Displaying publications 1 - 20 of 91 in total

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  1. Fulltext Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP
    Qian M, Zhang H, Kham SK, Liu S, Jiang C, Zhao X, et al.
    Genome Res, 2017 02;27(2):185-195.
    PMID: 27903646 DOI: 10.1101/gr.209163.116
    Chromosomal translocations are a genomic hallmark of many hematologic malignancies. Often as initiating events, these structural abnormalities result in fusion proteins involving transcription factors important for hematopoietic differentiation and/or signaling molecules regulating cell proliferation and cell cycle. In contrast, epigenetic regulator genes are more frequently targeted by somatic sequence mutations, possibly as secondary events to further potentiate leukemogenesis. Through comprehensive whole-transcriptome sequencing of 231 children with acute lymphoblastic leukemia (ALL), we identified 58 putative functional and predominant fusion genes in 54.1% of patients (n = 125), 31 of which have not been reported previously. In particular, we described a distinct ALL subtype with a characteristic gene expression signature predominantly driven by chromosomal rearrangements of the ZNF384 gene with histone acetyltransferases EP300 and CREBBP ZNF384-rearranged ALL showed significant up-regulation of CLCF1 and BTLA expression, and ZNF384 fusion proteins consistently showed higher activity to promote transcription of these target genes relative to wild-type ZNF384 in vitro. Ectopic expression of EP300-ZNF384 and CREBBP-ZNF384 fusion altered differentiation of mouse hematopoietic stem and progenitor cells and also potentiated oncogenic transformation in vitro. EP300- and CREBBP-ZNF384 fusions resulted in loss of histone lysine acetyltransferase activity in a dominant-negative fashion, with concomitant global reduction of histone acetylation and increased sensitivity of leukemia cells to histone deacetylase inhibitors. In conclusion, our results indicate that gene fusion is a common class of genomic abnormalities in childhood ALL and that recurrent translocations involving EP300 and CREBBP may cause epigenetic deregulation with potential for therapeutic targeting.
  2. Fulltext Whole-genome noncoding sequence analysis in T-cell acute lymphoblastic leukemia identifies oncogene enhancer mutations
    Hu S, Qian M, Zhang H, Guo Y, Yang J, Zhao X, et al.
    Blood, 2017 06 15;129(24):3264-3268.
    PMID: 28408461 DOI: 10.1182/blood-2017-03-771162
  3. Viva-Asia Blood and Marrow Transplantation Groups - A Survey of Consortium Activity over a 12-year Period (2000 to 2011)
    Tan AM, Ha C, Li CF, Chan GC, Lee V, Tan PL, et al.
    Ann Acad Med Singap, 2016 Mar;45(3):106-9.
    PMID: 27146463
  4. Understanding patients' and caregivers' perspectives and educational needs in Parkinson's disease: a multi-ethnic Asian study
    Choo XY, Lim SY, Chinna K, Tan YJ, Yong VW, Lim JL, et al.
    Neurol Sci, 2020 Oct;41(10):2831-2842.
    PMID: 32314118 DOI: 10.1007/s10072-020-04396-4
    INTRODUCTION: Little is known regarding the educational needs and perspectives of people living with Parkinson's disease (PD), particularly in Asia.

    OBJECTIVE: To assess knowledge and perceptions regarding PD in a large multiethnic urban Asian cohort of patients and caregivers.

    METHODS: We conducted a survey at a university hospital neurology clinic, using a novel Knowledge and Perception of Parkinson's Disease Questionnaire (KPPDQ).

    RESULTS: The KPPDQ had satisfactory psychometric properties among patients and caregivers. Five hundred subjects were recruited with a 97% response rate (211 patients, 273 caregivers). Non-motor symptoms such as urinary problems, visual hallucinations and pain were relatively poorly recognized. Many (≈ 50-80%) respondents incorrectly believed that all PD patients experience tremor, that PD is usually familial, and that there is a cure for PD. About one-half perceived PD to be caused by something the patient had done in the past, and that PD medications were likely to cause internal organ damage. Issues of stigma/shame were relevant to one-third of patients, and 70% of patients perceived themselves to be a burden to others. Two-thirds of participants felt that PD imposed a heavy financial toll. Participants were about equally divided as to whether they would consider treatment with deep brain stimulation, tube feeding or invasive ventilation. Over three-quarters of patients expressed a preference to die at home.

