The Genetic Drivers of Juvenile, Young, and Early-Onset Parkinson's Disease in India.

BACKGROUND: Recent studies have advanced our understanding of the genetic drivers of Parkinson's disease (PD). Rare variants in more than 20 genes are considered causal for PD, and the latest PD genome-wide association study (GWAS) identified 90 independent risk loci. However, there remains a gap in our understanding of PD genetics outside of the European populations in which the vast majority of these studies were focused. OBJECTIVE: The aim was to identify genetic risk factors for PD in a South Asian population. METHODS: A total of 674 PD subjects predominantly with age of onset (AoO) ≤50 years (encompassing juvenile, young, or early-onset PD) were recruited from 10 specialty movement disorder centers across India over a 2-year period; 1376 control subjects were selected from the reference population GenomeAsia, Phase 2. We performed various case-only and case-control genetic analyses for PD diagnosis and AoO. RESULTS: A genome-wide significant signal for PD diagnosis was identified in the SNCA region, strongly colocalizing with SNCA region signal from European PD GWAS. PD cases with pathogenic mutations in PD genes exhibited, on average, lower PD polygenic risk scores than PD cases lacking any PD gene mutations. Gene burden studies of rare, predicted deleterious variants identified BSN, encoding the presynaptic protein Bassoon that has been previously associated with neurodegenerative disease. CONCLUSIONS: This study constitutes the largest genetic investigation of PD in a South Asian population to date. Future work should seek to expand sample numbers in this population to enable improved statistical power to detect PD genes in this understudied group. © 2023 Denali Therapeutics and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Clinical Study of 668 Indian Subjects with Juvenile, Young, and Early Onset Parkinson's Disease.

OBJECTIVE: To determine the demographic pattern of juvenile-onset parkinsonism (JP, <20 years), young-onset (YOPD, 20-40 years), and early onset (EOPD, 40-50 years) Parkinson's disease (PD) in India. MATERIALS AND METHODS: We conducted a 2-year, pan-India, multicenter collaborative study to analyze clinical patterns of JP, YOPD, and EOPD. All patients under follow-up of movement disorders specialists and meeting United Kingdom (UK) Brain Bank criteria for PD were included. RESULTS: A total of 668 subjects (M:F 455:213) were recruited with a mean age at onset of 38.7 ± 8.1 years. The mean duration of symptoms at the time of study was 8 ± 6 years. Fifteen percent had a family history of PD and 13% had consanguinity. JP had the highest consanguinity rate (53%). YOPD and JP cases had a higher prevalence of consanguinity, dystonia, and gait and balance issues compared to those with EOPD. In relation to nonmotor symptoms, panic attacks and depression were more common in YOPD and sleep-related issues more common in EOPD subjects. Overall, dyskinesias were documented in 32.8%. YOPD subjects had a higher frequency of dyskinesia than EOPD subjects (39.9% vs. 25.5%), but they were first noted later in the disease course (5.7 vs. 4.4 years). CONCLUSION: This large cohort shows differing clinical patterns in JP, YOPD, and EOPD cases. We propose that cutoffs of <20, <40, and <50 years should preferably be used to define JP, YOPD, and EOPD.

Evidence of mutations in RIC3 acetylcholine receptor chaperone as a novel cause of autosomal-dominant Parkinson's disease with non-motor phenotypes.

