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A rare case of compound heterozygous Southeast Asian double α-globin gene deletion and Haemoglobin Quong Sze in a Malay proband

Vijian D, Wan Ab Rahman WS, Kannan TP, Zulkafli Z, Mohd Noor NH, Bahar R, et al.

Malays J Pathol, 2024 Aug;46(2):321-324.
PMID: 39207010

INTRODUCTION: Haemoglobin (Hb) Quong Sze is a non-deletional α-thalassaemia subtype that occurs due to missense mutation at codon 125 of the HBA2 gene. Interaction between Hb QS with Southeast Asian double α-globin gene deletion results in non-deletional HbH disease, which is more severe than deletional HbH.
CASE REPORT: A 3-month-old baby boy was presented with neonatal anaemia and mild hepatomegaly. Full blood count revealed severe hypochromic microcytic anaemia. There was an abundance of HbH inclusion bodies in his red blood cells. High-performance liquid chromatography showed a reduced HbA2 level with the presence of pre-run peak. Capillary electrophoresis showed the presence of HbH and Hb Barts. Molecular analysis found a common α0-thalassaemia (--SEA) in one allele and mutation in codon 125 in the other allele.
DISCUSSION: Non-deletional HbH disease due to a combination of deletional and non-deletional mutations may present with severe clinical manifestations than those with deletion mutations, which warrants accurate diagnosis using molecular techniques.
Trinucleotide insertion in the SMN2 promoter may not be related to the clinical phenotype of SMA

Harahap NI, Takeuchi A, Yusoff S, Tominaga K, Okinaga T, Kitai Y, et al.

Brain Dev, 2015 Aug;37(7):669-76.
PMID: 25459970 DOI: 10.1016/j.braindev.2014.10.006

More than 90% of spinal muscular atrophy (SMA) patients show homozygous deletion of SMN1 (survival motor neuron 1). They retain SMN2, a highly homologous gene to SMN1, which may partially compensate for deletion of SMN1. Although the promoter sequences of these two genes are almost identical, a GCC insertion polymorphism has been identified at c.-320_-321 in the SMN1 promoter. We have also found this insertion polymorphism in an SMN2 promoter in an SMA patient (Patient A) who has SMA type 2/3.
Screening of the LIX1 gene in Japanese and Malaysian patients with SMA and/or SMA-like disorder

Sasongko TH, Gunadi, Yusoff S, Atif AB, Fatemeh H, Rani A, et al.

Brain Dev, 2010 May;32(5):385-9.
PMID: 19664890 DOI: 10.1016/j.braindev.2009.06.008

The majority of spinal muscular atrophy (SMA) patients showed homozygous deletion or other mutations of SMN1. However, the genetic etiology of a significant number of SMA patients has not been clarified. Recently, mutation in the gene underlying cat SMA, limb expression 1 (LIX1), has been reported. Similarity in clinical and pathological features of cat and human SMA may give an insight into possible similarity of the genetic etiology.
Intellectual and physical activities, but not social activities, are associated with better global cognition: a multi-site evaluation of the cognition and lifestyle activity study for seniors in Asia (CLASSA)

Lam LC, Ong PA, Dikot Y, Sofiatin Y, Wang H, Zhao M, et al.

Age Ageing, 2015 Sep;44(5):835-40.
PMID: 26271049 DOI: 10.1093/ageing/afv099

population ageing will lead to a leap in the dementia population in Asia. However, information about potentials for low-cost and low-risk interventions is limited.
Fulltext High resolution melting analysis of the NR1I3 genetic variants: Is there an association with neonatal hyperbilirubinemia?

Cheung TP, Van Rostenberghe H, Ismail R, Nawawi NN, Abdullah NA, Ramli N, et al.

