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
References
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TL;DR: It is concluded that PD is rare in Bulgarian Gypsies, compared to Caucasians with 119 cases.
Abstract: We studied the prevalence of Parkinson’s disease (PD) in Gypsies and Caucasians in Bulgaria. Cases were ascertained by examination in a clinic, a screening questionnaire and a door-to-door survey in a region of Sofia, Bulgaria. The prevalence of PD in the Gypsies was found to be 16/100,000 based on 1 case compared to 137/100,000 for Caucasians with 119 cases. It is concluded that PD is rare in Bulgarian Gypsies.
14 citations
"Movement disorders: Indian scenario..." refers background or result in this paper
...Indians normally consume curcumin, a yellow curry powder, from early age and this may be one protective factor against developing PD as evident from animal studies[16] Two interesting studies from mixed Anglo‑Indian population in India and another study from Bulgaria in Europe where migrated Gypsies from North India had documented lower frequency of PD when compared to native Caucasians....
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...[12] However the prevalence of PD is lower than many Caucasian populations.[17] The possible causes may be due to younger population of India, possible existence of some protective environmental or ethnic factors....
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...Indians normally consume curcumin, a yellow curry powder, from early age and this may be one protective factor against developing PD as evident from animal studies[16] Two interesting studies from mixed Anglo‐Indian population in India and another study from Bulgaria in Europe where migrated Gypsies from North India had documented lower frequency of PD when compared to native Caucasians.[5,17] There were no comprehensive studies on Parkinsonism plus syndrome from India....
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TL;DR: This work investigated mutations in the autosomal dominant genes SNCA, A53T, A30P, E46K and LRRK2 and G2019S in 140 South Indian PD patients who have not been studied before.
14 citations
"Movement disorders: Indian scenario..." refers background in this paper
...[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: The results suggest that mutations in PARK2 gene may be a common cause of PD among South Indian early onset patients.
14 citations
TL;DR: It is suggested that LRRK2 has minimal role as a candidate and susceptibility gene in PD pathogenesis among East Indians and any significant allele/ genotype or haplotype associations with PD are unlikely.
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.
13 citations
TL;DR: 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.
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.
12 citations
"Movement disorders: Indian scenario..." refers background in this paper
...Genetic study on dystonia in India is rare with only two report till date on DYT1 and GCH1 gene from the eastern Indian population.[70,32] Several nucleotide variants were identified among which the Asp216His variant was found to be associated with primary dystonia....
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...[31] Interestingly one patient with GCH1 mutation presented with dopa responsive truncal dystonia without any diurnal variation.[32]...
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...79% (3/19) of East Indian DRD patient cohort.[32] Since DRD and JPD often show several overlapping phenotypes, therefore future studies should focus on these two diseases to identify the underlying causal gene for the better management of the disease....
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