BACKGROUND: The known genetic determinants of Parkinson's disease (PD) do not explain all cases investigated to date. Contemporary sequencing technologies hold promise for enhanced causal variant discovery. We attempted to identify the putative causal variant in an Indian PD family by whole exome sequencing (WES). METHODS: WES data generated for two affected cousins from a 14-member PD family with some non-motor phenotypes were analysed. Variants prioritised were checked for segregation with disease by targeted sequencing. An independent PD cohort (n=280) was screened for additional mutations in the prioritised gene. Variants were functionally validated in PC12 cells differentiated into neurons. RESULTS: A heterozygous mutation c.169C>A, p.P57T in RIC3 acetylcholine receptor chaperone (11p15) segregated with disease in the family confirming an autosomal-dominant mode of inheritance. Another heterozygous mutation c.502G>C, p.V168L was detected in an unrelated PD case. Both mutations were absent in 144 healthy control and in 74 non-PD WES data available in-house and in 186 age and sex-matched controls screened by PCR sequencing. RIC3 is a known chaperone of neuronal nicotinic acetylcholine receptor subunit α-7 (CHRNA7). Dominant negative effect of RIC3 mutants in transfected PC12 cells was reflected by the reduced levels of endogenous CHRNA7 in the membrane fractions in western blots and lower colocalisation profiles in confocal micrographs. CONCLUSION: The novel demonstration of a chaperone-mediated receptor density alteration due to RIC3 mutants provides strong evidence for the role of cholinergic pathway for the first time in PD aetiology. This may also be insightful for some non-motor symptoms and personalised treatment.

Discovery of a frameshift mutation in podocalyxin-like (PODXL) gene, coding for a neural adhesion molecule, as causal for autosomal-recessive juvenile Parkinsonism.

BACKGROUND: Mutations in known genes for inherited forms of Parkinson's disease (PD) account for <30% of familial PD (FPD) implying that more causal gene(s) remain to be identified. We attempted to discover the putative causal variant in an Indian family with autosomal-recessive juvenile Parkinsonism (ARJP), tested negative for mutations in PARK2, PINK1 and DJ1. METHODS: Whole exomes of two affected siblings were sequenced. Variants prioritised were screened for segregation with disease in the family by targeted sequencing. Gene thus identified was screened for index/additional exonic mutations, if any, in an independent PD cohort by PCR sequencing. Variants observed were functionally validated in differentiated PC12 cells. RESULTS: A novel homozygous frameshift mutation, c.89_90insGTCGCCCC in exon 1 of podocalyxin-like gene (PODXL, 7q32-33), resulting in loss of protein, segregated with disease in the family. Mutant allele was absent in 186 healthy controls screened by PCR sequencing and in control exomes available in the laboratory and public databases. Screening of additional 212 sporadic and 68 FPD cases identified three novel heterozygous missense variants namely c.1285C>A, c.1118G>A and c.881G>A in three unrelated cases. Significant differences in neurite branching and length (p<0.0001) were observed in PC12 cells with wild-type and mutant constructs. CONCLUSIONS: Based on the genetic and functional evidence in this study and literature support on the role of PODXL in neural development, a novel frameshift mutation in PODXL seems to be the likely cause of ARJP in this family. This is the first report suggesting the possible role of a neurodevelopmental pathway in PD aetiology.

Genome-Wide Polygenic Score Predicts Large Number of High Risk Individuals in Monogenic Undiagnosed Young Onset Parkinson's Disease Patients from India.

Parkinson's disease (PD) is a genetically heterogeneous neurodegenerative disease with poorly defined environmental influences. Genomic studies of PD patients have identified disease-relevant monogenic genes, rare variants of significance, and polygenic risk-associated variants. In this study, whole genome sequencing data from 90 young onset Parkinson's disease (YOPD) individuals are analyzed for both monogenic and polygenic risk. The genetic variant analysis identifies pathogenic/likely pathogenic variants in eight of the 90 individuals (8.8%). It includes large homozygous coding exon deletions in PRKN and SNV/InDels in VPS13C, PLA2G6, PINK1, SYNJ1, and GCH1. Eleven rare heterozygous GBA coding variants are also identified in 13 (14.4%) individuals. In 34 (56.6%) individuals, one or more variants of uncertain significance (VUS) in PD/PD-relevant genes are observed. Though YOPD patients with a prioritized pathogenic variant show a low polygenic risk score (PRS), patients with prioritized VUS or no significant rare variants show an increased PRS odds ratio for PD. This study suggests that both significant rare variants and polygenic risk from common variants together may contribute to the genesis of PD. Further validation using a larger cohort of patients will confirm the interplay between monogenic and polygenic variants and their use in routine genetic PD diagnosis and risk assessment.

