Search

Aim: To investigate the patients' perception of their disease, its management and the impact of the COVID-19 pandemic on persons living with amyotrophic lateral sclerosis (ALS) in Malaysia. Patients & methods: An online survey comprising 42 questions was conducted on ALS patients during the peak of the COVID-19 pandemic. Results: Responses were received from 37/60 (62%) participants with ALS directly or through their caregivers. During the COVID-19 pandemic, two-thirds of patients were negatively impacted by the sudden disruption to their hospital appointments, rehabilitation sessions and reduced social interactions. Conclusion: This study provided insight into patients' perception of their care and management of ALS in Malaysia which will facilitate in implementing changes that can improve care to persons living with this devastating illness.

We report the clinical and genetic characteristics of hereditary transthyretin amyloidosis in the multi-ethnic Malaysian population. Subjects with genetically confirmed transthyretin amyloidosis seen between 2001 till August 2020 were included. There were 30 patients and 14 asymptomatic carriers, of which 26 (59.1%) were men. The majority (86.7%) were ethnic Chinese while two (6.7%) each were Malay and Sri Lankan Tamil ethnicity respectively. Among patients, mean age of symptom-onset was 55.9 ± 9.8 years with mean duration from symptom-onset to diagnosis of 3.2 ± 2.5 years. Common presenting symptoms were sensory symptoms of upper limbs (43.3%), symmetric sensory symptoms of both lower limbs (16.7%) and autonomic symptoms (16.7%). Nerve conduction studies showed sensorimotor polyneuropathy in 25 (83.3%) patients (22, axonal). Abnormal echocardiograms were seen in 24 (80%) patients, although 15 were asymptomatic. Of six different TTR mutations found, Ala97Ser was the commonest, and found exclusively in 84.6% of Chinese patients. Other mutations among Chinese patients were Val30Met, Ala25Thr and Asp39Val. Our Malay and Tamil patients had Glu54Lys and Gly47Val mutations respectively. In conclusion, TTR Ala97Ser is the commonest mutation among ethnic Chinese Malaysians which presented with late-onset progressive sensorimotor polyneuropathy, autonomic dysfunction and subclinical cardiac involvement.

Despite intense preclinical research focusing on developing potential strategies of mitigating spinal cord injury (SCI), SCI still results in permanent, debilitating symptoms for which there are currently no effective pharmacological interventions to improve the recovery of the fine ultrastructure of the spinal cord. Spirulina platensis is thought to have potential neuroprotective effects. We have previously demonstrated its protective potential on the lesioned corticospinal tracts and behavioral recovery. In this study, spirulina, known for its neuroprotective properties was used to further explore its protective effects on spinal cord gray matter ultrastructural. Twenty-four Sprague-Dawley rats were used and divided into sham group (laminectomy without SCI), control group (SCI without S. platensis), and S. platensis group (SCI + 180 mg/kg S. platensis). All animals were anesthetized via intramuscular injection. A partial crush injury was induced at the level of T12. The rats were humanely sacrificed for 28 days postinjury for ultrastructural study. There were significant mean differences with respect to pairwise comparisons between the ultrastructural grading score of neuronal perikarya of control and the S. platensis following injury at day 28, which correlates with the functional locomotor recovery at this timepoint in our previous study. The group supplemented with spirulina, thus, revealed a better improvement in the fine ultrastructure of the spinal cord gray matter when compared to the control group thereby suggesting neuroprotective potentials of spirulina in mitigating the effects of spinal cord injury and inducing functional recovery.

Spinal cord injury (SCI) results from penetrating or compressive traumatic injury to the spine in humans or by the surgical compression of the spinal cord in experimental animals. In this study, th...

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 (

In the recent years, increased understanding of the molecular profiles of non-small cell lung cancer (NSCLC) has allowed for targeted treatment of actionable genetic mutations. The management of NSCLC now requires multiple molecular tests to guide the treatment strategy. In the light of this, there is a need to establish a molecular testing consensus statement for advanced NSCLC patients in Malaysia. This Malaysian consensus statement was developed by a panel of experts, chaired by a pathologist and composed of three other pathologists, four respiratory physicians and three oncologists. It reflects currently available scientific data and adaptations of recommendations from international guidelines to the local landscape. Expert recommendations on different aspects of molecular testing agreed upon by the panel are provided as structured discussions. These recommendations address the appropriate patients and samples to be tested, as well as when and how these tests should be performed. The algorithms for molecular testing in metastatic NSCLC, in the first line setting and upon disease progression beyond first line therapy, were developed.