    CONCLUSIONS: Important knowledge gaps, misperceptions and perspectives on PD were identified, highlighting the need for further efforts to raise awareness and provide accurate information regarding PD, and to address patient's and caregivers' needs and preferences.

  5. Fulltext Understanding monogenic Parkinson's disease at a global scale
    Junker J, Lange LM, Vollstedt EJ, Roopnarain K, Doquenia MLM, Annuar AA, et al.
    medRxiv, 2024 Apr 09.
    PMID: 38529492 DOI: 10.1101/2024.03.12.24304154
    Until recently, about three-quarters of all monogenic Parkinson's disease (PD) studies were performed in European/White ancestry, thereby severely limiting our insights into genotype-phenotype relationships at global scale. The first systematic approach to embrace monogenic PD worldwide, The Michael J. Fox Foundation Global Monogenic PD (MJFF GMPD) Project, contacted authors of publications reporting individuals carrying pathogenic variants in known PD-causing genes. In contrast, the Global Parkinson's Genetics Program's (GP2) Monogenic Network took a different approach by targeting PD centers not yet represented in the medical literature. Here, we describe combining both efforts in a "merger project" resulting in a global monogenic PD cohort with build-up of a sustainable infrastructure to identify the multi-ancestry spectrum of monogenic PD and enable studies of factors modifying penetrance and expression of monogenic PD. This effort demonstrates the value of future research based on team science approaches to generate comprehensive and globally relevant results.
  6. Treatment of startle and related disorders
    Lim TT, Por CY, Beh YY, Schee JP, Tan AH
    Clin Park Relat Disord, 2023;9:100218.
    PMID: 37808566 DOI: 10.1016/j.prdoa.2023.100218
  7. Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases
    Li JF, Dai YT, Lilljebjörn H, Shen SH, Cui BW, Bai L, et al.
    Proc Natl Acad Sci U S A, 2018 12 11;115(50):E11711-E11720.
    PMID: 30487223 DOI: 10.1073/pnas.1814397115
    Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with MEF2D fusions, TCF3-PBX1 fusions, ETV6-RUNX1-positive/ETV6-RUNX1-like, DUX4 fusions, ZNF384 fusions, BCR-ABL1/Ph-like, high hyperdiploidy, and KMT2A fusions), we defined six additional gene expression subgroups: G9 was associated with both PAX5 and CRLF2 fusions; G10 and G11 with mutations in PAX5 (p.P80R) and IKZF1 (p.N159Y), respectively; G12 with IGH-CEBPE fusion and mutations in ZEB2 (p.H1038R); and G13 and G14 with TCF3/4-HLF and NUTM1 fusions, respectively. In pediatric BCP ALL, subgroups G2 to G5 and G7 (51 to 65/67 chromosomes) were associated with low-risk, G7 (with ≤50 chromosomes) and G9 were intermediate-risk, whereas G1, G6, and G8 were defined as high-risk subgroups. In adult BCP ALL, G1, G2, G6, and G8 were associated with high risk, while G4, G5, and G7 had relatively favorable outcomes. This large-scale transcriptome sequence analysis of BCP ALL revealed distinct molecular subgroups that reflect discrete pathways of BCP ALL, informing disease classification and prognostic stratification. The combined results strongly advocate that RNA sequencing be introduced into the clinical diagnostic workup of BCP ALL.
  8. Fulltext Toward e-Scales: Digital Administration of the International Parkinson and Movement Disorder Society Rating Scales
    Monje MHG, Fuller RLM, Cubo E, Mestre TA, Tan AH, Stout JC, et al.
    Mov Disord Clin Pract, 2021 Feb;8(2):208-214.
    PMID: 33553489 DOI: 10.1002/mdc3.13135
  9. Fulltext The Parkinson's disease e-diary: Developing a clinical and research tool for the digital age
    Vizcarra JA, Sánchez-Ferro Á, Maetzler W, Marsili L, Zavala L, Lang AE, et al.
    Mov Disord, 2019 05;34(5):676-681.
    PMID: 30901492 DOI: 10.1002/mds.27673
  10. Fulltext The Association Between Bullous Pemphigoid and Neurological Disorders in A Selected Malaysian Population
    Kwan Z, Lai YN, Ch'ng CC, Tan AH, Tan LL, Robinson S, et al.
    Med J Malaysia, 2015 Apr;70(2):81-5.
    PMID: 26162382 MyJurnal
    BACKGROUND: An association of bullous pemphigoid with neurological disorders has been reported. The objectives of this study were to review the clinical characteristics of patients with bullous pemphigoid and compare the association between bullous pemphigoid and various neurological disorders and comorbidities.

