49 results on '"Ahmad-Annuar, A."'
Search Results
2. Editorial: Genetic and molecular diversity in Parkinson's disease
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Nor Azian Abdul Murad, Siti Aishah Sulaiman, Azlina Ahmad-Annuar, Norlinah Mohamed Ibrahim, Wael Mohamed, Shahrul Azmin Md Rani, and Kin Ying Mok
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Parkinson's disease ,genetics ,diversity ,genome-wide association study ,Asians ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2022
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3. Missense Mutation of Brain Derived Neurotrophic Factor (BDNF) Alters Neurocognitive Performance in Patients with Mild Traumatic Brain Injury: A Longitudinal Study
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Narayanan, Vairavan, Veeramuthu, Vigneswaran, Ahmad-Annuar, Azlina, Ramli, Norlisah, Waran, Vicknes, Chinna, Karuthan, Bondi, Mark William, Delano-Wood, Lisa, and Ganesan, Dharmendra
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Clinical and Health Psychology ,Psychology ,Traumatic Head and Spine Injury ,Prevention ,Neurosciences ,Brain Disorders ,Physical Injury - Accidents and Adverse Effects ,Traumatic Brain Injury (TBI) ,Behavioral and Social Science ,Genetics ,Clinical Research ,Acquired Cognitive Impairment ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Mental health ,Adult ,Alleles ,Brain Concussion ,Brain-Derived Neurotrophic Factor ,Cognition ,Demography ,Female ,Humans ,Longitudinal Studies ,Male ,Mutation ,Missense ,Neuropsychological Tests ,Polymorphism ,Single Nucleotide ,General Science & Technology - Abstract
The predictability of neurocognitive outcomes in patients with traumatic brain injury is not straightforward. The extent and nature of recovery in patients with mild traumatic brain injury (mTBI) are usually heterogeneous and not substantially explained by the commonly known demographic and injury-related prognostic factors despite having sustained similar injuries or injury severity. Hence, this study evaluated the effects and association of the Brain Derived Neurotrophic Factor (BDNF) missense mutations in relation to neurocognitive performance among patients with mTBI. 48 patients with mTBI were prospectively recruited and MRI scans of the brain were performed within an average 10.1 (SD 4.2) hours post trauma with assessment of their neuropsychological performance post full Glasgow Coma Scale (GCS) recovery. Neurocognitive assessments were repeated again at 6 months follow-up. The paired t-test, Cohen's d effect size and repeated measure ANOVA were performed to delineate statistically significant differences between the groups [wildtype G allele (Val homozygotes) vs. minor A allele (Met carriers)] and their neuropsychological performance across the time point (T1 = baseline/ admission vs. T2 = 6th month follow-up). Minor A allele carriers in this study generally performed more poorly on neuropsychological testing in comparison wildtype G allele group at both time points. Significant mean differences were observed among the wildtype group in the domains of memory (M = -11.44, SD = 10.0, p = .01, d = 1.22), executive function (M = -11.56, SD = 11.7, p = .02, d = 1.05) and overall performance (M = -6.89 SD = 5.3, p = .00, d = 1.39), while the minor A allele carriers showed significant mean differences in the domains of attention (M = -11.0, SD = 13.1, p = .00, d = .86) and overall cognitive performance (M = -5.25, SD = 8.1, p = .01, d = .66).The minor A allele carriers in comparison to the wildtype G allele group, showed considerably lower scores at admission and remained impaired in most domains across the timepoints, although delayed signs of recovery were noted to be significant in the domains attention and overall cognition. In conclusion, the current study has demonstrated the role of the BDNF rs6265 Val66Met polymorphism in influencing specific neurocognitive outcomes in patients with mTBI. Findings were more detrimentally profound among Met allele carriers.
- Published
- 2016
4. LRRK2 N551K and R1398H variants are protective in Malays and Chinese in Malaysia: A case–control association study for Parkinson's disease
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Aroma Agape Gopalai, Jia Lun Lim, Hui‐Hua Li, Yi Zhao, Thien Thien Lim, Gaik B. Eow, Santhi Puvanarajah, Shanthi Viswanathan, Mohamed Ibrahim Norlinah, Zariah Abdul Aziz, Soo Kun Lim, Chong Tin Tan, Ai Huey Tan, Shen‐Yang Lim, Eng‐King Tan, and Azlina Ahmad Annuar
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LRRK2 ,N551K ,Parkinson's disease ,R1398H ,Genetics ,QH426-470 - Abstract
Abstract Background The LRRK2 gene is associated with Parkinson's disease (PD) as a number of mutations within the gene have been shown to be susceptibility factors. Studies on various global populations have determined that mutations such as G2019S, G2385R, and R1628P in LRRK2 increase the risk of developing PD while the N551K‐R1398H haplotype is associated with conferring protection against developing PD. Here we report a study looking at the N551K and R1398H variants for the first time in the Malaysian population. Methods Cases (523) which conformed to the United Kingdom PD Brain Bank Criteria for PD were recruited through trained neurologists and age‐ and ethnically matched controls (491) were individuals free of any neurological disorder. The N551K and R1398H mutations were genotyped using the Taqman SNP genotyping assay. Results A significant protective association for N551K was found in those of Malay ancestry, with a protective trend seen for R1398H. A meta‐analysis of Chinese individuals in this cohort with other published cohorts of Chinese ancestry indicated a significant protective role for N551K and R1398H. Conclusion This study reports that the N551K‐R1398H haplotype is also relevant to the Malaysian population, with a significant protective effect found in those of Malay and Chinese ancestries.
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- 2019
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5. Genetic Testing for Parkinson's Disease and Movement Disorders in Less Privileged Areas: Barriers and Opportunities.
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Tan, Ai Huey, Cornejo‐Olivas, Mario, Okubadejo, Njideka, Pal, Pramod Kumar, Saranza, Gerard, Saffie‐Awad, Paula, Ahmad‐Annuar, Azlina, Schumacher‐Schuh, Artur F., Okeng'o, Kigocha, Mata, Ignacio F., Gatto, Emilia M., and Lim, Shen‐Yang
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MOVEMENT disorders ,PARKINSON'S disease ,GENETIC testing ,MEDICAL mistrust ,MEDICAL ethics ,CAREGIVER attitudes ,RESOURCE-limited settings - Abstract
This article explores the challenges and opportunities surrounding genetic testing for Parkinson's disease and other movement disorders in low- and middle-income countries (LMICs). Limited availability and accessibility of genetic testing services, along with financial constraints and limited test options, pose significant barriers in these areas. The shortage of healthcare professionals specializing in neurology, movement disorders, clinical genetics, and genetic counseling further hampers access to genetic testing. Cultural factors, health literacy, and ethical considerations also influence the acceptability of genetic testing. The article proposes various strategies to overcome these barriers, including improving education and training programs for both patients and healthcare professionals, disseminating information through culturally appropriate channels, and advocating for equitable access to genetic testing in LMICs. [Extracted from the article]
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- 2024
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6. MTRR gene variant rs1801394 found in Malaysian patients with neural tube defects
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Amelia Cheng Wei Tan, Noraishah Mydin Abdul-Aziz, Abu Bakar Azizi, Siti Waheeda Mohd-Zin, Nur'Awatif Ishak, Azlina Ahmad-Annuar, and Meow-Keong Thong
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Sanger sequencing ,Genetics ,education.field_of_study ,Cognitive Neuroscience ,Population ,Neuroscience (miscellaneous) ,Single-nucleotide polymorphism ,Biology ,MTRR ,Cellular and Molecular Neuroscience ,symbols.namesake ,Neurology ,Genotype ,symbols ,Missense mutation ,education ,Gene ,Exome sequencing - Abstract
Neural tube defects (NTDs) are congenital anomalies resulting from the failure of neural tube closure during embryogenesis. The precise molecular mechanisms underlying this multifactorial disease is poorly understood, although single nucleotide polymorphisms in genes involved in the one-carbon metabolism cycle are believed to contribute towards NTD development. Among them is 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). Protein function prediction algorithms (PolyPhen-2, PROVEAN, SIFT, SMART-Ensembl) were employed to evaluate its pathogenicity potential caused by the replacement of isoleucine with methionine. Seven NTD patients and 12 of their parents were recruited for this study. DNA samples were collected through blood or saliva whereby the extracted DNAs were then sent for whole exome sequencing (WES). Zygosity of the variant was confirmed from WES data of each subject and further validated through polymerase chain reaction (PCR) and Sanger sequencing. The results revealed that 57% of patients and 83% of parents carried rs1801394 mutation in their MTRR gene, based on either homozygous (G/G) or heterozygous (A/G) genotypes. Bioinformatics analysis of this missense mutation predicted that this change is damaging to MTRR protein function by 2 of the 3 predictor algorithms and that the change from isoleucine to methionine amino acid affects flavodoxin domain of the protein. This impacts enzyme activity within the one-carbon metabolism pathway, which is linked to the aetiology of NTDs. From population databases, this variant was considered common with a MAF >0.3, however, it was not found in the Singapore Genome Variation Project (SGVP), whose population is a closer representation of the Malaysian subjects investigated here. Hence, we explored the prevalence of this variant in other studies and found that its association with NTDs differed across populations worldwide. Finally, we conclude that rs1801394 may be an NTD risk factor in the Malaysian population and should be further investigated as a potential prenatal screening tool.
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- 2020
7. Rare homozygous PRKN exon 8 and 9 deletion in Malay familial early-onset Parkinson’s disease
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Azlina Ahmad Annuar, Yi Wen Tay, Shen-Yang Lim, Ai Huey Tan, and Jia Lun Lim
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Genetics ,Exon ,business.industry ,language ,Early onset Parkinson's disease ,Medicine ,General Medicine ,business ,language.human_language ,Malay - Published
- 2021
8. Glucocerebrosidase (GBA) gene variants in a multi-ethnic Asian cohort with Parkinson's disease: mutational spectrum and clinical features
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Kalai Arasu Muthusamy, Azlina Ahmad-Annuar, Christine Klein, Peter Bauer, Khairul Azmi Ibrahim, Yuen Kang Chia, Zariah Abdul Aziz, Yi Wen Tay, Joshua Chin Ern Ooi, Thien Thien Lim, Ai Huey Tan, Jia Lun Lim, Arndt Rolfs, Ahmad Shahir Mawardi, Irene Looi, Santhi Datuk Puvanarajah, Shen-Yang Lim, and Katja Lohmann
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Sanger sequencing ,Genetics ,Parkinson's disease ,business.industry ,Parkinson Disease ,Disease ,medicine.disease ,Psychiatry and Mental health ,symbols.namesake ,Exon ,Neurology ,Asian People ,Cohort ,Mutation ,symbols ,Medicine ,Missense mutation ,Glucosylceramidase ,Humans ,Genetic Predisposition to Disease ,Neurology (clinical) ,Allele ,business ,Glucocerebrosidase ,Biological Psychiatry - Abstract
GBA variants are associated with increased risk and earlier onset of Parkinson’s disease (PD), and more rapid disease progression especially with “severe” variants typified by p.L483P. GBA mutation screening studies from South-East Asia, with > 650 million inhabitants of diverse ancestries, are very limited. We investigated the spectrum of GBA variants, and associated clinico-demographic features, in a multi-ethnic PD cohort in Malaysia. Patients (n = 496) were recruited from seven centres, primarily of Chinese (45%), Malay (37%), and Indian (13%) ethnicities. All GBA coding exons were screened using a next-generation sequencing-based PD gene panel and verified with Sanger sequencing. We identified 14 heterozygous GBA alleles consisting of altogether 17 missense variants (8 classified as pathogenic or likely pathogenic for PD) in 25 (5.0%) patients, with a substantially higher yield among early (