1·8 billion people of diverse ethnicities and cultures live in the Western Pacific Region. The increasing longevity of populations in this region is a major contributor to the exponential increase in Parkinson's disease prevalence worldwide. Differences exist between Parkinson's disease in the Western Pacific Region and in Europe and North America that might provide important insights into our understanding of the disease and approaches to management. For example, some genetic factors (such as LRRK2 mutations or variants) differ, environmental exposures might play differential roles in modulating the risk of Parkinson's disease, and fewer dyskinesias are reported, with some differences in the profile of non-motor symptoms and comorbidities. Gaps in awareness of the disease and inequitable access to treatments pose challenges. Further improvements in infrastructure, clinical governance, and services, and concerted collaborative efforts in training and research, including greater representation of the Western Pacific Region in clinical trials, will improve care of patients with Parkinson's disease in this region and beyond.

Nonhematologic adverse events (AEs) of docetaxel constitute an extra burden in the treatment of cancer patients and necessitate either a dose reduction or an outright switch of docetaxel for other regimens. These AEs are frequently associated with genetic polymorphisms of genes encoding for proteins involved docetaxel disposition. Therefore, we investigated that association in Malaysian breast cancer patients.A total of 110 Malaysian breast cancer patients were enrolled in the present study, and their blood samples were investigated for different single nucleotide polymorphisms using polymerase chain reaction restriction fragment length polymorphism. AEs were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0.Fatigue, nausea, oral mucositis, and vomiting were the most common nonhematologic AEs. Rash was associated with heterozygous and mutant genotypes of ABCB1 3435CT (P .05). Moreover, patients carrying the GG genotype of ABCB1 2677GA/T reported more fatigue than those carrying the heterozygous genotype GA (P .05). The presence of ABCB1 3435-T, ABCC2 3972-C, ABCC2 1249-G, and ABCB1 2677-G alleles was significantly associated with nausea and oral mucositis. The coexistence of ABCB1 3435-C, ABCC2 3972-C, ABCC2 1249-G, and ABCB1 2677-A was significantly associated with vomiting (P .05).The prevalence of nonhematologic AEs in breast cancer patients treated with docetaxel has been relatively high. The variant allele of ABCB1 3435CT polymorphism could be a potential predictive biomarker of docetaxel-induced rash, and homozygous wild-type ABCB1 2677GA/T might predict for a greater risk of fatigue. In addition, the concurrent presence of specific alleles could be predictive of vomiting, nausea, and oral mucositis.

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.

Objectives The Neural Tube Defects Research Group of University of Malaya was approached to analyze a tablet named TELSE, which may have resulted in a baby born with central nervous system malformation at the University of Malaya Medical Centre. In this animal experimental study, we investigated the content of TELSE and exposure of its contents that resulted in failure of primary neurulation. Results Liquid Chromatography Tandem Mass spectrophotometry analysis of the TELSE tablet confirmed the presence of trimethoprim as the active compound. The TELSE tablet-treated females produced significant numbers of embryos with exencephaly (n = 8, 36.4%, *P

We present a case of beta-propeller protein-associated neurodegeneration, a form of neurodegeneration with brain iron accumulation. The patient harbored a novel mutation in the WDR45 gene. A detailed video and description of her clinical condition are provided. Her movement disorder phenomenology was characterized primarily by limb stereotypies and gait dyspraxia. The patient's disability was advanced by the time iron-chelating therapy with deferiprone was initiated, and no clinical response in terms of cognitive function, behavior, speech, or movements were observed after one year of treatment.

