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Molecular study and genotype/phenotype correlation of β Thalassemia in Malaysia

Sivalingam M, Looi ML, Zakaria SZ, Hamidah NH, Alias H, Latiff ZA, et al.

Int J Lab Hematol, 2012 Aug;34(4):377-82.
PMID: 22335963 DOI: 10.1111/j.1751-553X.2012.01405.x

INTRODUCTION: To study the ß-gene mutations spectrum, the genotype/phenotype correlation, the modulatory effect of co-inherited factors such as α-gene mutations and of Xmn1 polymorphism in a large cohort of Malaysian patients.
METHODS: A total of 264 cases clinically diagnosed as Thalassemia major (TM) (111), Thalassemia intermedia (21), HbE-β Thalassemia (131), and 1 HbE homozygous were studied. The detection of α and ß gene mutations and characterization of Xmn1 polymorphism were performed by multiplex PCR, amplification refractory mutation system (ARMS), DNA sequencing, and restriction fragment length polymorphism (RFLP)-PCR.
RESULTS: A total of 19 ß Thalassemia mutations were characterized. CD26 and CD41/42 were the most common found in the Malay and Chinese population, respectively. The sensitivity of the clinical diagnosis for β TM, thalassemia intermedia, and HbE/β thalassemia was 94.0%, 15.2%, and 89.2%, respectively. Patients with Xmn1 heterozygosity [+/-] required less frequent transfusion compared with those without the polymorphism. Co-inheritance of α-thalassemia alleviates the severity of HbE-β thalassemia in our cohort.
CONCLUSION: Molecular analysis should be used for a better diagnosis and management of β thalassemia.

Matched MeSH terms: beta-Thalassemia/genetics*
Molecular heterogeneity of beta-thalassaemia in Malaysia: a practical approach to diagnosis

Thong MK, Law HY, Ng IS

Ann Acad Med Singap, 1996 Jan;25(1):79-83.
PMID: 8779552

The beta-thalassaemia mutations in 20 Malaysian children with beta-thalassaemia major were characterised by using a multi-modal approach, consisting of a slot-blot hybridisation with selected allele-specific oligonucleotides (ASO), followed by reverse dot-blot assay (RDB), amplification refractory mutation system (ARMS) and genomic sequencing. This strategy yielded a 94.4% mutation detection rate. The 6 most common mutations were codons 41/42 (-TTCT), IVS II nt 654(C --> T), IVS I nt 5(G --> C), IVS I nt 1(G -->T), codon 35 (-C) and codon 19 (A --> G), which accounted for 83.3% of all mutations detected. A strategy of initial screening with the above 6 selected ASOs for slot-blot hybridisation followed by RDB assay for the less common Asian mutations would give a mutation identification of 91.7%. Another feasible approach would be to analyse alleles from a particular racial group, by a judicious selection of 4 ASOs common to that particular subpopulation and then supplement this with RDB assay. This could yield a 100% coverage for the Chinese subpopulation in Malaysia. With these strategies, a practical approach has been identified to overcome the pitfalls posed by the molecular heterogeneity of beta-thalassaemia to enable prenatal diagnosis and carrier screening to be carried out. Regional collaborative studies are to be encouraged as an indispensable tool in providing better health care services to our patients.

Matched MeSH terms: beta-Thalassemia/diagnosis; beta-Thalassemia/ethnology; beta-Thalassemia/genetics*
Molecular defects in the beta-globin gene identified in different ethnic groups/populations during prenatal diagnosis for beta-thalassemia: a Malaysian experience

Tan JA, George E, Tan KL, Chow T, Tan PC, Hassan J, et al.

