Shyamal K Das

Burdwan Medical College, Burdwān, Bengal, India

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Publications (22)70.44 Total impact

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    ABSTRACT: Wilson disease (WD) is caused by defects in ATP7B gene due to impairment of normal function of the copper transporting P-type ATPase. This study describes a comprehensive genetic analysis of 199 Indian WD patients including mutations detected in our previous studies, undertakes functional assessment of the nucleotide variants in ATP7B promoter and correlates genotype with disease phenotype. The patient cohort harbors a total of 10 common and 48 rare mutations in the coding region of ATP7B including 21 novel changes. The common mutations represent 74% of characterized coding mutant alleles with p.C271X (63/260) and p.G1101R (7/31) being the most prevalent in eastern and western Indian patients, respectively. The mutation spectrum between east and west is mostly different with only three mutations (p.G1061E, p.N1270S and p.A1049A-fs) being shared between both the groups. Eight novel and 10 reported variants have been detected in the promoter and non-coding regions (5' and 3'UTRs) of ATP7B. Promoter reporter assay demonstrated that 3 novel variants and 5 reported polymorphisms alter the gene expression to a considerable extent; hence might play important role in ATP7B gene regulation. We devised the neurological involvement score to capture the spectrum of neurological involvement in WD patients. By utilizing the age at onset, neurological involvement score and ATP7B mutation background, we generated a genotype-phenotype matrix that could be effectively used to depict the phenotypic spectra of WD affected individuals and serve as a platform to identify prospective "outliers" to be investigated for their remarkable phenotypic divergence.
    Parkinsonism & Related Disorders 09/2013; · 3.27 Impact Factor
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    ABSTRACT: Introduction: Alzheimer's disease (AD) is characterized by amnesia, though non-memory-cognitive domains like visual are also affected. We planned to study frequency of visual dysfunctions in AD and their relationship with dementia severity.Materials and Methods: This study was conducted in the Cognitive clinic of Department of Neurology, Bangur Institute of Neurosciences, Kolkata, between January 2007 and December 2010. 55 patients of AD were evaluated by neurological and neuropsychological assessments and by special tests for visual dysfunctions.Results: Common visual dysfunctions were visuo-constructional (87.3%), visuo-perceptual (63.6%), object agnosia(47.3%), prosopagnosia (45.5%), visual hallucination (27.3%) and simultanagnosia (12.7%). Symptoms of ventral visual pathway dysfunction were more common than that of dorsal pathway. MMSE score and number of visual manifestations had a good correlation.Conclusions: Visual dysfunctions are common in AD, elicitation of which helps us to understand the cause of disability so that appropriate steps can be taken.
    American Journal of Alzheimer s Disease and Other Dementias 07/2013; · 1.52 Impact Factor
  • Parkinsonism & Related Disorders 01/2013; · 3.27 Impact Factor
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    ABSTRACT: Parkinson's disease (PD) is a common neurodegenerative movement disorder. Among the candidate genes, DJ-1 accounts for about 1% of the cases in different populations. We aim to find the contribution of the gene towards PD among Indians. By screening DJ-1 in 308 PD patients of eastern India and 248 ethnically matched controls, a total of 21 nucleotide variants - including two nonsynonymous changes - were detected. p.Arg98Gln was identified in 6 unrelated patients and 2 controls while p.Val35Ile, a novel change, was found only in 2 unrelated patients. A SNP (rs7517357) was observed to be moderately associated with increased risk of PD (p< 0.05). The deletion allele (g.168_185del) of a known 18 bp del/ins/dup polymorphism was found to be over represented (p< 0.05) among older patients (> 40 years) compared to the controls (> 45 years). Two of the patients, also heterozygotes for PINK1 mutation, had more severe disease phenotypes, consistent with the reported interaction between PINK1 and DJ-1 gene products [19]. Our results demonstrate that up to 3.9% (12/308) of PD patients of eastern India harbor DJ-1 variants that should be explored further for any causal relationship with PD.
