Review Article
Movement disorders: Indian scenario: A clinico‑genetic review Shyamal Kumar Das, Bhaskar Ghosh1, Gautami Das2, Arindam Biswas3, Jharna Ray3 Department of Neurology, Burdwan Medical College, Burdwan, 1Department of Neurology, B R Singh Hospital and Center for Medical Education and Research, 3Department of Neurology, S. N. Pradhan Centre for Neurosciences, University of Calcutta, Kolkata, West Bengal, India, 2Department of Neurology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, USA
Abstract Address for correspondence: Dr. Shyamal Kumar Das, Q No. 31, Minto Park Government Housing, 247/1, A. J. C. Bose Road, Kolkata ‑ 700 027, West Bengal, India. E‑mail: [email protected] Received : 01‑10‑2013 Review completed : 08-10-2013 Accepted : 20‑10‑2013
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. Key words: Dystonia, epidemiology, essential tremor, genetics, huntington disease,
neurodegeneration with brain iron accumulation, Parkinson’s disease, Wilson’s disease
Introduction
Epidemiology
Movement disorder (MD) is a forthcoming branch of neurology. MDs implies abnormal movement or paucity of movement either voluntary or automatic which is not attributable to weakness or spasticity or any other medical causes directly interfering musculoskeletal system, such as, advanced rheumatoid arthritis or slowing of medical condition like hypothyroidism. It has been broadly subdivided into two types: Hypokinetic and hyperkinetic MDs. Prototype of hypokinetic disorders are Parkinson’s disease (PD) and Parkinsonism plus syndromes and that of hyperkinetic type is dystonia, chorea, ballism, athetosis, tics, tremor, myoclonus and stereotypes. In this review, the recent studies on epidemiology, clinical features and genetic aspects of major disorders have been highlighted. We have excluded cerebellar ataxia and less frequent disorders for limited space.
MD constitutes 3‑8% of neurological disorders in India with a crude prevalence rate (CPR) varying from 31 to 45/100,000 above 60 years of age[1,2] and they are more frequent in rural India.[3] Hospital based study has shown that MDs account for 20% of all neurological diseases.[4] Another study has revealed that out of 493 residents in elderly homes of one southern city, one‑third were suffering from MDs comprising of 24% Parkinsonism, 4.5% essential tremors (ETs) while others were 4.2%.[5]
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Viral encephalitis is an important cause of acute onset MD in India. In a study from north India, about one‑third of encephalitic patients had MD. Japanese encephalitis (JE) was the infection in 67.6% of the cases. MD were common in males and frequent after JE having nigral involvement in magnetic resonance imaging (MRI). Often dystonia and Parkinsonism was co‑associated and the presence of dystonia indicates worse outcome.[6] In another study of 1282 adult cases of JE from central India, dystonia was detected in 46% of cases.[7] A small study of 17 patients with oromandibular dystonia had 14 cases of JE and 3 cases of non‑specific encephalitis. Their mean age was 14 years (2‑53) and majority were women. Cranial MRI was abnormal in 13 patients and majority were in substantia nigra. Half of the cases improved within next 6 months.[8] 457
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Cases of reversible Parkinsonism following organophosphorus exposure [9] and due to osmotic disequilibrium have also been documented from India. [10] Drugs are important cause of MD. In a MD clinic, the prevalence of drug‑induced MD was 10.15%. Dyskinesia and dystonias were common and the drugs such as levodopa and trihexyphendiyl were commonly held responsible.[11]
Mean Age, Survival and Mortality The mean age of the PD subjects (62.3 years) is lower in comparison to western reports by one decade. Average annual mortality rate was 2.89, which is comparable globally.[16] The mean age of survival time was 13.5 years and that of death was 71.31 years.[16]
Quality of Life (QOF) and Non‑motor Symptoms (NMS)
Parkinson’s Disease In community‑based studies, CPR varied from 6 to 40/100,000 and age adjusted prevalence rate varied from 52.85 to 192/100,000 [Table 1].[1,12‑16] As Parkinsonism is a disease of old age and life expectancy is gradually increasing in India, prevalence of the disease is expected to increase. Higher prevalence of PD among Parsi population is due to higher aged population when compared to national population [Table 1].[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. Lower prevalence is further endorsed by a community study, which also documented an age adjusted incidence rate of 5.71 (95% CI: 3.59‑9.40), which is the lowest rate over the globe. 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.
Risk Factors The risk factors reported from various case‑control studies from India, male gender, family history of PD and ET, exposure to pesticide, herbicide and other toxins, rural and slum living, viral infections (JE), previous history of depression and depression of longer duration and hypertension were associated with increased risk of PD, while tobacco chewing, smoking and keeping pets have been found as protective factors.[16‑20]
The NMS was almost universal in a study from south India and each having at least one NMS feature.[21] The severity of NMS was higher in women and had strong association with the severity of motor symptoms. NMS in the domain of cardiovascular, mood/cognition and perceptual problems were prominent in affected subjects when compared to control.[21] The stage and duration of the disease, financial insecurity impairs QOF however, family and community relation was preserved due to close family and social bonding among Indian.[22] Depression plays an important role in determining the disability and QOF among PD patients.[23] With an increasing age, greater impairment in delayed memory and recognition task were noted among Indian patients. Increasing severity induces greater impairment in mental status, delayed recall and information. Lower education had worse influence in cognitive domain.[24] Another study has shown right hemispheric dysfunction among PD patients on neuropsychological evaluation.[25]
Essential Tremors This is one of the most common MDs in the community in our county and the first Indian data on ET is available from Parsi Community in Mumbai. The overall prevalence rate was 16.63/1000 populations and higher rate is due to higher aging population.[26] In a community survey on heterogeneous population, prevalence rate was found to be 3.95/1000 (95% CI: 3.40‑4.56). Although age‑specific prevalence showed increasing rate but sex‑specific prevalence did not differ. Risk of ET was higher among slumdwellers than
Table 1: The prevalence of Parkinson disease from different regions of India
Region
Author
West India[12] North India[13] South India[1] South India[14] East India[3] East India[15] East India[16]
Bharucha et al. Razdan et al. Gourie‑Devi et al. Gourie‑Devi et al. Das and Sanyal Saha et al. Das et al.
458
Year of study
Population surveyed (R/U)
Crude prevalence rate
Age adjusted rate
1988 1994 1982‑84 1993‑95 1989‑90 1992‑93 2003‑2005
14010 (U) 63645 (R) 39926 (R and U) 102557(R and U) 37286 (R) 20842 (R) 100802
328.3 14.1 7 33 16.09 53 40.67
148*
76# 68^ 52.85
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non‑slum population by 2.29 times. Family history was positive in about one‑fifth of the cases.[27] A clinic based study found 59.4% of patients suffered from ET. Only 43% patients reported progression; response to alcohol was seen in only one patient, positive family history was present in 52.4% and the inheritance was autosomal dominant pattern in 36.4%.[28] In this study, mean age was 44.5 ± 16.0 years and duration of symptoms was 5.3 ± 6.3 years. Subtype analysis of tremor showed ET (59.43%), dystonic and task specific (21.69%), psychogenic (13.20%), alcohol (1.88%), rubral, drug induced, thyrotoxic and physiological in 0.94% in each of these categories. Tremor is of fast frequency type and may be related to younger onset of sample population. Distribution of tremor was in hands (96.8%), followed by head (26.98%), voice (12.69%) and lower limbs (20.63%).
Dystonia A community study on dystonia from India has reported CPR of primary dystonias was 43.91/100,000 and age‑standardized rate was 49.06. All cases were focal type and predominantly of limb (Writer’s cramp) variety.[29] Mean onset of dystonias was earlier in women (43.5 years) when compared to men (46.6 years). The study on primary dystonia showed higher prevalence when compared with that of many studies globally and more cases of limb dystonias than blepharospasm and cervical dystonias in western reports.[29] A case control study of Meige’s syndrome has shown the risk due to habitual chewing of tobacco and betel nuts among Indians.[30] Secondary dystonia was less common (CPR‑11.45/100,000) and usually due to sequel to encephalitis, drug and stroke. [29] Clinic based study has shown infections, hypoxia, trauma and kernicterus as common causes of secondary dystonias.[31] Interestingly one patient with GCH1 mutation presented with dopa responsive truncal dystonia without any diurnal variation.[32]
Wilson Disease (WD) Many Indian data are available on WD.[33] In a WD clinic from South India, about 15‑20 new cases are registered annually.[33] The clinical manifestations of WD are varied and challenging. In the cohort of 282 patients, WD is more common in male (male: female ratio, 2.28:1). Mean age of onset was 15.9 years. The mean duration of illness at the time of diagnosis was 28 months. Commonest clinical presentations were neurological (69.1%); followed by hepatic, (14.9%); hepato‑neurologic, (3.5%); pure psychiatric, (2.4%); osseomuscular (2.1%); and ‘‘presymptomatic,’’ (5.3%). Presymptomatic patients and those with the hepatic form of WD were younger. In contrast, psychiatric forms were older than neurologic Neurology India | Sep-Oct 2013 | Vol 61 | Issue 5