Gene, 2015 Dec 1;573(2):198-204.
PMID: 26188155 DOI: 10.1016/j.gene.2015.07.045

Constitutive androstane receptor (CAR) encoded by the nuclear receptor subfamily 1, group I, member 3 (NR1I3) gene regulates the elimination of bilirubin through activating the components of the bilirubin clearance pathway. Hence, NR1I3 genetic variants may affect bilirubin metabolism and result in neonatal hyperbilirubinemia. Thus far, research which investigates the association between NR1I3 variants and neonatal hyperbilirubinemia has not been undertaken in any population. The present study aimed to evaluate the influence of MPJ6_1I3008 (rs10157822), IVS8+116T>G (rs4073054) and 540A>G (rs2307424) on neonatal hyperbilirubinemia development in the Malay population. Buccal swabs were collected from 232 hyperbilirubinemia and 277 control term newborns with gestational age ≥37weeks and birth weight ≥2500g. The NR1I3 variants were genotyped by using high resolution melting (HRM) assays and verified by DNA sequencing. Gender, mode of delivery and birth weight did not differ between hyperbilirubinemia and control groups. The genotypic and allelic frequencies of MPJ6_1I3008, IVS8+116T>G and 540A>G were not significantly different between the groups. However, stratification by gender revealed a significant inverse association between homozygous variant genotype of MPJ6_1I3008 and risk of neonatal hyperbilirubinemia in the females (OR, 0.44; 95% CI, 0.20-0.95; p=0.034). This study demonstrates that the homozygous variant genotype of MPJ6_1I3008 was associated with a significant reduced risk of neonatal hyperbilirubinemia in the females.
Fulltext Blood Transfusion Knowledge among Nurses in Malaysia: A University Hospital Experience

Mohd Noor NH, Saad NH, Khan M, Hassan MN, Ramli M, Bahar R, et al.

Int J Environ Res Public Health, 2021 10 25;18(21).
PMID: 34769712 DOI: 10.3390/ijerph182111194

Blood transfusion is a fundamental and life-saving procedure where the consequence of errors can be fatal. Nurses' knowledge plays an essential role in ensuring quality and safety in blood transfusion. The objective of this study was to assess blood transfusion-associated knowledge of tertiary hospital nurses on the east coast of Malaysia. This was a cross-sectional study with 200 registered nurses involved in blood transfusion procedures at Hospital Universiti Sains Malaysia. The knowledge of the nurses was evaluated by using the routine blood transfusion knowledge questionnaire based on five parts, and <50%, 50-74%, or ≥75% of the knowledge was considered as poor, moderate, or high, respectively. Based on the scoring system, the overall knowledge of blood transfusion among Malaysian nurses (33.2 ± 8.4 years) was estimated to be 54.9 ± 7.6%. In individual items, the scoring was 81.0%, 45.4%, 49.2%, 63.0%, and 90.0% in knowledge prior to blood transfusion, on pre-transfusion, on post-transfusion, on complications, and on transfusion policy, respectively. The findings of this study indicated that most of the nurses' overall knowledge of blood transfusion was at a moderate level; therefore, training courses and continuous medical education are warranted to improve knowledge and skills of the nurses to ensure good practices of blood transfusion.
Hematological Profile of Hb Adana Among High School Students in Northeast Peninsular Malaysia

Siti Asmaa MJ, Miin Phoon L, Zakaria NA, Hussin S, Bahar R, Hassan MN, et al.

