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: This is the largest series regarding epilepsy in Wilson's disease and it was noted that patients whose seizures were not controlled had MRI suggestive of cavitation of white matter, though the reverse was not true.
46 citations
"Movement disorders: Indian scenario..." refers background in this paper
...Many Indian data are available on WD.[33] In a WD clinic from South India, about 15‑20 new cases are registered annually....
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...[40] A scale has been developed for monitoring progression and also for therapeutic interventions in patients with WD.[42] Brain Iron Accumulation Brain iron accumulation or Hallervorden‑Spatz disease is a rare autosomal recessive disorder that involves 460 Neurology India | Sep-Oct 2013 | Vol 61 | Issue 5 progressive extrapyramidal manifestations....
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...Differentiation of white matter tracts from cortex may contribute for seizure in WD.[37]...
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...copper transporting gene ATP7B and suspected modifiers ATOX1 and COMMD1 has been implicated for WD....
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...Differentiation of white matter tracts from cortex may contribute for seizure in WD.[37] MRI is frequently used in the evaluation of various extrapyramidal disorders....
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TL;DR: Genetically determined NBIA cases from the Indian subcontinent suggest presence of unusual phenotypes of PANK2 and novel mutations, suggesting the existence of further genetic or sporadic forms of N BIA syndromes.
Abstract: Neurodegeneration with brain iron accumulation (NBIA) is etiologically, clinically, and by imaging a heterogeneous group including NBIA types 1 [pantothenate kinase-associated neurodegeneration (PKAN)] and 2 (PLA2G6-associated neurodegeneration), neuroferritinopathy, and aceruloplasminaemia. Data on genetically defined Indian-subcontinent NBIA cases are limited. We report 6 patients from the Indian-subcontinent with a movement disorder and MRI basal ganglia iron deposition, compatible with diagnosis of an NBIA syndrome. All patients were screened for abnormalities in serum ceruloplasmin and ferritin levels and mutations in NBIA-associated genes [pantothenate kinase 2 (PANK2), PLA2G6 and ferritin light chain (exon 4)]. We present clinical, imaging and genetic data correlating phenotype-genotype relations. Four patients carried PANK2 mutations, two of these were novel. The clinical phenotype was mainly dystonic with generalized dystonia and marked orobulbar features in the 4 adolescent-onset cases. One of the four had a late-onset (age 37) unilateral jerky postural tremor. His mutation, c.1379C>T, appears associated with a milder phenotype. Interestingly, he developed the eye-of-the-tiger sign only 10 years after onset. Two of the six presented with adult-onset levodopa (L-dopa)-responsive asymmetric re-emergent rest tremor, developing L-dopa-induced dyskinesias, and good benefit to deep brain stimulation (in one), thus resembling Parkinson's disease (PD). Both had an eye-of-the-tiger sign on MRI but were negative for known NBIA-associated genes, suggesting the existence of further genetic or sporadic forms of NBIA syndromes. In conclusion, genetically determined NBIA cases from the Indian subcontinent suggest presence of unusual phenotypes of PANK2 and novel mutations. The phenotype of NBIA of unknown cause includes a PD-like presentation.
45 citations
TL;DR: The studies suggest that the overall prevalence of HD in Indian populations may not be as high as in Western populations, and one four-repeat CCG allele which has not been found in any population so far is reported here for the first time.
Abstract: We have analysed the distribution of CAG and adjacent polymorphic CCG repeats in the Huntingtin gene in 28 clinically diagnosed unrelated Huntington's disease (HD) patients and in normal individuals belonging to different ethnic groups of India. The range of expanded CAG repeats in HD patients varied from 41 to 56 repeats, whereas in normal individuals this number varied between 11 and 31 repeats. We identified six CCG alleles from a total of 380 normal chromosomes that were pooled across different ethnic populations of India. There were two predominant alleles: (CCG)7 (72.6%) and (CCG)10 (20%). We report here for the first time one four-repeat CCG allele which has not been found in any population so far. We found 30 haplotypes (two loci CAG-CCG) for 380 normal chromosomes. In the present study, no statistically significant preponderance of expanded HD alleles was found on either (CCG)7 or (CCG)10 backgrounds. Our studies suggest that the overall prevalence of HD in Indian populations may not be as high as in Western populations. Further studies are necessary to identify the origin of HD mutation in these populations.
43 citations
TL;DR: In order to evaluate the functional significance of WD mutations, the correlation between the mutations and several phenotypic manifestations was explored and the consequences of IVS4þ11insGT mutation could not be predicted.