patients. Commonest neurologic manifestation was parkinsonism, (62.3%) followed by dystonia (35.4%), cerebellar, (28%), pyramidal signs (16%) chorea, (9%), myoclonus (3.4%); athetosis, (2.2%); and behavioral abnormalities (16%). All neurological patients had Kayser‑Fleischer rings, whereas it was present in 86% of hepatic patients and 59% in pre‑symptomatic patients. Positive family history was noted in 47% and consanguinity in 54%. Patients born of consanguineous parents had an earlier age of onset and shorter duration of illness before presentation. Serum ceruloplasmin was decreased in 93% and 24‑h urinary copper excretion was increased in 70% of patients. Overall, 69% patients were on d‑penicillamine therapy and (65%) on zinc sulfate therapy. Follow‑up data of 80% of patients over 46 months, revealed improvement in 78%, unchanged in 9% and deterioration in 3%. About 10% patients died. A return to previous level of functioning is not universal. [34] Gabapentin has been useful in d‑penicillamine induced status dystonia.[35] A study from Eastern India with 34 children suffering from WD shows that the mean age of the children was 7.7 ± 2.13 years. About 78.2% of cases responded to medical treatment.[36] WD was diagnosed in 8.3% of cases from a large cohort of 491 epileptic patients and hence presentation with seizure needs to be considered for WD in India. 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. Among the plethora of MRI features in WD, only “face of the giant panda” sign has been recognized as the distinguishing characteristic for WD from other early onset extra pyramidal disorders which included Huntington’s disease (HD), young‑onset PD, mitochondrial disorders, Brain iron accumulation, non‑Wilsonian hepatolenticular degeneration, toxic/ metabolic disorder and others cases.[38] Indian literature is not clear about the role of zinc as a monotherapy from the initiation of treatment of WD as there are reports of sustained improvement and deterioration following zinc therapy alone.[39‑41] Interestingly long standing therapy with d‑penicillamine did not cause neuromuscular abnormalities and 30 pregnancies involving 16 WD women had no teratogenicity on low dose d‑penicillamine and zinc therapy.[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 459
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progressive extrapyramidal manifestations. Autosomal dominant form may also be available. Classical and atypical clinical presentations are known. The most common clinical presentation was limb or cranial onset progressive dystonia. The patients with early onset had more frequent truncal and axial dystonia, including retrocollis, oromandibular‑facial dystonia and chorea, dysarthria, pyramidal signs, gait disturbance, cognitive impairment, delay in motor milestones, retinitis pigmentosa, optic atrophy, oculomotor abnormalities, positive family history and acanthocytosis. Although rare, cerebellar ataxia, behavioral abnormalities, Parkinsonism and apraxia of eyelid opening were exclusively seen in late onset patients. The present study highlights the heterogeneity of this disease entity in India and also describes certain unusual clinical features.[43]
Genetics of Movement Disorders Apart from WD, HD, etc., which are monogenetic disease, most of these diseases have complex etiology indicating the interaction of both genetic and environmental factors. However, recent evidences suggest that even the so called “monogenic diseases” can also have modifier loci. In this chapter genetics of few MDs including PD, Dystonia, WD and HD from India will be described. In addition to this review, Indian Genetic Disease Database release 1.0 (http: www.igdd.iicb.res.in) also covers 52
diseases with information on 5760 individuals carrying the mutant alleles of causal genes.[44]
Parkinson’s Disease Eighteen genetic loci with 13 underlying genes have been identified till date for PD, however, only 6 genes [Alpha‑synuclein (SNCA), Leucine rich repeat kinase‑2 (LRRK2), Parkin, PTEN induced putative kinase 1 (PINK1), DJ‑1, ATPase type 13A2 (ATP13A2)] could be conclusively proved to be causal towards the disease.[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. Mutations reported in Parkin are highest, absent in SNCA and rare in DJ‑1, PINK1 and LRRK2. The frequency of mutation in Parkin varies from 1.96% to 39.1% among Indians. In India studies to understand the molecular basis of PD is rapidly getting pace. 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., from different parts of India. Recent genome wide association studies on Asian and Caucasian populations have identified a number of associated genes in PD including ethnicity specific susceptible genes.[68,69] Majority of the mutations in the
Table 2: Studies on different PARK loci for identification of pathogenic mutations among PD cases in India
PARK loci
Gene (position)
PARK 1/PARK 4
SNCA (4q21)
Sample Population
169 140
PARK 2
Parkin (6q25‑q27)
102 259 138 69 140
PARK 6 PARK 7
PINK1 (1p35‑p36) DJ‑1 (1p36)
PARK 8
LRRK2 (12q12)
250 150 308 800
150
186 140 308
Region/mutation screened
Mutations identified (frequency) %
References
North and South Reported mutation: A30P, A53T South Reported mutation: A30P, A53T, E46K South All 12 s and flanking intron North and South All 12 s and flanking intron East All 12 s and flanking intron North West All 12 s and flanking intron South All 12 s and flanking intron
Not found
Nagar et al., 2001
Not found
Vishwanathan et al., 2012
1.96 8.5 7.24 39.1 2.14
Madegowda et al., 2005 Chaudhary et al., 2006 Biswas et al., 2006 Vinish et al., 2010 Padmaja et al., 2012
East All 8 s and flanking intron East no. 2‑7 and intron East All s and flanking intron North and South Reported mutation: G2019S, R1441C, R1441G, R1441H, I2012T, I2020T East Reported mutation: G2019S, R1441C, R1441G, R1441H, I2012T, I2020T, Y1699C South Reported mutation: G2019S South Reported mutation: G2019S East Reported mutation: G2019S, R1441C, R1441G, R1441H, Y1699C, G2358R
2 Not found 3.9 0.125
Biswas et al., 2010 Sanyal et al., 2011 Sadhukhan et al., 2012 Punia et al., 2006
Not found
Sanyal et al., 2010
Not found Not found Not found
Vijayan et al., 2011 Vishwanathan et al., 2012 Sadhukhan et al., 2012
PD ‑ Parkinson’s disease
460
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autosomal recessively inherited PD genes have been identified in heterozygous condition and current studies now suggest that homozygous mutants have a more severe form of the disease, while heterozygous variants are in fact risk factors. Since copy number variations have been reported in SNCA and Parkin, therefore, gene dosage study should now be routinely done among the candidate genes. None of the candidate gene studies in PD have actually done gene dosage analysis except Chaudhary et al. 2006 in Parkin gene.[49]
Dystonia Until date 25 dystonia loci and 16 dystonia genes have been identified. 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. Interestingly, with increasing age at onset there was a caudal to rostral shift in the affected site among patients. Dopa‑responsive dystonia (DRD) is one such disease that can have overlapping disease phenotype with juvenile PD (JPD). It is mostly caused by autosomal dominant mutations in the GCH1 gene (guanosine triphosphate cyclohydrolase1) and on rare occasion by autosomal recessive mutations in the tyrosine hydroxylase
or sepiapterin reductase genes. Three novel mutations in GCH1 gene have been found and represent 15.79% (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.
Wilson Disease WD is an autosomal recessive disorder results in copper accumulation in brain, liver and kidney. Mutations in copper transporting gene ATP7B and suspected modifiers ATOX1 and COMMD1 has been implicated for WD. The ATP7B comprised of 21 exons spanning ~ 80 kb on chromosome 13q14.3; with a 4.3 kb open reading frame encodes a protein of 1465 amino acid. About ~ 600 diseases causing mutations have been known to be associated with WD worldwide (www.wilsondisease.med.ualberta. ca). A total of 308 mutant chromosomes (ATP7B) were identified from four different geographical locations of India of which 86 are unique. The detailed mutation spectrum is presented in Tables 3 and 4. On screening ATP7B gene in 114 unrelated WD patients from eastern India, 17 mutations including five common mutations (p. Gly1061Glu, p.Tyr187Stop, p.Cys271Stop, p.Glu150His‑fs and c. 1708‑1G > C) were reported.[71,72] This accounts for 44% of WD patients.[72] In addition a total of 23 and
Table 3: Mutation in Indian Wilson disease patients
Nucleotide change
ATP7B gene Missense mutations c. 442C>T c. 997G>A c. 1544G>A c. 1847G>A c. 1771G>C C2071G>C c. 2128G>A c. 2189A>G c. 2302C>T c. 2332C>T c. 2333G>A c. 2383C>T
Exon/intron Amino acid change
2 2 4 5 5 7 8 8 8 8 8 9
Arg148Trp Gly333Arg Gly515Asp Arg616Glu Gly591Ser Gly691Arg Gly710Ser Asp730Gly Pro768Leu Arg778Trp Arg778Gln Leu795Phe
c. 2524G>T c. 2623A>G c. 2906G>A c. 2930C>T
10 11 13 13
c. 2968G>C c. 2975C>A c. 3008C>T c. 3007G>A
13 13 13 13
No. of chr. in different geographical References locations North South East West Total 1 ‑
1
‑
‑ ‑
2 ‑
‑ 1
‑
‑
1
2
1 1 2 2 1
1 1 ‑ 11
4 ‑
‑ ‑
‑
2
‑
Asp842Tyr Gly875Arg Arg969Glu Thr977Met
‑ ‑ ‑
6 4 ‑
‑ ‑ 1
Ala990Pro Pro992His Ala1003Val Ala1003Thr
5 ‑ 2
‑ 5 ‑
‑ ‑ ‑
1 6 1
6 1
3
1 1 4 11 1 8 1 6 4 7 1 5 5 5
Aggarwal et al. 2013 Santhosh et al. 2006 Aggarwal et al. 2013 Santhosh et al. 2006 Gupta et al. 2007 Aggarwal et al. 2013 Gupta et al. 2005 Aggarwal et al. 2013 Santhosh et al. 2006 Kumar et al. 2007 Aggarwal et al. 2013 Santhosh et al. 2006 Aggarwal et al. 2013 Aggarwal et al. 2013 Santhosh et al. 2008 Santhosh et al. 2006 Gupta et al. 2007 Aggarwal et al. 2013 Aggarwal et al. 2013 Kumar et al. 2005 Santhosh et al. 2006 Kumar et al. 2005 Aggarwal et al. 2013 (Contd...)
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Table 3: (Contd...)