    Disease markers 08/2012; 33(3):127-35. · 2.14 Impact Factor
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    ABSTRACT: The aim of this study is to examine the role of GCH1 among Indians affected with dopa responsive dystonia (DRD) and early onset Parkinson's disease (EOPD). The patients (n = 76 including 19 DRD and 36 EOPD) and controls (n = 138) were screened for variants in GCH1 by PCR amplification of exons, splice junctions and 1 kb upstream region followed by SSCP and DNA sequencing. Four novel variants (p.Met1Val, p.Val204_205del, IVS3+68A>G, and IVS5-6T>G) were identified in 10 patients but not in the controls. In addition to two nonsynonymous changes, identified in four DRD patients in heterozygous condition, one intronic variant (IVS5-6T>G) could be linked to pathogenesis of the disease since it has the potential of altering the splice site as assessed by in silico analysis. Patients carrying different nonsynonymous variants had remarkable variation in clinical phenotype. Consistent with earlier reports, severity of clinical phenotype and the age of onset varied among family members harboring the same mutation. No mutation was detected in the EOPD patients. Three novel mutations in GCH1 gene have been found and are shown to be associated with variable clinical phenotypes mostly within the spectrum of DRD. The mutations identified represent 15.79% (3/19) of east Indian DRD patient cohort.
    Journal of Neural Transmission 02/2012; 119(11):1343-50. · 3.05 Impact Factor
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    ABSTRACT: Leucine rich repeat kinase 2 (LRRK2) gene defects cause Parkinson's disease (PD). Recently, LRRK2 has also been shown by genome wide association (GWA) studies to be a susceptibility gene for the disease. In India mutations in LRRK2 is a rare cause of PD. We, therefore, genotyped 64 SNPs across LRRK2 in 161 control samples and finally studied 6 haplotype tagging SNPs for association-based study on 300 cases and 446 ethnically matched controls to explore the potential role of LRRK2 as a susceptibility gene in PD for East Indians. We did not find any significant allele/ genotype or haplotype associations with PD suggesting that common genetic variants within LRRK2 play limited role in modulating PD among East Indians. In addition, we also screened for the common mutations (viz. p.R1441C, p.R1441G, p.R1441H, p.Y1699C, p.G2019S), and a risk variant common among Asians (p.G2385R) but did not observe any of the above mentioned variants in our cohort. Our study, therefore, strongly suggests that LRRK2 has minimal role as a candidate and susceptibility gene in PD pathogenesis among East Indians.
    Disease markers 01/2012; 32(6):355-62. · 2.14 Impact Factor
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    ABSTRACT: Glycogen synthase kinase-3β (GSK3B) and cyclin-dependent kinase 5 (CDK5) are the 2 major protein kinases involved in abnormal phosphorylation of tau. To determine their potential role in the pathogenesis of Parkinson's disease (PD) we analyzed 2 functional single nucleotide polymorphisms (SNPs) of GSK3B (rs334558 and rs6438552) and rs735555 of CDK5 regulatory subunit 1 (CDK5R1) in 373 PD cases and 346 healthy controls of eastern India. The C,C and T,C haplotypes of GSK3B were respectively moderately associated with increased risk and protection for late onset PD (LOPD) (odds ratio [OR], 1.399; 95% confidence interval [CI], 1.069-1.829; p = 0.015, and OR, 0.436; 95% CI, 0.222-0.853; p = 0.016, respectively). Moreover, moderate to significant interaction between different loci were observed for the entire PD cohort or late onset PD only. However, among these interactions, individuals carrying the (C/C) genotype at both loci (rs6438552 and rs735555) had almost twice the risk of developing PD than those without this genotypic combination (OR, 1.871; 95% CI, 1.181-2.964; p = 0.009). Thus, synergistic effect between the 2 major tau kinases, through these SNPs, appears to determine the risk profile for PD.
    Neurobiology of aging 12/2010; 33(7):1485.e9-15. · 5.94 Impact Factor
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    ABSTRACT: Wilson disease (WD) results from accumulation of copper and caused due to mutations in ATP7B, a copper transporting ATPase. Besides regular hepatic and neurological symptoms, WD patients occasionally manifest atypical symptoms due to unknown cause. To understand the molecular etiology of atypical WD manifestations, we screened COMMD1, a gene implicated in canine copper toxicosis, in 109 WD patients including those with atypical symptoms. In a patient showing apoptotic symptoms and high urinary copper surpassing normal WD levels, we identified a novel, putative mutation in COMMD1. Two other changes were also identified in the gene. We have examined genotype-phenotype correlation between the detected changes and the atypical presentation of the WD patient.
    Behavioral and Brain Functions 01/2010; 6:33. · 2.79 Impact Factor
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    ABSTRACT: Mutations in PINK1 have been identified in familial and sporadic cases of early onset Parkinson's disease (PD). To determine the contribution of PINK1 variants in Indian PD patients, the gene was screened in 250 patients and 205 ethnically matched controls by polymerase chain reaction, single-stranded conformation polymorphism and DNA sequencing. Two potentially pathogenic variants (Arg246Gln & Arg276Gln) were detected in the heterozygous state in 5 patients; none of the patients carried homozygous or compound heterozygous mutations. In addition, 13 other variants were identified, including a known polymorphism (Ala340Thr), a few synonymous or intronic changes, none of which are likely to be pathogenic. Unlike the Chinese population, the Ala340Thr variant did not show any association with PD in Indian population. Six single nucleotide polymorphisms (SNPs) selected from dbSNP were genotyped in 531 normal, healthy individuals representing different ethnic groups of India. Most of the SNP markers were observed to be highly heterozygous among Indians, which could be used for segregation analysis of PINK1 alleles in familial PD cases.