Clin Exp Med, 2004 Dec;4(3):142-7.
PMID: 15599663 DOI: 10.1007/s10238-004-0048-x

Beta-thalassemia is the most-common genetic disorder of hemoglobin synthesis in Malaysia, and about 4.5% of the population are heterozygous carriers of the disorder. Prenatal diagnosis was performed for 96 couples using the Amplification Refractory Mutation System and Gap-Polymerase Chain Reaction. We identified 17 beta-globin defects-initiation codon for translation (T-G), -29 (A-G), -28 (A-G), CAP +1 (A-C), CD 8/9 (+G), CD 15 (G-A), CD 17 (A-T), CD 19 (A-G), Hb E (G-A), IVS1-1 (G-T), IVS1-5 (G-C), CD 41/42 (-CTTT), CD 71-72 (+A), IVS2-654 (CT), poly A(A-G), 100-kb Ggamma(Agammadeltabeta) degrees and 45-kb Filipino deletions. The 192 beta-alleles studied comprised Chinese (151 patients), Malay (21), Orang Asli from East Malaysia (15), Filipino (1), Indian (1), Indonesian Chinese (2), and Thai (1). In the Chinese, 2 beta-globin defects at CD 41/42 and IVS2-654 were responsible for 74% of beta-thalassemia. beta-mutations at CD 19, IVS1-1 (G-T), IVS1-5, poly A, and hemoglobin E caused 76% of the hemoglobin disorders in the Malays. The Filipino 45-kb deletion caused 73.3% of bthalassemia in the Orang Asli. Using genomic sequencing, the rare Chinese beta-mutation at CD 43 (G-T) was confirmed in 2 Chinese, and the Mediterranean mutation IVS1-1 (G-A) was observed in a Malay beta-thalassemia carrier. The beta-globin mutations confirmed in this prenatal diagnosis study were heterogenous and 65 (68%) couples showed a different globin defect from each other. The use of specific molecular protocols has allowed rapid and successful prenatal diagnosis of beta-thalassemia in Malaysia.

Matched MeSH terms: beta-Thalassemia/diagnosis*; beta-Thalassemia/genetics*; beta-Thalassemia/epidemiology
Fulltext Molecular characterization of α- and β-thalassaemia among Malay patients

Yatim NF, Rahim MA, Menon K, Al-Hassan FM, Ahmad R, Manocha AB, et al.

Int J Mol Sci, 2014 May 19;15(5):8835-45.
PMID: 24857915 DOI: 10.3390/ijms15058835

Both α- and β-thalassaemia syndromes are public health problems in the multi-ethnic population of Malaysia. To molecularly characterise the α- and β-thalassaemia deletions and mutations among Malays from Penang, Gap-PCR and multiplexed amplification refractory mutation systems were used to study 13 α-thalassaemia determinants and 20 β-thalassaemia mutations in 28 and 40 unrelated Malays, respectively. Four α-thalassaemia deletions and mutations were demonstrated. --SEA deletion and αCSα accounted for more than 70% of the α-thalassaemia alleles. Out of the 20 β-thalassaemia alleles studied, nine different β-thalassaemia mutations were identified of which βE accounted for more than 40%. We concluded that the highest prevalence of (α- and β-thalassaemia alleles in the Malays from Penang are --SEA deletion and βE mutation, respectively.

Matched MeSH terms: beta-Thalassemia/genetics*; beta-Thalassemia/pathology
Fulltext Molecular characterisation and frequency of Ggamma Xmn I polymorphism in Chinese and Malay beta-thalassaemia patients in Malaysia

Wong YC, George E, Tan KL, Yap SF, Chan LL, Tan JA

Malays J Pathol, 2006 Jun;28(1):17-21.
PMID: 17694955

The molecular basis of variable phenotypes in P-thalassaemia patients with identical genotypes has been associated with co-inheritance of alpha-thalassaemia and persistence of HbF production in adult life. The Xmn I restriction site at -158 position of the Ggamma-gene is associated with increased expression of the Ggamma-globin gene and higher production of HbF This study aims to determine the frequency of the digammaferent genotypes of the Ggamma Xmn I polymorphism in P-thalassaemia patients in two ethnic groups in Malaysia. Molecular characterisation and frequency of the Ggamma Xmn I polymorphism were studied in fifty-eight Chinese and forty-nine beta-thalassaemia Malay patients by Xmn I digestion after DNA amplification of a 650 bp sequence. The in-house developed technique did not require further purification or concentration of amplified DNA before restriction enzyme digestion. The cheaper Seakem LE agarose was used instead of Nusieve agarose and distinct well separated bands were observed. Genotyping showed that the most frequent genotype observed in the Malaysian Chinese was homozygosity for the absence of the Xmn I site (-/-) (89.7%). In the Malays, heterozygosity of the Xmn I site (+/-) was most common (63.3%). Homozygosity for the Xmn I site (+/+) was absent in the Chinese, but was confirmed in 8.2% of the Malays. The ratio of the (+) allele (presence of the Xmn I site) to the (-) allele (absence of the Xmn I site)) was higher in the Malays (0.66) compared to the Chinese (0.05). The (+/-) and (+/+) genotypes are more commonly observed in the Malays than the Chinese in Malaysia.

