Movement disorders: Indian scenario: a clinico-genetic review.
TL;DR: Common problems of MDs in India with regard to epidemiology, clinical features and genetics are highlighted.
Abstract: Movement disorder (MD) is an important branch of neurology and has great potentiality in management because of improved diagnosis and therapeutic strategies. Over the last three decades, emphasis has been laid on the evaluation of various MDs in India by a limited number of interested neurologists and basic scientists. In this review, we want to highlight common problems of MDs in India with regard to epidemiology, clinical features and genetics.
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TL;DR: The core neuroanatomical features of resilience against PD and evidence for ethnicity-based differential prevalence are presented and similar neural correlates of resilience are envisaged in the Anglo-Indian population.
Abstract: Disease genetics in admixed populations like Hispanic-Americans, African-Americans, etc. are gaining importance due to high disease burden in them. Furthermore, epidemiological studies conclusively prove ethnicity-based differential prevalence of Parkinson's disease (PD), since the American-Caucasians are more susceptible than Asian-Indians and Africans. Contradictorily, Anglo-Indians, an admixture of Europeans and Asian-Indians are five-times less susceptible than Indians. We evaluated the neural basis of this phenomenon using the cytomorphological features of susceptibility to nigrostriatal neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The nigral dopaminergic neuronal numbers, their size and tyrosine hydroxylase (TH), PitX3 and Nurr1 expression were compared in MPTP-susceptible C57BL/6J mice, MPTP-resistant CD-1 mice and their crossbreds using stereology, morphometry and densitometry. Apoptotic index was evaluated by TUNEL-assay and caspase-3 expression. Striatal volume, TH and glial derived neurotrophic factor (GDNF) expression were studied. The normal CD-1 and crossbreds had significantly more, although smaller, nigral dopaminergic neurons than C57BL/6J, and a larger striatum. The crossbreds had higher TH, Nurr1 and PitX3 levels. MPTP administration caused loss of ~50-60 % nigral dopaminergic neurons in C57BL/6J and ~15 % in CD-1, but none in crossbreds. MPTP-induced cellular shrinkage in C57BL/6J was contrasted by nuclear enlargement without somal alterations in resistant strains. MPTP lowered the striatal TH and GDNF in C57BL/6J. Elevated striatal GDNF in CD-1 and crossbreds could be of compensatory nature and complemented the reduced nigral caspase-3 expression to attenuate and/or block apoptosis. Similar neural correlates of resilience are envisaged in the Anglo-Indian population. Thus, we present the core neuroanatomical features of resilience against PD and evidence for ethnicity-based differential prevalence.
23 citations
Cites background from "Movement disorders: Indian scenario..."
...However, in the Asian-Indian population, studies report absence of mutations in SNCA/α-synuclein gene while mutations in DJ-1, PINK1 and LRRK2 genes are rare [39, 40]; hence, we did not choose a genetic model of the disease....
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TL;DR: Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations.
Abstract: BACKGROUND Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations. OBJECTIVES To resolve the role of LRRK2 in the Indian population. METHODS We performed targeted resequencing of the LRRK2 locus in 288 cases and 298 controls and resolved the haplotypic structure of LRRK2 in a combined cohort of 800 cases and 402 controls in the Indian population. We assessed the frequency of novel missense variants in the white and East Asian population by leveraging exome sequencing and densely genotype data, respectively. We did computational modeling and biochemical approach to infer the potential role of novel variants impacting the LRRK2 protein function. Finally, we assessed the phosphorylation activity of identified novel coding variants in the LRRK2 gene. RESULTS We identified four novel missense variants with frequency ranging from 0.0008% to 0.002% specific for the Indian population, encompassing armadillo and kinase domains of the LRRK2 protein. A common genetic variability within LRRK2 may contribute to increased risk, but it was nonsignificant after correcting for multiple testing, because of small cohort size. The computational modeling showed destabilizing effect on the LRRK2 function. In comparison to the wild-type, the kinase domain variant showed 4-fold increase in the kinase activity. CONCLUSIONS Our study, for the first time, identified novel missense variants for LRRK2, specific for the Indian population, and showed that a novel missense variant in the kinase domain modifies kinase activity in vitro. © 2018 International Parkinson and Movement Disorder Society.