Leads from xenobiotic metabolism genes for Parkinson's disease among north Indians.

OBJECTIVE: Pesticide/neurotoxin/free radical-induced oxidative stress leading to dopaminergic neuronal vulnerability is known to promote sporadic Parkinson's disease (PD). This study investigated the contribution of polymorphisms in genes from drug-metabolizing enzymes (DMEs) and the oxidative stress pathway to PD susceptibility and severity among a north Indian cohort. METHODS: Three hundred and thirty-nine PD patients diagnosed using UK PD brain bank criteria and 344 age-, sex-, and ethnicity-matched controls were recruited. Univariate and multivariate analyses were carried out to test allelic, genotypic, and haplotypic associations, and gene-gene interactions were assessed for 18 polymorphisms from 13 genes. Disease severity was calculated on the basis of the Hoehn and Yahr (HY) scale and Unified Parkinson's Disease Rating Scale III scores and was compared among the genotypic categories of markers. RESULTS: An association of GSTO1-rs4925 (P=0.04) and NQO1-rs1800566 (P=0.02) in univariate and multivariate analysis (P=0.01 and P=0.03, respectively) with disease susceptibility was observed. Significant and novel association of PON2-rs7493 (P=0.00009 with UPDRS III, P=0.003 with HY) with disease severity was retained after Bonferroni correction. On categorizing the cohort into young-onset PD (YOPD, n=90 cases, 104 controls) and late-onset PD ( n=249 cases, 240 controls), the association of several single nucleotide polymorphisms (SNPs) in DMEs was observed with YOPD. CONCLUSIONS: The association of NQO1, PON2, and DME genes (this study) and NAT2 (previous study) with PD among Indians may point toward an inherent population-specific genetic predisposition. This, probably compounded by an increase in environmental toxins and the indiscriminate use of pesticides in our country in the last few decades, may suggest likely gene-environment interactions, which may explain the increasing incidence of YOPD among Indians.

Evaluation of markers of oxidative stress, antioxidant function and astrocytic proliferation in the striatum and frontal cortex of Parkinson's disease brains.

Dopaminergic neurons die in Parkinson's disease (PD) due to oxidative stress and mitochondrial dysfunction in the substantia nigra (SN). We evaluated if oxidative stress occurs in other brain regions like the caudate nucleus (CD), putamen (Put) and frontal cortex (FC) in human postmortem PD brains (n = 6). While protein oxidation was elevated only in CD (P < 0.05), lipid peroxidation was increased only in FC (P < 0.05) and protein nitration was unchanged in PD compared to controls. Interestingly, mitochondrial complex I (CI) activity was unaffected in PD compared to controls. There was a 3-5 fold increase in the total glutathione (GSH) levels in the three regions (P < 0.01 in FC and CD; P < 0.05 in Put) but activities of antioxidant enzymes catalase, superoxide dismutase, glutathione reductase and glutathione-s-tranferase were not increased. Total GSH levels were elevated in these areas because of decreased activity of gamma glutamyl transpeptidase (γ-GT) (P < 0.05) activity suggesting a decreased breakdown of GSH. There was an increase in expression of glial fibrillary acidic protein (GFAP) (P < 0.001 in FC; P < 0.05 in CD) and glutathione peroxidase (P < 0.05 in CD and Put) activity due to proliferation of astrocytes. We suggest that increased GSH and astrocytic proliferation protects non-SN brain regions from oxidative and mitochondrial damage in PD.

Role of dysautonomic symptoms in distinguishing Parkinson's disease (PD) from multiple system atrophy (MSA-P) within a year of developing motor symptoms.