Nucleotide change
Exon/intron Amino acid change
No. of chr. in different geographical References locations North South East West Total
c. 3029A>G
13
Lys1010Arg
‑
7
‑
c. 3089G>A c. 3091A>G c. 3182G>A
14 14 14
Gly1030Asp Thr1031Ala Gly1061Glu
‑ ‑
‑ 2
1 21
c. 3282C>G
15
Phe1094Leu
‑
5
‑
c. 3301G>A c. 3305T>C
15 15
Gly1101Arg Ile1102Thr
‑ 7
‑ ‑
‑ 2
c. 3311G>A c. 3458G>A c. 3532A>G c. 3722C>T c. 3809A>G
15 16 16 18 18
Cys1104Thr Trp1153Stop Thr1178Ala Ala1241Val Asp1270Ser
1
‑
‑
c. 3818C>T c. 3890T>A c. 3895C>T
18 18 18
c. 3767A>G c. 4021G>A
7 2 3
2 1 26
5 3 1
2
3 10
1 2 1 1 6
‑ ‑ ‑
‑ 1 3
1 ‑ ‑
Pro1273Leu Val1296Asp Leu1299Phe
‑ ‑
1 1
‑ ‑
3
2 1 4
18 19
Gln1256Arg Gly1341Ser
1 ‑
‑ 4
‑ ‑
1
1 5
c. 4070C>T Nonsense mutations c. 561T>A c. 813C>
20
Ala135V7al
2
2
2 2
Tyr187Stop Cys271Stop
‑ ‑
‑ 5
4 27
21
4 53
c. 2145C>A c. 2728A>T Insertion/deletion mutations c. 172insC c. 365_366delinsTTCGAAGC c. 678delG IVS4+11insGT c. 1716delG c. 1849InsG c. 2224insA c. 2227delT c. 2258insC c. 2298insC c. 2304_2305insC c. 2495insG c. 2582insG c. 2697_2723del27 c. 2736_2746del11 c. 2815insA c. 2977insA c. 3031insG c. 3147delC c. 3157_c. 3158insC c. 3424insC c. 3770insG c. 3839insTAC c. 4311insA c. 448del5 c. 892delC
8 12
Tyr715Stop Lys910Stop
‑ 2
1 ‑
‑ ‑
2 2 2 4 5 5 8 8 8 8 8 10 11 11 12 12 13 13 14 14 16 18 18 21 2 2
Ala58Ala‑fs Glu122fs Leu227fs
‑
‑
1
Met573fs Arg616Gly‑fs Tyr741Asn‑fs Tyr743fs Ala753Stop‑fs Pro767Pro‑fs Met769fs Lys832Lys‑fs Ala861Ala‑fs Ile899_Gln907del Ile913fs Trp939Stop Pro992stop Lys1010Ala‑fs Thr1050fs Leu1053fs Gln1142Pro‑fs Asn1257Lys‑fs Met1280Ile Lys1437Lys‑fs Glu150His‑fs Gln298Lys‑fs
3 2
11 2 1
‑
‑
1 1
‑ ‑
‑ ‑
1 ‑
‑ ‑
‑ 1
‑ 1
‑ ‑
1 ‑
5
1
2
1 2 1 5 5
‑ ‑ ‑
‑ ‑ ‑ 2 1
2 2 2 1 ‑ ‑
‑ ‑ ‑ ‑ ‑ ‑
‑ ‑ ‑ ‑ 12 1
Santhosh et al. 2006 Santhosh et al. 2008 Aggarwal et al. 2013 Gupta et al. 2007 Gupta et al. 2007 Santhosh et al. 2006 Aggarwal et al. 2013 Santhosh et al. 2006 Santhosh et al. 2008 Aggarwal et al. 2013 Gupta et al. 2007 Kumar et al. 2005 Aggarwal et al. 2013 Kumar et al. 2005 Aggarwal et al. 2013 Gupta et al. 2007 Santhosh et al. 2006 Santhosh et al. 2006 Aggarwal et al. 2013 Aggarwal et al. 2013 Santhosh et al. 2006 Santhosh et al. 2006 Aggarwal et al. 2013 Kumar et al. 2005 Santhosh et al. 2008 Aggarwal et al. 2013 Aggarwal et al. 2013
1 2
Gupta et al. 2005 Gupta et al. 2005 Santhosh et al. 2006 Aggarwal et al. 2013 Santhosh et al. 2006 Kumar et al. 2005
1 11 2 1 5 1 1 1 1 1 2 1 1 1 2 1 5 5 2 1 2 2 2 1 12 1
Gupta et al. 2005 Aggarwal et al. 2013 Aggarwal et al. 2013 Kumar et al. 2005 Aggarwal et al. 2013 Kumar et al. 2005 Kumar et al. 2005 Aggarwal et al. 2013 Kumar et al. 2005 Gupta et al. 2005 Aggarwal et al. 2013 Gupta et al. 2005 Kumar et al. 2005 Aggarwal et al. 2013 Aggarwal et al. 2013 Kumar et al. 2005 Kumar et al. 2005 Kumar et al. 2005 Aggarwal et al. 2013 Aggarwal et al. 2013 Kumar et al. 2005 Kumar et al. 2005 Kumar et al. 2005 Kumar et al. 2005 Gupta et al. 2005 Gupta et al. 2005 (Contd...)
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Table 3: (Contd...)
Nucleotide change
c. 2115delGT c. 1962delC c. 2363delC c. 3146delC c. 3418delT c. 3895delC Splice‑junction mutations c. 1869+1_4delGTAA c. 1946+2T>G IVS9‑1G>A c. 2865+1G>A c. 2866‑2A>G c. 3243+5G>A c. 3412+1G>A c. 1708‑1G>C 3903 (6T>C) c. 4021 G>A 4021 (3A>G) Silent mutations c. 2145C>T COMMD1 gene c. 521C>T
Exon/intron Amino acid change 7 7 8 14 16 18
Phe705Pro‑fs Phe654Phe‑fs Thr788Thr‑fs Ala1049Ala‑fs Val1140Ala‑fs Leu1299Leu‑fs
5 6 9 13 13 14 15 4 18 19 19
No. of chr. in different geographical References locations North South East West Total 1 ‑ 1 ‑ 1 ‑
‑ 2 ‑ ‑ ‑ 1
‑ ‑ ‑ 1 ‑ ‑ 2 1
1
‑
‑ 1 2 2
‑ ‑ ‑ ‑ ‑
‑ ‑ 1 2 1
2 12 ‑ ‑ ‑
8
Tyr715Tyr
‑
‑
‑
3
Thr174Met
‑
‑
1
1
1 2 1 1 1 1
Kumar et al. 2005 Santhosh et al. 2006 Kumar et al. 2005 Gupta et al. 2007 Kumar et al. 2005 Santhosh et al. 2006
2 1 1 1 2 2 2 12 1 2 1
Aggarwal et al. 2013 Aggarwal et al. 2013 Kumar et al. 2005 Aggarwal et al. 2013 Aggarwal et al. 2013 Aggarwal et al. 2013 Gupta et al. 2007 Gupta et al. 2005 Santhosh et al. 2006 Santhosh et al. 2006 Santhosh et al. 2006
1
Aggarwal et al. 2013
1
Gupta et al. 2010
Table was taken from Gupta et al. 2007 and modified
Table 4: Summary of ATP7B mutation
Mutation type
Number of mutations (no. of chr.)
Missense Nonsense Insertion/deletion Splice junction Silent Total
38 (147) 4 (60) 32 (73) 11 (27) 1 (1) 86 (308)
22 mutations were identified from North and South Indian WD patients respectively.[73‑76] The mutational pattern of WD in western India identified 36 disease causing mutations among 52 patients, 14 of 36 being novel. Two mutations, p.Cys271Stop and p. Glu122fs accounted for ~ 40% of the WD in western India. The Cys271Stop was the most common mutation observed in Western India with an allelic frequency of 20.2%.[77] It was observed from four population of India that the missense mutations account for 44% of the total mutations followed by insertion and deletion mutations. Of the mutations documented in India, c. 813C > A (p.Cys271Stop) is the most common (53/308; 17.2%). A total of 21 prevalent mutations have been found in Indian population; five each in northern, eastern and western Indian population and eight in southern Indian populations (one is common between eastern, southern and western population). COMMD1 screening in 109 WD patients identified a novel putative mutation (p. Thr174Met) in one patient with atypical features. This Neurology India | Sep-Oct 2013 | Vol 61 | Issue 5
suggests that COMMD1 variants may not have any major contribution toward phenotypic heterogeneity observed in WD.[78] Screening of ATOX1 gene did not identify any nucleotide changes in ATOX1 gene.
Huntington’s Disease HD is a progressive neurodegenerative autosomal dominant disorder, caused by an expansion of a polymorphic CAG repeats beyond 36 in exon 1 of huntingtin gene on chromosome 4. The CAG repeat varied from 41 to 56 in HD patients whereas in normal varied from 11 to 35.[79] The age at onset is inversely related to the number of CAG repeat in the expanded allele. In Indian populations, six CCG repeat allele has been reported including (CCG)7 in 89.3% cases, (CCG)10 in 10.7% cases and (CCG)4 in one case. The variation in GluR6 and CCG repeats in the huntingtin gene might modify the age of onset of HD.[80] In a study of 30 HD families (19 from Southern India and 11 from Northern India) comprising 75 members were evaluated. The HD mutation did not show any significant association with either the (CCG)7 or (CCG)10 allele, while haplotype analysis suggested over representation of the 7‑2‑I (CCG‑D4s127‑del 2642 loci) haplotype in a subset of families and provides evidence for multiple and geographically distinct origins for the HD mutation in India.[81] The mutated huntingtin protein (htt) aggregates in nucleus. An impairment of proteasomal degradation pathway and autophagy has been implicated in HD. 463
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Table 5: Details of NBIA
Types of NBIA
Gene
Inheritance
Pantothenate kinase associated neurodegeneration PLA2G6 associated neurodegeneration Mitochondrial membrane protein associated neurodegeneration Beta propeller protein associated neurodegeneration Fatty acid hydroxylase associated neurodegeneration Aceruloplasminemia Neuroferritinopathy Woodhouse‑Sakati syndrome Kufor‑Rakeb Idiopathic NBIA
PANK2
AR
PLA2G6
AR
C19of12
AR
WDR45
X‑linked
FA2H
AR
Ceruloplasmin Ferritin light DCAF17 ATP13A2 ‑
AR AD AR AR ‑
8. 9. 10.
11. 12. 13.
NBIA ‑ Neurodegeneration with brain iron accumulation
14.
Neurodegeneration with Brain Iron Accumulation (NBIA) NBIA is a rare, inherited, neurological MD. Before 2001, NBIA was called Hallervorden‑Spatz disease. There are nine forms of NBIA currently identified and have separate symptoms and identifying markers [Table 5]. Pantothenate Kinase Associated Neurodegeneration is the most common form of NBIA. It is caused by the mutation in the PANK2 gene. Molecular studies revealed PANK2 mutations in 4 patients from Indian subcontinent (Indian and Pakistani). No identifiable genetic cause was found in PLA2G6 and FTL gene.[82] We have tried to review recent Indian literature on MDs. Lot of scope of highlighting the heterogeneous presentations of various disorders, drug dosage required in controlling various disorders and side‑effects needs to be looked for. We hope to see publication of more data from India in future with the advancement of technology and infrastructures.