    METHODS: This was a retrospective case-control study involving 43 patients with bullous pemphigoid and 43 age-, sex- and ethnicity-matched controls.

    RESULTS: There was a statistically significant association between bullous pemphigoid and neurological disorders [Odds Ratio (OR) = 3.5, 95% Confidence Interval (CI) 1.3 to 9.2, p=0.011 and adjusted OR=3.5, 95% CI 1.2-10.3, p=0.026], in particular for dementia (p=0.002). Although stroke was more common among patients with bullous pemphigoid, this association was not statistically significant with OR of 1.9 (95% CI 0.7 to 5.2) and adjusted OR of 2.1 (95% CI 0.6 to 7.2). Similarly both ischaemic stroke (OR 1.5, 95% CI 0.5 to 4.2) and haemorrhagic stroke (OR 1.5, 95% CI 0.2 to 9.7) were more common. Other neurological disorders more common among patients with bullous pemphigoid were Parkinson's disease and epilepsy. Dyslipidaemia was significantly less common among patients with bullous pemphigoid (OR 0.4, 95% CI 0.1 to 0.9, p=0.033).

    CONCLUSION: A combination of an inflammatory process, prothrombotic state and endothelial activation leads to an increased frequency of neurological disorders among patients with bullous pemphigoid. Thus, a holistic approach to patient care, including screening for dementia and control of comorbidities, should be practised as bullous pemphigoid affects more than just the skin.
  11. Teaching Video NeuroImages: Purposeless groaning in progressive supranuclear palsy
    Low SC, Tan AH, Lim SY
    Neurology, 2017 01 03;88(1):e9.
    PMID: 28025406 DOI: 10.1212/WNL.0000000000003465
  12. Successful toxicity reduction during delayed intensification in the non-high-risk arm of Malaysia-Singapore Acute Lymphoblastic Leukaemia 2010 study
    Oh BLZ, Lee SHR, Foo KM, Chiew KH, Seeto ZZL, Chen ZW, et al.
    Eur J Cancer, 2021 01;142:92-101.
    PMID: 33246161 DOI: 10.1016/j.ejca.2020.10.010
    In non-high-risk (non-HR) patients, the Malaysia-Singapore Acute Lymphoblastic Leukaemia 2003 (MS2003) study achieved good outcomes. However, its delayed-intensification (DI) phase, comprising repeated blocks of protocol III (2003-PIII), was toxic and caused significant treatment delays. The successor MS2010 study attempted to lower DI toxicity by replacing myelosuppressive drugs (doxorubicin, cytarabine) with vincristine and asparaginase.

    PATIENTS AND METHODS: We analysed 1748 admissions for fever in 315 Singapore children with non-HR acute lymphoblastic leukaemia (ALL) (MS2003, n = 183; MS2010, n = 132), comprising 76% of the total cohort (n = 413), to study the impact of these changes.