OBJECTIVE: Can dysautonomic symptoms occurring within a year of developing motor symptoms distinguish Multiple system atrophy-Parkinsonian (MSA-P) from Parkinson's disease (PD)? PATIENTS AND METHODS: Seventy-two Parkinsonian patients diagnosed as probable PD or MSA-P. RESULTS: PD (n = 58, 80.6%) and MSA (n = 14, 19.4%) patients were of similar age and had motor symptoms for similar duration. PD first presents with motor symptoms (68.3%) while MSA-P presents with dysautonomia (85.7%). Urinary incontinence was reported by MSA-P (64%) at their first visit and was absent in most PD (98%) patients. CONCLUSIONS: Urinary incontinence and orthostatic symptoms occurring in a parkinsonian patient within one-year history of motor symptoms suggests a diagnosis of MSA-P with high accuracy and their absence suggests PD.

The Spectrum of Movement Disorders in Tertiary Care Centers in India: A Tale of Three Cities.

BACKGROUND: Movement disorders constitute a major burden among the neurological disorders. Overall prevalence and distribution of disorders requiring medical resources remain unknown. OBJECTIVE: To understand the pattern of movement disorders burden in India. MATERIALS AND METHODS: Retrospective electronic database review of new patients attending movement disorders clinics in three cities from 2012 to 2018 was done. RESULTS: 14,561 patients (M:F-9,578:4,983) with mean age at assessment of 60.5 ± 14.9 years (Range: 1-98 years) were analyzed. The major broad syndromic diagnosis included: Parkinsonism (n = 9560, 64.9%), Dystonia (n = 2159, 14.8%), Tremors (n = 1129, 7.7%), Ataxia (n = 475, 3.3%), Chorea (n = 402, 2.7%), Peripheral induced movement disorders (n = 400, 2.7%), Gait Disorders (n = 156, 1.1%), Tics (n = 112, 0.8%), Restless Leg Syndrome (n = 89, 0.6%), and Myoclonus (n = 58, 0.4%). The syndromic diagnosis also included the functional disorders (0.6%). CONCLUSION: This large database from India show the burden of different movement disorders in tertiary clinics. In addition, it also gives insight into disorders requiring more resources for evaluation and management.

Compound heterozygous variants in Wiskott-Aldrich syndrome like (WASL) gene segregating in a family with early onset Parkinson's disease.

BACKGROUND: Knowledge of genetic determinants in Parkinson's disease is still limited. Familial forms of the disease continue to provide a rich resource to capture the genetic spectrum in disease pathogenesis, and this approach is exploited in this study. METHODS: Informative members from a three-generation family of Indian ethnicity manifesting a likely autosomal recessive mode of inheritance of Parkinson's disease were used for whole exome sequencing. Variant data analysis and in vitro functional characterisation of variant(s) segregating with the phenotype were carried out in HEK-293 and SH-SY5Y cells using gene constructs of interest. RESULTS: Two compound heterozygous variants, a rare missense (c.1139C > T:p.P380L) and a novel splice variant (c.1456 + 2 delTAGA, intron10) in Wiskott-Aldrich syndrome like gene (WASL, 7q31), both predicted to be deleterious were shared among the proband and two affected siblings. WASL, a gene not previously linked to a human Mendelian disorder is known to regulate actin polymerisation via Arp2/3 complex. Based on exon trapping assay using pSPL3 vector in HEK-293 cells, the splice variant showed skipping of exon10. Characterisation of the missense variant in SH-SY5Y cells demonstrated: i) significant alterations in neurite length and number; ii) decreased reactive oxygen species tolerance in mutation carrying cells on Tetrabutylphosphonium hydroxide induction and iii) increase in alpha-synuclein protein. Screening for WASL variants in two independent PD cohorts identified four individuals with heterozygous but none with biallelic variants. CONCLUSION: WASL, with demonstrated functional relevance in neurons may be yet another strong candidate gene for autosomal recessive PD encouraging assessment of its contribution across populations.

Role of polymorphisms in dopamine synthesis and metabolism genes and association of DBH haplotypes with Parkinson's disease among North Indians.