    Parkinsonism & Related Disorders 11/2009; 16(3):167-71. · 3.27 Impact Factor
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    ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disease of the central nervous system and its prevalence increases with age. Microtubule-associated protein tau (MAPT), a neuronal protein is involved in the pathogenesis of several neurodegenerative diseases including PD. To determine the broader significance of this association with PD, replicative studies in distinct ethnic populations are required. In this study, we investigated MAPT for its potential association with PD using five haplotype-tagging SNPs and the del-In9 polymorphism of MAPT in 301 PD patients and 243 healthy controls from eastern India. Our case-control analysis did not show a significant association with any of the markers and PD. However, a risk haplotype [GAC+G] for PD was identified (OR=1.563; 95% CI=1.045-2.337; p=0.03). In addition, haplotype AAC+A (OR=2.787; 95% CI=1.372-5.655; p=0.004) was strongly associated with early onset PD (age at onset < or =40 years) and AAC+G haplotype showed a weak association (OR=2.233; 95% CI=1.018-4.895; p=0.045) with late onset PD (age at onset >40 years). This observation highlights the significance of rs7521 in modifying the age at onset of PD under a common haplotype background. We also identified AGC+A as a risk haplotype for sporadic cases (OR=2.773, 95% CI=1.198-6.407, p=0.016). This is the first association study from India conducted on MAPT among PD patients and provides valuable information for comparison with other ethnic groups.
    Neuroscience Letters 06/2009; 460(1):16-20. · 2.03 Impact Factor
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    ABSTRACT: To ascertain the prevalence of active epilepsy, febrile seizures (FS), cerebral palsy (CP) and tic disorders (TD) in aged 19 years or less. This was a cross-sectional observational study conducted as a two-stage door-to-door survey of a stratified randomly selected population in 2003-04. Trained field workers screened the population followed by case examination by the field neurologist. A total of 16979 (male 8898, female 8081) subjects aged <or= 19 years were surveyed. The prevalence rates per 100,000 population of active epilepsy, FS, CP and TD with 95% confidence intervals are 700.87 (580.60-838.68), 1113.14 (960.07-1283.59), 282.70 (CI 208.43-374.82) and 35.34 (12.96-76.92) respectively. Active epilepsy prevalence shows a rising trend and that of other disorders a declining trend with age. Of the epileptics who had brain CT scans, 23.4% showed single or multiple lesions suggestive of neurocysticercosis. Regarding treatment, 23.5% of the epileptics never received any antiepileptic drugs. Among those with history of FS, 9.5% developed epilepsy later on. The prevalence of FS among slum dwellers is lower than in the non-slum population. Among CP cases, 39.6% gave history of birth anoxia, 16.7% kernicterus and 31.3% epilepsy. Prevalence of CP is significantly associated with lower education status. The prevalence of CP and TD is lower than reported from western countries. CP prevalence is also comparatively lower than in many community studies from India. Compared to western nations, higher proportion of FS cases develops epilepsy. A third of the CP cases have seizures which is higher than in many Indian studies. Birth anoxia is a common cause of CP and educational underachievement is frequent.
    The Indian Journal of Pediatrics 12/2008; 76(2):139-46. · 0.72 Impact Factor
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    ABSTRACT: Epilepsy is a major health problem in India, but community based incidence study is rare. This study was undertaken to determine the incidence rate in a rural community of the state of West Bengal, India. The study was done through house to house survey by a dedicated team of neurologists, who carried out the survey cum case detection over 5 years. A total of 38 cases were detected during the survey period in a population of 20,966. The age adjusted (to World Standard Population) average annual incidence rate was 42.08 per 100,000 persons per year (95% confidence interval, 29.75-57.86). This rate was higher than many developed countries, but lower than the developing countries. Cerebral infection was the most common putative factor observed. An increasing trend of incidence of epilepsy has been observed over the years during the period of the study.