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31. Netravathi M, Pal PK, Indira Devi B. A clinical profile of 103 patients with secondary movement disorders: Correlation of etiology with phenomenology. Eur J Neurol 2012;19:226‑33. 32. Naiya T, Misra AK, Biswas A, Das SK, Ray K, Ray J. Occurrence of GCH1 gene mutations in a group of Indian dystonia patients. J Neural Transm 2012;119:1343‑50. 33. Taly AB, Prashanth LK, Sinha S. Wilson’s disease: An Indian perspective. Neurol India 2009;57:528‑40. 34. Taly AB, Meenakshi‑Sundaram S, Sinha S, Swamy HS, Arunodaya GR. Wilson disease: Description of 282 patients evaluated over 3 decades. Medicine (Baltimore) 2007;86:112‑21. 35. Paliwal VK, Gupta PK, Pradhan S. Gabapentin as a rescue drug in D‑penicillamine‑induced status dystonicus in patients with Wilson disease. Neurol India 2010;58:761‑3. 36. Tryambak S, Sumanta L, Radheshyam P, Sutapa G. Clinical profile, prognostic indicators and outcome of Wilson’s disease in children: A hospital based study. Trop Gastroenterol 2009;30:163‑6. 37. Prashanth LK, Sinha S, Taly AB, A Mahadevan, Vasudev MK, Shankar SK. Spectrum of epilepsy in Wilson’s disease with electroencephalographic, MR imaging and pathological correlates. J Neurol Sci 2010;291:44‑51. 38. Prashanth LK, Sinha S, Taly AB, Vasudev MK. Do MRI features distinguish Wilson’s disease from other early onset extrapyramidal disorders? An analysis of 100 cases. Mov Disord 2010;25:672‑8. 39. Murthy BS, Murthy JM, Krishnaveni A, Reddy MV, Das SM. Wilson’s disease in south India and experience with zinc therapy. J Assoc Physicians India 1988;36:417‑9. 40. Sinha S, Taly AB. Withdrawal of penicillamine from zinc sulphate‑penicillamine maintenance therapy in Wilson’s disease: Promising, safe and cheap. J Neurol Sci 2008;264:129‑32. 41. Mishra D, Kalra V, Seth R. Failure of prophylactic zinc in Wilson disease. Indian Pediatr 2008;45:151‑3. 42. Aggarwal A, Aggarwal N, Nagral A, Jankharia G, Bhatt M. A novel global assessment scale for Wilson’s disease (GAS for WD). Mov Disord 2009;24:509‑18. 43. Sachin S, Goyal V, Singh S, Shukla G, Sharma MC, Gaikwed S, et al. Clinical spectrum of Hallervorden‑Spatz syndrome in India. J Clin Neurosci 2009;16:253‑8. 44. Pradhan S, Sengupta M, Dutta A, Bhattacharyya K, Bag SK, Dutta C, et al. Indian genetic disease database. Nucleic Acids Res 2011;39:D933‑8. 45. Lesage S, Brice A. Parkinson’s disease: From monogenic forms to genetic susceptibility factors. Hum Mol Genet 2009;18:R48‑59. 46. Nagar S, Juyal RC, Chaudhary S, Behari M, Gupta M, Rao SN, et al. Mutations in the alpha‑synuclein gene in Parkinson’s disease among Indians. Acta Neurol Scand 2001;103:120‑2. 47. Vishwanathan Padmaja M, Jayaraman M, Srinivasan AV, Srikumari Srisailapathy CR, Ramesh A. The SNCA (A53T, A30P, E46K) and LRRK2 (G2019S) mutations are rare cause of Parkinson’s disease in South Indian patients. Parkinsonism Relat Disord 2012;18:801‑2. 48. Madegowda RH, Kishore A, Anand A. Mutational screening of the parkin gene among South Indians with early onset Parkinson’s disease. J Neurol Neurosurg Psychiatry 2005;76:1588‑90. 49. Chaudhary S, Behari M, Dihana M, Swaminath PV, Govindappa ST, Jayaram S, et al. Parkin mutations in familial and sporadic Parkinson’s disease among Indians. Parkinsonism Relat Disord 2006;12:239‑45. 50. Biswas A, Gupta A, Naiya T, Das G, Neogi R, Datta S, et al. Molecular pathogenesis of Parkinson’s disease: Identification of mutations in the Parkin gene in Indian patients. Parkinsonism Relat Disord 2006;12:420‑6. 51. Vinish M, Prabhakar S, Khullar M, Verma I, Anand A. Genetic screening reveals high frequency of PARK2 mutations and reduced Parkin expression conferring risk for Parkinsonism in North West India. J Neurol Neurosurg Psychiatry 2010;81:166‑70. 52. Padmaja MV, Jayaraman M, Srinivasan AV, Srisailapathy CR, Ramesh A. PARK2 gene mutations in early onset Parkinson’s disease patients of South India. Neurosci Lett 2012;523:145‑7. 53. Biswas A, Sadhukhan T, Majumder S, Misra AK, Das SK, Variation Consortium IG, et al. Evaluation of PINK1 variants in Indian Parkinson’s disease patients. Parkinsonism Relat Disord 2010;16:167‑71. Neurology India | Sep-Oct 2013 | Vol 61 | Issue 5
54. Sanyal J, Sarkar B, Banerjee TK, Mukherjee SC, Ray BC, Raghavendra Rao V. Evaluating intra‑genetic variants of DJ‑1 among Parkinson’s disease patients of eastern India. Neurol Res 2011;33:349‑53. 55. Sadhukhan T, Biswas A, Das SK, Ray K, Ray J. DJ‑1 variants in Indian Parkinson’s disease patients. Dis Markers 2012;33:127‑35. 56. Punia S, Behari M, Govindappa ST, Swaminath PV, Jayaram S, Goyal V, et al. Absence/rarity of commonly reported LRRK2 mutations in Indian Parkinson’s disease patients. Neurosci Lett 2006;409:83‑8. 57. Sanyal J, Sarkar B, Ojha S, Banerjee TK, Ray BC, Rao VR. Absence of commonly reported leucine‑rich repeat kinase 2 mutations in Eastern Indian Parkinson’s disease patients. Genet Test Mol Biomarkers 2010;14:691‑4. 58. Vijayan B, Gopala S, Kishore A. LRRK2 G2019S mutation does not contribute to Parkinson’s disease in South India. Neurol India 2011;59:157‑60. 59. Sadhukhan T, Vishal M, Das G, Sharma A, Mukhopadhyay A, Das SK, et al. Evaluation of the role of LRRK2 gene in Parkinson’s disease in an East Indian cohort. Dis Markers 2012;32:355‑62. 60. Biswas A, Maulik M, Das SK, Indian Genome Variation Consortium, Ray K, Ray J. Parkin polymorphisms: Risk for Parkinson’s disease in Indian population. Clin Genet 2007;72:484‑6. 61. Punia S, Das M, Behari M, Mishra BK, Sahani AK, Govindappa ST, et al. Role of polymorphisms in dopamine synthesis and metabolism genes and association of DBH haplotypes with Parkinson’s disease among North Indians. Pharmacogenet Genomics 2010;20:435‑41. 62. Juyal RC, Das M, Punia S, Behari M, Nainwal G, Singh S, et al. Genetic susceptibility to Parkinson’s disease among South and North Indians: I. Role of polymorphisms in dopamine receptor and transporter genes and association of DRD4 120‑bp duplication marker. Neurogenetics 2006;7:223‑9. 63. Singh M, Khan AJ, Shah PP, Shukla R, Khanna VK, Parmar D. Polymorphism in environment responsive genes and association with Parkinson disease. Mol Cell Biochem 2008;312:131‑8. 64. Singh M, Khanna VK, Shukla R, Parmar D. Association of polymorphism in cytochrome P450 2D6 and N‑acetyltransferase‑2 with Parkinson’s disease. Dis Markers 2010;28:87‑93. 65. Biswas A, Sadhukhan T, Bose K, Ghosh P, Giri AK, Das SK, et al. Role of glutathione S‑transferase T1, M1 and P1 polymorphisms in Indian Parkinson’s disease patients. Parkinsonism Relat Disord 2012;18:664‑5. 66. Das G, Misra AK, Das SK, Ray K, Ray J. Microtubule‑associated protein tau (MAPT) influences the risk of Parkinson’s disease among Indians. Neurosci Lett 2009;460:16‑20. 67. Das G, Misra AK, Das SK, Ray K, Ray J. Role of tau kinases (CDK5R1 and GSK3B) in Parkinson’s disease: A study from India. Neurobiol Aging 2012;33:1485.e9‑15. 68. Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, et al. Genome‑wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nat Genet 2009;41:1303‑7. 69. Simón‑Sánchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, et al. Genome‑wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 2009;41:1308‑12. 70. Naiya T, Biswas A, Neogi R, Datta S, Misra AK, Das SK, et al. Clinical characterization and evaluation of DYT1 gene in Indian primary dystonia patients. Acta Neurol Scand 2006;114:210‑5. 71. Gupta A, Aikath D, Neogi R, Datta S, Basu K, Maity B, et al. Molecular pathogenesis of Wilson disease: Haplotype analysis, detection of prevalent mutations and genotype‑phenotype correlation in Indian patients. Hum Genet 2005;118:49‑57. 72. Gupta A, Chattopadhyay I, Dey S, Nasipuri P, Das SK, Gangopadhyay PK, et al. Molecular pathogenesis of Wilson disease among Indians: A perspective on mutation spectrum in ATP7B gene, prevalent defects, clinical heterogeneity and implication towards diagnosis. Cell Mol Neurobiol 2007;27:1023‑33. 73. Kumar S, Thapa BR, Kaur G, Prasad R. Identification and molecular characterization of 18 novel mutations in the ATP7B gene from Indian Wilson disease patients: Genotype. Clin Genet 2005;67:443‑5. 74. Kumar S, Thapa B, Kaur G, Prasad R. Analysis of most common mutations R778G, R778L, R778W, I1102T and H1069Q in Indian Wilson disease patients: Correlation between genotype/phenotype/copper ATPase activity. Mol Cell Biochem 2007;294:1‑10. 465
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75. Santhosh S, Shaji RV, Eapen CE, Jayanthi V, Malathi S, Chandy M, et al. ATP7B mutations in families in a predominantly Southern Indian cohort of Wilson’s disease patients. Indian J Gastroenterol 2006;25:277‑82. 76. Santhosh S, Shaji RV, Eapen CE, Jayanthi V, Malathi S, Finny P, et al. Genotype phenotype correlation in Wilson’s disease within families – A report on four south Indian families. World J Gastroenterol 2008;14:4672‑6. 77. Aggarwal A, Chandhok G, Todorov T, Parekh S, Tilve S, Zibert A, et al. Wilson disease mutation pattern with genotype‑phenotype correlations from Western India: Confirmation of p.C271* as a common Indian mutation and identification of 14 novel mutations. Ann Hum Genet 2013;apr 2/101111/ahg.12024. 78. Gupta A, Chattopadhyay I, Mukherjee S, Sengupta M, Das SK, Ray K. A novel COMMD1 mutation Thr174Met associated with elevated urinary copper and signs of enhanced apoptotic cell death in a Wilson Disease patient. Behav Brain Funct 2010;6:33. 79. Pramanik S, Basu P, Gangopadhaya PK, Sinha KK, Jha DK, Sinha S, et al. Analysis of CAG and CCG repeats in Huntingtin gene among
HD patients and normal populations of India. Eur J Hum Genet 2000;8:678‑82. 80. Chattopadhyay B, Ghosh S, Gangopadhyay PK, Das SK, Roy T, Sinha KK, et al. Modulation of age at onset in Huntington’s disease and spinocerebellar ataxia type 2 patients originated from eastern India. Neurosci Lett 2003;345:93‑6. 81. Saleem Q, Roy S, Murgood U, Saxena R, Verma IC, Anand A, et al. Molecular analysis of Huntington’s disease and linked polymorphisms in the Indian population. Acta Neurol Scand 2003;108:281‑6. 82. Aggarwal A, Schneider SA, Houlden H, Silverdale M, Paudel R, Paisan‑Ruiz C, et al. Indian‑subcontinent NBIA: Unusual phenotypes, novel PANK2 mutations, and undetermined genetic forms. Mov Disord 2010;25:1424‑31. How to cite this article: Das SK, Ghosh B, Das G, Biswas A, Ray J. Movement disorders: Indian scenario: A clinico-genetic review. Neurol India 2013;61:457-66. Source of Support: Nil, Conflict of Interest: None declared.