OBJECTIVES: Genetic and non-genetic components are believed to govern the etiology of common complex traits such as Parkinson's disease (PD). In view of the biochemical evidence of depleted dopamine levels in the affected brains and also the most common and effective therapeutic modality of administration of levodopa in PD, genes from the dopaminergic pathway emerge as major determinants. We have earlier shown the role of DRD4-120 bp duplication marker in PD susceptibility. In this study, contribution of six genes involved in dopamine synthesis and metabolism to PD susceptibility and disease severity was assessed in a North Indian PD cohort. METHODS: 339 patients diagnosed using UKPD brain bank criteria and 344 matched controls were recruited and disease severity was assessed using the Hoehn and Yahr scale and Unified Parkinson Disease Rating Scale III scores. Allelic, genotypic and haplotypic associations with PD were computed; severity was compared among the genotypic categories of markers; gene-gene interactions were assessed using multiple logistic regression. RESULTS: A highly significant association of dopamine beta-hydroxylase (DBH) haplotypes (rs1611115T>C - rs1108580A>G - rs5320A>G - rs129882C>T) with PD was observed; haplotypes C-A-G-C [P=0.000005, Odds ratio (95% confidence interval): OR (95% CI)=1.76 (1.38-2.25)] and C-A-G-T [P=0.000001, OR (95% CI)=0.49 (0.37-0.65)] retaining significance after Bonferroni correction. rs129882, a 3'UTR SNP in DBH showed significant association with disease severity [Hoehn and Yahr (P=0.005) and Unified Parkinson Disease Rating Scale (P=0.006)]. CONCLUSION: Observed association of DBH SNP/SNP haplotypes with PD susceptibility and its role in modulating disease severity reiterates the importance of dopamine pathway in sporadic PD etiology in general and potential therapeutic implications of DBH in particular.

Urogenital symptoms in Parkinson's disease and multiple system atrophy-Parkinsonism: at onset and later.

METHODS: One hundred and eighty-one parkinsonian patients were evaluated to determine if urogenital symptoms at presentation to the Neurology clinic can differentiate them as PD or MSA-P. An autonomic questionnaire was used to document urinary and genital symptoms. RESULTS: Mean age at presentation and disease duration in PD and MSA-P were similar. Urinary symptoms occurred twice as frequently in MSA-P than in PD. Storage symptoms (frequency, urgency, urge incontinence, nocturia) were common in both Parkinsonian disorders. Male MSA-P reported genital symptoms (erectile and ejaculatory failure) three times more frequently than in PD. CONCLUSIONS: Urogenital symptoms occurred in MSA-P when they had mild motor few symptoms unlike in PD where they occur when motor symptoms were severe. Urogenital dysfunction occurred early and was present in all MSA-P patients within two years. Presence of urogenital symptoms in early stages of Parkinsonism strongly favors MSA-P rather than PD. Absence of urogenital symptoms in advanced Parkinsonism makes MSA-P unlikely.

Novel and reported variants in Parkinson's disease genes confer high disease burden among Indians.

BACKGROUND: Genetic heterogeneity in Parkinson's disease (PD) has been unambiguously reported across different populations. Assuming a higher genetic load, we tested variant burden in PD genes to an early onset PD cohort from India. METHODS: Whole exome sequencing was performed in 250 PD patients recruited following MDS-UPDRS criteria. The number of rare variants in the 20 known PD genes per exome were used to calculate average rare variant burden with the 616 non-PD exomes available in-house as a comparison group. SKAT-O test was used for gene level analysis. RESULTS: 80 patients harboured rare variants in 20 PD genes, of which six had known pathogenic variants accounting for 2.4% of the cohort. Of 80 patients, 12 had homozygous and nine had likely compound heterozygous variants in recessive PD genes and 59 had heterozygous variants in only dominant PD genes. Of the 16 novel variants of as yet unknown significance identified, four homozygous across ATP13A2, PRKN, SYNJ1 and PARK7; and 12 heterozygous among LRRK2, VPS35, EIF4G1 and CHCHD2 were observed. SKAT-O test suggested a higher burden in GBA (punadjusted = 0.002). Aggregate rare variant analysis including 75 more individuals with only heterozygous variants in recessive PD genes (excluding GBA), with an average of 0.85 protein-altering rare variants per PD patient exome versus 0.51 in the non-PD group, revealed a significant enrichment (p < 0.0001). CONCLUSION: This first study in an early onset PD cohort among Indians identified 16 novel variants in known genes and also provides evidence for a high genetic burden in this ethnically distinct population.

