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.

Task-specific oromandibular dystonia secondary to chewing Khat (Catha edulis)- A series of 35 cases.

BACKGROUND: The leaves of "Khat" (Catha edulis), an indigenous shrub of Yemen and Arabian Peninsula are habitually chewed by the inhabitants for psychostimulant properties. OBJECTIVE: To describe a unique task specific Oro-mandibular dystonia (OMD) in Yemenese men, with a temporal association with chewing "Khat". METHODS: Multicentric, retrospective analysis (2009-2020) of patients with OMD associated with "Khat" chewing, evaluating clinical features and response to Onabotulinum toxin A. RESULTS: 35 Yemenese men with a negative family history, normal neuroimaging mean age of 44.31(±3.21) years and prolonged (20.31 ± 3.27 years) history of chewing Khat, around 5.16(±0.80) hours/day presented with OMD-20 jaw opening, 13 jaw closing and 2 mixed affecting chewing (n = 6), speech (n = 3), or both (n = 26). Additional lingual dystonia was seen in five. CONCLUSIONS: Chewing of khat is a repetitive task involving the jaw musculature and may be one of the causative factors of this task specific OMD. Recognition can prevent disability in these regions.

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.

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.

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.

Impact of home confinement during COVID-19 pandemic on sleep parameters in Parkinson's disease.

BACKGROUND: Literature shows that home confinement during coronavirus disease 2019 (COVID-19) pandemic has significantly affected sleep. However, such information regarding subjects having Parkinson's disease (PD) is unavailable. METHODS: This cross-sectional study was conducted using a questionnaire, developed and validated by experts. PD subjects from nine centers across India were included. Questionnaire assessed presence as well as change in sleep-related parameters and PD symptoms during home confinement. Restless legs syndrome (RLS) and REM sleep behavior disorder (REMBD) was diagnosed using validated questionnaire. Additionally, changes in physical activity, adoption of new hobbies during home confinement and perceived quality of life were assessed. RESULTS: Of 832 subjects, 35.4% reported sleep disturbances. New-onset/worsening of sleep disturbances (NOWS) was reported by 23.9% subjects. Among those with sleep disturbances (n = 295), insomnia symptoms worsened in half (51.5%) and nearly one-fourth reported worsening of RLS (24.7%) and REMBD (22.7%) each. NOWS was common in subjects lacking adequate family support during home confinement (P = 0.03); home confinement > 60 days (P = 0.05) and duration of PD > 7 years (P = 0.008). Contrarily, physical activity >1 h/day and engagement in new hobbies during home confinement were associated with better sleep. NOWS was associated with worsening of motor as well as non-motor symptoms of PD (P < 0.001) and poorer life quality (P < 0.001). CONCLUSION: Home confinement during COVID-19 pandemic was significantly associated with NOWS among PD subjects. NOWS was associated with global worsening of PD symptoms and poorer life quality. Physical activity >1 h/day and adoption of new hobbies during home confinement were associated with better sleep.

Genetic Architecture of Parkinson's Disease in the Indian Population: Harnessing Genetic Diversity to Address Critical Gaps in Parkinson's Disease Research.

Over the past two decades, our understanding of Parkinson's disease (PD) has been gleaned from the discoveries made in familial and/or sporadic forms of PD in the Caucasian population. The transferability and the clinical utility of genetic discoveries to other ethnically diverse populations are unknown. The Indian population has been under-represented in PD research. The Genetic Architecture of PD in India (GAP-India) project aims to develop one of the largest clinical/genomic bio-bank for PD in India. Specifically, GAP-India project aims to: (1) develop a pan-Indian deeply phenotyped clinical repository of Indian PD patients; (2) perform whole-genome sequencing in 500 PD samples to catalog Indian genetic variability and to develop an Indian PD map for the scientific community; (3) perform a genome-wide association study to identify novel loci for PD and (4) develop a user-friendly web-portal to disseminate results for the scientific community. Our "hub-spoke" model follows an integrative approach to develop a pan-Indian outreach to develop a comprehensive cohort for PD research in India. The alignment of standard operating procedures for recruiting patients and collecting biospecimens with international standards ensures harmonization of data/bio-specimen collection at the beginning and also ensures stringent quality control parameters for sample processing. Data sharing and protection policies follow the guidelines established by local and national authorities.We are currently in the recruitment phase targeting recruitment of 10,200 PD patients and 10,200 healthy volunteers by the end of 2020. GAP-India project after its completion will fill a critical gap that exists in PD research and will contribute a comprehensive genetic catalog of the Indian PD population to identify novel targets for PD.