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Movement disorders: Indian scenario: A clinico‑genetic review Shyamal Kumar Das, Bhaskar Ghosh1, Gautami Das2, Arindam Biswas3, Jharna Ray3 Department of Neurology, Burdwan Medical College, Burdwan, 1Department of Neurology, B R Singh Hospital and Center for Medical Education and Research, 3Department of Neurology, S. N. Pradhan Centre for Neurosciences, University of Calcutta, Kolkata, West Bengal, India, 2Department of Neurology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, USA
Abstract Address for correspondence: Dr. Shyamal Kumar Das, Q No. 31, Minto Park Government Housing, 247/1, A. J. C. Bose Road, Kolkata ‑ 700 027, West Bengal, India. E‑mail: [email protected] Received : 01‑10‑2013 Review completed : 08-10-2013 Accepted : 20‑10‑2013
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. Key words: Dystonia, epidemiology, essential tremor, genetics, huntington disease,
neurodegeneration with brain iron accumulation, Parkinson’s disease, Wilson’s disease
Introduction
Epidemiology
Movement disorder (MD) is a forthcoming branch of neurology. MDs implies abnormal movement or paucity of movement either voluntary or automatic which is not attributable to weakness or spasticity or any other medical causes directly interfering musculoskeletal system, such as, advanced rheumatoid arthritis or slowing of medical condition like hypothyroidism. It has been broadly subdivided into two types: Hypokinetic and hyperkinetic MDs. Prototype of hypokinetic disorders are Parkinson’s disease (PD) and Parkinsonism plus syndromes and that of hyperkinetic type is dystonia, chorea, ballism, athetosis, tics, tremor, myoclonus and stereotypes. In this review, the recent studies on epidemiology, clinical features and genetic aspects of major disorders have been highlighted. We have excluded cerebellar ataxia and less frequent disorders for limited space.
MD constitutes 3‑8% of neurological disorders in India with a crude prevalence rate (CPR) varying from 31 to 45/100,000 above 60 years of age[1,2] and they are more frequent in rural India.[3] Hospital based study has shown that MDs account for 20% of all neurological diseases.[4] Another study has revealed that out of 493 residents in elderly homes of one southern city, one‑third were suffering from MDs comprising of 24% Parkinsonism, 4.5% essential tremors (ETs) while others were 4.2%.[5]
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Viral encephalitis is an important cause of acute onset MD in India. In a study from north India, about one‑third of encephalitic patients had MD. Japanese encephalitis (JE) was the infection in 67.6% of the cases. MD were common in males and frequent after JE having nigral involvement in magnetic resonance imaging (MRI). Often dystonia and Parkinsonism was co‑associated and the presence of dystonia indicates worse outcome.[6] In another study of 1282 adult cases of JE from central India, dystonia was detected in 46% of cases.[7] A small study of 17 patients with oromandibular dystonia had 14 cases of JE and 3 cases of non‑specific encephalitis. Their mean age was 14 years (2‑53) and majority were women. Cranial MRI was abnormal in 13 patients and majority were in substantia nigra. Half of the cases improved within next 6 months.[8] 457
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Cases of reversible Parkinsonism following organophosphorus exposure [9] and due to osmotic disequilibrium have also been documented from India. [10] Drugs are important cause of MD. In a MD clinic, the prevalence of drug‑induced MD was 10.15%. Dyskinesia and dystonias were common and the drugs such as levodopa and trihexyphendiyl were commonly held responsible.[11]
Mean Age, Survival and Mortality The mean age of the PD subjects (62.3 years) is lower in comparison to western reports by one decade. Average annual mortality rate was 2.89, which is comparable globally.[16] The mean age of survival time was 13.5 years and that of death was 71.31 years.[16]
Quality of Life (QOF) and Non‑motor Symptoms (NMS)
Parkinson’s Disease In community‑based studies, CPR varied from 6 to 40/100,000 and age adjusted prevalence rate varied from 52.85 to 192/100,000 [Table 1].[1,12‑16] As Parkinsonism is a disease of old age and life expectancy is gradually increasing in India, prevalence of the disease is expected to increase. Higher prevalence of PD among Parsi population is due to higher aged population when compared to national population [Table 1].[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. Lower prevalence is further endorsed by a community study, which also documented an age adjusted incidence rate of 5.71 (95% CI: 3.59‑9.40), which is the lowest rate over the globe. 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.
Risk Factors The risk factors reported from various case‑control studies from India, male gender, family history of PD and ET, exposure to pesticide, herbicide and other toxins, rural and slum living, viral infections (JE), previous history of depression and depression of longer duration and hypertension were associated with increased risk of PD, while tobacco chewing, smoking and keeping pets have been found as protective factors.[16‑20]
The NMS was almost universal in a study from south India and each having at least one NMS feature.[21] The severity of NMS was higher in women and had strong association with the severity of motor symptoms. NMS in the domain of cardiovascular, mood/cognition and perceptual problems were prominent in affected subjects when compared to control.[21] The stage and duration of the disease, financial insecurity impairs QOF however, family and community relation was preserved due to close family and social bonding among Indian.[22] Depression plays an important role in determining the disability and QOF among PD patients.[23] With an increasing age, greater impairment in delayed memory and recognition task were noted among Indian patients. Increasing severity induces greater impairment in mental status, delayed recall and information. Lower education had worse influence in cognitive domain.[24] Another study has shown right hemispheric dysfunction among PD patients on neuropsychological evaluation.[25]
Essential Tremors This is one of the most common MDs in the community in our county and the first Indian data on ET is available from Parsi Community in Mumbai. The overall prevalence rate was 16.63/1000 populations and higher rate is due to higher aging population.[26] In a community survey on heterogeneous population, prevalence rate was found to be 3.95/1000 (95% CI: 3.40‑4.56). Although age‑specific prevalence showed increasing rate but sex‑specific prevalence did not differ. Risk of ET was higher among slumdwellers than
Table 1: The prevalence of Parkinson disease from different regions of India
Region
Author
West India[12] North India[13] South India[1] South India[14] East India[3] East India[15] East India[16]
Bharucha et al. Razdan et al. Gourie‑Devi et al. Gourie‑Devi et al. Das and Sanyal Saha et al. Das et al.
458
Year of study
Population surveyed (R/U)
Crude prevalence rate
Age adjusted rate
1988 1994 1982‑84 1993‑95 1989‑90 1992‑93 2003‑2005
14010 (U) 63645 (R) 39926 (R and U) 102557(R and U) 37286 (R) 20842 (R) 100802
328.3 14.1 7 33 16.09 53 40.67
148*
76# 68^ 52.85
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non‑slum population by 2.29 times. Family history was positive in about one‑fifth of the cases.[27] A clinic based study found 59.4% of patients suffered from ET. Only 43% patients reported progression; response to alcohol was seen in only one patient, positive family history was present in 52.4% and the inheritance was autosomal dominant pattern in 36.4%.[28] In this study, mean age was 44.5 ± 16.0 years and duration of symptoms was 5.3 ± 6.3 years. Subtype analysis of tremor showed ET (59.43%), dystonic and task specific (21.69%), psychogenic (13.20%), alcohol (1.88%), rubral, drug induced, thyrotoxic and physiological in 0.94% in each of these categories. Tremor is of fast frequency type and may be related to younger onset of sample population. Distribution of tremor was in hands (96.8%), followed by head (26.98%), voice (12.69%) and lower limbs (20.63%).
Dystonia A community study on dystonia from India has reported CPR of primary dystonias was 43.91/100,000 and age‑standardized rate was 49.06. All cases were focal type and predominantly of limb (Writer’s cramp) variety.[29] Mean onset of dystonias was earlier in women (43.5 years) when compared to men (46.6 years). The study on primary dystonia showed higher prevalence when compared with that of many studies globally and more cases of limb dystonias than blepharospasm and cervical dystonias in western reports.[29] A case control study of Meige’s syndrome has shown the risk due to habitual chewing of tobacco and betel nuts among Indians.[30] Secondary dystonia was less common (CPR‑11.45/100,000) and usually due to sequel to encephalitis, drug and stroke. [29] Clinic based study has shown infections, hypoxia, trauma and kernicterus as common causes of secondary dystonias.[31] Interestingly one patient with GCH1 mutation presented with dopa responsive truncal dystonia without any diurnal variation.[32]
Wilson Disease (WD) Many Indian data are available on WD.[33] In a WD clinic from South India, about 15‑20 new cases are registered annually.[33] The clinical manifestations of WD are varied and challenging. In the cohort of 282 patients, WD is more common in male (male: female ratio, 2.28:1). Mean age of onset was 15.9 years. The mean duration of illness at the time of diagnosis was 28 months. Commonest clinical presentations were neurological (69.1%); followed by hepatic, (14.9%); hepato‑neurologic, (3.5%); pure psychiatric, (2.4%); osseomuscular (2.1%); and ‘‘presymptomatic,’’ (5.3%). Presymptomatic patients and those with the hepatic form of WD were younger. In contrast, psychiatric forms were older than neurologic Neurology India | Sep-Oct 2013 | Vol 61 | Issue 5