Matched MeSH terms: beta-Thalassemia/genetics*
Molecular basis of transfusion dependent beta-thalassemia major patients in Sabah

Teh LK, George E, Lai MI, Tan JA, Wong L, Ismail P

J Hum Genet, 2014 Mar;59(3):119-23.
PMID: 24369358 DOI: 10.1038/jhg.2013.131

Beta-thalassemia is one of the most prevalent inherited diseases and a public health problem in Malaysia. Malaysia is geographically divided into West and East Malaysia. In Sabah, a state in East Malaysia, there are over 1000 estimated cases of β-thalassemia major patients. Accurate population frequency data of the molecular basis of β-thalassemia major are needed for planning its control in the high-risk population of Sabah. Characterization of β-globin gene defects was done in 252 transfusion dependent β-thalassemia patients incorporating few PCR techniques. The study demonstrates that β-thalassemia mutations inherited are ethnically dependent. It is important to note that 86.9% of transfusion-dependent β-thalassemia major patients in Sabah were of the indigenous population and homozygous for a single mutation. The Filipino β(0)-deletion was a unique mutation found in the indigenous population of Sabah. Mutations common in West Malaysia were found in 11 (4.3%) patients. Four rare mutations (Hb Monroe, CD 8/9, CD 123/124/125 and IVS I-2) were also found. This study is informative on the population genetics of β-thalassemia major in Sabah.

Matched MeSH terms: beta-Thalassemia/genetics*; beta-Thalassemia/therapy*
Molecular basis of beta-thalassemia in the Maldives

Furuumi H, Firdous N, Inoue T, Ohta H, Winichagoon P, Fucharoen S, et al.

Hemoglobin, 1998 Mar;22(2):141-51.
PMID: 9576331

We have systematically analyzed beta-thalassemia genes using polymerase chain reaction-related techniques, dot-blot hybridization with oligonucleotide probes, allele specific-polymerase chain reaction, and sequencing of amplified DNA fragments from 41 unrelated patients, including 37 beta-thalassemia homozygotes, three with beta-thalassemia/Hb E, and one with beta-thalassemia/Hb S. Four different beta-thalassemia mutations were detected in 78 alleles. These are the IVS-I-5 (G-->C), codon 30 (AGG-->ACG) [also indicated as IVS-I (-1)], IVS-I-1 (G-->A), and codons 41/42 (-TTCT) mutations. The distribution of the beta-thalassemia mutations in the Maldives is 58 alleles (74.3%) with the IVS-I-5 (G-->C) mutation, 12 (15.4%) with the codon 30 (AGG-->ACG) mutation, seven (9%) with the IVS-I-1 (G-->A) mutation, and one with the codons 41/42 (-TTCT) mutation. The first three mutations account for 98.7% of the total number of beta-thalassemia chromosomes studied. These mutations are clustered in the region spanning 6 bp around the junction of exon 1 and the first intervening sequence of the beta-globin gene. These observations have significant implications for setting up a thalassemia prevention and control program in the Maldives. Analysis of haplotypes and frameworks of chromosomes bearing each beta-thalassemia mutation suggested that the origin and spread of these mutations were reflected by the historical record.

Matched MeSH terms: beta-Thalassemia/complications; beta-Thalassemia/ethnology; beta-Thalassemia/genetics*; beta-Thalassemia/epidemiology
Molecular basis of beta thalassemia in the south of Thailand

Laosombat V, Fucharoen SP, Panich V, Fucharoen G, Wongchanchailert M, Sriroongrueng W, et al.

Am J Hematol, 1992 Nov;41(3):194-8.
PMID: 1415194

A total of 103 beta thalassemia genes from 78 children (45 with Hb E/beta thalassemia, 8 with beta thalassemia heterozygotes, and 25 with homozygous beta thalassemia) were analyzed using dot-blot hybridization of the polymerase chain reaction-amplified DNA and direct DNA sequencing. Nine mutations were characterized in 98/103 (95%) of beta thalassemia alleles, of which six (a 4 bp deletion in codons 41-42, a G-C transition at position 5 of IVS-1, A-G transition at codon 19, an A-T transition at codon 17, an A-G transition at position -28 upstream of the beta globin gene, a G-T transition at position 1 of IVS-1), accounted for 92%. The spectrum of beta thalassemia mutations in Chinese Thai is similar to that reported among the Chinese from other parts of the world. The distribution of beta thalassemia mutations in Muslim Thai is similar to that reported among Malaysians. The most common beta thalassemia mutation in Thai and Chinese Thai patients is the frameshift mutation at codons 41-42, in comparison with the Muslim Thai in whom the G-C transition at position 5 of the IVS-1 mutation predominates. The heterogeneity of molecular defects causing beta thalassemia should aid in the planning of a prenatal diagnosis program for beta thalassemia in the South of Thailand.