- Published
- 2021
9. Editorial: Genetic and molecular diversity in Parkinson’s disease.
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Abdul Murad, Nor Azian, Sulaiman, Siti Aishah, Ahmad-Annuar, Azlina, Ibrahim, Norlinah Mohamed, Mohamed, Wael, Md Rani, Shahrul Azmin, and Kin Ying Mok
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PROTEIN kinases ,ACUTE phase proteins ,GENETIC variation ,PARKINSON'S disease ,DISEASE prevalence ,MICROBIAL virulence - Published
- 2022
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10. Mutation analysis of SOD1, C9orf72, TARDBP and FUS genes in ethnically-diverse Malaysian patients with amyotrophic lateral sclerosis (ALS)
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Nortina Shahrizaila, Marina L. Kennerson, Melina Ellis, Azlina Ahmad-Annuar, Suzanna Edgar, Khean Jin Goh, and Nur Adilah Abdul-Aziz
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Adult ,Male ,Aging ,Population ,DNA Mutational Analysis ,Biology ,medicine.disease_cause ,TARDBP ,Cohort Studies ,symbols.namesake ,Superoxide Dismutase-1 ,C9orf72 ,medicine ,Missense mutation ,Humans ,Mutation frequency ,education ,Genetic Association Studies ,Aged ,Sanger sequencing ,Genetics ,Mutation ,education.field_of_study ,DNA Repeat Expansion ,C9orf72 Protein ,General Neuroscience ,Amyotrophic Lateral Sclerosis ,Malaysia ,Middle Aged ,DNA-Binding Proteins ,symbols ,RNA-Binding Protein FUS ,Female ,Neurology (clinical) ,Geriatrics and Gerontology ,Trinucleotide repeat expansion ,Developmental Biology - Abstract
Recent studies have identified SOD1, FUS, TARDBP and C9orf72 as major ALS-related genes in both European and Asian populations. However, significant differences exist in the mutation frequencies of these genes between various ancestral backgrounds. This study aims to identify the frequency of mutations in the common causative ALS genes in a multi-ethnic Malaysian cohort. We screened 101 Malaysian ALS patients including 3 familial and 98 sporadic cases for mutations in the coding regions of SOD1, FUS, and TARDBP by Sanger sequencing. The C9orf72 hexanucleotide repeat expansion was screened using the repeat-primed polymerase chain reaction assay. Mutations were found in 5.9% (6 of 101) of patients including 3.0% (3 of 101) of patients with the previously reported SOD1 missense mutations (p.V48A and p.N87S) and 3.0% (3 of 101) of patients with the C9orf72 repeat expansion. No mutations were found in the FUS and TARDBP genes. This study is the first to report the mutation frequency in an ethnically diverse Malaysian ALS population and warrants further investigation to reveal novel genes and disease pathways.
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- 2021
11. Association study of MCCC1/LAMP3 and DGKQ variants with Parkinson's disease in patients of Malay ancestry
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Thien Thien Lim, Azlina Ahmad-Annuar, Soo Kun Lim, Wee Kooi Cheah, Yi Wen Tay, Tzi Shin Toh, Khairul Azmi Ibrahim, Ai Huey Tan, Yuganthini Vijayanathan, Irene Looi, Santhi Datuk Puvanarajah, Shanthi Viswanathan, Jia Lun Lim, Eng-King Tan, Gaik Bee Eow, Ebonne Yulin Ng, Aroma Agape Gopalai, Shen-Yang Lim, Zariah Abdul-Aziz, and Ping Chong Bee
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Genotype ,DGKQ ,Parkinson's ,Population ,Genome-wide association study ,Dermatology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,0302 clinical medicine ,Diacylglycerol kinase theta ,Asian People ,Medicine ,Humans ,Genetic Predisposition to Disease ,030212 general & internal medicine ,Allele ,education ,Genetic association ,Malay ,Genetics ,education.field_of_study ,business.industry ,ancestry ,Variants ,Malaysia ,Lysosome-Associated Membrane Glycoproteins ,Parkinson Disease ,General Medicine ,Penetrance ,language.human_language ,Neoplasm Proteins ,Psychiatry and Mental health ,Carbon-Carbon Ligases ,Case-Control Studies ,language ,Neurology (clinical) ,business ,MCCC1/LAMP3 ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
BackgroundGenome-wide association studies (GWAS) have shown that variants in the 3-methylcrotonyl-CoA carboxylase (MCCC1)/lysosome-associated membrane protein 3 (LAMP3) loci (rs10513789, rs12637471, rs12493050) reduce the risk of Parkinson’s disease (PD) in Caucasians, Chinese and Ashkenazi-Jews while the rs11248060 variant in the diacylglycerol kinase theta (DGKQ)gene increases the risk of PD in Caucasian and Han Chinese cohorts. However, their roles in Malays are unknown. Therefore, this study aims to investigate the association of these variants with the risk of PD in individuals of Malay ancestry. MethodsA total of 1114 subjects comprising of 536 PD patients and 578 healthy controls of Malay ancestry were recruited and genotyped using Taqman® allelic discrimination assays. ResultsThe G allele of rs10513789 (OR = 0.83,p = 0.001) and A allele of rs12637471 (OR = 0.79,p = 0.007) in theMCCC1/LAMP3locus were associated with a protective effect against developing PD in the Malay population. A recessive model of penetrance showed a protective effect of the GG genotype for rs10513789 and the AA genotype for rs12637471. No association with PD was found with the otherMCCC1/LAMP3rs12493050 variant or with theDGKQ(rs11248060) variant. No significant associations were found between the four variants with the age at PD diagnosis. ConclusionMCCC1/LAMP3variants rs10513789 and rs12637471 protect against PD in the Malay population.
- Published
- 2021
12. Underrepresented Populations in Parkinson's Genetics Research: Current Landscape and Future Directions.
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Schumacher‐Schuh, Artur Francisco, Bieger, Andrei, Okunoye, Olaitan, Mok, Kin Ying, Lim, Shen‐Yang, Bardien, Soraya, Ahmad‐Annuar, Azlina, Santos‐Lobato, Bruno Lopes, Strelow, Matheus Zschornack, Salama, Mohamed, Rao, Shilpa C., Zewde, Yared Zenebe, Dindayal, Saiesha, Azar, Jihan, Prashanth, Lingappa Kukkle, Rajan, Roopa, Noyce, Alastair J., Okubadejo, Njideka, Rizig, Mie, and Lesage, Suzanne
- Abstract
Background: Human genetics research lacks diversity; over 80% of genome‐wide association studies have been conducted on individuals of European ancestry. In addition to limiting insights regarding disease mechanisms, disproportionate representation can create disparities preventing equitable implementation of personalized medicine. Objective: This systematic review provides an overview of research involving Parkinson's disease (PD) genetics in underrepresented populations (URP) and sets a baseline to measure the future impact of current efforts in those populations. Methods: We searched PubMed and EMBASE until October 2021 using search strings for "PD," "genetics," the main "URP," and and the countries in Latin America, Caribbean, Africa, Asia, and Oceania (excluding Australia and New Zealand). Inclusion criteria were original studies, written in English, reporting genetic results on PD from non‐European populations. Two levels of independent reviewers identified and extracted information. Results: We observed imbalances in PD genetic studies among URPs. Asian participants from Greater China were described in the majority of the articles published (57%), but other populations were less well studied; for example, Blacks were represented in just 4.0% of the publications. Also, although idiopathic PD was more studied than monogenic forms of the disease, most studies analyzed a limited number of genetic variants. We identified just nine studies using a genome‐wide approach published up to 2021, including URPs. Conclusion: This review provides insight into the significant lack of population diversity in PD research highlighting the immediate need for better representation. The Global Parkinson's Genetics Program (GP2) and similar initiatives aim to impact research in URPs, and the early metrics presented here can be used to measure progress in the field of PD genetics in the future. © 2022 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]
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- 2022
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13. LRRK2 N551K and R1398H variants are protective in Malays and Chinese in Malaysia: A case–control association study for Parkinson's disease
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Chong Tin Tan, Ai Huey Tan, Gaik Bee Eow, Azlina Ahmad Annuar, Zariah Abdul Aziz, Shanthi Viswanathan, Shen-Yang Lim, Aroma Agape Gopalai, Yi Zhao, Thien Thien Lim, Soo Kun Lim, Huihua Li, Jia Lun Lim, Mohamed Ibrahim Norlinah, Eng-King Tan, and Santhi Datuk Puvanarajah
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Parkinson's disease ,Genotype ,lcsh:QH426-470 ,Disease ,Neurological disorder ,030105 genetics & heredity ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,Cohort Studies ,03 medical and health sciences ,R1398H ,Asian People ,Internal medicine ,Genetics ,Humans ,Medicine ,Genetic Predisposition to Disease ,Molecular Biology ,Genetics (clinical) ,Malay ,business.industry ,Haplotype ,Malaysia ,Parkinson Disease ,LRRK2 ,Original Articles ,Middle Aged ,Prognosis ,medicine.disease ,N551K ,language.human_language ,SNP genotyping ,lcsh:Genetics ,030104 developmental biology ,Haplotypes ,Case-Control Studies ,Mutation ,Cohort ,language ,Female ,Original Article ,business ,Follow-Up Studies - Abstract
Background The LRRK2 gene is associated with Parkinson's disease (PD) as a number of mutations within the gene have been shown to be susceptibility factors. Studies on various global populations have determined that mutations such as G2019S, G2385R, and R1628P in LRRK2 increase the risk of developing PD while the N551K‐R1398H haplotype is associated with conferring protection against developing PD. Here we report a study looking at the N551K and R1398H variants for the first time in the Malaysian population. Methods Cases (523) which conformed to the United Kingdom PD Brain Bank Criteria for PD were recruited through trained neurologists and age‐ and ethnically matched controls (491) were individuals free of any neurological disorder. The N551K and R1398H mutations were genotyped using the Taqman SNP genotyping assay. Results A significant protective association for N551K was found in those of Malay ancestry, with a protective trend seen for R1398H. A meta‐analysis of Chinese individuals in this cohort with other published cohorts of Chinese ancestry indicated a significant protective role for N551K and R1398H. Conclusion This study reports that the N551K‐R1398H haplotype is also relevant to the Malaysian population, with a significant protective effect found in those of Malay and Chinese ancestries.