patients. Commonest neurologic manifestation was parkinsonism, (62.3%) followed by dystonia (35.4%), cerebellar, (28%), pyramidal signs (16%) chorea, (9%), myoclonus (3.4%); athetosis, (2.2%); and behavioral abnormalities (16%). All neurological patients had Kayser‑Fleischer rings, whereas it was present in 86% of hepatic patients and 59% in pre‑symptomatic patients. Positive family history was noted in 47% and consanguinity in 54%. Patients born of consanguineous parents had an earlier age of onset and shorter duration of illness before presentation. Serum ceruloplasmin was decreased in 93% and 24‑h urinary copper excretion was increased in 70% of patients. Overall, 69% patients were on d‑penicillamine therapy and (65%) on zinc sulfate therapy. Follow‑up data of 80% of patients over 46 months, revealed improvement in 78%, unchanged in 9% and deterioration in 3%. About 10% patients died. A return to previous level of functioning is not universal. [34] Gabapentin has been useful in d‑penicillamine induced status dystonia.[35] A study from Eastern India with 34 children suffering from WD shows that the mean age of the children was 7.7 ± 2.13 years. About 78.2% of cases responded to medical treatment.[36] WD was diagnosed in 8.3% of cases from a large cohort of 491 epileptic patients and hence presentation with seizure needs to be considered for WD in India. 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. Among the plethora of MRI features in WD, only “face of the giant panda” sign has been recognized as the distinguishing characteristic for WD from other early onset extra pyramidal disorders which included Huntington’s disease (HD), young‑onset PD, mitochondrial disorders, Brain iron accumulation, non‑Wilsonian hepatolenticular degeneration, toxic/ metabolic disorder and others cases.[38] Indian literature is not clear about the role of zinc as a monotherapy from the initiation of treatment of WD as there are reports of sustained improvement and deterioration following zinc therapy alone.[39‑41] Interestingly long standing therapy with d‑penicillamine did not cause neuromuscular abnormalities and 30 pregnancies involving 16 WD women had no teratogenicity on low dose d‑penicillamine and zinc therapy.[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 459
Das, et al.: Movement disorder in India
progressive extrapyramidal manifestations. Autosomal dominant form may also be available. Classical and atypical clinical presentations are known. The most common clinical presentation was limb or cranial onset progressive dystonia. The patients with early onset had more frequent truncal and axial dystonia, including retrocollis, oromandibular‑facial dystonia and chorea, dysarthria, pyramidal signs, gait disturbance, cognitive impairment, delay in motor milestones, retinitis pigmentosa, optic atrophy, oculomotor abnormalities, positive family history and acanthocytosis. Although rare, cerebellar ataxia, behavioral abnormalities, Parkinsonism and apraxia of eyelid opening were exclusively seen in late onset patients. The present study highlights the heterogeneity of this disease entity in India and also describes certain unusual clinical features.[43]
Genetics of Movement Disorders Apart from WD, HD, etc., which are monogenetic disease, most of these diseases have complex etiology indicating the interaction of both genetic and environmental factors. However, recent evidences suggest that even the so called “monogenic diseases” can also have modifier loci. In this chapter genetics of few MDs including PD, Dystonia, WD and HD from India will be described. In addition to this review, Indian Genetic Disease Database release 1.0 (http: www.igdd.iicb.res.in) also covers 52
diseases with information on 5760 individuals carrying the mutant alleles of causal genes.[44]
Parkinson’s Disease Eighteen genetic loci with 13 underlying genes have been identified till date for PD, however, only 6 genes [Alpha‑synuclein (SNCA), Leucine rich repeat kinase‑2 (LRRK2), Parkin, PTEN induced putative kinase 1 (PINK1), DJ‑1, ATPase type 13A2 (ATP13A2)] could be conclusively proved to be causal towards the disease.[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. Mutations reported in Parkin are highest, absent in SNCA and rare in DJ‑1, PINK1 and LRRK2. The frequency of mutation in Parkin varies from 1.96% to 39.1% among Indians. In India studies to understand the molecular basis of PD is rapidly getting pace. 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., from different parts of India. Recent genome wide association studies on Asian and Caucasian populations have identified a number of associated genes in PD including ethnicity specific susceptible genes.[68,69] Majority of the mutations in the
Table 2: Studies on different PARK loci for identification of pathogenic mutations among PD cases in India
PARK loci
Gene (position)
PARK 1/PARK 4
SNCA (4q21)
Sample Population
169 140
PARK 2
Parkin (6q25‑q27)
102 259 138 69 140
PARK 6 PARK 7
PINK1 (1p35‑p36) DJ‑1 (1p36)
PARK 8
LRRK2 (12q12)
250 150 308 800
150
186 140 308
Region/mutation screened
Mutations identified (frequency) %
References
North and South Reported mutation: A30P, A53T South Reported mutation: A30P, A53T, E46K South All 12 s and flanking intron North and South All 12 s and flanking intron East All 12 s and flanking intron North West All 12 s and flanking intron South All 12 s and flanking intron
Not found
Nagar et al., 2001
Not found
Vishwanathan et al., 2012
1.96 8.5 7.24 39.1 2.14
Madegowda et al., 2005 Chaudhary et al., 2006 Biswas et al., 2006 Vinish et al., 2010 Padmaja et al., 2012
East All 8 s and flanking intron East no. 2‑7 and intron East All s and flanking intron North and South Reported mutation: G2019S, R1441C, R1441G, R1441H, I2012T, I2020T East Reported mutation: G2019S, R1441C, R1441G, R1441H, I2012T, I2020T, Y1699C South Reported mutation: G2019S South Reported mutation: G2019S East Reported mutation: G2019S, R1441C, R1441G, R1441H, Y1699C, G2358R
2 Not found 3.9 0.125
Biswas et al., 2010 Sanyal et al., 2011 Sadhukhan et al., 2012 Punia et al., 2006
Not found
Sanyal et al., 2010
Not found Not found Not found
Vijayan et al., 2011 Vishwanathan et al., 2012 Sadhukhan et al., 2012
PD ‑ Parkinson’s disease
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autosomal recessively inherited PD genes have been identified in heterozygous condition and current studies now suggest that homozygous mutants have a more severe form of the disease, while heterozygous variants are in fact risk factors. Since copy number variations have been reported in SNCA and Parkin, therefore, gene dosage study should now be routinely done among the candidate genes. None of the candidate gene studies in PD have actually done gene dosage analysis except Chaudhary et al. 2006 in Parkin gene.[49]
Dystonia Until date 25 dystonia loci and 16 dystonia genes have been identified. 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. Interestingly, with increasing age at onset there was a caudal to rostral shift in the affected site among patients. Dopa‑responsive dystonia (DRD) is one such disease that can have overlapping disease phenotype with juvenile PD (JPD). It is mostly caused by autosomal dominant mutations in the GCH1 gene (guanosine triphosphate cyclohydrolase1) and on rare occasion by autosomal recessive mutations in the tyrosine hydroxylase
or sepiapterin reductase genes. Three novel mutations in GCH1 gene have been found and represent 15.79% (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.
Wilson Disease WD is an autosomal recessive disorder results in copper accumulation in brain, liver and kidney. Mutations in copper transporting gene ATP7B and suspected modifiers ATOX1 and COMMD1 has been implicated for WD. The ATP7B comprised of 21 exons spanning ~ 80 kb on chromosome 13q14.3; with a 4.3 kb open reading frame encodes a protein of 1465 amino acid. About ~ 600 diseases causing mutations have been known to be associated with WD worldwide (www.wilsondisease.med.ualberta. ca). A total of 308 mutant chromosomes (ATP7B) were identified from four different geographical locations of India of which 86 are unique. The detailed mutation spectrum is presented in Tables 3 and 4. On screening ATP7B gene in 114 unrelated WD patients from eastern India, 17 mutations including five common mutations (p. Gly1061Glu, p.Tyr187Stop, p.Cys271Stop, p.Glu150His‑fs and c. 1708‑1G > C) were reported.[71,72] This accounts for 44% of WD patients.[72] In addition a total of 23 and
Table 3: Mutation in Indian Wilson disease patients
Nucleotide change
ATP7B gene Missense mutations c. 442C>T c. 997G>A c. 1544G>A c. 1847G>A c. 1771G>C C2071G>C c. 2128G>A c. 2189A>G c. 2302C>T c. 2332C>T c. 2333G>A c. 2383C>T
Exon/intron Amino acid change
2 2 4 5 5 7 8 8 8 8 8 9
Arg148Trp Gly333Arg Gly515Asp Arg616Glu Gly591Ser Gly691Arg Gly710Ser Asp730Gly Pro768Leu Arg778Trp Arg778Gln Leu795Phe
c. 2524G>T c. 2623A>G c. 2906G>A c. 2930C>T
10 11 13 13
c. 2968G>C c. 2975C>A c. 3008C>T c. 3007G>A
13 13 13 13
No. of chr. in different geographical References locations North South East West Total 1 ‑
1
‑
‑ ‑
2 ‑
‑ 1
‑
‑
1
2
1 1 2 2 1
1 1 ‑ 11
4 ‑
‑ ‑
‑
2
‑
Asp842Tyr Gly875Arg Arg969Glu Thr977Met
‑ ‑ ‑
6 4 ‑
‑ ‑ 1
Ala990Pro Pro992His Ala1003Val Ala1003Thr
5 ‑ 2
‑ 5 ‑
‑ ‑ ‑
1 6 1
6 1
3
1 1 4 11 1 8 1 6 4 7 1 5 5 5
Aggarwal et al. 2013 Santhosh et al. 2006 Aggarwal et al. 2013 Santhosh et al. 2006 Gupta et al. 2007 Aggarwal et al. 2013 Gupta et al. 2005 Aggarwal et al. 2013 Santhosh et al. 2006 Kumar et al. 2007 Aggarwal et al. 2013 Santhosh et al. 2006 Aggarwal et al. 2013 Aggarwal et al. 2013 Santhosh et al. 2008 Santhosh et al. 2006 Gupta et al. 2007 Aggarwal et al. 2013 Aggarwal et al. 2013 Kumar et al. 2005 Santhosh et al. 2006 Kumar et al. 2005 Aggarwal et al. 2013 (Contd...)
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Das, et al.: Movement disorder in India
Table 3: (Contd...)