Dyspnea after subthalamic deep brain stimulation in Parkinson's disease: a case-control study.

OBJECTIVE: Dyspnea can be present as non-motor symptom in patients with Parkinson's disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor and non-motor symptoms in PD. However, new-onset dyspnea has been reported after DBS surgery. We have studied respiratory characteristics of PD patients with bilateral STN-DBS to assess the impact of DBS on pulmonary function. METHODS: STN-DBS PD patients with dyspnea after surgery (cases) were matched with STN-DBS PD patients without dyspnea (controls). Motor and pulmonary function were assessed with stimulation and without medication (on stim/off med), and without stimulation and medication (off stim/off med). Pulmonary function was investigated with spirometry and dyspnea with the Medical Research Council Dyspnea Scale (MRCDS) and the Borg Scale (BS). RESULTS: Seven cases (five men, 58.30 ± 6.70 years of age) and seven controls (six men, 61.10 ± 6.30 years of age) were enrolled. MRCDS and BS revealed the presence of dyspnea in both groups. No significant changes in pulmonary function were found in both cases and controls in on stim/off med vs. off stim/off med condition (p < 0.05), and in cases vs. controls in on stim/ off med condition (p < 0.05). CONCLUSIONS: No impact of STN-DBS on pulmonary function was found in cases. Impaired perception of dyspnea and spread of stimulation surrounding the STN might account for new-onset dyspnea after DBS surgery. Dyspnea was detected also in controls using ad hoc questionnaires. Our findings suggest further investigation of this non-motor symptom in PD patients.

Corrigendum to "Wilson's Disease: Clinical Practice Guidelines of the Indian National Association for the Study of Liver (INASL), The Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition (ISPGHAN) and the Movement Disorders Society of India (MDSI)" [J Clin Exp Hepatol 9 (2019) 74-98].

[This corrects the article DOI: 10.1016/j.jceh.2018.08.009.].

Wilson's Disease: Clinical Practice Guidelines of the Indian National Association for Study of the Liver, the Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition, and the Movement Disorders Society of India.

Clinical practice guidelines for Wilson's disease (WD) have been published by the American Association for the Study of Liver Diseases and European Association for the Study of the Liver in 2008 and 2012, respectively. Their focus was on the hepatic aspects of the disease. Recently, a position paper on pediatric WD was published by the European Society of Pediatric Gastroenterology Hepatology and Nutrition. A need was felt to harmonize guidelines for the hepatic, pediatric, and neurological aspects of the disease and contextualize them to the resource-constrained settings. Therefore, experts from national societies from India representing 3 disciplines, hepatology (Indian National Association for Study of the Liver), pediatric hepatology (Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition), and neurology (Movement Disorders Society of India) got together to evolve fresh guidelines. A literature search on retrospective and prospective studies of WD using MEDLINE (PubMed) was performed. Members voted on each recommendation, using the nominal voting technique. The Grades of Recommendation, Assessment, Development and Evaluation system was used to determine the quality of evidence. Questions related to diagnostic tests, scoring system, and its modification to a version suitable for resource-constrained settings were posed. While ceruloplasmin and 24-h urine copper continue to be important, there is little role of serum copper and penicillamine challenge test in the diagnostic algorithm. A new scoring system - Modified Leipzig score has been suggested with extra points being added for family history and serum ceruloplasmin lower than 5 mg/dl. Liver dry copper estimation and penicillamine challenge test have been removed from the scoring system. Differences in pharmacological approach to neurological and hepatic disease and global monitoring scales have been included. Rising bilirubin and worsening encephalopathy are suggested as indicators predicting need for liver transplant but need to be validated. The clinical practice guidelines provide recommendations for a comprehensive management of WD which will be of value to all specialties.