- Published
- 2019
14. Genetic analysis of the cytoplasmic dynein subunit families.
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K Kevin Pfister, Paresh R Shah, Holger Hummerich, Andreas Russ, James Cotton, Azlina Ahmad Annuar, Stephen M King, and Elizabeth M C Fisher
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Genetics ,QH426-470 - Abstract
Cytoplasmic dyneins, the principal microtubule minus-end-directed motor proteins of the cell, are involved in many essential cellular processes. The major form of this enzyme is a complex of at least six protein subunits, and in mammals all but one of the subunits are encoded by at least two genes. Here we review current knowledge concerning the subunits, their interactions, and their functional roles as derived from biochemical and genetic analyses. We also carried out extensive database searches to look for new genes and to clarify anomalies in the databases. Our analysis documents evolutionary relationships among the dynein subunits of mammals and other model organisms, and sheds new light on the role of this diverse group of proteins, highlighting the existence of two cytoplasmic dynein complexes with distinct cellular roles.
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- 2006
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15. Ala97Ser mutation is common among ethnic Chinese Malaysians with transthyretin familial amyloid polyneuropathy
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Khean Jin Goh, Nor Ashikin Md Sari, Chong Tin Tan, Nortina Shahrizaila, Soon Chai Low, Azlina Ahmad-Annuar, Kon-Ping Lin, Cheng-Yin Tan, and Kum Thong Wong
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Adult ,Male ,China ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,parasitic diseases ,Internal Medicine ,Medicine ,Humans ,Prealbumin ,Aged ,Genetics ,Amyloid Neuropathies, Familial ,biology ,business.industry ,Ethnic chinese ,Middle Aged ,humanities ,Transthyretin ,Southern china ,Mutation (genetic algorithm) ,Mutation ,biology.protein ,Amyloid polyneuropathy ,Female ,business ,030217 neurology & neurosurgery - Abstract
Ethnic Chinese Malaysians are descended from immigrants from Southern China in the nineteenth century. Although familial amyloid polyneuropathy (FAP) is a rare autosomal dominant peripheral neuropa...
- Published
- 2019
16. Linkage analysis and whole exome sequencing reveals AHNAK2 as a novel genetic cause for autosomal recessive CMT in a Malaysian family
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Shelisa Tey, Marina L. Kennerson, Alexander P. Drew, Khean Jin Goh, Yesim Parman, Azlina Ahmad-Annuar, Byung-Ok Choi, Derek Atkinson, Michaela Auer-Grumbach, Ki Wha Chung, Garth A. Nicholson, Esra Battaloglu, Sarimah Samulong, Nortina Shahrizaila, Yi-Chung Li, and Albena Jordanova
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0301 basic medicine ,Genetic Markers ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,Genetic Linkage ,Biopsy ,Mutant ,Mutation, Missense ,Loss of Heterozygosity ,Locus (genetics) ,Genes, Recessive ,Biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Consanguinity ,0302 clinical medicine ,Genetic linkage ,Charcot-Marie-Tooth Disease ,Exome Sequencing ,Genetics ,Humans ,Genetic Predisposition to Disease ,Allele ,Gene ,Genetics (clinical) ,Exome sequencing ,Alleles ,Family Health ,Neurons ,Messenger RNA ,Malaysia ,Chromosome Mapping ,Membrane Proteins ,Fibroblasts ,Human genetics ,Pedigree ,nervous system diseases ,Cytoskeletal Proteins ,030104 developmental biology ,Haplotypes ,Female ,Human medicine ,Lod Score ,030217 neurology & neurosurgery - Abstract
Charcot-Marie-Tooth (CMT) disease is a form of inherited peripheral neuropathy that affects motor and sensory neurons. To identify the causative gene in a consanguineous family with autosomal recessive CMT (AR-CMT), we employed a combination of linkage analysis and whole exome sequencing. After excluding known AR-CMT genes, genome-wide linkage analysis mapped the disease locus to a 7.48-Mb interval on chromosome 14q32.11-q32.33, flanked by the markers rs2124843 and rs4983409. Whole exome sequencing identified two non-synonymous variants (p.T40P and p.H915Y) in the AHNAK2 gene that segregated with the disease in the family. Pathogenic predictions indicated that p.T40P is the likely causative allele. Analysis of AHNAK2 expression in the AR-CMT patient fibroblasts showed significantly reduced mRNA and protein levels. AHNAK2 binds directly to periaxin which is encoded by the PRX gene, and PRX mutations are associated with another form of AR-CMT (CMT4F). The altered expression of mutant AHNAK2 may disrupt the AHNAK2-PRX interaction in which one of its known functions is to regulate myelination.
- Published
- 2019
17. Mutation analysis of genes within the dynactin complex in a cohort of hereditary peripheral neuropathies
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Shelisa Tey, Marina L. Kennerson, Alexander P. Drew, Garth A. Nicholson, Azlina Ahmad-Annuar, and Nortina Shahrizaila
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0301 basic medicine ,Genetics ,Mutation ,Hereditary spastic paraplegia ,Biology ,medicine.disease ,medicine.disease_cause ,DCTN1 ,03 medical and health sciences ,030104 developmental biology ,medicine ,Dynactin ,ACTR1B ,Gene ,ACTR1A ,Exome ,Genetics (clinical) - Abstract
The cytoplasmic dynein-dynactin genes are attractive candidates for neurodegenerative disorders given their functional role in retrograde transport along neurons. The cytoplasmic dynein heavy chain (DYNC1H1) gene has been implicated in various neurodegenerative disorders, and dynactin 1 (DCTN1) genes have been implicated in a wide spectrum of disorders including motor neuron disease, Parkinson's disease, spinobulbar muscular atrophy and hereditary spastic paraplegia. However, the involvement of other dynactin genes with inherited peripheral neuropathies (IPN) namely, hereditary sensory neuropathy, hereditary motor neuropathy and Charcot-Marie-Tooth disease is under reported. We screened eight genes; DCTN1-6 and ACTR1A and ACTR1B in 136 IPN patients using whole-exome sequencing and high-resolution melt (HRM) analysis. Eight non-synonymous variants (including one novel variant) and three synonymous variants were identified. Four variants have been reported previously in other studies, however segregation analysis within family members excluded them from causing IPN in these families. No variants of disease significance were identified in this study suggesting the dynactin genes are unlikely to be a common cause of IPNs. However, with the ease of querying gene variants from exome data, these genes remain worthwhile candidates to assess unsolved IPN families for variants that may affect the function of the proteins.
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- 2016
18. Association of LRRK2 Haplotype With Age at Onset in Parkinson Disease
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Azlina Ahmad-Annuar, Bin Xiao, Ebonne Yulin Ng, Shen-Yang Lim, Xiao Deng, Eng-King Tan, and John Carson Allen
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0301 basic medicine ,Male ,Genotype ,Disease ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,03 medical and health sciences ,0302 clinical medicine ,Research Letter ,Medicine ,Humans ,Age of Onset ,Association (psychology) ,Genetic Association Studies ,Aged ,Genetics ,business.industry ,Haplotype ,Parkinson Disease ,Middle Aged ,LRRK2 ,United Kingdom ,nervous system diseases ,030104 developmental biology ,Mutation (genetic algorithm) ,Mutation ,Female ,Neurology (clinical) ,Age of onset ,business ,030217 neurology & neurosurgery - Abstract
This study examines the effect of LRRK2 risk variants on the age at onset of Parkinson disease.
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- 2017
19. Improved inherited peripheral neuropathy genetic diagnosis by whole‐exome sequencing
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Aditi Kidambi, Megan H. Brewer, Alexander P. Drew, Garth A. Nicholson, Shelisa Tey, Marina L. Kennerson, Carolyn Ly, Azlina Ahmad-Annuar, and Danqing Zhu
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inherited peripheral neuropathy ,Genetics ,BSCL2 ,Original Articles ,Disease ,Biology ,Charcot-Marie-Tooth disease ,BICD2 ,Phenotype ,genetic diagnosis ,Missense mutation ,whole-exome sequencing ,Genetic diagnosis ,Molecular Biology ,Gene ,Genetics (clinical) ,Exome sequencing - Abstract
Inherited peripheral neuropathies (IPNs) are a group of related diseases primarily affecting the peripheral motor and sensory neurons. They include the hereditary sensory neuropathies (HSN), hereditary motor neuropathies (HMN), and Charcot-Marie-Tooth disease (CMT). Using whole-exome sequencing (WES) to achieve a genetic diagnosis is particularly suited to IPNs, where over 80 genes are involved with weak genotype–phenotype correlations beyond the most common genes. We performed WES for 110 index patients with IPN where the genetic cause was undetermined after previous screening for mutations in common genes selected by phenotype and mode of inheritance. We identified 41 missense sequence variants in the known IPN genes in our cohort of 110 index patients. Nine variants (8%), identified in the genes MFN2, GJB1, BSCL2, and SETX, are previously reported mutations and considered to be pathogenic in these families. Twelve novel variants (11%) in the genes NEFL, TRPV4, KIF1B, BICD2, and SETX are implicated in the disease but require further evidence of pathogenicity. The remaining 20 variants were confirmed as polymorphisms (not causing the disease) and are detailed here to help interpret sequence variants identified in other family studies. Validation using segregation, normal controls, and bioinformatics tools was valuable as supporting evidence for sequence variants implicated in disease. In addition, we identified one SETX sequence variant (c.7640T>C), previously reported as a putative mutation, which we have confirmed as a nonpathogenic rare polymorphism. This study highlights the advantage of using WES for genetic diagnosis in highly heterogeneous diseases such as IPNs and has been particularly powerful in this cohort where genetic diagnosis could not be achieved due to phenotype and mode of inheritance not being previously obvious. However, first tier testing for common genes in clinically well-defined cases remains important and will account for most positive results.
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- 2015
20. Parkinson's disease with homozygous PINK1 p.Leu489Pro mutations in two Indian sisters.
- Author
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Shen-Yang Lim, Ahmad-Annuar, Azlina, Lohmann, Katja, Ai Huey Tan, Yi Wen Tay, Jia Lun Lim, Ramli, Norlisah, Pei Chiek Teh, Kuppusamy, Rishikesan, Chong Tin Tan, Khean Jin Goh, Viswanathan, Shanthi, Bauer, Peter, Rolfs, Arndt, and Klein, Christine
- Subjects
- *
PARKINSON'S disease , *DYSKINESIAS , *SISTERS , *INDIANS (Asians) , *PHENOTYPES - Abstract
We describe the clinical features of two sisters with Parkinson's disease (PD) of Indian descent living in Malaysia. Both were homozygous for the known PINK1 mutation p.Leu489Pro (c.1466T>C). The proband, who has been followed up by us over a span of 35 years, had a fairly "classic" clinical presentation for PARK-PINK1, including young onset, a clear response to dopamine replacement therapy, and development of troublesome motor fluctuations and dyskinesias. Her dyskinesias improved substantially with clozapine treatment, which to our knowledge has not specifically been reported for PARK-PINK1; this treatment has been sustained for nearly a decade. The clinical phenotype of the older sister was more akin to later-onset "idiopathic" PD; however, her brain MRI showed abnormal signal in the posterior limb of the internal capsules and the hypothalamus. Our report contributes to the scarce literature on monogenic PD in the Malaysian / Indian population, and further supports the pathogenicity of the PINK1 p.Leu489Pro variant. [ABSTRACT FROM AUTHOR]