Are current recommendations to diagnose orthostatic hypotension in Parkinson's disease satisfactory?

We interviewed 50 Parkinson's disease (PD) patients using a questionnaire to verify the reliability of orthostatic symptoms in warning the presence of orthostatic hypotension (OH). OH is defined as 20 mm Hg systolic or 10 mm Hg diastolic BP fall within 3 min of tilting or standing but if this fall occurs after 3 min we called it 'late OH' (L-OH). We compared if OH in Parkinson's disease (PD) was more frequent after head-up tilt or on standing and if the period of postural challenge matters in detecting OH. Twenty-one (42%) patients had OH that occurred twice more often after tilting (n = 20) than on standing (n = 10). OH occurred within 3 min of tilting in 9 patients (18%) and appeared beyond the currently recommended 3 min in 11 patients (55%) (L-OH). Ten of the 20 patients developing OH on tilting were symptomatic. The 10 patients who had OH on standing were asymptomatic. Reporting of symptoms was independent of age or severity of BP fall. Most (90%) patients reporting orthostatic symptoms on standing had OH on tilting for 3 min. Orthostatic symptoms in PD have a high specificity but low sensitivity in predicting OH. In Parkinson's disease OH occurs often after tilting than on standing and is delayed (after 3 min). As OH in PD is often asymptomatic and delayed it could contribute to falls and increase morbidity. We suggest routine evaluation of OH in PD by tilting them longer than the recommended 3 minutes to detect delayed OH.

Primary cardiac cytotoxic T-cell lymphoma presenting with neurological deficits: a case report.

BACKGROUND: Primary cardiac lymphoma is extremely rare in immunocompetent patients. Clinical manifestations vary, and, most often, diagnosis is not made until autopsy. The majority of reported primary cardiac lymphoma cases have been of B-cell origin, while T-cell cardiac lymphomas have been extremely rare. Occasionally, lymphomas and other systemic malignancies clinically present as paraneoplastic neurological syndromes. METHODS: We report a unique case of primary cardiac peripheral T-cell lymphoma of cytotoxic phenotype, clinically presenting with neurological features of external ophthalmoplegia and lower cranial nerve paresis mimicking mitochondrial cytopathy, that was recognized at autopsy. Brain and thoracoabdominal viscera retrieved at autopsy were fixed in 10% buffered formalin and processed for paraffin embedding. In addition to routine histology, immunohistochemistry for immunophenotypic characterization of lymphoma cells was performed. Fresh skeletal muscle was processed for cryosectioning and histochemical staining. RESULTS: On gross examination, the heart showed multiple circumscribed, whitish nodules on both sides. Histological examination of these nodules revealed lymphomatous deposits-cells expressing CD45, CD2, CD3, CD5, CD7, CD8, perforin, and granzyme B. Histological sections from the brain showed foci of demyelination and patchy perivascular lymphoid cell aggregates in leptomeninges and within the parenchyma. These lymphoid cells expressed CD2, CD3, and CD5, with the T cells being predominantly CD4 (CD4:CD8>2), which was unlike the CD8-predominant lymphomatous infiltrate in the heart. Hence, these lymphoid cells in the brain, rather than disseminated lymphoma cells, were considered to be related to the demyelinating process. There was no evidence of lymphomatous deposits in the rest of the viscera examined. CONCLUSION: A diagnosis of primary cardiac peripheral T-cell lymphoma of cytotoxic phenotype clinically manifesting as paraneoplastic demyelinating lesions in the brain was described.

Absence/rarity of commonly reported LRRK2 mutations in Indian Parkinson's disease patients.