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    ABSTRACT: We aim to identify the molecular defects in the ATP7B, the causal gene for Wilson disease (WD), in eastern Indian patients and attempt to assess the overall mutation spectrum in India for detection of mutant allele for diagnostic purposes. Patients from 109 unrelated families and their first-degree relatives comprising 400 individuals were enrolled in this study as part of an ongoing project. Genomic DNA was prepared from the peripheral blood of Indian WD patients. PCR was done to amplify the exons and flanking regions of the WD gene followed by sequencing, to identify the nucleotide variants. In addition to previous reports, we recently identified eight mutations including three novel (c.3412 + 1G > A, c.1771 G > A, c.3091 A > G) variants, and identified patients with variable phenotype despite similar mutation background suggesting potential role of modifier locus. So far we have identified 17 mutations in eastern India including five common mutations that account for 44% of patients. Comparative study on WD mutations between different regions of India suggests high genetic heterogeneity and the absence of a single or a limited number of common founder mutations. Genotype-phenotype correlation revealed that no particular phenotype could be assigned to a particular mutation and even same set of mutations in different patients showed different phenotypes.
    Cellular and Molecular Neurobiology 12/2007; 27(8):1023-33. · 2.29 Impact Factor
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    ABSTRACT: An epidemiological study on dystonia has not been reported from India. As part of a major study to find out the prevalence of major neurological disorders in the large urban city of Kolkata, Eastern India, we planned to determine the prevalence of primary dystonia. The study design was a cross-sectional study of a sample population obtained through stratified random selection and conducted in a two-stage procedure of screening by a nonprofessional team followed by confirmation of screened positive cases by the study neurologist. A total population of 52,377 was screened, and 29 subjects with dystonia were diagnosed. Out of them 23 subjects had primary dystonias [crude prevalence rate (CPR), 43.91/100,000; 95% confidence interval (CI), 28.41-64.81; age-standardized rates to world standard population, 49.06 (95% CI,31.74-72.41)] and all cases were focal type and predominantly of limb dystonia variety. Mean onset of dystonias were earlier in women (43.5 years) as compared to men (46.6 years). Thus our study on primary dystonia shows higher prevalence when compared with that of many studies globally, predominantly of focal type, earlier onset among women, and more cases of limb dystonias when compared with more prominent blepharospasm and cervical dystonias in western reports.
    Movement Disorders 11/2007; 22(14):2031-6. · 4.56 Impact Factor
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    ABSTRACT: Wilson disease (WD) is an autosomal recessive disorder caused by defects in the ATPase, Cu(2+) transporting, beta-polypeptide gene (ATP7B) resulting in accumulation of copper in liver and brain. WD can be thwarted if detected at a presymptomatic stage, but occasional recombination during carrier detection with dinucleotide repeat markers flanking the WD locus may lead to faulty diagnosis. We examined the use of intragenic single-nucleotide polymorphism (SNP) markers to avoid this limitation. We prepared genomic DNA from the peripheral blood of Indian WD patients. By use of PCR, we amplified the exons and flanking regions of the WD gene and then performed sequencing to identify the nucleotide variants. We genotyped the SNPs in 1871 individuals by use of the Sequenom mass array system. We made linkage disequilibrium plots using Haploview software. We identified 1 mutation accounting for 11% (19 of 174) of WD chromosomes among patients in addition to 4 prevalent mutations characterized previously. Among 24 innocuous allelic variants identified, we selected 3 SNPs found to have high heterozygosity (>0.40) for the detection of mutant WD chromosomes. On analyzing these SNPs in 28 test individuals, who were sibs to 17 unrelated WD patients, we obtained unequivocal genotyping in 25 cases (approximately 89%). The remaining 3 cases were genotyped by dinucleotide repeat marker (D13S133). Sets of SNP markers are highly heterozygous across most world populations and could be used in combination with analysis of prevalent mutations as a comprehensive strategy for determining presymptomatic and carrier sibs of WD patients.
    Clinical Chemistry 09/2007; 53(9):1601-8. · 7.15 Impact Factor
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    ABSTRACT: Information on essential stroke parameters are lacking in India. This population-based study on stroke disorder was undertaken in the city of Kolkata, India, to determine the subtypes, prevalence, incidence, and case fatality rates of stroke. This was a longitudinal descriptive study comprising 2-stage door-to-door survey of a stratified randomly selected sample of the city population, conducted twice per year for 2 successive years from March 2003 to February 2005. Out of the screened population of 52,377 (27 626 men, 24 751 women), the age standardized prevalence rate of stroke to world standard population is 545.10 (95% CI, 479.86 to 617.05) per 100,000 persons. The age standardized average annual incidence rate to world standard population of first-ever-in-a-lifetime stroke is 145.30 (95% CI, 120.39 to 174.74) per 100,000 persons per year. Thirty-day case fatality rate is 41.08% (95% CI, 30.66 to 53.80). Women have higher incidence and case fatality rates. Despite divergence on socioeconomic status between the slum and nonslum dwellers, stroke parameters were not significantly different. The age standardized prevalence and incidence rates of stroke in this study are similar to or higher than many Western nations. The overall case fatality rate is among the highest category of stroke fatality in the world. The women have higher incidence and case fatality rates compared with men.