- Published
- 2021
21. Clinical phenotype of Parkinson's disease with a homozygous PRKN p.Cys441Arg mutation.
- Author
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Shen-Yang Lim, Ahmad-Annuar, Azlina, Lohmann, Katja, Ai Huey Tan, Yi Wen Tay, Jia Lun Lim, Kai Bin Lim, Lei Cheng Lit, Bauer, Peter, Rolfs, Arndt, and Klein, Christine
- Subjects
- *
PARKINSON'S disease , *PHENOTYPES , *DEEP brain stimulation , *ORAL medication , *BRAIN surgery , *DYSKINESIAS - Abstract
We describe the clinical features of a Malaysian woman with Parkinson's disease (PD) who carried the PRKN p.Cys441Arg mutation in the homozygous state. She had a fairly "classic" clinical presentation for PARK-Parkin, including juvenile onset and a clear response to dopaminergic medication complicated by motor fluctuations and dyskinesias. She had a substantial benefit with apomorphine infusion treatment, which to our knowledge has not been reported for PARK-Parkin. Our report contributes to the very scarce literature on monogenic causes of PD in the Malaysian population, and highlights an alternative treatment option to oral dopaminergic medication or deep brain stimulation surgery. [ABSTRACT FROM AUTHOR]
- Published
- 2021
22. Analysis of dynein intermediate chains, light intermediate chains and light chains in a cohort of hereditary peripheral neuropathies
- Author
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Nortina Shahrizaila, Alexander P. Drew, Azlina Ahmad-Annuar, Garth A. Nicholson, Shelisa Tey, and Marina L. Kennerson
- Subjects
Cytoplasmic Dyneins ,Male ,Genetics ,Dynein ,Catabolite repression ,Peripheral Nervous System Diseases ,Biology ,Immunoglobulin light chain ,Phenotype ,Human genetics ,Sensory neuron ,Peripheral ,DNA-Binding Proteins ,Cellular and Molecular Neuroscience ,medicine.anatomical_structure ,Mutation ,medicine ,Humans ,Female ,Genetic Testing ,Gene ,Genetics (clinical) - Abstract
The cytoplasmic dynein heavy chain (DYNC1H1) gene has been increasingly associated with neurodegenerative disorders including axonal Charcot-Marie-Tooth disease (CMT2), intellectual disability and malformations of cortical development. In addition, evidence from mouse models (Loa, catabolite repressor-activator (Cra) and Sprawling (Swl)) has shown that mutations in Dync1h1 cause a range of neurodegenerative phenotypes with motor and sensory neuron involvement. In this current study, we examined the possible contribution of other cytoplasmic dynein subunits that bind to DYNC1H1 as a cause of inherited peripheral neuropathy. We focused on screening the cytoplasmic dynein intermediate, light intermediate and light chain genes in a cohort of families with inherited peripheral neuropathies. Nine genes were screened and ten variants were detected, but none was identified as pathogenic, indicating that cytoplasmic dynein intermediate, light intermediate and light chains are not a cause of neuropathy in our cohort.
- Published
- 2014
23. Analysis of non-synonymous-coding variants of Parkinson's disease-related pathogenic and susceptibility genes in East Asian populations
- Author
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Anne Y.Y. Chan, Wing Lok Au, Yusun Jung, Jimmy Lee, Jianjun Liu, Kyuyoung Song, Siow Ann Chong, Shen-Yang Lim, Azlina Ahmad-Annuar, Kumar M. Prakash, Jia Nee Foo, Eng-King Tan, Juyeon Kim, Yen Yek Ng, Tin Aung, Vincent Mok, Tat Hung Koh, Herty Liany, Sun Ju Chung, Louis C.S. Tan, Eranga N. Vithana, Chiea Chuen Khor, Tien Yin Wong, Ishak D. Irwan, and E. Shyong Tai
- Subjects
Male ,Genotype ,Population ,Genome-wide association study ,Disease ,Biology ,Polymorphism, Single Nucleotide ,Open Reading Frames ,Asian People ,Genetics ,Humans ,Genetic Predisposition to Disease ,education ,Molecular Biology ,Gene ,Genetics (clinical) ,Loss function ,Aged ,Genetic association ,education.field_of_study ,Genetic Variation ,Parkinson Disease ,Sequence Analysis, DNA ,General Medicine ,Odds ratio ,Middle Aged ,LRRK2 ,Female - Abstract
To evaluate the contribution of non-synonymous-coding variants of known familial and genome-wide association studies (GWAS)-linked genes for Parkinson's disease (PD) to PD risk in the East Asian population, we sequenced all the coding exons of 39 PD-related disease genes and evaluated the accumulation of rare non-synonymous-coding variants in 375 early-onset PD cases and 399 controls. We also genotyped 782 non-synonymous-coding variants of these genes in 710 late-onset PD cases and 9046 population controls. Significant enrichment of LRRK2 variants was observed in both early- and late-onset PD (odds ratio = 1.58; 95% confidence interval = 1.29-1.93; P = 8.05 × 10(-6)). Moderate enrichment was also observed in FGF20, MCCC1, GBA and ITGA8. Half of the rare variants anticipated to cause loss of function of these genes were present in healthy controls. Overall, non-synonymous-coding variants of known familial and GWAS-linked genes appear to make a limited contribution to PD risk, suggesting that clinical sequencing of these genes will provide limited information for risk prediction and molecular diagnosis.
- Published
- 2014
24. Evaluation of novel Parkinson's disease candidate genes in the Chinese population
- Author
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Wing Lok Au, Anne Y.Y. Chan, Jia Nee Foo, Elaine G.Y. Chew, Jianjun Liu, Azlina Ahmad Annuar, Eng-King Tan, Vincent Mok, Shen-Yang Lim, Sun Ju Chung, Kumar M. Prakash, Louis C.S. Tan, Kyuyoung Song, Herty Liany, and Lee Kong Chian School of Medicine (LKCMedicine)
- Subjects
CD36 Antigens ,Risk ,0301 basic medicine ,Nonsynonymous substitution ,Heterozygote ,Aging ,Candidate gene ,Population ,Disease ,Biology ,Compound heterozygosity ,03 medical and health sciences ,0302 clinical medicine ,Asian People ,Loss of Function Mutation ,Genetics ,Humans ,Genetic Predisposition to Disease ,Biological sciences::Genetics [Science] ,education ,Gene ,Genotyping ,Genetic Association Studies ,education.field_of_study ,Parkinson's Disease ,General Neuroscience ,Parkinson Disease ,Heterozygote advantage ,030104 developmental biology ,Neurology (clinical) ,Geriatrics and Gerontology ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Recent whole-exome sequencing studies in European patients with Parkinson's disease (PD) have identified potential risk variants across 33 novel PD candidate genes. We aim to determine if these reported candidate genes are similarly implicated in Asians by assessing common, rare, and novel nonsynonymous coding variants by sequencing all 33 genes in 198 Chinese samples and genotyping coding variants in an independent set of 9756 Chinese samples. We carried out further targeted sequencing of CD36 in an additional 576 Chinese and Korean samples. We found that only 8 of 43 reported risk variants were polymorphic in our Chinese samples. We identified several heterozygotes for rare loss-of-function mutations, including the reported CD36 p.Gln74Ter variant, in both cases and controls. We also observed 2 potential compound heterozygotes among PD cases for rare loss-of-function mutations in CD36 and SSPO. The other reported variants were common in East Asians and not associated with PD, completely absent, or only found in controls. Therefore, the 33 reported candidate genes and associated variants are unlikely to confer significant PD risk in the East Asian population. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore) Accepted version
- Published
- 2019
25. Clinical Phenotype of LRRK2 R1441C in 2 Chinese Sisters.
- Author
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Lim, Shen-Yang, Lim, Jia Lun, Ahmad-Annuar, Azlina, Lohmann, Katja, Tan, Ai Huey, Lim, Kai Bin, Tay, Yi Wen, Shing, Yee Lee, Muthusamy, Kalai Arasu, Bauer, Peter, Rolfs, Arndt, and Klein, Christine
- Subjects
CHINESE people ,PARKINSON'S disease ,ASHKENAZIM ,DEEP brain stimulation ,SISTERS - Abstract
Pathogenic and risk variants in the LRRK2 gene are among the main genetic contributors to Parkinson's disease (PD) worldwide, and LRRK2-targeted therapies for patients with PARK-LRRK2are now entering clinical trials. However, in contrast to the LRRK2 G2019S mutation commonly found in Caucasians, North-African Arabs, and Ashkenazi Jews, relatively little is known about other causative LRRK2 mutations, and data on genotype-phenotype correlations are largely lacking. This report is from an ongoing multicentre study in which next-generation sequencing-based PD gene panel testing has so far been conducted on 499 PD patients of various ethnicities from Malaysia. We describe 2 sisters of Chinese ancestry with PD who carry the R1441C mutation in LRRK2 (which in Asians has been reported in only 2 Chinese patients previously), and highlight interesting clinical observations made over a decade of close follow-up. We further explored the feasibility of using a brief, expert-administered rating scale (the Clinical Impression of Severity Index; CISI-PD) to capture data on global disease severity in a large (n = 820) unselected cohort of PD patients, including severely disabled individuals typically excluded from research studies. All patients in this study were managed and evaluated by the same PD neurologist, and these data were used to make broad comparisons between the monogenic PD cases versus the overall "real world" PD cohort. This report contributes to the scarce literature on R1441C PARK-LRRK2, offering insights into natural history and epidemiological aspects, and provides support for the application of a simple and reliable clinical tool that can improve the inclusion of under-represented patient groups in PD research. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
26. X-linked Charcot-Marie-Tooth disease predominates in a cohort of multiethnic Malaysian patients
- Author
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Sarimah Samulong, Lao Kah Meng, Khean Jin Goh, Shelisa Tey, Azlina Ahmad-Annuar, Liaw Chiew Suan, and Nortina Shahrizaila
- Subjects
Genetics ,medicine.medical_specialty ,Physiology ,Point mutation ,Disease ,Biology ,Southeast asian ,Phenotype ,Cellular and Molecular Neuroscience ,Tooth disease ,Physiology (medical) ,Internal medicine ,Gene duplication ,Cohort ,Genotype ,medicine ,Neurology (clinical) - Abstract
Introduction: Data regarding Charcot–Marie–Tooth disease is lacking in Southeast Asian populations. We investigated the frequency of the common genetic mutations in a multiethnic Malaysian cohort. Methods: Patients with features of Charcot–Marie–Tooth disease or hereditary liability to pressure palsies were investigated for PMP22 duplication, deletion, and point mutations and GJB1, MPZ, and MFN2 point mutations. Results: Over a period of 3 years, we identified 25 index patients. A genetic diagnosis was reached in 60%. The most common were point mutations in GJB1, accounting for X-linked Charcot–Marie–Tooth disease (24% of the total patient population), followed by PMP22 duplication causing Charcot–Marie–Tooth disease type 1A (20%). We also discovered 2 novel GJB1 mutations, c.521C>T (Proline174Leucine) and c.220G>A (Valine74Methionine). Conclusions: X-linked Charcot–Marie–Tooth disease was found to predominate in our patient cohort. We also found a better phenotype/genotype correlation when applying a more recently recommended genetic approach to Charcot–Marie–Tooth disease. Muscle Nerve 49: 198–201, 2014