10 citations
Cites background from "Movement disorders: Indian scenario..."
..., G2019S) primarily identified in the white population—and excluded the role of these LRRK2 variants in the Indian PD population.(23,25,50,51) Here, we performed the first comprehensive study using targeted sequencing in Indian PD patients, which led to the identification of populationspecific novel variants and underscores the relevance of allelic heterogeneity in PD....
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TL;DR: The relevance, importance, and translational impediments of contemporary advances to implement public health principles into practice has neither been attempted nor impacted on disease burden or the authors' preparedness to prevent eventualities.
Abstract: It is now recognized worldwide that anticipation and prevention of diseases have significant advantages for the health and healthy ageing of the population. Early recognition of the disease in a vulnerable population such as in children aged 60 years enhances our preparedness for any eventualities and future burden of the diseases to society. It is also recognized that current public health practices alone cannot bring about the desired outcome. When tackling public health-related issues, such problems must be recognized and state-of-the-art principles and innovations from genomic sciences, information technologies, and medical specialties must be encompassed and embraced. These will enhance strategies for preparedness and provide us with a better understanding of how to identify, manage, and control disease burdens. The ever expanding landscape of genomics research also includes experimental and computational approaches for effectively utilizing DNA sequence information. From these perspectives, the intricacies of Mendelian single gene disorders are the least challenging compared to intricacies of multi-dimensional host factors for infectious diseases or complex disorders such as cancer. The concepts of public health in India are on firm footing; however, integration of contemporary advances to implement public health principles into practice has neither been attempted nor impacted on disease burden or our preparedness to prevent eventualities. At the same time, translational genomics is gradually paving the way for personalized medicine. Principles of personalized medicine remain to be fully understood and practiced despite the pharmacogenomics-based future of drug development, and treatment has not been as exciting as the advances in genomics we are witnessing today. The relevance, importance, and translational impediments of these advances will be discussed.
9 citations
01 Jan 2019
TL;DR: A chronicle of Indian Movement Disorders is written based on personal interviews with various senior Movement Disorder specialists of India as mentioned in this paper, which is a right time to look back into the history of Indian Neurology with specific reference to the Movement Disorders and pen down these chronicles since the inception of modern neurology in India.
Abstract: Movement Disorders are currently growing to be one of the major subspecialties of neurology worldwide, primarily by developments of research and therapeutics in this field. As any specialty grows, it leads to the formation of its society and the publication of journal to disseminate the knowledge. The International Parkinson’s Disease and Movement Disorders Society (IPMDS, formerly known as Movement Disorders Society) played its role with inception since 1980s. Further development of Movement Disorders subspecialty leads each region and country to have their own national societies and publications. Similarly, the seeds of Movement Disorders were sown in India in mid-1980s but it took a major stride in last few years with the formation of Movement Disorders Society of India (MDSI) in 2014 and following this, it is now at the crux of starting its journal—Annals of Movement Disorders (AOMD). This would be a right time to look back into the history of Indian Neurology with specific reference to the Movement Disorders and pen down these chronicles since the inception of modern neurology in India. The current chronicles of Indian Movement Disorders is penned based on personal interviews with various senior Movement Disorder specialists of India. However, it should also be remembered that many of the chronicles are limited by the memories of people and their biases with whom the interviews are conducted.
3 citations
Cites background from "Movement disorders: Indian scenario..."
...Das contributed on the epidemiology of various movement disorders.[18] The other important contribution of Indian literature has been on SCA-12....
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TL;DR: The most frequent diagnosis was Parkinson's disease, followed by essential tremor and dystonia, and most patients were over 60 years of age, white, married and teachers.