Cureus, 2024 Mar;16(3):e57353.
PMID: 38694420 DOI: 10.7759/cureus.57353

Background Hb Adana is a non-deletional alpha (α)-thalassaemia variant resulting from mutations in α1- or α2-globin codon 59 (αCD59), leading to the production of unstable α-globin. Clinical manifestations can vary from silent carrier status to dependence on blood transfusions, hepatosplenomegaly, skeletal deformities, and spinal cord compression. Despite the significance of Hb Adana inheritance, studying this variant poses challenges due to the scarcity of molecular tests and the potential for routine diagnoses to be overlooked. This study aims to investigate the prevalence of Hb Adana among local high school students and assess the hematological parameters and hemoglobin analysis of Hb Adana in Malaysia. Methodology This retrospective study analyzed 13,721 blood samples collected from high school students participating in Malaysia's National Thalassaemia Screening Program at Hospital Raja Perempuan Zainab II (HRPZ II). Deletional α-thalassaemia was detected using multiplex gap-polymerase chain reaction (PCR), while common non-deletional α-thalassaemia was identified using multiplex amplification refractory mutation system (ARMS) PCR. Data were extracted from the HRPZ II database for analysis. Results Among the participants, 2327 individuals were found to have either common deletional (n=1037, 44.6%) or non-deletional (n=1290, 55.4%) α-thalassaemia. Hb Constant Spring was the most prevalent non-deletional α-thalassaemia, accounting for 53.03% of cases. Thirty-one participants (1.33%) exhibited αCD59α/αα, and one (0.04%) had αCD59α/-α3.7. Among the 32 subjects with Hb Adana, 87.5% were Malay, and 12.5% were Orang Asli. Additionally, seven cases of HbE/Hb Adana co-inheritance were identified. Hemoglobin levels in heterozygous Hb Adana individuals ranged from mild anemia to normal, between 95 g/L and 153 g/L. Mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were approximately 73 fL and 23 pg, respectively. Conclusion This study delineates the distribution of α-thalassaemia mutation patterns among high school students in Kelantan, Northeast Peninsular Malaysia. Our findings indicate that Hb Adana is rare in our region and co-inheritance with an α-gene deletion results in α+-thalassaemia and with HbE, α0-thalassaemia. All heterozygous Hb Adana individuals exhibited low MCVs and MCHs.
Fulltext Treatment of dementia and mild cognitive impairment with or without cerebrovascular disease: Expert consensus on the use of Ginkgo biloba extract, EGb 761®

Kandiah N, Ong PA, Yuda T, Ng LL, Mamun K, Merchant RA, et al.

CNS Neurosci Ther, 2019 02;25(2):288-298.
PMID: 30648358 DOI: 10.1111/cns.13095

BACKGROUND: The Ginkgo biloba special extract, EGb 761® has been widely used in the treatment of neuropsychiatric disorders, including Alzheimer's disease (AD).
METHODS: To guide clinical practice in the Asian region, the Asian Clinical Expert Group on Neurocognitive Disorders compiled evidence-based consensus recommendations regarding the use of EGb 761® in neurocognitive disorders with/without cerebrovascular disease.
RESULTS: Key randomized trials and robust meta-analyses have demonstrated significant improvement in cognitive function, neuropsychiatric symptoms, activities of daily living (ADL) and quality of life with EGb 761® versus placebo in patients with mild-to-moderate dementia. In those with mild cognitive impairment (MCI), EGb 761® has also demonstrated significant symptomatic improvement versus placebo. World Federation of Societies of Biological Psychiatry guidelines list EGb 761® with the same strength of evidence as acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) antagonists e.g. memantine (Grade 3 recommendation; Level B evidence). Only EGb 761® had Level B evidence in improving cognition, behaviour, and ADL in both AD and vascular dementia patients. Safety analyses show EGb 761® to have a positive risk-benefit profile. While concerns have been raised regarding a possible increased bleeding risk, several randomized trials and two meta-analyses have not supported this association.
CONCLUSIONS: The Expert Group foresee an important role for EGb 761® , used alone or as an add-on therapy, in the treatment of MCI and dementias, particularly when patients do not derive benefit from acetylcholinesterase inhibitors or NMDA antagonists. EGb 761® should be used in alignment with local clinical practice guidelines.
El Niño driven haze over the Southern Malaysian Peninsula and Borneo

Khan MF, Hamid AH, Rahim HA, Maulud KNA, Latif MT, Nadzir MSM, et al.