- Published
- 2013
27. Genome-wide association study of Parkinson's disease in East Asians
- Author
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Hui Qi Low, Jimmy Lee, Hong Liu, Ai Huey Tan, Anne Y.Y. Chan, Tin Aung, Khai Koon Heng, Soo-Hong Chew, Chiea Chuen Khor, Jianjun Liu, Wing Lok Au, Eranga N. Vithana, Shen-Yang Lim, Mythily Subramaniam, Jin-Xin Bei, Richard P. Ebstein, Jia Nee Foo, Chiung Mei Chen, Kumar M. Prakash, Hao Deng, Seang-Mei Saw, Kyuyoung Song, Adeline Seow, Yi-Chun Chen, Tien Yin Wong, Vincent Mok, Hui-Fang Shang, Wee-Yang Meah, Azlina Ahmad-Annuar, Siow Ann Chong, Eng-King Tan, Furen Zhang, Zhong Pei, Rong Peng, Sun Ju Chung, Yih-Ru Wu, E-Shyong Tai, Ching-Yu Cheng, Fook Tim Chew, Louis C.S. Tan, Ishak D. Irwan, Hao Pang, and Lee Kong Chian School of Medicine (LKCMedicine)
- Subjects
0301 basic medicine ,Mainland China ,Adult ,Male ,Parkinson's disease ,Genotype ,Single-nucleotide polymorphism ,Genome-wide association study ,Disease ,Biology ,Logistic regression ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,0302 clinical medicine ,Meta-Analysis as Topic ,Risk Factors ,medicine ,Genetics ,Ethnicity ,Humans ,Medicine [Science] ,Genetic Predisposition to Disease ,Molecular Biology ,Genetics (clinical) ,Genetic association ,Parkinson's Disease ,Asia, Eastern ,Parkinson Disease ,General Medicine ,Middle Aged ,medicine.disease ,030104 developmental biology ,Genetic Loci ,Case-Control Studies ,Female ,030217 neurology & neurosurgery ,Imputation (genetics) ,Biomarkers ,Demography ,Genome-Wide Association Study - Abstract
Genome-wide association studies (GWAS) on Parkinson’s disease (PD) have mostly been done in Europeans and Japanese. No study has been done in Han Chinese, which make up nearly a fifth of the world population. We conducted the first Han Chinese GWAS analysing a total of 22,729 subjects (5,125 PD cases and 17,604 controls) from Singapore, Hong Kong, Malaysia, Korea, mainland China and Taiwan. We performed imputation, merging and logistic regression analyses of 2,402,394 SNPs passing quality control filters in 779 PD cases, 13,227 controls, adjusted for the first three principal components. 90 SNPs with association P 1.45) on PD risk. Our results also demonstrate some differences in the genetic contribution to PD between Europeans and Asians. Further pan-ethnic meta-analysis with European GWAS cohorts may unravel new PD loci. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore) Accepted version
- Published
- 2016
28. Identification of the genomic mutation in Epha4(rb-2J/rb-2J) mice
- Author
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Noraishah Mydin Abdul-Aziz, Kerri York, Nor-Linda Abdullah, Ahmed I. Marwan, Pike See Cheah, Aminah Abdullah, Hadri Hadi Md Yusof, King Hwa Ling, Siti Waheeda Mohd-Zin, Sarah M. Williams, Azlina Ahmad-Annuar, and Nicholas D. E. Greene
- Subjects
0301 basic medicine ,Male ,Gene Expression ,Biology ,Hippocampus ,Polymerase Chain Reaction ,Receptor tyrosine kinase ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Genomic mutation ,In vivo ,Genetics ,Ephrin ,Animals ,Molecular Biology ,Alleles ,Sequence Deletion ,Mice, Knockout ,Embryogenesis ,Erythropoietin-producing hepatocellular (Eph) receptor ,Receptor, EphA4 ,General Medicine ,Exons ,Genomics ,Molecular biology ,Mice, Inbred C57BL ,Sterile Alpha Motif ,030104 developmental biology ,Knockout mouse ,biology.protein ,Codon, Terminator ,RNA ,Female ,Tyrosine kinase ,030217 neurology & neurosurgery ,Polymorphism, Restriction Fragment Length ,Biotechnology ,Signal Transduction - Abstract
The EphA4 receptor tyrosine kinase is involved in numerous cell-signalling activities during embryonic development. EphA4 has the ability to bind to both types of ephrin ligands, the ephrinAs and ephrinBs. The C57BL/6J-Epha4rb-2J/GrsrJ strain, denoted Epha4rb-2J/rb-2J, is a spontaneous mouse mutant that arose at The Jackson Laboratory. These mutants exhibited a synchronous hind limb locomotion defect or “hopping gait” phenotype, which is also characteristic of EphA4 null mice. Genetic complementation experiments suggested that Epha4rb-2Jcorresponds to an allele of EphA4, but details of the genomic defect in this mouse mutant are currently unavailable. We found a single base-pair deletion in exon 9 resulting in a frame shift mutation that subsequently resulted in a premature stop codon. Analysis of the predicted structure of the truncated protein suggests that both the kinase and sterile α motif (SAM) domains are absent. Definitive determination of genotype is needed for experimental studies of mice carrying the Epha4rb-2Jallele, and we have also developed a method to ease detection of the mutation through RFLP. Eph-ephrin family members are reportedly expressed as numerous isoforms. Hence, delineation of the specific mutation in EphA4 in this strain is important for further functional studies, such as protein–protein interactions, immunostaining and gene compensatory studies, investigating the mechanism underlying the effects of altered function of Eph family of receptor tyrosine kinases on phenotype.
- Published
- 2016
29. Association of HLA locus variant in Parkinson's disease
- Author
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Eng-King Tan, Li-Ping Tan, Wing Lok Au, Huihua Li, Yi Zhao, Azlina Ahmad-Annuar, Aroma Agape Gopalai, Soo Kun Lim, Norlinah Mohamed Ibrahim, Shen-Yang Lim, Kumar M. Prakash, L. C S Tan, E. W L Teng, and Yip Boon Chong
- Subjects
Oncology ,Genetics ,medicine.medical_specialty ,business.industry ,Genome-wide association study ,Locus (genetics) ,Odds ratio ,Human leukocyte antigen ,Disease ,Logistic regression ,Confidence interval ,Internal medicine ,Medicine ,Allele ,business ,Genetics (clinical) - Abstract
A variant (rs3129882) in the genome-wide association study (GWAS)-linked variant [in the human leukocyte antigen (HLA) gene region] has been reported to associate with an increased risk of Parkinson's disease (PD) in Caucasian population. Studies among Chinese are limited. To address this, we analysed rs3129882 in a total of 1312 subjects of Chinese ethnicity from independent Asian centers comprising of 675 controls and 637 PD cases. The rs3129882 variant was associated with a decreased risk in our ethnic Chinese PD patients. Logistic regression analysis taking into consideration variables of age, gender and race showed that allele A reduced the risk of PD via a dominant model [odds ratio (OR) = 0.77, 95% confidence interval (CI) = 0.62, 0.96, p = 0.018]. As HLA is a highly polymorphic region, it is possible that ethnic-specific effect or environmental agents may modulate the effect of this GWAS-linked locus in influencing the risk of PD.
- Published
- 2012
30. Glucocerebrocidase gene variants in Malays with Parkinson’s disease
- Author
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N.A. Abdul Murad, N.F. Mohamad Pakarul Razy, Rahima Jamal, A. Ahmad Annuar, Saiful Effendi Syafruddin, N. Mohamed Ibrahim, and Shen-Yang Lim
- Subjects
Genetics ,Parkinson's disease ,Neurology ,business.industry ,Medicine ,Neurology (clinical) ,Geriatrics and Gerontology ,business ,medicine.disease ,Gene - Published
- 2018
31. PARK16 is associated with PD in the Malaysian population
- Author
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Yi Zhao, Zariah Abdul Aziz, Viswanathan Shanthi, Puvanarajah Santhi, Gaik Bee Eow, Chong Tin Tan, Thien T hien Lim, Ai Huey Tan, Mohamed Ibrahim Norlinah, Aroma Agape Gopalai, Eng-King Tan, Azlina Ahmad-Annuar, Huihua Li, Soo Kun Lim, and Shen-Yang Lim
- Subjects
0301 basic medicine ,Oncology ,Adult ,Male ,medicine.medical_specialty ,Single-nucleotide polymorphism ,Locus (genetics) ,Logistic regression ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Ethnicity ,Medicine ,SNP ,Humans ,Genetic Predisposition to Disease ,Allele ,Genetics (clinical) ,Alleles ,Genetic Association Studies ,Aged ,Genetics ,Aged, 80 and over ,business.industry ,Malaysia ,Parkinson Disease ,Odds ratio ,Middle Aged ,Psychiatry and Mental health ,030104 developmental biology ,Meta-analysis ,Cohort ,Female ,business ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
PARK16 was identified as a risk factor for Parkinson's disease in a Japanese cohort; however, subsequent studies in the other populations including the Chinese, European, Caucasian, and Chilean have shown a protective role instead. To investigate this locus in our Malaysian cohort, 1,144 individuals were screened for five SNPs in the PARK16 locus and logistic regression analysis showed that the A allele of the rs947211 SNP reduced the risk of developing PD via a recessive model (Odds ratio 0.57, P-value 0.0003). Pooled analysis with other Asian studies showed that A allele of the rs947211 SNP decreased the risk of developing PD via a recessive model (Odds ratio 0.71, P-value 0.0001). In addition, when meta-analysis was performed with other Asian population, three SNPs (rs823128, rs823156, and rs11240572) reduced risk of developing PD via a dominant model. © 2016 Wiley Periodicals, Inc.
- Published
- 2015
32. No association ofDYNC1H1with sporadic ALS in a case‐control study of a northern European derived population: A tagging SNP approach
- Author
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Paresh Shah, Elizabeth M. C. Fisher, David Goldstein, Robert H. Brown, HR Horvitz, Peter C. Sapp, KR Ahmadi, Carsten Russ, and Azlina Ahmad-Annuar
- Subjects
Cytoplasmic Dyneins ,Male ,Linkage disequilibrium ,Population ,Locus (genetics) ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,White People ,Genetic variation ,medicine ,Humans ,Genetic Predisposition to Disease ,Amyotrophic lateral sclerosis ,education ,Expressed Sequence Tags ,Genetics ,education.field_of_study ,Genetic diversity ,Amyotrophic Lateral Sclerosis ,Haplotype ,Dyneins ,General Medicine ,medicine.disease ,Neurology ,Case-Control Studies ,Female ,Neurology (clinical) - Abstract
The cytoplasmic dynein-dynactin complex has been implicated in the aetiology of motor neuron degeneration in both mouse models and human forms of motor neuron disease. We have previously shown that mutations in the cytoplasmic dynein 1 heavy chain 1 gene (Dync1h1) are causal in a mouse model of late-onset motor neuron degeneration but have found no association of the homologous sites in human DYNC1H1 with human motor neuron disease. Here we extend these analyses to investigate the DYNC1H1 genomic locus to determine if it is associated with sporadic amyotrophic lateral sclerosis (ALS) in a northern European-derived population. Among the 16 single nucleotide polymorphisms (SNPs) we examined, just two SNPs (rs2251644 and rs941793) were sufficient to tag the majority of haplotypic variation (r2 > or = 0.85) and these were tested in a case-control association study with 266 North American sporadic ALS patients and 225 matched controls. We found no association between genetic variation at DYNC1H1 and sporadic ALS (rs2251644; p = 0.538, rs941793; p = 0.204, haplotype; p = 0.956). In addition we investigated patterns of diversity at DYNC1H1 in Japanese and Cameroonian populations to establish the evolutionary history for this gene and observed reduced genetic diversity in the northern Europeans suggestive of selection at this locus.