Clustering of motor and nonmotor traits in leucine-rich repeat kinase 2 G2019S Parkinson's disease nonparkinsonian relatives: A multicenter family study.

OBJECTIVES: The objective of this study was to determine phenotypic features that differentiate nonparkinsonian first-degree relatives of PD leucine-rich repeat kinase 2 (LRRK2) G2019S multiplex families, regardless of carrier status, from healthy controls because nonparkinsonian individuals in multiplex families seem to share a propensity to present neurological features. METHODS: We included nonparkinsonian first-degree relatives of LRRK2 G2019S familial PD cases and unrelated healthy controls participating in established multiplex family LRRK2 cohorts. Study participants underwent neurologic assessment including cognitive screening, olfaction testing, and questionnaires for daytime sleepiness, depression, and anxiety. We used a multiple logistic regression model with backward variable selection, validated with bootstrap resampling, to establish the best combination of motor and nonmotor features that differentiates nonparkinsonian first-degree relatives of LRRK2 G2019S familial PD cases from unrelated healthy controls. RESULTS: We included 142 nonparkinsonian family members and 172 unrelated healthy controls. The combination of past or current symptoms of anxiety (adjusted odds ratio, 4.16; 95% confidence interval, 2.01-8.63), less daytime sleepiness (adjusted odds ratio [1 unit], 0.90; 95% confidence interval, 0.83-0.97], and worse motor UPDRS score (adjusted odds ratio [1 unit], 1.4; 95% confidence interval, 1.20-1.67) distinguished nonparkinsonian family members, regardless of LRRK2 G2019S mutation status, from unrelated healthy controls. The model accuracy was good (area under the curve = 79.3%). CONCLUSIONS: A set of motor and nonmotor features distinguishes first-degree relatives of LRRK2 G2019S probands, regardless of mutation status, from unrelated healthy controls. Environmental or non-LRRK2 genetic factors in LRRK2-associated PD may influence penetrance of the LRRK2 G2019S mutation. The relationship of these features to actual PD risk requires longitudinal observation of LRRK2 familial PD cohorts. © 2018 International Parkinson and Movement Disorder Society.

Reversible man-in-the-barrel syndrome in myasthenia gravis.

Man-in-the-barrel syndrome (MBS) is an uncommon presentation due to bilateral, predominantly proximal muscle weakness that has not been described to be associated with myasthenia gravis. We describe a case of myasthenia gravis presenting as MBS. Additionally, he had significant wasting of the deltoids bilaterally with fibrillations on electromyography (EMG) at rest and brief duration (3-6 ms) bi/triphasic motor unit potentials (MUPs) on submaximal effort apart from a decremental response on repetitive nerve stimulation (RNS) at 2 Hz. While electrophysiology is an important tool in the diagnosis of myasthenia gravis, pathological EMG patterns do not exclude the diagnosis of myasthenia gravis.

Bilateral pedunculopontine nucleus stimulation for progressive supranuclear palsy.