Sci Total Environ, 2020 Aug 15;730:139091.
PMID: 32413602 DOI: 10.1016/j.scitotenv.2020.139091

The Southeast Asian (SEA) region is no stranger to forest fires - the region has been suffering from severe air pollution (known locally as 'haze') as a result of these fires, for decades. The fires in SEA region are caused by a combination of natural (the El Niño weather pattern) and manmade (slash-and-burn and land clearing for plantations) factors. These fires cause the emissions of toxic aerosols and pollutants that can affect millions of people in the region. Thus, this study aims to identify the impact of the SEA haze on the Southern region of the Malaysian Peninsula and Borneo region of East Malaysia using the entire air quality observation data at surface level in 2015. Overall, the concentration of PM10 was about two-fold higher during the haze period compared to non-haze period. The concentrations of CO, flux of CO and flux of BC were aligned with PM10 during the entire observation period. The wind field and cluster of trajectory indicated that the Southern Malaysian Peninsula and Borneo were influenced mainly from the wildfires and the combustion of peat soil in the Indonesian Borneo. This study finds that wildfires from Borneo impacted the Southern Malaysian Borneo more seriously than that from Sumatra region.
Fulltext The Role of Epigenetics in the Development and Progression of Multiple Myeloma

Ismail NH, Mussa A, Zakaria NA, Al-Khreisat MJ, Zahidin MA, Ramli NN, et al.

Biomedicines, 2022 Oct 31;10(11).
PMID: 36359286 DOI: 10.3390/biomedicines10112767

Multiple myeloma (MM) is an exceptionally complicated and heterogeneous disease that is caused by the abnormal proliferation of malignant monoclonal plasma cells initiated in the bone marrow. In disease progression, a multistep process including differentiation, proliferation, and invasion is involved. Despite great improvement in treatment outcomes in recent years due to the substantial discovery of novel therapeutic drugs, MM is still regarded as an incurable disease. Patients with MM are afflicted by confronting remission periods accompanied by relapse or progression outcomes, which inevitably progress to the refractory stage. In this regard, MM may need new medications or modifications in therapeutic strategies to overcome resistance. A variety of genetic abnormalities (e.g., point mutations, translocations, and deletions) and epigenetic changes (e.g., DNA methylation, histone modification, and non-coding RNA) contribute to the pathogenesis and development of MM. Here, we review the significant roles of epigenetic mechanisms in the development and progression of MM. We also highlight epigenetic pathways as potential novel treatment avenues for MM, including their interplay, use of epigenetic inhibitors, and major involvement in immuno-oncology.
Conformation sensitive gel electrophoresis for the detection of calreticulin mutations in BCR-ABL1-negative myeloproliferative neoplasms

Zakaria NA, Rosle NA, Siti Asmaa MJ, Aziee S, Haiyuni MY, Samat NA, et al.

Int J Lab Hematol, 2021 Dec;43(6):1451-1457.
PMID: 34125992 DOI: 10.1111/ijlh.13628

INTRODUCTION: Calreticulin (CALR) mutations in myeloproliferative neoplasms (MPN) have been reported to be key markers in the molecular diagnosis, particularly in patients lacking JAK2 V617F mutation. In most current reports, CALR mutations were analysed by either allele-specific PCR (AS-PCR), or the more expensive quantitative real-time PCR, pyrosequencing and next-generation sequencing. Hence, we report the use of an alternative method, the conformation sensitive gel electrophoresis (CSGE) for the detection of CALR mutations in BCR-ABL1-negative MPN patients.
METHODS: Forty BCR-ABL1-negative MPN patients' DNA: 19 polycythemia vera (PV), 7 essential thrombocytosis (ET) and 14 primary myelofibrosis (PMF), were screened for CALR mutations by CSGE. PCR primers were designed to amplify sequences spanning between exons 8 and 9 to target the mutation hotspots in CALR. Amplicons displaying abnormal CSGE profiles by electrophoresis were directly sequenced, and results were analysed by BioEdit Sequence Alignment Editor v7.2.6. CSGE results were compared with AS-PCR and confirmed by Sanger sequencing.
RESULTS: CSGE identified 4 types of mutations; 2 PMF patients with either CALR type 1 (c.1099_1150del52) or type 2 (c.1155_1156insTTGTC), 1 ET patient with nucleotide deletion (c.1121delA) and insertion (c.1190insA) and 1 PV patient with p.K368del (c.1102_1104delAAG) and insertion (c.1135insA) inframe mutations. Three patients have an altered KDEL motif at the C-terminal of CALR protein. In comparison, AS-PCR only able to detect two PMF patients with mutations, either type 1 and type 2.
CONCLUSION: CSGE is inexpensive, sensitive and reliable alternative method for the detection of CALR mutations in BCR-ABL1-negative MPN patients.
Fulltext Multiplex amplification refractory mutation system (MARMS) for the detection of β-globin gene mutations among the transfusion-dependent β-thalassemia Malay patients in Kelantan, Northeast of Peninsular Malaysia