Introduction. Familial amyloid polyneuropathy (FAP) is a rare autosomal dominant peripheral neuropathy. We report a case series of Malaysian FAP patients. Methods. Patients with definite (genetically confirmed) FAP seen at the University of Malaya Medical Centre between 2008 till 2019 were included in the series. The patients’ demographic and clinical features and investigations including nerve conduction studies and electromyography (NCS/EMG), echocardiography, sural nerve biopsy and hATTR mutation are reported. Results. A total 21 index cases were seen. Nineteen (90%) were ethnic Chinese, one ethnic (5%) Malay and one (5%) ethnic Indian; Fourteen (67%) were men. Mean age of onset of symptoms was 56.1 ± 10.5 years (range: 31-73). Nineteen (90%) patients presented with numbness and weakness of the limbs while two had postural hypotension. Fifteen (71%) patients had positive family history. NCS/EMG showed sensorimotor polyneuropathy in 19 (90%) patients; fifteen (71%) showing axonal neuropathy. Amyloid deposits were seen on nerve biopsy in ten patients and rectal, leptomeningeal and endomyocardial biopsies in 1 patient respectively. The latter was diagnosed as familial amyloid cardiomyopathy (FAC). Sixteen patients (76%) had abnormal cardiac echocardiogram with amyloid deposits. Fifteen Chinese patients (71%) carried the Ala97Ser hATTR mutation while the FAC patient has Asp39Val mutation. Our Malay patient had Glu54Lys mutation and Indian patient had Gly67Val mutation. Two patients carried Val30Met mutation. Autonomic function test was abnormal in all 7 patients in whom they were carried out. Conclusion. FAP in Malaysians is seen mainly among ethnic Chinese, in whom Ala97Ser may be a common mutation. This is also the reported “hotspot” mutation for FAP reported in Taiwan but not in China. Similar to Taiwan, Chinese-Malaysians are descended from immigrants from Southern China. Similar to Taiwanese patients, our FAP patients with Ala97Ser mutation, present with late-onset progressive sensorimotor polyneuropathy and cardiac involvement was common.

Spina bifida is among the phenotypes of the larger condition known as neural tube defects (NTDs). It is the most common central nervous system malformation compatible with life and the second leading cause of birth defects after congenital heart defects. In this review paper, we define spina bifida and discuss the phenotypes seen in humans as described by both surgeons and embryologists in order to compare and ultimately contrast it to the leading animal model, the mouse. Our understanding of spina bifida is currently limited to the observations we make in mouse models, which reflect complete or targeted knockouts of genes, which perturb the whole gene(s) without taking into account the issue of haploinsufficiency, which is most prominent in the human spina bifida condition. We thus conclude that the need to study spina bifida in all its forms, both aperta and occulta, is more indicative of the spina bifida in surviving humans and that the measure of deterioration arising from caudal neural tube defects, more commonly known as spina bifida, must be determined by the level of the lesion both in mouse and in man.

Normal pressure hydrocephalus (NPH) is a syndrome comprising gait disturbance, cognitive decline and urinary incontinence that is an unique model of reversible brain injury, but it presents as a challenging spectrum of disease cohorts. Diffusion Tensor Imaging (DTI), with its ability to interrogate structural white matter patterns at a microarchitectural level, is a potentially useful tool for the confirmation and characterization of disease cohorts at the clinical-research interface. However, obstacles to its widespread use involve the need for consistent DTI analysis and interpretation tools across collaborator sites. We present the use of DTI profiles, a simplistic methodology to interpret white matter injury patterns based on the morphology of diffusivity parameters. We examined 13 patients with complex NPH, i.e., patients with NPH and overlay from multiple comorbidities, including vascular risk burden and neurodegenerative disease, undergoing extended CSF drainage, clinical assessments, and multi-modal MR imaging. Following appropriate exclusions, we compared the morphology of DTI profiles in such complex NPH patients (n = 12, comprising 4 responders and 8 non-responders) to exemplar DTI profiles from a cohort of classic NPH patients (n = 16) demonstrating responsiveness of white matter injury to ventriculo-peritoneal shunting. In the cohort of complex NPH patients, mean age was 71.3 ± 7.6 years (10 males, 2 females) with a mean MMSE score of 21.1. There were 5 age-matched healthy controls, mean age was 73.4 ± 7.2 years (1 male, 4 females) and mean MMSE score was 26.8. In the exemplar cohort of classic NPH patients, mean age was 74.7 ± 5.9 years (10 males, 6 females) and mean MMSE score was 24.1. There were 9 age-matched healthy controls, mean age was 69.4 ± 9.7 years (4 males, 5 females) and mean MMSE score was 28.6. We found that, despite the challenges of acquiring DTI metrics from differing scanners across collaborator sites and NPH patients presenting as differing cohorts along the spectrum of disease, DTI profiles for responsiveness to interventions were comparable. Distinct DTI characteristics were demonstrated for complex NPH responders vs. non-responders. The morphology of DTI profiles for complex NPH responders mimicked DTI patterns found in predominantly shunt-responsive patients undergoing intervention for classic NPH. However, DTI profiles for complex NPH non-responders was suggestive of atrophy. Our findings suggest that it is possible to use DTI profiles to provide a methodology for rapid description of differing cohorts of disease at the clinical-research interface. By describing DTI measures morphologically, it was possible to consistently compare white matter injury patterns across international collaborator datasets.