Nucleotide change
Exon/intron Amino acid change
No. of chr. in different geographical References locations North South East West Total
c. 3029A>G
13
Lys1010Arg
‑
7
‑
c. 3089G>A c. 3091A>G c. 3182G>A
14 14 14
Gly1030Asp Thr1031Ala Gly1061Glu
‑ ‑
‑ 2
1 21
c. 3282C>G
15
Phe1094Leu
‑
5
‑
c. 3301G>A c. 3305T>C
15 15
Gly1101Arg Ile1102Thr
‑ 7
‑ ‑
‑ 2
c. 3311G>A c. 3458G>A c. 3532A>G c. 3722C>T c. 3809A>G
15 16 16 18 18
Cys1104Thr Trp1153Stop Thr1178Ala Ala1241Val Asp1270Ser
1
‑
‑
c. 3818C>T c. 3890T>A c. 3895C>T
18 18 18
c. 3767A>G c. 4021G>A
7 2 3
2 1 26
5 3 1
2
3 10
1 2 1 1 6
‑ ‑ ‑
‑ 1 3
1 ‑ ‑
Pro1273Leu Val1296Asp Leu1299Phe
‑ ‑
1 1
‑ ‑
3
2 1 4
18 19
Gln1256Arg Gly1341Ser
1 ‑
‑ 4
‑ ‑
1
1 5
c. 4070C>T Nonsense mutations c. 561T>A c. 813C>
20
Ala135V7al
2
2
2 2
Tyr187Stop Cys271Stop
‑ ‑
‑ 5
4 27
21
4 53
c. 2145C>A c. 2728A>T Insertion/deletion mutations c. 172insC c. 365_366delinsTTCGAAGC c. 678delG IVS4+11insGT c. 1716delG c. 1849InsG c. 2224insA c. 2227delT c. 2258insC c. 2298insC c. 2304_2305insC c. 2495insG c. 2582insG c. 2697_2723del27 c. 2736_2746del11 c. 2815insA c. 2977insA c. 3031insG c. 3147delC c. 3157_c. 3158insC c. 3424insC c. 3770insG c. 3839insTAC c. 4311insA c. 448del5 c. 892delC
8 12
Tyr715Stop Lys910Stop
‑ 2
1 ‑
‑ ‑
2 2 2 4 5 5 8 8 8 8 8 10 11 11 12 12 13 13 14 14 16 18 18 21 2 2
Ala58Ala‑fs Glu122fs Leu227fs
‑
‑
1
Met573fs Arg616Gly‑fs Tyr741Asn‑fs Tyr743fs Ala753Stop‑fs Pro767Pro‑fs Met769fs Lys832Lys‑fs Ala861Ala‑fs Ile899_Gln907del Ile913fs Trp939Stop Pro992stop Lys1010Ala‑fs Thr1050fs Leu1053fs Gln1142Pro‑fs Asn1257Lys‑fs Met1280Ile Lys1437Lys‑fs Glu150His‑fs Gln298Lys‑fs
3 2
11 2 1
‑
‑
1 1
‑ ‑
‑ ‑
1 ‑
‑ ‑
‑ 1
‑ 1
‑ ‑
1 ‑
5
1
2
1 2 1 5 5
‑ ‑ ‑
‑ ‑ ‑ 2 1
2 2 2 1 ‑ ‑
‑ ‑ ‑ ‑ ‑ ‑
‑ ‑ ‑ ‑ 12 1
Santhosh et al. 2006 Santhosh et al. 2008 Aggarwal et al. 2013 Gupta et al. 2007 Gupta et al. 2007 Santhosh et al. 2006 Aggarwal et al. 2013 Santhosh et al. 2006 Santhosh et al. 2008 Aggarwal et al. 2013 Gupta et al. 2007 Kumar et al. 2005 Aggarwal et al. 2013 Kumar et al. 2005 Aggarwal et al. 2013 Gupta et al. 2007 Santhosh et al. 2006 Santhosh et al. 2006 Aggarwal et al. 2013 Aggarwal et al. 2013 Santhosh et al. 2006 Santhosh et al. 2006 Aggarwal et al. 2013 Kumar et al. 2005 Santhosh et al. 2008 Aggarwal et al. 2013 Aggarwal et al. 2013
1 2
Gupta et al. 2005 Gupta et al. 2005 Santhosh et al. 2006 Aggarwal et al. 2013 Santhosh et al. 2006 Kumar et al. 2005
1 11 2 1 5 1 1 1 1 1 2 1 1 1 2 1 5 5 2 1 2 2 2 1 12 1
Gupta et al. 2005 Aggarwal et al. 2013 Aggarwal et al. 2013 Kumar et al. 2005 Aggarwal et al. 2013 Kumar et al. 2005 Kumar et al. 2005 Aggarwal et al. 2013 Kumar et al. 2005 Gupta et al. 2005 Aggarwal et al. 2013 Gupta et al. 2005 Kumar et al. 2005 Aggarwal et al. 2013 Aggarwal et al. 2013 Kumar et al. 2005 Kumar et al. 2005 Kumar et al. 2005 Aggarwal et al. 2013 Aggarwal et al. 2013 Kumar et al. 2005 Kumar et al. 2005 Kumar et al. 2005 Kumar et al. 2005 Gupta et al. 2005 Gupta et al. 2005 (Contd...)
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Table 3: (Contd...)
Nucleotide change
c. 2115delGT c. 1962delC c. 2363delC c. 3146delC c. 3418delT c. 3895delC Splice‑junction mutations c. 1869+1_4delGTAA c. 1946+2T>G IVS9‑1G>A c. 2865+1G>A c. 2866‑2A>G c. 3243+5G>A c. 3412+1G>A c. 1708‑1G>C 3903 (6T>C) c. 4021 G>A 4021 (3A>G) Silent mutations c. 2145C>T COMMD1 gene c. 521C>T
Exon/intron Amino acid change 7 7 8 14 16 18
Phe705Pro‑fs Phe654Phe‑fs Thr788Thr‑fs Ala1049Ala‑fs Val1140Ala‑fs Leu1299Leu‑fs
5 6 9 13 13 14 15 4 18 19 19
No. of chr. in different geographical References locations North South East West Total 1 ‑ 1 ‑ 1 ‑
‑ 2 ‑ ‑ ‑ 1
‑ ‑ ‑ 1 ‑ ‑ 2 1
1
‑
‑ 1 2 2
‑ ‑ ‑ ‑ ‑
‑ ‑ 1 2 1
2 12 ‑ ‑ ‑
8
Tyr715Tyr
‑
‑
‑
3
Thr174Met
‑
‑
1
1
1 2 1 1 1 1
Kumar et al. 2005 Santhosh et al. 2006 Kumar et al. 2005 Gupta et al. 2007 Kumar et al. 2005 Santhosh et al. 2006
2 1 1 1 2 2 2 12 1 2 1
Aggarwal et al. 2013 Aggarwal et al. 2013 Kumar et al. 2005 Aggarwal et al. 2013 Aggarwal et al. 2013 Aggarwal et al. 2013 Gupta et al. 2007 Gupta et al. 2005 Santhosh et al. 2006 Santhosh et al. 2006 Santhosh et al. 2006
1
Aggarwal et al. 2013
1
Gupta et al. 2010
Table was taken from Gupta et al. 2007 and modified
Table 4: Summary of ATP7B mutation
Mutation type
Number of mutations (no. of chr.)
Missense Nonsense Insertion/deletion Splice junction Silent Total
38 (147) 4 (60) 32 (73) 11 (27) 1 (1) 86 (308)
22 mutations were identified from North and South Indian WD patients respectively.[73‑76] The mutational pattern of WD in western India identified 36 disease causing mutations among 52 patients, 14 of 36 being novel. Two mutations, p.Cys271Stop and p. Glu122fs accounted for ~ 40% of the WD in western India. The Cys271Stop was the most common mutation observed in Western India with an allelic frequency of 20.2%.[77] It was observed from four population of India that the missense mutations account for 44% of the total mutations followed by insertion and deletion mutations. Of the mutations documented in India, c. 813C > A (p.Cys271Stop) is the most common (53/308; 17.2%). A total of 21 prevalent mutations have been found in Indian population; five each in northern, eastern and western Indian population and eight in southern Indian populations (one is common between eastern, southern and western population). COMMD1 screening in 109 WD patients identified a novel putative mutation (p. Thr174Met) in one patient with atypical features. This Neurology India | Sep-Oct 2013 | Vol 61 | Issue 5
suggests that COMMD1 variants may not have any major contribution toward phenotypic heterogeneity observed in WD.[78] Screening of ATOX1 gene did not identify any nucleotide changes in ATOX1 gene.
Huntington’s Disease HD is a progressive neurodegenerative autosomal dominant disorder, caused by an expansion of a polymorphic CAG repeats beyond 36 in exon 1 of huntingtin gene on chromosome 4. The CAG repeat varied from 41 to 56 in HD patients whereas in normal varied from 11 to 35.[79] The age at onset is inversely related to the number of CAG repeat in the expanded allele. In Indian populations, six CCG repeat allele has been reported including (CCG)7 in 89.3% cases, (CCG)10 in 10.7% cases and (CCG)4 in one case. The variation in GluR6 and CCG repeats in the huntingtin gene might modify the age of onset of HD.[80] In a study of 30 HD families (19 from Southern India and 11 from Northern India) comprising 75 members were evaluated. The HD mutation did not show any significant association with either the (CCG)7 or (CCG)10 allele, while haplotype analysis suggested over representation of the 7‑2‑I (CCG‑D4s127‑del 2642 loci) haplotype in a subset of families and provides evidence for multiple and geographically distinct origins for the HD mutation in India.[81] The mutated huntingtin protein (htt) aggregates in nucleus. An impairment of proteasomal degradation pathway and autophagy has been implicated in HD. 463
Das, et al.: Movement disorder in India
Table 5: Details of NBIA
Types of NBIA
Gene
Inheritance
Pantothenate kinase associated neurodegeneration PLA2G6 associated neurodegeneration Mitochondrial membrane protein associated neurodegeneration Beta propeller protein associated neurodegeneration Fatty acid hydroxylase associated neurodegeneration Aceruloplasminemia Neuroferritinopathy Woodhouse‑Sakati syndrome Kufor‑Rakeb Idiopathic NBIA
PANK2
AR
PLA2G6
AR
C19of12
AR
WDR45
X‑linked
FA2H
AR
Ceruloplasmin Ferritin light DCAF17 ATP13A2 ‑
AR AD AR AR ‑
8. 9. 10.
11. 12. 13.
NBIA ‑ Neurodegeneration with brain iron accumulation
14.
Neurodegeneration with Brain Iron Accumulation (NBIA) NBIA is a rare, inherited, neurological MD. Before 2001, NBIA was called Hallervorden‑Spatz disease. There are nine forms of NBIA currently identified and have separate symptoms and identifying markers [Table 5]. Pantothenate Kinase Associated Neurodegeneration is the most common form of NBIA. It is caused by the mutation in the PANK2 gene. Molecular studies revealed PANK2 mutations in 4 patients from Indian subcontinent (Indian and Pakistani). No identifiable genetic cause was found in PLA2G6 and FTL gene.[82] We have tried to review recent Indian literature on MDs. Lot of scope of highlighting the heterogeneous presentations of various disorders, drug dosage required in controlling various disorders and side‑effects needs to be looked for. We hope to see publication of more data from India in future with the advancement of technology and infrastructures.