Matched MeSH terms: beta-Thalassemia/diagnosis; beta-Thalassemia/genetics*; beta-Thalassemia/epidemiology*
Molecular Characterisation of α- and β-Thalassaemia among Indigenous Senoi Orang Asli Communities in Peninsular Malaysia

Koh DXR, Raja Sabudin RZA, Mohd Yusoff M, Hussin NH, Ahmad R, Othman A, et al.

Ann. Hum. Genet., 2017 Sep;81(5):205-212.
PMID: 28620953 DOI: 10.1111/ahg.12201

Thalassaemia is a public health problem in Malaysia, with each ethnic group having their own common mutations. However, there is a lack on data on the prevalence and common mutations among the indigenous people. This cross-sectional study was performed to determine the common mutations of α- and β-thalassaemia among the subethnic groups of Senoi, the largest Orang Asli group in Peninsular Malaysia. Blood samples collected from six Senoi subethnic groups were analysed for full blood count and haemoglobin analysis (HbAn). Samples with abnormal findings were then screened for α- and β-globin gene mutations. Out of the 752 samples collected, 255 showed abnormal HbAn results, and 122 cases showing abnormal red cell indices with normal HbAn findings were subjected to molecular screening. DNA analysis revealed a mixture of α- and β-globin gene mutations with 25 concomitant cases. The types of gene abnormalities detected for α-thalassaemia were termination codon (T>C) Hb CS (αCS α), Cd59 (G>A) haemoglobin Adana (Hb Adana) (αCd59 α), initiation codon (ATG>A-G) (αIniCd α), two-gene deletion (-SEA ), and single-gene 3.7-kb deletion (-α3.7 ). For β-thalassaemia, there were Cd26 (G>A) Hb E (βE ), Cd19 (A>G) Haemoglobin Malay (Hb Malay) (βCd19 ), and IVS 1-5 (G>C) (βIVS 1-5 ).

Matched MeSH terms: beta-Thalassemia/genetics*; beta-Thalassemia/epidemiology
Mild beta-thalassemia intermedia caused by compound heterozygosity for (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia and molecular characterization of the defect in four Chinese families

Tan JAMA, Yap SF, Tan KL, Wong YC, Wee YC, Kok JL

Acta Haematol., 2003;109(4):169-75.
PMID: 12853688 DOI: 10.1159/000070965

Molecular characterization of the compound heterozygous condition - (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia - in four families showing mild beta-thalassemia intermedia was carried out using DNA amplification techniques. Using the Amplification Refractory Mutation System (ARMS) to confirm the beta-mutations and DNA amplification to detect the 100-kb Chinese-specific (G)gamma((A)gammadeltabeta)(o)-deletion, ()two families were confirmed to possess (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia with the IVSII No. 654 beta(+)-allele. In the third family, the (G)gamma((A)gammadeltabeta)(o)-deletion was confirmed in the father and the mother was a beta-thalassemia carrier with the cd 41-42 beta(o)-allele. Their affected child with (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia was found to be transfusion dependent. The same (G)gamma((A)gammadeltabeta)(o)-deletion and beta-thalassemia (cd 41-42) was also confirmed in a fourth family. In addition, the mother was also diagnosed with Hb H disease (genotype -alpha(3.7)/-(SEA)). Both the children were found to possess (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia but they were not transfusion dependent and this could be due to co-inheritance of alpha-thalassemia-2 (genotype-alpha(3.7)/alphaalpha) in the children together with their compound heterozygous condition.