Introduction Choline acetyltransferase (CHAT) gene mutations cause a rare presynaptic congenital myasthenic syndrome due to impaired acetylcholine resynthesis. Methods We report 2 Kadazandusun brothers with novel heterozygous CHAT mutations. Results The siblings were from a family of 7 children of nonconsanguineous parents, 3 who died from apneic crises. Both presented in infancy with ptosis and exertional limb weakness, but only 1 apnea episode was reported in the older sibling. The elder brother had a positive edrophonium test, and both were negative for acetylcholine receptor antibodies but improved with pyridostigmine treatment. A subsequent repetitive nerve stimulation test showed marked decremental response in the abductor digiti minimi only after prolonged ulnar nerve stimulation. Two novel CHAT gene mutations, p.Val306Leu and p.Ser704del were detected; the parents carried 1 mutation each. Conclusions Differences in survival demonstrate phenotypic variability within the same family and a relatively good long-term outcome of the surviving siblings.

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.

Objective: The diversity of tumour characteristics among glioma patients, even within same tumour grade, is a big challenge for disease outcome prediction. A possible approach for improved radiological imaging could come from combining information obtained at the molecular level. This review assembles recent evidence highlighting the value of using radiogenomic biomarkers to infer the underlying biology of gliomas and its correlation with imaging features. Methods: A literature search was done for articles published between 2002 and 2017 on Medline electronic databases. Of 249 titles identified, 38 fulfilled the inclusion criteria, with 14 articles related to quantifiable imaging parameters (heterogeneity, vascularity, diffusion, cell density, infiltrations, perfusion, and metabolite changes) and 24 articles relevant to molecular biomarkers linked to imaging. Results: Genes found to correlate with various imaging phenotypes were EGFR, MGMT, IDH1, VEGF, PDGF, TP53, and Ki-67. EGFR is the most studied gene related to imaging characteristics in the studies reviewed (41.7%), followed by MGMT (20.8%) and IDH1 (16.7%). A summary of the relationship amongst glioma morphology, gene expressions, imaging characteristics, prognosis and therapeutic response are presented. Conclusion: The use of radiogenomics can provide insights to understanding tumour biology and the underlying molecular pathways. Certain MRI characteristics that show strong correlations with EGFR, MGMT and IDH1 could be used as imaging biomarkers. Knowing the pathways involved in tumour progression and their associated imaging patterns may assist in diagnosis, prognosis and treatment management, while facilitating personalised medicine. Advances in knowledge: Radiogenomics can offer clinicians better insight into diagnosis, prognosis, and prediction of therapeutic responses of glioma.

Members of the Eph receptor tyrosine kinase have previously been implicated in cranial neural tube development. Failure of neural tube closure leads to the devastating conditions known as anencephaly and spina bifida. EphA2 and EphA4 are expressed at the tips of the closing spinal neural folds prior and during neural tube closure. We investigated the possible role of murine EphA2 and EphA4 during the last step of primary neural tube closure, which is adhesion and fusion. The individual mouse knockouts of EphA2 and EphA4 per se do not exhibit neural tube defects (NTDs). The embryos generated by the crossing of double heterozygotes Epha2tm1Jrui/+Epha4rb-2J/+ displayed NTDs with a wide degree of severity including close exencephaly and close spina bifida (spina bifida occulta). Interestingly, mutants displaying NTDs had skin covering the underlying lesion. The tissue sections revealed the elevated neural folds had not adhered and fused. The phenotypes seen in Epha2tm1Jrui/+Epha4rb-2J/+ double heterozygous embryos suggest both genes play a compensatory role with each other in the adhesion and fusion of the neural tube. In this study, there exists a >50% penetrance of NTDs in the mouse mutants, which genetically have a single allele each of EphA2 and EphA4 absent.