- Published
- 2006
33. Rapid‐Onset Dystonia‐Parkinsonism in a Chinese Girl with a De Novo ATP1A3 c.2267G>A (p.R756H) Genetic Mutation
- Author
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Chong Tin Tan, Azlina Ahmad-Annuar, Ai Huey Tan, Shen-Yang Lim, Laurie J. Ozelius, Anthony E. Lang, and Allison Brashear
- Subjects
Dystonia ,Genetics ,Pediatrics ,medicine.medical_specialty ,Levodopa ,Ataxia ,Normal diet ,business.industry ,Alternating hemiplegia of childhood ,Parkinsonism ,Case Reports ,medicine.disease ,Dysarthria ,Neurology ,ATP1A3 ,medicine ,Neurology (clinical) ,medicine.symptom ,business ,medicine.drug - Abstract
Rapid-onset dystonia parkinsonism (RDP) is a rare disorder characterized by abrupt onset of dystonia and parkinsonism. The condition is the result of mutations in ATP1A3. Careful characterization of neurological manifestations associated with ATP1A3 mutations, which can cause RDP and alternating hemiplegia of childhood (AHC), is important to understand how specific mutations can lead to different presentations. This case of RDP is notable because (1) the patient harbored an ATP1A3 variant at the c.2267G>A site, resulting in a nonsynonymous p.R756H mutation, which has not been reported in typical adolescent-onset RDP, and (2) reports of Asian cases are very rare and this is the first patient of pure Chinese descent. Our patient, of pure Southern Chinese ancestry, was previously healthy until 9 May 2002 (at the age of 10 years), when she became clumsy. This was preceded by a self-limited febrile episode a week earlier. The next day, she had dysarthria, drooling, unsteady gait, and poor handwriting. This progressed over 10 days to a state of being unable to speak, swallow, or walk. She was recognized to have a severe dystonic syndrome when assessed by a pediatric neurologist 3 weeks later. By this time, she had made some recovery and was able to walk with assistance and swallow. Investigations were unremarkable, including routine blood tests, cerebrospinal fluid analysis, brain MRI, and EEG. Slit-lamp examination was negative for Kayser-Fleischer rings. She was diagnosed with postviral encephalitis and given levodopa/carbidopa (100/25 mg, 2 tablets three times daily [TID]), but this was ineffective. The patient was first assessed at the University of Malaya, Kuala Lumpur, in August 2011, at age 19. She had made gains in functional activities (e.g., no longer falling frequently and able to type fairly quickly on a computer). She was eating a normal diet without choking episodes. The patient was a top scorer in her school examinations, and there were no psychiatric manifestations. There was no relevant family history and no parental consanguinity. Her parents were also examined by us and confirmed to be neurologically intact. Examination revealed facial grimacing and jaw-opening dystonia, especially when speaking, severely slurred speech, and antecollis. There was severe and generalized nonpainful dystonia affecting all limbs and the trunk. Her movements were slow, but this was considered to probably be a result of the severe dystonia and there were no other parkinsonian features, such as rigidity or tremor (limb tone at rest was, in fact, reduced; these findings were confirmed by S.-Y.L. and A.E.L.). There was no ataxia, upper motor neuron signs, or abnormalities of eye movements or hearing. The patient’s DNA was analyzed for ATP1A3 mutations, and she was found to have a mutation in exon 17 at cDNA position c.2267G>A (NM_152296.4), resulting in a p.R756H amino acid substitution (NP_689509; laboratory of L.J.O.). Neither of the patient’s parents had this mutation. DNA profiling was performed using short tandem repeat (STR) analysis at 15 STR loci (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818, and FGA) by an accredited national forensics laboratory; this confirmed that the patient was the biological child of the parents in question. Benzhexol 2 mg TID subjectively reduced limb stiffness and improved speech, but caused sleepiness and dizziness and was stopped. Her condition has remained stable (see accompanying Video 1 from November 2013), with a Burke-Fahn-Marsden Dystonia Rating Scale Movement Scale score of 67, a Disability Scale score of 13; an RDP Severity Scale score of 4; and the following UPDRS scores (largely felt to be a result of the severe dystonia; see Video 1): Total of 55.5, Parts I of 0, II of 16, III of 38.5, and IV of 1; and Montreal Cognitive Assessment score of 29/30. To our knowledge, the ATP1A3 p.R756H mutation has not been reported in typical adolescent-onset RDP. This mutation
- Published
- 2014
34. LRRK2 G2385R and R1628P mutations are associated with an increased risk of Parkinson's disease in the Malaysian population
- Author
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Gaik Bee Eow, Yi Zhao, Thien T hien Lim, Yip B oon Chong, Shelisa Tey, Eng-King Tan, Shanthi Viswanathan, Zariah Abdul Aziz, Azlina Ahmad-Annuar, Chong T in Tan, Aroma Agape Gopalai, Santhi Datuk Puvanarajah, Ai H uey Tan, Norlinah Mohamed Ibrahim, Jing Y i Chua, Irene Looi, Li P ing Tan, Soo K un Lim, and Shen-Yang Lim
- Subjects
Male ,medicine.medical_specialty ,Parkinson's disease ,Article Subject ,lcsh:Medicine ,Locus (genetics) ,Disease ,Biology ,Protein Serine-Threonine Kinases ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Malaysian population ,Asian People ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Aged ,Genetics ,General Immunology and Microbiology ,lcsh:R ,Case-control study ,Malaysia ,Parkinson Disease ,General Medicine ,Middle Aged ,medicine.disease ,LRRK2 ,Increased risk ,Case-Control Studies ,North african ,Female ,Research Article - Abstract
TheLRRK2gene has been associated with both familial and sporadic forms of Parkinson’s disease (PD). The G2019S variant is commonly found in North African Arab and Caucasian PD patients, but this locus is monomorphic in Asians. The G2385R and R1628P variants are associated with a higher risk of developing PD in certain Asian populations but have not been studied in the Malaysian population. Therefore, we screened the G2385R and R1628P variants in 1,202 Malaysian subjects consisting of 695 cases and 507 controls. The G2385R and R1628P variants were associated with a 2.2-fold (P=0.019) and 1.2-fold (P=0.054) increased risk of PD, respectively. Our data concur with other reported findings in Chinese, Taiwanese, Singaporean, and Korean studies.
- Published
- 2014
35. Pharmacogenetics of taxanes: impact of gene polymorphisms of drug transporters on pharmacokinetics and toxicity
- Author
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Rakesh Naidu, Murali Munisamy, Muhammad Azrif Bin Ahmad Annuar, Johnson Stanslas, Gwo Fuang Ho, and Rafid Salim Jabir
- Subjects
Drug ,Paclitaxel ,media_common.quotation_subject ,Breast Neoplasms ,Docetaxel ,Pharmacology ,Biology ,Organic Anion Transporters, Sodium-Independent ,Polymorphism, Single Nucleotide ,chemistry.chemical_compound ,Solute Carrier Organic Anion Transporter Family Member 1B3 ,Pharmacokinetics ,Genetics ,Humans ,Precision Medicine ,media_common ,CYP3A4 ,business.industry ,Multidrug resistance-associated protein 2 ,Multidrug Resistance-Associated Protein 2 ,chemistry ,Pharmacogenetics ,Toxicity ,Molecular Medicine ,Female ,Taxoids ,Personalized medicine ,business - Abstract
Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.
- Published
- 2012
36. Missense Mutation of Brain Derived Neurotrophic Factor (BDNF) Alters Neurocognitive Performance in Patients with Mild Traumatic Brain Injury: A Longitudinal Study
- Author
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Vigneswaran Veeramuthu, Dharmendra Ganesan, Norlisah Ramli, Vairavan Narayanan, Vicknes Waran, Lisa Delano-Wood, Mark W. Bondi, Azlina Ahmad-Annuar, Karuthan Chinna, and Reddy, Hemachandra
- Subjects
Male ,0301 basic medicine ,Oncology ,Critical Care and Emergency Medicine ,Social Sciences ,lcsh:Medicine ,Poison control ,Neuropsychological Tests ,Learning and Memory ,Cognition ,0302 clinical medicine ,Medicine and Health Sciences ,Psychology ,2.1 Biological and endogenous factors ,Brain Damage ,Longitudinal Studies ,Aetiology ,lcsh:Science ,Trauma Medicine ,Cognitive Impairment ,Multidisciplinary ,Cognitive Neurology ,Neuropsychology ,Single Nucleotide ,Neurology ,Neurological ,Mental health ,Female ,Traumatic Injury ,rs6265 ,Research Article ,Adult ,medicine.medical_specialty ,Physical Injury - Accidents and Adverse Effects ,Missense Mutation ,General Science & Technology ,Traumatic brain injury ,Cognitive Neuroscience ,Mutation, Missense ,Traumatic Brain Injury (TBI) ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Memory ,Clinical Research ,Internal medicine ,Behavioral and Social Science ,Genetics ,Acquired Cognitive Impairment ,medicine ,Humans ,Polymorphism ,Allele ,Traumatic Head and Spine Injury ,Brain Concussion ,Alleles ,Neuropsychological Testing ,Demography ,business.industry ,Prevention ,Brain-Derived Neurotrophic Factor ,lcsh:R ,Neurosciences ,Glasgow Coma Scale ,Biology and Life Sciences ,Repeated measures design ,medicine.disease ,Brain Disorders ,Surgery ,030104 developmental biology ,Genetic Loci ,Mutation ,Cognitive Science ,lcsh:Q ,Missense ,business ,Neurocognitive ,030217 neurology & neurosurgery ,Neuroscience - Abstract
The predictability of neurocognitive outcomes in patients with traumatic brain injury is not straightforward. The extent and nature of recovery in patients with mild traumatic brain injury (mTBI) are usually heterogeneous and not substantially explained by the commonly known demographic and injury-related prognostic factors despite having sustained similar injuries or injury severity. Hence, this study evaluated the effects and association of the Brain Derived Neurotrophic Factor (BDNF) missense mutations in relation to neurocognitive performance among patients with mTBI. 48 patients with mTBI were prospectively recruited and MRI scans of the brain were performed within an average 10.1 (SD 4.2) hours post trauma with assessment of their neuropsychological performance post full Glasgow Coma Scale (GCS) recovery. Neurocognitive assessments were repeated again at 6 months follow-up. The paired t-test, Cohen’s d effect size and repeated measure ANOVA were performed to delineate statistically significant differences between the groups [wildtype G allele (Val homozygotes) vs. minor A allele (Met carriers)] and their neuropsychological performance across the time point (T1 = baseline/ admission vs. T2 = 6th month follow-up). Minor A allele carriers in this study generally performed more poorly on neuropsychological testing in comparison wildtype G allele group at both time points. Significant mean differences were observed among the wildtype group in the domains of memory (M = -11.44, SD = 10.0, p = .01, d = 1.22), executive function (M = -11.56, SD = 11.7, p = .02, d = 1.05) and overall performance (M = -6.89 SD = 5.3, p = .00, d = 1.39), while the minor A allele carriers showed significant mean differences in the domains of attention (M = -11.0, SD = 13.1, p = .00, d = .86) and overall cognitive performance (M = -5.25, SD = 8.1, p = .01, d = .66).The minor A allele carriers in comparison to the wildtype G allele group, showed considerably lower scores at admission and remained impaired in most domains across the timepoints, although delayed signs of recovery were noted to be significant in the domains attention and overall cognition. In conclusion, the current study has demonstrated the role of the BDNF rs6265 Val66Met polymorphism in influencing specific neurocognitive outcomes in patients with mTBI. Findings were more detrimentally profound among Met allele carriers.