    RESULTS: The new 2010-PVa which has no doxorubicin, was associated with significantly fewer hospitalisations due to fever (0.08 versus 0.30 admissions per block [A/blk], p 

  13. Small intestinal bacterial overgrowth in Parkinson's disease
    Tan AH, Mahadeva S, Thalha AM, Gibson PR, Kiew CK, Yeat CM, et al.
    Parkinsonism Relat Disord, 2014 May;20(5):535-40.
    PMID: 24637123 DOI: 10.1016/j.parkreldis.2014.02.019
    BACKGROUND: Recent studies reported a high prevalence of small intestinal bacterial overgrowth (SIBO) in Parkinson's disease (PD), and a possible association with gastrointestinal symptoms and worse motor function. We aimed to study the prevalence and the potential impact of SIBO on gastrointestinal symptoms, motor function, and quality of life in a large cohort of PD patients.
    METHODS: 103 Consecutive PD patients were assessed using the lactulose-hydrogen breath test; questionnaires of gastrointestinal symptoms and quality of life (PDQ-39); the Unified PD Rating Scale (UPDRS) including "on"-medication Part III (motor severity) score; and objective and quantitative measures of bradykinesia (Purdue Pegboard and timed test of gait). Patients and evaluating investigators were blind to SIBO status.
    RESULTS: 25.3% of PD patients were SIBO-positive. SIBO-positive patients had a shorter mean duration of PD (5.2 ± 4.1 vs. 8.1 ± 5.5 years, P = 0.007). After adjusting for disease duration, SIBO was significantly associated with lower constipation and tenesmus severity scores, but worse scores across a range of "on"-medication motor assessments (accounting for 4.2-9.0% of the variance in motor scores). There was no association between SIBO and motor fluctuations or PDQ-39 Summary Index scores.
    CONCLUSIONS: This is the largest study to date on SIBO in PD. SIBO was detected in one quarter of patients, including patients recently diagnosed with the disease. SIBO was not associated with worse gastrointestinal symptoms, but independently predicted worse motor function. Properly designed treatment trials are needed to confirm a causal link between SIBO and worse motor function in PD.
    KEYWORDS: Gastrointestinal dysfunction; Parkinson's disease/Parkinsonism; Small intestinal bacterial overgrowth
  14. Sensory nerves are frequently involved in the spectrum of fisher syndrome
    Shahrizaila N, Goh KJ, Kokubun N, Tan AH, Tan CY, Yuki N
    Muscle Nerve, 2014 Apr;49(4):558-63.
    PMID: 23893512 DOI: 10.1002/mus.23973
    Differing patterns of neurophysiological abnormalities have been reported in patients with Fisher syndrome. Fisher syndrome is rare, and few series have incorporated prospective serial studies to define the natural history of nerve conduction studies in Guillain-Barré syndrome.
  15. Relapsing encephalopathy with dancing eyes and jerky limbs
    Mohd Fauzi NA, Abdullah S, Tan AH, Mohd Ramli N, Tan CY, Lim SY
    Parkinsonism Relat Disord, 2020 06;75:110-113.
    PMID: 30846242 DOI: 10.1016/j.parkreldis.2019.02.025
    We report a case of relapsing-remitting opsoclonus-myoclonus-ataxia syndrome (OMAS) in a patient with Hashimoto's encephalopathy, diagnosed after comprehensive evaluation. OMAS as a manifestation of Hashimoto's encephalopathy has been reported once previously. It is hoped that recognition of this entity and early initiation of immunotherapy will improve clinical outcomes for patients.
  16. Fulltext Rare homozygous PRKN exon 8 and 9 deletion in Malay familial early-onset Parkinson's disease
    Tay YW, Lim JL, Tan AH, Annuar AA, Lim SY
    Ann Acad Med Singap, 2021 04;50(4):353-355.
    PMID: 33990826 DOI: 10.47102/annals-acadmedsg.2020508
  17. Fulltext Rapid-Onset Dystonia-Parkinsonism in a Chinese Girl with a De Novo ATP1A3 c.2267G>A (p.R756H) Genetic Mutation
    Tan AH, Ozelius LJ, Brashear A, Lang AE, Ahmad-Annuar A, Tan CT, et al.
    Mov Disord Clin Pract, 2015 Mar;2(1):74-75.
    PMID: 30713883 DOI: 10.1002/mdc3.12122
  18. Radiological classification of meniscocapsular tears of the anterolateral portion of the lateral meniscus of the knee