Background The aim of this study is to review the medical history of patients with spina bifida, encompassing both aperta and occulta types born between the years 2003 until 2016, spanning a 13-year time period. We assessed each patient and maternal parent information, details of the defects, and conditions associated with the primary defect. We also include information on patients’ ambulation and education level (where available). Methods Data from the Department of Patient Information University of Malaya Medical Centre (UMMC), Malaysia was captured from spina bifida patients (ICD10: Q05 spina bifida). Data involved patients referred to UMMC between 2003 and 2016 and/or born in UMMC within that particular time frame. We filtered and extracted the information according to the data of clinical examination, medical review, and social history provided in the medical records. Results A total of 86 patient records with spina bifida were analyzed. Spina bifida prevalence rate in this study ranged from 1.87 to 8.9 per 1,000 live births depending on weightage. We note that ethnicity was a factor whereby the highest numbers of spina bifida were from Malays (n = 36, 41.86%), followed by equal numbers of Chinese and Indians (n = 24, 27.91%). The highest number of diagnoses reported was myelomeningocele type-spina bifida (n = 39, 45.35%). The most common site of the spina bifida lesion was located at the lumbar region irrespective of aperta or occulta types (n = 23, 26.74%). Data on other associated phenotypes of spina bifida such as hydrocephalus and encephalocele was also captured at 37.21% (n = 32) and 1.16% (n = 1), respectively. In terms of mobility, 32.84% (n = 22/67) of patients between the ages 4 and 16 years old were found to be mobile. As many as 36.07% of patients ranging from 5 to 16 years of age (n = 22/61) received formal education ranging from preschool to secondary school. Conclusion The prevalence of spina bifida in UMMC is as according to international statistics which is in the range of 0.5–10 per 1,000 live births. Majority of the reported cases were males, Malays, full term babies, and of the myelomeningocele phenotype located at the lumbar region.

Rash and oral mucositis are major non-haematological adverse events (AEs) of docetaxel, in addition to fatigue, nausea, vomiting and diarrhoea, which restrict the use of the drug in cancer therapy. Alpha-1-acid glycoprotein (AAG) is an acute phase reactant glycoprotein and is a primary carrier of docetaxel in the blood. Docetaxel has extensive binding (98%) to plasma proteins such as AAG, lipoproteins and albumin.To study the association between plasma AAG level and non-haematological AEs of docetaxel in Malaysian breast cancer patients of three major ethnic groups (Malays, Chinese and Indians).One hundred and twenty Malaysian breast cancer patients receiving docetaxel as single agent chemotherapy were investigated for AAG plasma level using enzyme-linked immunosorbent assay technique. Toxicity assessment was determined using Common Terminology Criteria of Adverse Events v4.0. The association between AAG and toxicity were then established.There was interethnic variation of plasma AAG level; it was 182 ± 85 mg/dl in Chinese, 237 ± 94 mg/dl in Malays and 240 ± 83 mg/dl in Indians. It was found that low plasma levels of AAG were significantly associated with oral mucositis and rash.This study proposes plasma AAG as a potential predictive biomarker of docetaxel non-haematological AEs namely oral mucositis and rash.

Purposeless groaning has been reported in advanced progressive supranuclear palsy. We present a case of purposeless groaning occurring as a primary complaint in a patient with advanced Parkinson’s disease. Purposeless groaning is thought to be a manifestation of disinhibition and perseveration due to frontal-subcortical dysfunction. Proper recognition of this phenomenon will help clinicians to avoid unnecessary investigations and treatment (e.g., prescription of opioid medications).