- Published
- 2016
37. No association with common Caucasian genotypes in exons 8, 13 and 14 of the human cytoplasmic dynein heavy chain gene (DNCHC1) and familial motor neuron disorders
- Author
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Paresh Shah, Pamela J. Shaw, Holger Hummerich, J. Kirby, Majid Hafezparast, Andrew H. Crosby, Azlina Ahmad-Annuar, Karen E. Morrison, Philip A. Wilkinson, LJ Bradley, Abi S. Witherden, Thomas T. Warner, Elizabeth M. C. Fisher, Christos Proukakis, Richard W. Orrell, and Joanne E. Martin
- Subjects
Genotype ,Hereditary spastic paraplegia ,Dynein ,DNA Mutational Analysis ,Molecular Sequence Data ,Biology ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,White People ,Exon ,medicine ,Humans ,Amyotrophic lateral sclerosis ,Motor Neuron Disease ,Gene ,Genetics ,Family Health ,Mutation ,Reverse Transcriptase Polymerase Chain Reaction ,Dyneins ,Spinal muscular atrophy ,Exons ,Genomics ,Sequence Analysis, DNA ,Motor neuron ,medicine.disease ,Protein Subunits ,medicine.anatomical_structure ,nervous system ,Female ,Neurology (clinical) - Abstract
We have shown in a mouse model of motor neuron disease, the legs-at-odd-angles (Loa) mutant, and that mutations in the cytoplasmic dynein heavy chain gene (Dnchc1) cause motor neuron degeneration. Mice exhibiting the Loa phenotype suffer progressive loss of locomotor function and homozygous animals have neuronal inclusion bodies that are positive for SOD1, CDK5, neurofilament and ubiquitin proteins. As this phenotype models some aspects of human motor neuron degeneration disorders, we think there is a reasonable likelihood that dynein may be a causative gene or susceptibility factor in human motor neuron disease. Therefore we have screened exons of this gene in a set of human patients with familial forms of disparate motor neuron degeneration diseases, affecting both upper and lower motor neurons: amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and hereditary spastic paraplegia. As part of this study, we have determined that DNCHC1 is a large gene of 78 exons spanning 86 kb genomic length. We have focused on the exons known to be mutated in Loa, and in a very similar mouse mutation, cramping 1 (Cra1); both mutations result in loss of anterior horn cells. The exons studied are highly conserved in a wide range of eukaryotes. We screened our patient samples by sequencing and although we detect single nucleotide polymorphisms, our results show these occur at the same frequency in our patient group as in control samples of unaffected individuals. Therefore we do not find any association between familial motor neuron disease and the genotypes presented here in the exons screened.
- Published
- 2003
38. An integrated genetic, radiation hybrid, physical and transcription map of a region of distal mouse chromosome 12, including an imprinted locus and the 'Legs at odd angles' (Loa) mutation
- Author
-
Joanna Rankin, Elizabeth M. C. Fisher, Abi S. Witherden, Azlina Ahmad-Annuar, Holger Hummerich, Simon T. Ball, Sharon J. Nicholson, Nessan Bermingham, Derek Huntley, Joanne E. Martin, Majid Hafezparast, Marek Sergot, Demet Araç, Jo Peters, and Marjan Iravani
- Subjects
Genetics ,Chromosomes, Human, Pair 14 ,Radiation Hybrid Mapping ,Positional cloning ,Transcription, Genetic ,Physical Chromosome Mapping ,Chromosome Mapping ,Locus (genetics) ,General Medicine ,Biology ,Synteny ,Chromosomes ,Contig Mapping ,Genomic Imprinting ,Mice ,Gene Order ,Animals ,Humans ,Radiation hybrid mapping ,Genomic imprinting ,Gene ,Chromosome 12 - Abstract
A variety of loci with interesting patterns of regulation such as imprinted expression, and critical functions such as involvement in tumour necrosis factor pathways, map to a distal portion of mouse chromosome 12. This region also contains disease related loci including the 'Legs at odd angles' mutation (Loa) that we are pursuing in a positional cloning project. To further define the region and prepare for comparative sequencing projects, we have produced genetic, radiation hybrid, physical and transcript maps of the region, with probes providing anchors between the maps. We show a summary of 95 markers and 91 genomic clones that has enabled us to identify 18 transcripts including new genes and candidates for Loa which will help in future studies of gene context and regulation.
- Published
- 2002
39. P1.31 Genetic mutations in sarcoglycanopathies in a Malaysian population
- Author
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R.Y. Looi, T. Thomas, Nortina Shahrizaila, M.K. Thong, Kum Thong Wong, Azlina Ahmad-Annuar, T.B. Khoo, and Khean Jin Goh
- Subjects
Genetics ,Neurology ,Malaysian population ,business.industry ,Pediatrics, Perinatology and Child Health ,Medicine ,Neurology (clinical) ,business ,Genetics (clinical) ,Sarcoglycanopathies - Published
- 2010
40. P1.21 Genetic mutations in dysferlinopathy in a Malaysian population
- Author
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Azlina Ahmad-Annuar, Nortina Shahrizaila, M.K. Thong, Kum Thong Wong, Khean Jin Goh, and R.Y. Looi
- Subjects
Genetics ,Dysferlinopathy ,Neurology ,Malaysian population ,Pediatrics, Perinatology and Child Health ,medicine ,Neurology (clinical) ,Biology ,medicine.disease ,Genetics (clinical) - Published
- 2010
41. Genetic Analysis of the Cytoplasmic Dynein Subunit Families
- Author
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James P Cotton, Holger Hummerich, Elizabeth M. C. Fisher, Azlina Ahmad Annuar, K. Kevin Pfister, Paresh Shah, Andreas Russ, and Stephen M. King
- Subjects
Cytoplasmic Dyneins ,Yeast and Fungi ,Cytoplasm ,Cancer Research ,lcsh:QH426-470 ,Evolution ,Eukaryotes ,Protein subunit ,ved/biology.organism_classification_rank.species ,Dynein ,Genetics/Functional Genomics ,Review ,Biology ,Microtubules ,Biochemistry ,Motor protein ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Microtubule ,Chlorocebus aethiops ,Cytoplasmic dynein complex ,Genetics ,Animals ,Humans ,Model organism ,Molecular Biology ,Gene ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,0303 health sciences ,Models, Genetic ,ved/biology ,Chlamydomonas ,Dyneins ,Cell Biology ,lcsh:Genetics ,Multigene Family ,COS Cells ,Bioinformatics - Computational Biology ,030217 neurology & neurosurgery - Abstract
Cytoplasmic dyneins, the principal microtubule minus-end-directed motor proteins of the cell, are involved in many essential cellular processes. The major form of this enzyme is a complex of at least six protein subunits, and in mammals all but one of the subunits are encoded by at least two genes. Here we review current knowledge concerning the subunits, their interactions, and their functional roles as derived from biochemical and genetic analyses. We also carried out extensive database searches to look for new genes and to clarify anomalies in the databases. Our analysis documents evolutionary relationships among the dynein subunits of mammals and other model organisms, and sheds new light on the role of this diverse group of proteins, highlighting the existence of two cytoplasmic dynein complexes with distinct cellular roles.
- Published
- 2006
42. X-linked Charcot-Marie-Tooth disease predominates in a cohort of multiethnic Malaysian patients.
- Author
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Shahrizaila, Nortina, Samulong, Sarimah, Tey, Shelisa, Suan, Liaw Chiew, Meng, Lao Kah, Goh, Khean Jin, and Ahmad‐Annuar, Azlina
- Abstract
ABSTRACT Introduction: Data regarding Charcot-Marie-Tooth disease is lacking in Southeast Asian populations. We investigated the frequency of the common genetic mutations in a multiethnic Malaysian cohort. Methods: Patients with features of Charcot-Marie-Tooth disease or hereditary liability to pressure palsies were investigated for PMP22 duplication, deletion, and point mutations and GJB1, MPZ, and MFN2 point mutations. Results: Over a period of 3 years, we identified 25 index patients. A genetic diagnosis was reached in 60%. The most common were point mutations in GJB1, accounting for X-linked Charcot-Marie-Tooth disease (24% of the total patient population), followed by PMP22 duplication causing Charcot-Marie-Tooth disease type 1A (20%). We also discovered 2 novel GJB1 mutations, c.521C>T (Proline174Leucine) and c.220G>A (Valine74Methionine). Conclusions: X-linked Charcot-Marie-Tooth disease was found to predominate in our patient cohort. We also found a better phenotype/genotype correlation when applying a more recently recommended genetic approach to Charcot-Marie-Tooth disease. Muscle Nerve 49: 198-201, 2014 [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
43. Paradigms for the identification of new genes in motor neuron degeneration.
- Author
-
Hafezparast, Majid, Ahmad-Annuar, Azlina, Hummerich, Holger, Shah, Paresh, Ford, Melisa, Baker, Cathy, Bowen, Sam, Martin, Joanne E., and Fisher, Elizabeth M.C.
- Subjects
- *
MOTOR neuron diseases , *DEGENERATION (Pathology) , *GENETICS , *AMYOTROPHIC lateral sclerosis , *NEUROMUSCULAR diseases , *NEURONS - Abstract
Discusses the paradigms for the identification of genes in motor neuron degeneration. Percentage of amyotrophic lateral sclerosis (ALS) are is familial; Gene mutations that are directly causal for motor neuron degeneration in humans; Characteristics of human genetics.
- Published
- 2003
- Full Text
- View/download PDF
44. No association with common Caucasian genotypes in exons 8, 13 and 14 of the human cytoplasmic dynein heavy chain gene ( DNCHC1 ) and familial motor neuron disorders.
- Author
-
Ahmad-Annuar, Azlina, Shah, Paresh, Hafezparast, Majid, Hummerich, Holger, Witherden, Abi S., Morrison, Karen E., Shaw, Pamela J., Kirby, Janine, Warner, Thomas T., Crosby, Andrew, Proukakis, Christos, Wilkinson, Philip, Orrell, Richard W., Bradley, Lloyd, Martin, Joanne E., and Fisher, Elizabeth M.C.