Matched MeSH terms: beta-Thalassemia/genetics*; beta-Thalassemia/therapy
Microcytic to hypochromic ratio as a discriminant index of thalassaemia trait in subjects with hypochromic anaemia

Wee SY, Muhamed Said SS, Raja Sabudin RZA, Alauddin H, Ithnin A

Malays J Pathol, 2020 Aug;42(2):195-201.
PMID: 32860371

INTRODUCTION: Differentiating between thalassaemia and iron deficiency anaemia (IDA) in hypochromic anaemia is a challenge to pathologists as it influences the choice of subsequent specialized confirmatory tests. In this study, we aimed to evaluate the performance of microcytic to hypochromic ratio (MicroR/ Hypo-He, M/H ratio) as a discriminant index in hypochromic anaemia.
MATERIALS AND METHODS: A retrospective study was carried out on 318 subjects with hypochromic anaemia, which comprised 162 IDA and 156 thalassaemia trait subjects with α-thalassemia, β-thalassemia and HbE trait. Optimal cut-off value, sensitivity and specificity of M/H ratio for thalassaemia trait discrimination was determined using Receiver Operating Characteristic (ROC) analysis.
RESULTS: Subjects with thalassaemia trait showed higher MicroR compared to IDA ( p< 0.001) while subjects with IDA demonstrated higher Hypo-He than thalassaemia trait (p < 0.001). M/H ratio was significantly higher in thalassaemia trait compared to IDA, with medians of 3.77 (interquartile range: 2.57 - 6.52) and 1.73 (interquartile range: 1.27 - 2.38), respectively (p < 0.001). M/H ratio ≥ 2.25 was the optimal cut-off value for discriminating thalassaemia trait from IDA in hypochromic anaemia, with the area under ROC curve (AUC) of 0.83, sensitivity of 80.8% and specificity of 71.6%.
CONCLUSIONS: M/H ratio is a useful discriminant index to distinguish thalassaemia trait from IDA in hypochromic anaemia prior to diagnostic analysis for thalassaemia confirmation. High M/H ratio is suggestive of thalassaemia trait than of IDA. However, more studies are required to establish the role of M/H ratio as a screening tool for thalassaemia discrimination in hypochromic anaemia.

Matched MeSH terms: beta-Thalassemia/diagnosis; beta-Thalassemia/pathology
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
Fulltext Melioidosis in a splenectomized boy with beta-thalassemia major

Hoe TS, Deng CT, Khuzaiah R

Southeast Asian J. Trop. Med. Public Health, 1993 Sep;24(3):601-2.
PMID: 8160075
Matched MeSH terms: beta-Thalassemia/complications*
Fulltext Mapping of the beta-thalassaemia carrier in Sabah: an initial step to strengthen the Thalassaemia Prevention Program in Malaysia

Asit Sena, Saidatul Norbaya Buang, Mohd Shahriel Md Daud, Soh Chin Li, Zaleha Sulaiman, Kaharnisah Mat Noor, et al.

Malaysian Journal of Medicine and Health Sciences, 2019;15(104):13-13.
MyJurnal

Introduction: Thalassaemia is an autosomal recessive disorder affecting 5 percent of the Malaysian population. The state of Sabah has the highest number of transfusion dependent thalassaemia and β-thalassaemia carrier in Malay-sia. For Malaysia to be successful in the prevention of thalassaemia, Sabah needs to be focused on the preventive activities in areas with high prevalence of β-thalassaemia carriers. Thus, identifying the mapping of β-thalassaemia is crucial for planning for prevention activities. The objective of this study was to identify the prevalence of β-thalas-saemia by districts and ethnic groups in Sabah. Methods: This study used data from Form 4 Thalassaemia Screening Records in 2017. The data were cleaned and analysed using Excel spreadsheet to calculate for the national and state specific prevalence of β-thalassaemia carrier. Subsequently, the data was used for mapping of high-risk districts and ethnic groups in Sabah. Results: A total of 31,655 Form 4 students from 242 secondary schools were screened in Sa-bah in 2017 and 1150 (3.6%) were diagnosed as β-thalassemia carrier. The prevalence of β thalassaemia carrier was higher in the West Coast of Sabah which include Kota Marudi District (11.1%), Nabawan (9.0%), Tambunan (8%), Tongod (7.5%), Ranau (7.0%), Kota Belud (5.0%), Kudat (4.6%), Tenom (4.1%) and Tuaran (4.0%). In the East Coast of Sabah, there was only the Beluran District (5.0%) had prevalence that higher than the state average. β-thalassae-mia carriers were more likely to be of Dusun, Kadazan Dusun followed by Bajau, Murut and Rungus ethnic group. Conclusion: The distribution of β-thalassaemia carrier in Sabah was concentrated in the West Coast of Sabah and more common among the Dusun, Kadazan Dusun followed by Bajau, Murut and Rungus ethnic group. Thus, the thalassaemia prevention activities should be focuses in these areas and ethnic groups.