It has been shown that animal spinal cord compression (using methods such as clips, balloons, spinal cord strapping, or calibrated forceps) mimics the persistent spinal canal occlusion that is common in human spinal cord injury (SCI). These methods can be used to investigate the effects of compression or to know the optimal timing of decompression (as duration of compression can affect the outcome of pathology) in acute SCI. Compression models involve prolonged cord compression and are distinct from contusion models, which apply only transient force to inflict an acute injury to the spinal cord. While the use of forceps to compress the spinal cord is a common choice due to it being inexpensive, it has not been critically assessed against the other methods to determine whether it is the best method to use. To date, there is no available review specifically focused on the current compression methods of inducing SCI in rats; thus, we performed a systematic and comprehensive publication search to identify studies on experimental spinalization in rat models, and this review discusses the advantages and limitations of each method.

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

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.

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

It is estimated that between 10-20% of amyotrophic lateral sclerosis (ALS) is familial and these cases encompass recessive and dominant modes of inheritance. So far, mutations in three genes, superoxide dismutase 1 (SOD1), the p150 subunit of dynactin (DCTN1), and alsin have been shown to be directly causal for motor neuron degeneration in humans. However, clearly the disorder is genetically heterogeneous and other causal genes remain to be found that explain the vast majority of familial ALS cases. Human genetics can be problematical in that it is difficult to detect linkage in disorders in which multiple loci give similar phenotypes and where families are often small. In addition, the vertical collection of generations is often not possible with late onset disorders. An excellent genetic model of humans is provided by the mouse. We can use mouse models of neurodegeneration to find new genes in the human population. These models are not exact replicas of the human condition, but are the mouse equivalent and are incredibly valuable resources for highlighting genes and biochemical pathways disrupted in ALS and other diseases. In addition mouse models give us access to both control and affected tissues, at all stages of development and disease, thus greatly facilitating our understanding of pathogenesis. They also provide us with model systems for testing new therapies. Here we describe the approach taken to the characterization of new models of motor neuron disease and illustrate this with examples, including a recently characterized mouse model, Legs at odd angles (Loa).

Purpose of review The purpose of this review is to present recent advances in the both the creation and the use of mouse models of human neurodegenerative disease. We briefly touch on the technologies used to make these models, and then focus on recent results from new models. We discuss why such models are useful when they do - and do not - mimic the human disorder. Recent findings The numbers of mouse models are increasing dramatically and are starting to yield important results for human disease. We present a selection of new and important models and the results of recent investigations of these animals. Summary An accepted protocol when studying any form of human neurodegenerative disease is to investigate the genetics, pathology, neurophysiology, response to therapeutics, etc., of the disorder in the mouse. This approach is clearly bearing fruit for our understanding and treatment of human neurodegeneration.

Degenerative disorders of motor neurons include a range of progressive fatal diseases such as amyotrophic lateral sclerosis (ALS), spinal-bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). Although the causative genetic alterations are known for some cases, the molecular basis of many SMA and SBMA-like syndromes and most ALS cases is unknown. Here we show that missense point mutations in the cytoplasmic dynein heavy chain result in progressive motor neuron degeneration in heterozygous mice, and in homozygotes this is accompanied by the formation of Lewy-like inclusion bodies, thus resembling key features of human pathology. These mutations exclusively perturb neuron-specific functions of dynein.

Objective The lack of epidemiological data and molecular diagnostic services in Malaysia has hampered the setting-up of a comprehensive management plan for patients with myotonic dystrophy type 1 (DM1), leading to delayed diagnosis, treatment and support for patients and families. The aim of this study was to estimate the prevalence of DM1 in the 3 major ethnic groups in Malaysia and evaluate the feasibility of a single tube triplet-primed PCR (TP-PCR) method for diagnosis of DM1 in Malaysia. Design, setting and participants We used PCR to determine the size of CTG repeats in 377 individuals not known to be affected by DM and 11 DM1 suspected patients, recruited from a tertiary hospital in Kuala Lumpur. TP-PCR was performed on selected samples, followed by Southern blot hybridisation of PCR amplified fragments to confirm and estimate the size of CTG expansion. Outcome measures The number of individuals not known to be affected by DM with (CTG)>18 was determined according to ethnic group and as a whole population. The χ2 test was performed to compare the distribution of (CTG)>18 with 12 other populations. Additionally, the accuracy of TP-PCR in detecting CTG expansion in 11 patients with DM1 was determined by comparing the results with that from Southern blot hybridisation. Results Of the 754 chromosomes studied, (CTG)>18 frequency of 3.60%, 1.57% and 4.00% in the Malay, Chinese and Indian subpopulations, respectively, was detected, showing similarities to data from Thai, Taiwanese and Kuwaiti populations. We also successfully detected CTG expansions in 9 patients using the TP-PCR method followed by the estimation of CTG expansion size via Southern blot hybridisation. Conclusions The results show a low DM1 prevalence in Malaysia with the possibility of underdiagnosis and demonstrates the feasibility of using a clinical and TP-PCR-based approach for rapid and cost-effective DM1 diagnosis in developing countries.