Abstract: Background Knowing the epidemiological profile is relevant for improving healthcare practices. Movement disorders are neurological disorders characterized by the presence of involuntary movements. They have a negative impact on patients' quality of life. Objectives To outline the frequencies of the different diagnoses seen among patients, along with their demographic characteristics, at a hospital in Sao Paulo (SP), Brazil, and to highlight the clinical aspects of those with Parkinson's disease. Design and setting Retrospective descriptive epidemiological analysis at a specialized outpatient clinic in a state public hospital in Sao Paulo. Methods Patients treated at this clinic over a four-year period were analyzed. Diagnoses, demographic variables and associations with clinical aspects of Parkinson's disease were evaluated. Results Out of the 680 medical records analyzed, 58.4% related to females. Most patients were over 60 years of age, white, married and teachers. The most frequent diagnosis was Parkinson's disease, followed by essential tremor and dystonia. Parkinson's disease presented in the mixed clinical form; the most common initial symptom was tremor. The akinetic-rigid clinical form occurred in younger individuals and mostly presented with postural instability and freezing of gait in the early years of disease. Conclusions Parkinson's disease, essential tremor and dystonia were the most frequent diagnoses. Characteristics like sex, frequency of other pathological conditions and the clinical and demographic aspects of Parkinson's disease were consistent with the data in the relevant literature.
2 citations
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TL;DR: Assessment of contribution of six genes involved in dopamine synthesis and metabolism to PD susceptibility and its role in modulating disease severity reiterates the importance of dopamine pathway in sporadic PD etiology in general and potential therapeutic implications of DBH in particular.
Abstract: Objectives Genetic and non-genetic components are believed to govern the etiology of common complex traits such as Parkinson's disease (PD). In view of the biochemical evidence of depleted dopamine levels in the affected brains and also the most common and effective therapeutic modality of administration of levodopa in PD, genes from the dopaminergic pathway emerge as major determinants. We have earlier shown the role of DRD4-120 bp duplication marker in PD susceptibility. In this study, contribution of six genes involved in dopamine synthesis and metabolism to PD susceptibility and disease severity was assessed in a North Indian PD cohort. Methods 339 patients diagnosed using UKPD brain bank criteria and 344 matched controls were recruited and disease severity was assessed using the Hoehn and Yahr scale and Unified Parkinson Disease Rating Scale III scores. Allelic, genotypic and haplotypic associations with PD were computed; severity was compared among the genotypic categories of markers; gene-gene interactions were assessed using multiple logistic regression. Results A highly significant association of dopamine beta-hydroxylase (DBH) haplotypes (rs1611115T>C - rs1108580A>G - rs5320A>G - rs129882C>T) with PD was observed; haplotypes C-A-G-C [P=0.000005, Odds ratio (95% confidence interval): OR (95% CI)=1.76 (1.38-2.25)] and C-A-G-T [P=0.000001, OR (95% CI)=0.49 (0.37-0.65)] retaining significance after Bonferroni correction. rs129882, a 3'UTR SNP in DBH showed significant association with disease severity [Hoehn and Yahr (P=0.005) and Unified Parkinson Disease Rating Scale (P=0.006)]. Conclusion Observed association of DBH SNP/SNP haplotypes with PD susceptibility and its role in modulating disease severity reiterates the importance of dopamine pathway in sporadic PD etiology in general and potential therapeutic implications of DBH in particular.
25 citations
TL;DR: Evaluating the role of familial, environmental and occupational factors in the development of Parkinson’s disease in this region of India found that family history of Parkinson's disease and familial tremor, exposure to insecticides and pesticides, well water use for drinking purposes, and acute organophosphate poisoning were associated with the development.