Abstract: To the Editor: Mutations inATP7B (memberof cation transporting ATPase family) causeWilsondisease (WD) (1, 2) and result in progressive accumulation of copper in several tissues, principally the liver and the brain (1, 2), resulting in chronic liver disease and/or neurological impairment (3). More than 200 mutations in different domains of ATP7B have been identified worldwide (http://www.medgen. med.ualberta.ca/database.html). These mutations are appearing to be disease-specific and predict the disturbance in WD gene function. Till now, no data have been published on the spectrum of mutations in Indian patients with WD. Forty-three patients residing in the states (Punjab, Haryana, Jammu and Kashmir, Western UP, and Chandigarh) of North-West India were included for mutation analysis. The diagnosis of WD was made on the basis of clinical symptomatology and various biochemical tests as described previously (4). Mutation analysis of ATP7B was performed as described by Thomas et al. (3) and Gabor et al. (5) with minor modifications. We have characterized 22 mutations comprising 14 insertion/deletion, five missense, two splice site, and one nonsense (Table 1).Wehave also identified six polymorphisms including G2973A, IVS18-6(T!C), C3498T, C4266A, C4416G, and T4451A in ATP7B. The characterized mutations were confirmed by DNA sequencing in 25–30 controls. The C2975A, G3007A, T3305C, and G3311A mutations and G2973A, IVS18-6(T!C), and C3498T polymorphisms have been reported previously (3, 6–9). Most of the insertion/deletion mutations (1849insG, 2224insA, 2258insC, 2363delC, 2582insG, 2815insA, 3418delT, 3770insG, and 4311insA) create a downstream premature termination codon at amino acid positions (623, 753, 753, 806, 865, 884, 1147, 1257, and 1147, respectively) of ATP7B, resulting in the production of shortened non-functional protein. The IVS9-1(G!A) mutation in the acceptor site of intron 9 would result in the removal of exon 10 from the transcript with a loss of 43 amino acids from the transduction domain. The consequences of IVS4þ11insGT mutation could not be predicted. However, it has been demonstrated in several studies that this kind of splice site mutation leads to either shortening or lengthening of the protein product (10, 11). One nonsense mutation (A2728T) in exon-12 would produce a truncated WD protein after the translation of 30% of coding region of ATP7B. Most of the mutations were found in the compound heterozygous state together with other mutations. The mutation frequencies in WD chromosomes were accounted to be 19.7% in exon 13, 9.3% in exon 15, 5.8% in exon 18, 3.4% in each of exon 8, 12, and 16, and 1.2% in each of exon 7, 11, and 21. The C2975A, T3305C, 2997insA, and 3031insC mutations were observed in 25.5% of the WD chromosomes. In order to evaluate the functional significance of WD mutations, we explored the correlation between the mutations and several phenotypic manifestations. The KF rings were present in all WD patients with neurological and neurological plus hepatological manifestations. However, KF rings were present only in 52.3% of the WD patients with hepatic manifestations. All homozygous and most of the compound heterozygous (14 of 21) WD patients presented with hepatic manifestations, and rest of the compound heterozygous patients had neurological problems. No significant difference was observed between compound heterozygous and homozygous WD patients for serum ceruloplasmin and serum copper levels (mean SD, 8.70 5.18 mg/dl, 37.95 8.82 mg/ dl and 7.40 3.04 mg/dl, 33.00 10.07 mg/dl, respectively). However, hepatic copper content in Clin Genet 2005: 67: 443–445 Copyright # Blackwell Munksgaard 2005 Printed in Singapore. All rights reserved CLINICAL GENETICS doi: 10.1111/j.1399-0004.2005.00440.x
40 citations
Journal Article•
TL;DR: Identical WD phenotype among siblings in only 6 of 8 families with >1 child affected by WD suggests that factors other than ATP7B mutations influence WD phenotype, and lacks of a single dominant mutation is described.
Abstract: Objective: To analyze ATP7B mutations in Wilson’s disease (WD) patients from the Indian subcontinent and to correlate these with WD phenotype. Meth ods: We studied 27 WD patients from 25 unrelated families. Twenty-two families were from three south ern Indian states – Tamil Nadu, Andhra Pradesh and Kerala. We applied conformation- sensitive gel elec trophoresis (CSGE) to screen for the mutations in patients and their families. PCR products exhibiting aberrant patterns in CSGE were subjected to direct DNA sequencing. As siblings affected by WD within a family share identical ATP7B genotype, we com pared WD phenotype among affected siblings within families. Results: ATP7B mutations were detected in 22 of the 25 probands –13 were homozygotes and 9 were compound heterozygotes. Eleven novel muta tions were detected. Only two common mutations were found: G3182A in 4 (16%) and C813A in 3 (12%) probands. ‘Hot spots’ for ATP7B mutations were exons 18 and 13. Lack of common dominant mutations prevented correlation of individual ATP7B mutations with WD phenotype. Symptomatic WD in a live sibling was not found in any family. In 8 fami lies, a sibling died of presumed WD – in 6 of these, WD phenotype was identical to that in the proband. Conclusions: We describe the spectrum of ATP7B mutations including 11 novel mutations in Indian WD patients and document lack of a single dominant mutation. Identical WD phenotype among siblings in only 6 of 8 families with >1 child affected by WD suggests that factors other than ATP7B mutations influence WD phenotype. [Indian J Gastroenterol 2006;25:277-282]
39 citations