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.

This study aimed to identify candidate proteins which may serve as potential biological markers for cervical cancer using 2D-DIGE. Serum samples of controls, patients with cervical intraepithelial neoplasia grade 3 (CIN 3), squamous cell carcinoma of early (SCC I and II) and late (SCC III and IV) stage were subjected to 2D-DIGE. Differentially expressed spots were identified by tandem mass spectrometry. Validation of candidate proteins in serum and tissue samples were then performed by ELISA and immunohistochemistry (IHC) analysis respectively. A total of 20 differentially expressed proteins were identified. These proteins were found to play key roles in the apoptosis pathway, complement system, various types of transportation such as hormones, fatty acids, lipid, vitamin E and drug transportation, coagulation cascade, regulation of iron and immunologic response. Based on their functional relevancy to the progression of various cancers, 4 proteins namely the complement factor H, CD5-like antigen, gelsolin and ceruloplasmin were chosen for further validation using ELISA. Biological network analysis showed that ceruloplasmin and gelsolin are closely interacted with the oncogene NF-κb. These two proteins were further validated using the IHC. Gelsolin and ceruloplasmin may serve as potential predictive biomarkers for the progression of high grade lesions.

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.

Pathogenic mutations of the choline acetyltransferase (ChAT) gene alters its function and causes reduced synthesis of acetylcholine and its depletion in synaptic vesicles. This results in a rare presynaptic form of congenital myasthenic syndrome which presents at birth or in infancy characterised by apnoeic attacks. We present Kadazandusun family, an ethnic group native to Sabah, in north Borneo, with ChAT deficiency in which 5 of 6 siblings of non-consanguineous parents were affected. 2 died in their infancy from apnoeic atatacks while another sibling died at the age of 12 years from a severe apnoeic episode after an intercurrent infection. We reviewed 2 brothers, the eldest and the 4th at 24 and 18 years of age respectively, although both had presented in infancy with bilateral ptosis and limb weakness. The elder brother had episodes of apnoea and weakness on exposure to cold well water in their village. A congenital myasthenic syndrome was suspected and both brothers were treated on pyridostigmine after positive Tensilon tests and negative acetylcholine receptor antibody tests. On review, both had muscle weakness after moderate to severe exertion and repetitive nerve stimulation test of the abductor digiti minimi, which was normal at rest, showed sustained decremental response after prolonged 5 min stimulation at 10 Hz. Screening of the ChAT gene showed compound heterozygous mutation in both brothers, c.1069G>C and c.2263_2265delTCT in exons 6 and 15 respectively. Each parent was heterozygous for one of the mutations, which were not seen in any of 50 normal controls obtained from the native population of Sabah. In summary, we present a Kadazandusun family with ChAT deficiency congenital myasthenic syndrome, in which, 3 affected siblings died from apnoeic episodes, while another 2 survived to adulthood. This variable severity could be attributed to treatment with pyridostigmine as well as recognised improvement with age in this condition.

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.