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2. 3. 4. 5. 6. 7. 464
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31. Netravathi M, Pal PK, Indira Devi B. A clinical profile of 103 patients with secondary movement disorders: Correlation of etiology with phenomenology. Eur J Neurol 2012;19:226‑33. 32. Naiya T, Misra AK, Biswas A, Das SK, Ray K, Ray J. Occurrence of GCH1 gene mutations in a group of Indian dystonia patients. J Neural Transm 2012;119:1343‑50. 33. Taly AB, Prashanth LK, Sinha S. Wilson’s disease: An Indian perspective. Neurol India 2009;57:528‑40. 34. Taly AB, Meenakshi‑Sundaram S, Sinha S, Swamy HS, Arunodaya GR. Wilson disease: Description of 282 patients evaluated over 3 decades. Medicine (Baltimore) 2007;86:112‑21. 35. Paliwal VK, Gupta PK, Pradhan S. Gabapentin as a rescue drug in D‑penicillamine‑induced status dystonicus in patients with Wilson disease. Neurol India 2010;58:761‑3. 36. Tryambak S, Sumanta L, Radheshyam P, Sutapa G. Clinical profile, prognostic indicators and outcome of Wilson’s disease in children: A hospital based study. Trop Gastroenterol 2009;30:163‑6. 37. Prashanth LK, Sinha S, Taly AB, A Mahadevan, Vasudev MK, Shankar SK. Spectrum of epilepsy in Wilson’s disease with electroencephalographic, MR imaging and pathological correlates. J Neurol Sci 2010;291:44‑51. 38. Prashanth LK, Sinha S, Taly AB, Vasudev MK. Do MRI features distinguish Wilson’s disease from other early onset extrapyramidal disorders? An analysis of 100 cases. Mov Disord 2010;25:672‑8. 39. Murthy BS, Murthy JM, Krishnaveni A, Reddy MV, Das SM. Wilson’s disease in south India and experience with zinc therapy. J Assoc Physicians India 1988;36:417‑9. 40. Sinha S, Taly AB. Withdrawal of penicillamine from zinc sulphate‑penicillamine maintenance therapy in Wilson’s disease: Promising, safe and cheap. J Neurol Sci 2008;264:129‑32. 41. Mishra D, Kalra V, Seth R. Failure of prophylactic zinc in Wilson disease. Indian Pediatr 2008;45:151‑3. 42. Aggarwal A, Aggarwal N, Nagral A, Jankharia G, Bhatt M. A novel global assessment scale for Wilson’s disease (GAS for WD). Mov Disord 2009;24:509‑18. 43. Sachin S, Goyal V, Singh S, Shukla G, Sharma MC, Gaikwed S, et al. Clinical spectrum of Hallervorden‑Spatz syndrome in India. J Clin Neurosci 2009;16:253‑8. 44. Pradhan S, Sengupta M, Dutta A, Bhattacharyya K, Bag SK, Dutta C, et al. Indian genetic disease database. Nucleic Acids Res 2011;39:D933‑8. 45. Lesage S, Brice A. Parkinson’s disease: From monogenic forms to genetic susceptibility factors. Hum Mol Genet 2009;18:R48‑59. 46. Nagar S, Juyal RC, Chaudhary S, Behari M, Gupta M, Rao SN, et al. Mutations in the alpha‑synuclein gene in Parkinson’s disease among Indians. Acta Neurol Scand 2001;103:120‑2. 47. Vishwanathan Padmaja M, Jayaraman M, Srinivasan AV, Srikumari Srisailapathy CR, Ramesh A. The SNCA (A53T, A30P, E46K) and LRRK2 (G2019S) mutations are rare cause of Parkinson’s disease in South Indian patients. Parkinsonism Relat Disord 2012;18:801‑2. 48. Madegowda RH, Kishore A, Anand A. Mutational screening of the parkin gene among South Indians with early onset Parkinson’s disease. J Neurol Neurosurg Psychiatry 2005;76:1588‑90. 49. Chaudhary S, Behari M, Dihana M, Swaminath PV, Govindappa ST, Jayaram S, et al. Parkin mutations in familial and sporadic Parkinson’s disease among Indians. Parkinsonism Relat Disord 2006;12:239‑45. 50. Biswas A, Gupta A, Naiya T, Das G, Neogi R, Datta S, et al. Molecular pathogenesis of Parkinson’s disease: Identification of mutations in the Parkin gene in Indian patients. Parkinsonism Relat Disord 2006;12:420‑6. 51. Vinish M, Prabhakar S, Khullar M, Verma I, Anand A. Genetic screening reveals high frequency of PARK2 mutations and reduced Parkin expression conferring risk for Parkinsonism in North West India. J Neurol Neurosurg Psychiatry 2010;81:166‑70. 52. Padmaja MV, Jayaraman M, Srinivasan AV, Srisailapathy CR, Ramesh A. PARK2 gene mutations in early onset Parkinson’s disease patients of South India. Neurosci Lett 2012;523:145‑7. 53. Biswas A, Sadhukhan T, Majumder S, Misra AK, Das SK, Variation Consortium IG, et al. Evaluation of PINK1 variants in Indian Parkinson’s disease patients. Parkinsonism Relat Disord 2010;16:167‑71. Neurology India | Sep-Oct 2013 | Vol 61 | Issue 5
54. Sanyal J, Sarkar B, Banerjee TK, Mukherjee SC, Ray BC, Raghavendra Rao V. Evaluating intra‑genetic variants of DJ‑1 among Parkinson’s disease patients of eastern India. Neurol Res 2011;33:349‑53. 55. Sadhukhan T, Biswas A, Das SK, Ray K, Ray J. DJ‑1 variants in Indian Parkinson’s disease patients. Dis Markers 2012;33:127‑35. 56. Punia S, Behari M, Govindappa ST, Swaminath PV, Jayaram S, Goyal V, et al. Absence/rarity of commonly reported LRRK2 mutations in Indian Parkinson’s disease patients. Neurosci Lett 2006;409:83‑8. 57. Sanyal J, Sarkar B, Ojha S, Banerjee TK, Ray BC, Rao VR. Absence of commonly reported leucine‑rich repeat kinase 2 mutations in Eastern Indian Parkinson’s disease patients. Genet Test Mol Biomarkers 2010;14:691‑4. 58. Vijayan B, Gopala S, Kishore A. LRRK2 G2019S mutation does not contribute to Parkinson’s disease in South India. Neurol India 2011;59:157‑60. 59. Sadhukhan T, Vishal M, Das G, Sharma A, Mukhopadhyay A, Das SK, et al. Evaluation of the role of LRRK2 gene in Parkinson’s disease in an East Indian cohort. Dis Markers 2012;32:355‑62. 60. Biswas A, Maulik M, Das SK, Indian Genome Variation Consortium, Ray K, Ray J. Parkin polymorphisms: Risk for Parkinson’s disease in Indian population. Clin Genet 2007;72:484‑6. 61. Punia S, Das M, Behari M, Mishra BK, Sahani AK, Govindappa ST, et al. Role of polymorphisms in dopamine synthesis and metabolism genes and association of DBH haplotypes with Parkinson’s disease among North Indians. Pharmacogenet Genomics 2010;20:435‑41. 62. Juyal RC, Das M, Punia S, Behari M, Nainwal G, Singh S, et al. Genetic susceptibility to Parkinson’s disease among South and North Indians: I. Role of polymorphisms in dopamine receptor and transporter genes and association of DRD4 120‑bp duplication marker. Neurogenetics 2006;7:223‑9. 63. Singh M, Khan AJ, Shah PP, Shukla R, Khanna VK, Parmar D. Polymorphism in environment responsive genes and association with Parkinson disease. Mol Cell Biochem 2008;312:131‑8. 64. Singh M, Khanna VK, Shukla R, Parmar D. Association of polymorphism in cytochrome P450 2D6 and N‑acetyltransferase‑2 with Parkinson’s disease. Dis Markers 2010;28:87‑93. 65. Biswas A, Sadhukhan T, Bose K, Ghosh P, Giri AK, Das SK, et al. Role of glutathione S‑transferase T1, M1 and P1 polymorphisms in Indian Parkinson’s disease patients. Parkinsonism Relat Disord 2012;18:664‑5. 66. Das G, Misra AK, Das SK, Ray K, Ray J. Microtubule‑associated protein tau (MAPT) influences the risk of Parkinson’s disease among Indians. Neurosci Lett 2009;460:16‑20. 67. Das G, Misra AK, Das SK, Ray K, Ray J. Role of tau kinases (CDK5R1 and GSK3B) in Parkinson’s disease: A study from India. Neurobiol Aging 2012;33:1485.e9‑15. 68. Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, et al. Genome‑wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nat Genet 2009;41:1303‑7. 69. Simón‑Sánchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, et al. Genome‑wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 2009;41:1308‑12. 70. Naiya T, Biswas A, Neogi R, Datta S, Misra AK, Das SK, et al. Clinical characterization and evaluation of DYT1 gene in Indian primary dystonia patients. Acta Neurol Scand 2006;114:210‑5. 71. Gupta A, Aikath D, Neogi R, Datta S, Basu K, Maity B, et al. Molecular pathogenesis of Wilson disease: Haplotype analysis, detection of prevalent mutations and genotype‑phenotype correlation in Indian patients. Hum Genet 2005;118:49‑57. 72. Gupta A, Chattopadhyay I, Dey S, Nasipuri P, Das SK, Gangopadhyay PK, et al. Molecular pathogenesis of Wilson disease among Indians: A perspective on mutation spectrum in ATP7B gene, prevalent defects, clinical heterogeneity and implication towards diagnosis. Cell Mol Neurobiol 2007;27:1023‑33. 73. Kumar S, Thapa BR, Kaur G, Prasad R. Identification and molecular characterization of 18 novel mutations in the ATP7B gene from Indian Wilson disease patients: Genotype. Clin Genet 2005;67:443‑5. 74. Kumar S, Thapa B, Kaur G, Prasad R. Analysis of most common mutations R778G, R778L, R778W, I1102T and H1069Q in Indian Wilson disease patients: Correlation between genotype/phenotype/copper ATPase activity. Mol Cell Biochem 2007;294:1‑10. 465
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75. Santhosh S, Shaji RV, Eapen CE, Jayanthi V, Malathi S, Chandy M, et al. ATP7B mutations in families in a predominantly Southern Indian cohort of Wilson’s disease patients. Indian J Gastroenterol 2006;25:277‑82. 76. Santhosh S, Shaji RV, Eapen CE, Jayanthi V, Malathi S, Finny P, et al. Genotype phenotype correlation in Wilson’s disease within families – A report on four south Indian families. World J Gastroenterol 2008;14:4672‑6. 77. Aggarwal A, Chandhok G, Todorov T, Parekh S, Tilve S, Zibert A, et al. Wilson disease mutation pattern with genotype‑phenotype correlations from Western India: Confirmation of p.C271* as a common Indian mutation and identification of 14 novel mutations. Ann Hum Genet 2013;apr 2/101111/ahg.12024. 78. Gupta A, Chattopadhyay I, Mukherjee S, Sengupta M, Das SK, Ray K. A novel COMMD1 mutation Thr174Met associated with elevated urinary copper and signs of enhanced apoptotic cell death in a Wilson Disease patient. Behav Brain Funct 2010;6:33. 79. Pramanik S, Basu P, Gangopadhaya PK, Sinha KK, Jha DK, Sinha S, et al. Analysis of CAG and CCG repeats in Huntingtin gene among
HD patients and normal populations of India. Eur J Hum Genet 2000;8:678‑82. 80. Chattopadhyay B, Ghosh S, Gangopadhyay PK, Das SK, Roy T, Sinha KK, et al. Modulation of age at onset in Huntington’s disease and spinocerebellar ataxia type 2 patients originated from eastern India. Neurosci Lett 2003;345:93‑6. 81. Saleem Q, Roy S, Murgood U, Saxena R, Verma IC, Anand A, et al. Molecular analysis of Huntington’s disease and linked polymorphisms in the Indian population. Acta Neurol Scand 2003;108:281‑6. 82. Aggarwal A, Schneider SA, Houlden H, Silverdale M, Paudel R, Paisan‑Ruiz C, et al. Indian‑subcontinent NBIA: Unusual phenotypes, novel PANK2 mutations, and undetermined genetic forms. Mov Disord 2010;25:1424‑31. How to cite this article: Das SK, Ghosh B, Das G, Biswas A, Ray J. Movement disorders: Indian scenario: A clinico-genetic review. Neurol India 2013;61:457-66. Source of Support: Nil, Conflict of Interest: None declared.
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