Matched MeSH terms: beta-Thalassemia
Iron chelation therapy in the management of thalassemia: the Asian perspectives

Viprakasit V, Lee-Lee C, Chong QT, Lin KH, Khuhapinant A

Int J Hematol, 2009 Nov;90(4):435-445.
PMID: 19862602 DOI: 10.1007/s12185-009-0432-0

Worldwide, thalassemia is the most commonly inherited hemolytic anemia, and it is most prevalent in Asia and the Middle East. Iron overload represents a significant problem in patients with transfusion-dependent beta-thalassemia. Chelation therapy with deferoxamine has traditionally been the standard therapeutic option but its usage is tempered by suboptimal patient compliance due to the discomfort and demands associated with the administration regimen. Therefore, a great deal of attention has been focused on the development of oral chelating agents. Deferiprone, even though available for nearly two decades in Asia with recent encouraging data on cardiac iron removal and long-term efficacy, has serious adverse effects including agranulocytosis and neutropenia which has impeded it from routine clinical practice. A novel oral chelator; deferasirox is effective throughout a 24 h dosing period and both preclinical and clinical data indicate that it successfully removes both hepatic and cardiac iron. In Asia, optimal management of severe thalassemia patients and the availability and access to oral iron chelators still presents a major challenge in many countries. In this regard, the development and implementation of consensus guidelines for management of Asian patients with transfusion-dependent thalassemia will be a major step towards improving and maintaining the continuity of patient care.

Matched MeSH terms: beta-Thalassemia/economics; beta-Thalassemia/epidemiology; beta-Thalassemia/therapy
Interaction of Hb South Florida (codon 1; GTG-->ATG) and HbE, with beta-thalassemia (IVS1-1; G-->A): expression of different clinical phenotypes

Tan JA, Tan KL, Omar KZ, Chan LL, Wee YC, George E

Eur J Pediatr, 2009 Sep;168(9):1049-54.
PMID: 19034506 DOI: 10.1007/s00431-008-0877-9

INTRODUCTION: Interactions of different hemoglobin variants with thalassemia alleles can result in various clinical phenotypes. HbE-beta-thalassemia generally manifests with severe anemia where individuals exhibit beta-thalassemia major with regular blood transfusions or beta-thalassemia intermedia with periodic blood transfusions. This study presents a unique Malay family with three beta-globin gene defects-HbE, Hb South Florida, and IVS1-1 (G-->A).
MATERIALS AND METHODS: HbE activates a cryptic splice site that produces non-functional mRNAs. Hb South Florida is a rare beta-hemoglobin variant, and its interactions with other beta-thalassemia alleles have not been reported. IVS1-1 is a Mediterranean mutation that affects mRNA processing giving rise to beta(o)-thalassemia.
RESULTS AND DISCUSSION: Fifteen mutations along the beta-globin gene complex were analyzed using the amplification refractory mutation system. Hb South Florida was identified by direct sequencing using genomic DNA.
CONCLUSION: The affected child with HbE/IVS1-1 produced a beta-thalassemia major phenotype. Compound heterozygosity for Hb South Florida/IVS1-1 produced a beta-thalassemia carrier phenotype in the mother.

Matched MeSH terms: beta-Thalassemia/complications; beta-Thalassemia/genetics*; beta-Thalassemia/therapy
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 Human hemoglobin G-Makassar variant masquerading as sickle cell anemia

Mohamad AS, Hamzah R, Selvaratnam V, Yegapan S, Sathar J

Hematol Rep, 2018 Sep 05;10(3):7210.
PMID: 30344984 DOI: 10.4081/hr.2018.7210

Human hemoglobin of G-Makassar variant has been reported very rarely with Beta Thalassemia. In year 1969 Hb GMakassar was first identified in Makassar, Sulawesi (Celebes), Republic of Indonesia. The disease was first published in 1969 and 33 years later it has been reported at a family of Thailand origin. We report a 45-yearold Malay man who was investigated for anemia and thrombocytopenia then diagnosed with Hb G-Makassar. This finding describes as a new Hemoglobin GMakassar discovered in Malaysia after 14 years diagnosed in Thailand.

Matched MeSH terms: beta-Thalassemia
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
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*

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