    Stroke 04/2007; 38(3):906-10. · 6.16 Impact Factor
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    ABSTRACT: Parkinson's disease (PD), the second most common neurodegenerative disorder, affects at least 1% of the population over the age of 50. However, very little information is available regarding the molecular basis of PD among Indians. Since the largest number of mutations have been detected in the Parkin gene among all known PD loci, we aim to use Parkin as the candidate gene to assess its role in PD-related pathogenesis in Indian patients. A total of 138 PD patients, with the mean age of onset being 47+/-14 (age range, 5-77 years), and 100 controls were recruited for the study from eastern India. Parkin mutations were detected by amplification of exons of the gene along with the flanking splice junctions by polymerase chain reaction, single-stranded conformation polymorphism and DNA sequencing. A total of 18 nucleotide variants including six novel changes were detected. These include five missense mutations (Gln34Arg, Arg42Cys, Arg42His, Tyr143Cys and Arg334Cys) detected in eight patients in heterozygous condition and a homozygous deletion encompassing exons 3 and 4 in two sibs affected with PD. Clinical features of the Parkin mutants were compared. Among eastern Indian PD patients, mutation in Parkin was identified in 7.24% cases.
    Parkinsonism & Related Disorders 11/2006; 12(7):420-6. · 3.27 Impact Factor
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    ABSTRACT: The most common genetic neuromuscular disease of childhood, Duchenne and Becker muscular dystrophy (DMD/BMD) is caused by deletion, duplication or point mutation of the dystrophin gene located at Xp 21.2. In the present study DNA from seventy unrelated patients clinically diagnosed as having DMD/BMD referred from different parts of West Bengal, a few other states and Bangladesh are analyzed using the multiplex polymerase chain reaction (m-PCR) to screen for exon deletions and its distribution within the dystrophin gene. Out of seventy patients forty six (63%) showed large intragenic deletion in the dystrophin gene. About 79% of these deletions are located in the hot spot region i.e, between exon 42 to 53. This is the first report of frequency and distribution of deletion in dystrophin gene in eastern Indian DMD/BMD population.
    Neurology India 10/2006; 54(3):310-1. · 1.04 Impact Factor
  • Shyamal K Das, Kunal Ray
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    ABSTRACT: Wilson's disease (WD) is an inborn error of copper metabolism caused by a mutation to the copper-transporting gene ATP7B. The disease has an autosomal recessive mode of inheritance, and is characterized by excessive copper deposition, predominantly in the liver and brain. Diagnosis of the condition depends primarily on clinical features, biochemical parameters and the presence of the Kayser-Fleischer ring, and a new diagnostic scoring system has recently been proposed. Mutations in ATP7B can occur anywhere along the entire 21 exons, which makes the identification of gene defects particularly challenging. Identification of carriers and presymptomatic family members of affected individuals is achieved by polymerase-chain-reaction-based marker analysis. The traditional treatment for WD is based on copper chelation with agents such as D-penicillamine, but use of this drug has been questioned because of reported side effects. The use of agents such as trientine and ammonium tetrathiomolybdate has been advocated, although results of long-term trials are awaited. In selected cases, orthotropic hepatic transplantation can reverse the basic metabolic abnormality in WD and improve both hepatic and neurological symptoms. Studies of the underlying defects in ATP7B and its suspected modifiers ATOX1 and COMMD1 are expected to unravel the disease's genotype-phenotype correlation, and should lead to the design of improved drugs for ameliorating the suffering of patients.
    Nature Clinical Practice Neurology 10/2006; 2(9):482-93. · 7.64 Impact Factor
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    Clinical Chemistry 09/2006; 52(8):1611-2. · 7.15 Impact Factor

Publication Stats

200 Citations
70.44 Total Impact Points

Institutions

  • 2013
    • Burdwan Medical College
      Burdwān, Bengal, India
  • 2009–2013
    • University of Calcutta
      • S N Pradhan Centre for Neurosciences
      Calcutta, Bengal, India
  • 2007–2013
    • Indian Institute of Chemical Biology
      • Molecular and Human Genetics Division (IICB)
      Kolkata, Bengal, India
  • 2006–2009
    • Institute of Psychiatry, Kolkata
      Kolkata, Bengal, India