Docetaxel is an antitubulin chemotherapeutic agent approved for the treatment of breast, lung, ovarian and non-hormonal dependent prostate cancers. However, the success of this drug is limited by adverse effects (AEs), the severity of which ranged from tolerable to life threatening. Tapering the dose or diverting to another regimen would limit the use of docetaxel. Single nucleotide polymorphisms (SNPs) of genes encoding for enzymes and proteins involved in the metabolism and transport of docetaxel can cause accumulation of the drug and consequent AEs. Hence, we embarked on a study to investigate the association between SNPs of ABCB1, SLCO1B3 and CYP3A5 genes with docetaxel AEs in Malaysian breast cancer patients. Seventy five breast cancer patients receiving docetaxel as single agent chemotherapy in the adjuvant and metastatic settings were enrolled in this study. They were recruited from University Malaya Medical Centre and Universiti Kebangsaan Malaysia Medical Centre. The doses given were 90-100 mg/m2 in adjuvant setting and 75 mg/m2 in metastatic setting. The SNPs (CYP3A5 6986AG, ABCB1 3435CT and SLCO1B3 334TG) were analyzed using PCR-RFLP technique followed by DNA sequencing of selected samples. AEs were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. The SNPs were correlated with AEs using Chi-square and Fisher's exact tests. The patients aged 53.7±9.4 years consisted of three main ethnic groups (Chinese 37 (49%), Malays 32 (43%) and Indians 6 (8%). The most commonly reported AEs were fatigue (55%), nausea (40%), and mucositis (35%). There was a significant association of vomiting with race (p Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A210. Citation Format: Rafid Salim Jabir, Gwo Fuang Ho, Muhammad Azrif bin Ahmad Annuar, Johnson Stanslas. Single nucleotide polymorphisms of ABCB1, SLCO1B3, and CYP3A5: Potential biomarkers of docetaxel adverse effects in Malaysian breast cancer patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A210.

Background Impulse control disorder (ICD) and behaviours (ICB) represent a group of behavioural disorders that have become increasingly recognised in Parkinson’s disease (PD) patients who previously used dopaminergic medications, particularly dopamine agonists and levodopa. It has been suggested that these medications can lead to the development of ICB through the abnormal modulation of dopaminergic transmission and signalling in the mesocorticolimbic dopaminergic system. Several studies have reported an association between polymorphisms in the dopamine receptor (DRD) and N-methyl-D-aspartate 2B (GRIN2B) genes with the development of ICB in PD (PD-ICB) patients. Thus, this study aimed to investigate the association of selected polymorphisms within the DRD and GRIN2B genes with the development of ICB among PD patients using high resolution melt (HRM) analysis. Method We used high resolution melt (HRM) analysis to genotype 11 polymorphisms in 5 DRD genes [DRD1 (rs4532, rs4867798 and rs265981), DRD2 (ANKK1 rs1800497, rs104894220 and rs144999500), DRD3 (rs3732783 and rs6280), DRD4 (rs1800443), and DRD5 (rs144132215)] and 1 polymorphism in GRIN2B (rs7301328) in PD patients with (cases, n = 52) and without (controls, n = 39) ICB. Cases were obtained from two tertiary movement disorder centres [UKMMC (n = 9) and UMMC (n = 43)]. At both centres, the diagnosis of ICB was made using the QUIP questionnaire. Controls were recruited from PD patients who attended UKMMC and were found to be negative for ICB using the QUIP questionnaire. Results The HRM analysis showed that 7 of 11 polymorphisms [DRD1 (rs4532, rs4867798, and rs265981), DRD2 (ANKK1 rs1800497), DRD3 (rs3732783 and rs6280), and GRIN2B (rs7301328)] exhibited a clear distinction between wild-type and variant alleles. Variants of DRD2/ANKK1 rs1800497 (OR = 3.77; 95% CI, 1.38-10.30; p = 0.0044), DRD1 rs4867798 (OR = 24.53; 95% CI, 1.68-357.28; p = 0.0054), DRD1 rs4532 (OR = 21.33; 95% CI, 1.97-230.64; p = 0.0024), and GRIN2B rs7301328 (OR = 25.07; 95% CI, 1.30-483.41; p = 0.0097) were found to be associated with an increased risk of developing ICB among PD patients. Conclusion Our findings suggest that polymorphisms in dopamine [DRD1 (rs4532 and rs4867798) and DRD2/ANKK1 rs1800497] and glutamate (GRIN2B rs7301328) receptor genes confer increased risk of ICB development among PD patients. Electronic supplementary material The online version of this article (doi:10.1186/s12883-015-0316-2) contains supplementary material, which is available to authorized users.