Hanafi S, Hassan R, Bahar R, Abdullah WZ, Johan MF, Rashid ND, et al.

Am J Blood Res, 2014;4(1):33-40.
PMID: 25232503

The aim of this study was to adapt MARMS with some modifications to detect beta mutation in our cohort of thalassemia patients. We focused only on transfusion-dependent thalassemia Malay patients, the predominant ethnic group (95%) in the Kelantanese population. Eight mutations were identified in 46 out of 48 (95.83%) beta thalassemia alleles. Most of the patients (54.2%) were compound heterozygous with co-inheritance Cd 26 (G>A). The frequencies of spectrum beta chain mutation among these patients are presented in Table 2. Among the transfusion dependent beta thalassemia Malay patients studied, 26 patients were found to be compound heterozygous and the main alleles were Cd 26 (G>A). Compound heterozygous mutation of Cd 26 (G>A) and IVS 1-5 (G>C) were 12 (46.2%), Cd 26 (G>A) and Cd 41/42 (TTCT) were 9 (34.6%), Cd 26 (G>A) and IVS 1-1 (G>C) were 2 (7.7%) respectively. Meanwhile the minority were made of a single compound heterozygous of Cd 26 (G>A) and Cd 71/72, Cd 26 (>A) and Cd 17 (A>T), Cd 26 (G>A) and -28 (G>A) respectively. Twenty out of forty six patients were shown to have homozygous of IVS 1-5 (G>C) were 2 (10.0%), Cd 26 (G>A) were 15 (75.0%), Cd 19 (A>G) were 1 (5.0%), and IVS 1-1 (G>T) were 2 (10.0%). The beta chain mutations among the Kelantanese Malays followed closely the distribution of beta chain mutations among the Thais and the Malays of the Southern Thailand. The G-C transition at position 5 of the IVS 1-5 mutation was predominant among the Malay patients. In conclusion, this method has successfully identified the mutation spectrum in our cohort of transfusion-dependent beta thalassemia patients, and this method is equally effective in screening for mutation among thalassemia patients.
Fulltext The first Malay database toward the ethnic-specific target molecular variation

Halim-Fikri H, Etemad A, Abdul Latif AZ, Merican AF, Baig AA, Annuar AA, et al.

BMC Res Notes, 2015;8:176.
PMID: 25925844 DOI: 10.1186/s13104-015-1123-y

The Malaysian Node of the Human Variome Project (MyHVP) is one of the eighteen official Human Variome Project (HVP) country-specific nodes. Since its inception in 9(th) October 2010, MyHVP has attracted the significant number of Malaysian clinicians and researchers to participate and contribute their data to this project. MyHVP also act as the center of coordination for genotypic and phenotypic variation studies of the Malaysian population. A specialized database was developed to store and manage the data based on genetic variations which also associated with health and disease of Malaysian ethnic groups. This ethnic-specific database is called the Malaysian Node of the Human Variome Project database (MyHVPDb).

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