    George J, Saw KY, Ramlan AA, Packya N, Tan AH, Paul G
    Australas Radiol, 2000 Feb;44(1):19-22.
    PMID: 10761254
    In an arthroscopic-MRI correlation study of acute injuries to the knee it was found that anterolateral meniscocapsular separations of the lateral aspect of the knee were missed on MRI reporting. Eighty sports-related injuries of the knee were seen by experienced orthopaedic surgeons at the University of Malaya Medical Centre and at the National Sports Centre, Malaysia from January 1996 to July 1997. Fifty of the patients were suspected to have meniscal tears that were either lateral or medial on clinical examination and they were sent for MRI. Many of these patients were tertiary referrals. Magnetic resonance imaging examinations in 27 of the 50 patients were reported as not showing any intrasubstance or obvious meniscocapsular tears, but arthroscopy performed on them revealed anterolateral meniscocapsular tears of the lateral meniscus of varying degrees in nine of these patients. In retrospect the tears could be seen on MRI, and a pattern to the tears was noted and classified as follows. Type 0, normal; type 1, torn inferior or superior meniscocapsular attachment; type 2, both meniscofemoral and meniscotibial ligaments torn but with minimal separation of meniscus and capsule by fluid or synovitis; and type 3, marked separation of meniscus and capsule by fluid (> 3 mm). Ten patients who did not undergo arthroscopy for various personal and financial reasons underwent MRI which showed type 1 and type 2 tears, and were treated conservatively. These patients were all asymptomatic after 4-6 weeks with regard to clinical signs, suggesting a lateral meniscal tear. Magnetic resonance imaging therefore does reveal minor degrees of meniscocapsular tears anterolaterally when one understands the normal anatomy in this region.
  19. Fulltext R54C Mutation of NOTCH3 Gene in the First Rungus Family with CADASIL
    Lim KS, Tan AH, Lim CS, Chua KH, Lee PC, Ramli N, et al.
    PLoS One, 2015;10(8):e0135470.
    PMID: 26270344 DOI: 10.1371/journal.pone.0135470
    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke caused by mutations in NOTCH3 gene. We report the first case of CADASIL in an indigenous Rungus (Kadazan-Dusun) family in Kudat, Sabah, Malaysia confirmed by a R54C (c.160C>T, p.Arg54Cys) mutation in the NOTCH3. This mutation was previously reported in a Caucasian and two Korean cases of CADASIL. We recruited two generations of the affected Rungus family (n = 9) and found a missense mutation (c.160C>T) in exon 2 of NOTCH3 in three siblings. Two of the three siblings had severe white matter abnormalities in their brain MRI (Scheltens score 33 and 50 respectively), one of whom had a young stroke at the age of 38. The remaining sibling, however, did not show any clinical features of CADASIL and had only minimal changes in her brain MRI (Scheltens score 17). This further emphasized the phenotype variability among family members with the same mutation in CADASIL. This is the first reported family with CADASIL in Rungus subtribe of Kadazan-Dusun ethnicity with a known mutation at exon 2 of NOTCH3. The penetrance of this mutation was not complete during the course of this study.
  20. Fulltext Purposeless Groaning in Parkinson's Disease
    Lim SY, Tan AH, Lim JL, Ahmad-Annuar A
    J Mov Disord, 2018 May;11(2):87-88.
    PMID: 29860787 DOI: 10.14802/jmd.18004
    Purposeless groaning has been reported in advanced progressive supranuclear palsy. We present a case of purposeless groaning occurring as a primary complaint in a patient with advanced Parkinson's disease. Purposeless groaning is thought to be a manifestation of disinhibition and perseveration due to frontal-subcortical dysfunction. Proper recognition of this phenomenon will help clinicians to avoid unnecessary investigations and treatment (e.g., prescription of opioid medications).
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