Abstract: Background: Despite intensive research during the past several decades, the cause of Parkinson’s disease remains unknown. Infections, toxins, lifestyle and hereditary factors have all been supposed to play a role in the genesis of Parkinson’s disease. The final mechanisms of neuronal injury and death are probably similar, where both genetic and environmental factors are important, and these two factors interact along the etiopathogenic pathway. Objective: The purpose of the present study is to evaluate the role of familial, environmental and occupational factors in the development of Parkinson’s disease. Methods: We evaluated 345 cases of idiopathic Parkinson’s disease (215 males, 130 females; mean age 62 ± 2 years) and 370 controls (220 males, 150 females; mean age 62 ± 3 years) between January 2003 and January 2008 with regard to the following aspects in detail: place of living, family history of Parkinson’s disease and tremor, source of drinking water, exposure to insecticides, pesticides, herbicides and industrial toxins, acute poisoning, CNS infections and head injury. The duration of exposure to the risk factors and the history of Parkinson’s disease among the cases were investigated after obtaining written informed consent from cases and controls. Results and Conclusions: Family history of Parkinson’s disease and familial tremor (p = 0.035), exposure to insecticides and pesticides (p = 0.049), well water use for drinking purposes (p = 0.03), Japanese B encephalitis (p = 0.04) and acute organophosphate poisoning (p = 0.046) were associated with the development of Parkinson’s disease in this region of India. Further research is needed at the epidemiological, genetic and molecular levels for a better understanding of the etiopathogenesis of Parkinson’s disease as well as remedial aspects.
24 citations
TL;DR: All three patients with Wilson disease who developed severe paroxysmal dystonic spells after receiving D-penicillamine treatment responded well to gabapentin after failing to respond to other anti dystonia drugs.
Abstract: D-penicillamine induced status dystonicus is a unique but serious drug related complication in a subset of patients with Wilson disease. Patho-physiological basis of its occurrence is not known. It often responds poorly to anti dystonia medications. We present three patients with Wilson disease who developed severe paroxysmal dystonic spells after receiving D-penicillamine treatment. All three patients responded well to gabapentin after failing to respond to other anti dystonia drugs.
23 citations
"Movement disorders: Indian scenario..." refers background in this paper
...[34] Gabapentin has been useful in d‐penicillamine induced status dystonia.[35]...
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TL;DR: Six single nucleotide polymorphisms selected from dbSNP were genotyped in 531 normal, healthy individuals representing different ethnic groups of India and 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.
22 citations
"Movement disorders: Indian scenario..." refers background in this paper
...A number of association studies have been reported on the candidate[53,60] as well as the susceptibility genes involved in dopamine metabolism,[61‐63] xenobiotic metabolism,[64,65] neuronal cytoskeletal stability[66,67] etc....
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...[45] In India, candidate gene studies have been performed on SNCA,[46,47] Parkin,[48‑52] PINK1,[53] DJ‑1,[54,55] and LRRK2[47,56‑59] only [Table 2], with the maximum study being reported on Parkin....
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...[45] In India, candidate gene studies have been performed on SNCA,[46,47] Parkin,[48‐52] PINK1,[53] DJ‐1,[54,55] and LRRK2[47,56‐59] only [Table 2], with the maximum study being reported on Parkin....
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TL;DR: Prevalence of essential tremor (ET), one of the most common movement disorders, has not been properly evaluated amongst heterogeneous population in India.
Abstract: Background and purpose: Prevalence of essential tremor (ET), one of the most common movement disorders, has not been properly evaluated amongst heterogeneous population in India.
Methods: We conducted a cross-sectional epidemiological study on the prevalence of ET in a randomly stratified population in the metropolitan city of Kolkata (erstwhile Calcutta), India, by a field team headed by a specialist doctor. A two-stage house-to-house survey was carried out with a validated screening instrument.
Results: A population of 52377 was screened and a total of 184 cases of ET were identified as per pre-defined criteria and the prevalence rate adjusted to World Standard Population was 3.95 per 1000 (95% CI: 3.40–4.56). Age-specific prevalence showed increasing prevalence with aging. Sex-specific prevalence did not show significant difference between men and women. Socio-economic factors appeared to influence the prevalence and risk of ET was higher amongst slum dwellers versus non-slum population (odd ratio-2.29). Family history was positive in about one-fifth of the cases.
Conclusion: This study has documented that the prevalence of ET above 40 years in India is similar to that of many countries globally and common amongst slum dwellers and there are fewer familial cases.
21 citations
"Movement disorders: Indian scenario..." refers background in this paper
...Family history was positive in about one‐fifth of the cases.[27]...
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