Recent discovery of pathogenic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene in Parkinson's disease (PD) patients in different ethnic groups have raised a hope of diagnostic screening and genetic counseling. We investigated the six most commonly reported mutations in LRRK2 gene among Indian PD patients, using PCR-RFLP method. Mutations G2019S, R1441C, R1441G, and R1441H were screened in 1012 individuals (PD, 800; controls, 212) while mutations I2012T and I2020T were screened in 748 PD patients. We did not observe any of these six mutations in this study sample except in a single female young onset PD patient who showed a heterozygous G2019S mutation. The absence of mutations was reconfirmed by sequencing of probands from several autosomal dominant PD families. Our observations suggest that these mutations may be a rare cause of PD among Indians and therefore of little help for diagnostic screening and genetic counseling for Indian PD patients.

Parkin mutations in familial and sporadic Parkinson's disease among Indians.

We observed a mutation frequency of 8.5% in Parkin gene among Indian PD patients based on sequencing and gene dosage analysis of its exons. We identified nine point mutations of which seven are novel and hitherto unreported. These mutations accounted for 14.3% familial PD, 6.9% young onset and 5.9% late onset sporadic PD. Of the 20 PD patients with mutations only two had homozygous mutations and one was a compound heterozygote. Homozygous exonic deletions were absent but heterozygous exon rearrangements were observed in 9.2% of patients (19% familial PD and 4.5% young onset sporadic PD).

Perspectives towards predictive testing in Huntington disease.

OBJECTIVE: Genetic counseling for individuals undergoing presymptomatic testing is lacking in India although testing is easily available. This has an impact on family members of Huntington's disease (HD), an autosomal dominant disease, wherein the age at onset of symptoms varies. AIM: We examine if attitudes differ towards presymptomatic testing for HD amongst HD family members, physicians and laypersons. MATERIALS AND METHODS: A modified questionnaire enquiring about opinions on various personal, family, social and future health care with regards to presymptomatic testing of HD was designed. A physician explained briefly about HD and presymptomatic testing of HD and recorded responses of unaffected family members of HD (n=25) and laypersons (n=50). Medical doctors (n=50) answered the questionnaire based on their knowledge of HD. RESULTS: HD family members, Medical doctors and laypersons were similar in their opinion to undergo the testing. Majority (60%) of HD family members did not wish to communicate test results with their friends when compared to the other two groups. Medical doctors and HD family members were more concerned about certainty of developing disease when the test results are positive. Majority (80%) of Medical doctors and less than half in the other groups felt that their decision to have a child would strongly depend on test results. Large proportion (80%) of HD family members did not wish to report their test results to their employers. CONCLUSIONS: Individuals with knowledge about HD and the test differ in their decision of sharing test results and reproductive choices.

Early Onset Parkinson's disease due to DJ1 mutations: An Indian study.

INTRODUCTION: Early Onset Parkinson's Disease (EOPD) is genetically heterogeneous. PARK2 mutations are the commonest cause of autosomal recessive EOPD followed by PINK1.DJ1 mutations is rare and there is scarce literature on its phenotype and long term outcome. OBJECTIVES: We undertook a retrospective study to determine the prevalence of DJ1 mutation(s) in an Indian population and describe the clinical features and long term outcome of EOPD patients with these mutations. METHODS: One hundred EOPD patients and 114 controls were evaluated. All the seven coding exons of DJ1 gene were screened for novel and reported mutations by PCR- Sanger sequencing. RESULTS: A novel homozygous missense mutation (c.313 A > T, p. Ile105Phe) in exon 5 was seen in one patient and four unrelated patients had a homozygous missense single nucleotide variant rs71653619 (c.293 G > A, p.Arg98Gln). The clinical phenotype comprised of asymmetrical onset, slowly progressive Parkinsonism with levodopa induced motor restlessness in a patient with the novel mutation (c.313 A > T, p. Ile105Phe) while subjects with c.293 G > A, p.Arg98Gln had early onset levodopa responsive symmetrical Parkinsonism. CONCLUSION: DJ1 mutations account for ∼5% of EOPD patients from the Indian population. This study further adds to the clinical spectrum of EOPD with DJ1 mutations.