- Subjects
- *
MOTOR neuron diseases , *GENETIC mutation , *CYTOPLASMIC filaments , *GENETICS - Abstract
We have shown in a mouse model of motor neuron disease, the legs-at-odd-angles ( Loa ) mutant, and that mutations in the cytoplasmic dynein heavy chain gene ( Dnchc1 ) cause motor neuron degeneration. Mice exhibiting the Loa phenotype suffer progressive loss of locomotor function and homozygous animals have neuronal inclusion bodies that are positive for SOD1 , CDK5, neurofilament and ubiquitin proteins. As this phenotype models some aspects of human motor neuron degeneration disorders, we think there is a reasonable likelihood that dynein may be a causative gene or susceptibility factor in human motor neuron disease. Therefore we have screened exons of this gene in a set of human patients with familial forms of disparate motor neuron degeneration diseases, affecting both upper and lower motor neurons: amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and hereditary spastic paraplegia. As part of this study, we have determined that DNCHC1 is a large gene of 78 exons spanning 86 kb genomic length. We have focused on the exons known to be mutated in Loa , and in a very similar mouse mutation, cramping 1 ( Cra1 ); both mutations result in loss of anterior horn cells. The exons studied are highly conserved in a wide range of eukaryotes. We screened our patient samples by sequencing and although we detect single nucleotide polymorphisms, our results show these occur at the same frequency in our patient group as in control samples of unaffected individuals. Therefore we do not find any association between familial motor neuron disease and the genotypes presented here in the exons screened. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
45. Mouse models for neurological disease
- Author
-
Hafezparast, Majid, Ahmad-Annuar, Azlina, Wood, Nicholas W, Tabrizi, Sarah J, Fisher, Elizabeth MC, and Fisher, Elizabeth M C
- Subjects
- *
GENETICS , *GENOMES - Abstract
The mouse has many advantages over human beings for the study of genetics, including the unique property that genetic manipulation can be routinely carried out in the mouse genome. Most importantly, mice and human beings share the same mammalian genes, have many similar biochemical pathways, and have the same diseases. In the minority of cases where these features do not apply, we can still often gain new insights into mouse and human biology. In addition to existing mouse models, several major programmes have been set up to generate new mouse models of disease. Alongside these efforts are new initiatives for the clinical, behavioural, and physiological testing of mice. Molecular genetics has had a major influence on our understanding of the causes of neurological disorders in human beings, and much of this has come from work in mice. [Copyright &y& Elsevier]
- Published
- 2002
- Full Text
- View/download PDF
46. Identification of Genetic Variants in Progressive Supranuclear Palsy in Southeast Asia.
- Author
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Ng, Adeline Su Lyn, Tan, Ai Huey, Tan, Yi Jayne, Lim, Jia Lun, Lian, Michelle Mulan, Dy Closas, Alfand Marl, Ahmad‐Annuar, Azlina, Viswanathan, Shanthi, Chia, Yuen Kang, Foo, Jia Nee, Lim, Weng Khong, Tan, Eng‐King, and Lim, Shen‐Yang
- Subjects
- *
GENETIC testing , *GENETIC variation , *NEURODEGENERATION , *MOVEMENT disorders , *GENETICS - Abstract
Background Objectives Methods Results Conclusions Progressive supranuclear palsy (PSP) is largely a sporadic disease with few reported familial cases. Genome‐wide association studies (GWAS) in sporadic PSP in Caucasian populations have identified MAPT as the most commonly associated genetic risk locus with the strongest effect size. At present there are limited data on genetic factors associated with PSP in Asian populations.Our goal was to investigate the genetic factors associated with PSP in Southeast Asian PSP patients.Next‐generation sequencing (whole‐exome, whole‐genome and targeted sequencing) was performed in two Asian cohorts, comprising 177 PSP patients.We identified 17 pathogenic or likely pathogenic variants in 16 PSP patients (9%), eight of which were novel. The most common relevant genetic variants identified were in MAPT, GBA1, OPTN, SYNJ1, and SQSTM1. Other variants detected were in TBK1, PRNP, and ABCA7—genes that have been implicated in other neurodegenerative diseases. Eighteen patients had a positive family history, of whom two carried pathogenic MAPT variants, and one carried a likely pathogenic GBA1 variant. None of the patients had expanded repeats in C9orf72. Furthermore, we found 16 different variants of uncertain significance in 21 PSP patients in PSEN2, ABCA7, SMPD1, MAPT, ATP13A2, OPTN, SQSTM1, CYLD, and BSN.The genetic findings in our PSP cohorts appear to be somewhat distinct from those in Western populations, and also suggest an overlap of the genetic architecture between PSP and other neurodegenerative diseases. Further functional studies and validation in independent Asian cohorts will be useful for improving our understanding of PSP genetics and guiding genetic screening strategies in these populations. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
47. Rare homozygous PRKN exon 7 duplication in a Ibanese patient from Northwestern Borneo with young onset Parkinson's disease.
- Author
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Siaw Cheng Wong, Zhun Foo Tan, Yi-Wen Tay, Wan Chung Law, Ahmad-Annuar, Azlina, Ai Huey Tan, and Shen-Yang Lim
- Subjects
- *
PARKINSON'S disease , *MOVEMENT disorders - Abstract
We describe the clinical features of a Sarawakian man of Ibanese ethnicity with young-onset Parkinson's disease (PD), who carried a very rare homozygous PRKN exon 7 duplication. Truncal dystonia was a prominent feature on presentation, in addition to classical parkinsonian motor features. This report adds to the very limited literature on monogenic causes of PD in Southeast Asia and specifically the indigenous group in the Borneo region. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
48. PINK1 p.Leu347Pro mutations in Malays: Prevalence and illustrative cases.
- Author
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Tan, Ai Huey, Lohmann, Katja, Tay, Yi Wen, Lim, Jia Lun, Ahmad-Annuar, Azlina, Ramli, Norlisah, Chin, Yen Theng, Mawardi, Ahmad Shahir, Azmi, Khairul, Aziz, Zariah Abdul, Puvanarajah, Santhi Datuk, Bauer, Peter, Klein, Christine, Rolfs, Arndt, and Lim, Shen-Yang
- Subjects
- *
PARKINSON'S disease , *PYRAMIDAL tract , *BRAIN abnormalities , *AGE differences , *AGE of onset , *PROTEIN kinases , *RESEARCH , *RESEARCH methodology , *EVALUATION research , *COMPARATIVE studies , *DISEASE prevalence , *MALAYS (Asian people) - Abstract
Background: An improved understanding of the genetic determinants of Parkinson's disease (PD) in underrepresented populations, and better characterization of genotype-phenotype correlations in monogenic PD, are needed. Scarce literature exists regarding the genetic aetiology of PD in Malays, who comprise 200 million individuals in South-East Asia. Phenotypic data regarding PARK-PINK1 are also limited.Methods: A multi-ethnic cohort of PD patients from Malaysia (n = 499, including 185 Malays) were tested using a next-generation sequencing-based PD gene panel. The prevalence and clinico-radiological features of patients with the PINK1 p. Leu347Pro mutation are described. This mutation has previously only been reported in people of Filipino or Chamorro (native Guamanian) ancestry.Results: Homozygous p. Leu347Pro mutations were found in five unrelated Malay patients, yielding a prevalence of 6.9% among Malays with PD onset ≤50 years (2.7% of the Malay group overall). This variant was not detected in the homozygous state in 300 Malay controls, but two were heterozygous carriers (0.67%) indicating a relatively high population frequency in keeping with the high frequency of PARK-PINK1 among Malay patients. Interesting clinical features were observed, e.g., differences in the age at PD onset and clinical progression, despite having the same point mutations. Previously unreported brain MRI abnormalities involving the corticospinal tract and hypothalamus, and "loss of the swallow tail" sign, were documented.Conclusions: This report contributes to the very limited literature on PD genetics in the Malay population, and more broadly to the epidemiological, phenotypic and neuroimaging characterization of PARK-PINK1. It also further supports the pathogenicity of the p. Leu347Pro variant. [ABSTRACT FROM AUTHOR]- Published
- 2020
- Full Text
- View/download PDF
49. New insights from a multi-ethnic Asian progressive supranuclear palsy cohort.
- Author
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Lim, Shen-Yang, Dy Closas, Alfand Marl F., Tan, Ai Huey, Lim, Jia Lun, Tan, Yi Jayne, Vijayanathan, Yuganthini, Tay, Yi Wen, Abdul Khalid, Raihanah binti, Ng, Wai Keong, Kanesalingam, Ruban, Martinez-Martin, Pablo, Ahmad Annuar, Azlina, Lit, Lei Cheng, Foo, Jia Nee, Lim, Weng Khong, Ng, Adeline Su Lyn, and Tan, Eng-King
- Subjects
- *
PROGRESSIVE supranuclear palsy , *BURDEN of care , *BEHAVIOR disorders , *ASIANS , *DISEASE duration , *MOVEMENT disorders - Abstract
Progressive supranuclear palsy (PSP) is a rare, disabling, neurodegenerative disease, with few studies done in Asian populations. We prospectively characterized the clinical features and disease burden in a consecutively-recruited multi-ethnic Asian PSP cohort. Patients were extensively phenotyped using the Movement Disorder Society (MDS-PSP) clinical diagnostic criteria and the PSP-Clinical Deficits Scale (PSP-CDS). Caregiver burden was measured using the modified Zarit Burden Interview (ZBI). Investigations (neuroimaging and genetic tests) were reviewed. There were 104 patients (64.4% male; 67.3% Chinese, 21.2% Indians, 9.6% Malays), consisting of 48.1% Richardson syndrome (PSP-RS), 37.5% parkinsonian phenotype (PSP–P), and 10.6% progressive gait freezing phenotype (PSP-PGF). Mean age at motor onset was 66.3 ± 7.7 years, with no significant differences between the PSP phenotypes. Interestingly, REM-sleep behaviour disorder (RBD) symptoms and visual hallucinations (considered rare in PSP) were reported in 23.5% and 22.8% of patients, respectively, and a family history of possible neurodegenerative or movement disorder in 20.4%. PSP-CDS scores were highest (worst) in PSP-RS; and correlated moderately with disease duration (r s = 0.45, P < 0.001) and weakly with caregiver burden (r s = 0.22, P = 0.029) in the overall cohort. Three of 48 (6.3%) patients who had whole-exome sequencing harboured pathogenic/likely pathogenic GBA variants. Significant heterogeneity in clinical features and disease burden, and high rates of RBD symptoms, visual hallucinations, and familial involvement were observed in this relatively large cohort. Our findings highlight important considerations when assessing Asian patients, and provide further support for the notion of overlapping neurobiology between PSP and Lewy body disorders. • Asian PSP patients were prospectively classified using MDS-PSP diagnostic criteria. • A novel rating scale (PSP-CDS) was applied to evaluate disease severity. • PD-linked gene variants were found in well-defined Richardson syndrome cases. • Patients/caregivers frequently reported RBD symptoms and/or visual hallucinations. • There may be racial differences in disease occurrence and underlying genetics in PSP. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
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