The pedunculopontine nucleus (PPN) is a potential target for gait disorders. We report 4 cases of bilateral PPN stimulation in progressive supranuclear palsy (PSP) patients with short-term (6 months) and long-term (18 months) follow-ups. Patients with PSP who had gait disturbances, but were able to walk with or without assistance, were selected. The patients' median age was 64 years and the disease duration 3 years. Bilateral PPN deep brain stimulation (DBS) was performed. The pacemaker was programmed using a bipolar mode and lower frequencies (20-45 Hz). The PSP rating scores (PSPRS) and their gait subscores (No. 25, 26, 27 and 28) along with PSP staging scores were used as primary end points. The total Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS III and the 39-item Parkinson's Disease Questionnaire were considered as secondary end points. Video recordings of the gaits were performed before surgery and at the 6- and 18-month follow-ups. These were retrospectively reviewed by a blinded neurologist for the primary end points. At the 6- and 18-month follow-ups, the median change in PSPRS was from 33 (baseline) to 37.5 and 47, respectively. Similarly, the PSP staging changed from 3 to 2.5 and 3.5, item 25 from 1.5 to 2 and 3.5, item 26 from 2.5 to 2 and 3.5, item 27 from 3.5 to 3 and 3.5 and item 28 from 1.5 to 1.5 and 3. Two patients in the study with the PSP-parkinsonism phenotype experienced improvement in their gait until the last follow-up. Bilateral PPN DBS can be safely performed in PSP patients despite mid-brain atrophy.

The value of GRE, ADC and routine MRI in distinguishing Parkinsonian disorders.

OBJECTIVES: To study different radiological signs and sequences including apparent diffusion coefficient (ADC) and gradient echo (GRE) to differentiate degenerative parkinsonian syndromes. BACKGROUND: Multiple system atrophy (MSA), Parkinson's disease (PD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CbD) differ in the pattern of neurodegeneration and cellular damage. Measuring the ADC, GRE sequences for paramagnetic substances and simple anatomical assessments have been reported individually to assist in separating some of these disorders, but have not been compared. METHODS: brain MRIs from May 2002 to February 2008 were retrospectively evaluated by raters blinded to the clinical diagnosis for predefined MRI signs on T1, T2 and GRE sequences. ADC values were quantitatively measured. Medical records were objectively analyzed using standard clinical criteria for different parkinsonian syndromes. RESULTS: 195 cases comprising of 61 PD, 15 MSA-P, 7 MSA-C, 21 PSP, 6 Corticobasal syndrome, 21 not fitting criteria and 64 controls were evaluated. 73% of patients with MSA-P had hypointensity of the putamen (compared to the pallidum) on GRE. The specificity of this sign to diagnose MSA-P was 90% versus PD and 76% versus PSP. When GRE hypointensity was combined with atrophy of the putamen the specificity improved to 98% (versus PD) and 95% (versus PSP) without altering the sensitivity. The ADC values were significantly higher in the middle cerebellar peduncle in cases with MSA-C versus controls, PD and PSP (p<0.001). CONCLUSIONS: The combination of hypointensity and atrophy of the putamen on GRE is useful in differentiating MSA-P from other parkinsonian syndromes.

Surgical correction of kyphosis in patients with camptocormia due to Parkinson's disease: a retrospective evaluation.

Camptocormia or 'bent spine syndrome' is a rare manifestation of Parkinson's disease. The postural deformity can be a great source of disability. Camptocormia is typically not responsive to dopaminergic medication. Results with deep brain stimulation to treat camptocormia have been mixed but generally poor. The authors report two cases of camptocormia in Parkinson's disease treated with spinal corrective surgery. Despite prolonged postoperative courses, including a high complication rate and the need for multiple revisions, both patients benefited from the procedures.

Bilateral pallidal stimulation for x-linked dystonia parkinsonism.

OBJECTIVE: To report the clinical benefits of bilateral deep brain stimulation (DBS) of the globus pallidus internus (GPi) in a patient with X-linked dystonia parkinsonism (XDP). DESIGN: Case report. SETTING: Tertiary referral center. Patient A 40-year-old Filipino man with genetically confirmed XDP and severely disabling generalized dystonia. Intervention Bilateral GPi DBS. MAIN OUTCOME MEASURES: The primary outcome measures were the Burke-Fahn-Marsden Dystonia Scale (BFMDS) severity and disability scores, and the secondary outcome measure was the Unified Parkinson Disease Rating Scores. RESULTS: At the 1-year postoperative follow-up, there was 80.4% improvement in the BFMDS severity score and 66.7% improvement in the BFMDS disability score. CONCLUSION: Bilateral GPi DBS seems to be very effective in improving dystonia in XDP.