disease fatal organisms.

Matched MeSH terms: beta-Thalassemia

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