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We present a report on an 18-year-old boy with Niemann-Pick disease Type C (NP-C) who presented with progressive decline in scholastic performance since 9 years of age. At 12 years, he developed abnormal behavior and after 2 years had insidious onset, progressive gait ataxia and dysarthria followed by dystonia of the right upper extremity, excessive drooling, dysphagia and nasal regurgitation. He had coarse facies, depressed nasal bridge, high arched palate, crowded teeth, splenomegaly and peculiar facial grin. In addition, impaired vertical saccadic and pursuit eye movements, brisk muscle stretch reflexes and limb and gait ataxia were observed. He had a low IQ of 47 on Binet-Kamat test. The ultrasound examination of the abdomen confirmed the presence of moderate splenomegaly. Magnetic resonance imaging brain showed symmetrical leucoencephalopathy and mild cerebellar atrophy. Bone marrow aspiration showed numerous foamy macrophages and sea-blue histiocytes suggesting the diagnosis of NP-C.

Botulinum toxins are, as a group, among the most potent neuromuscular toxins known, yet they are clinically useful in the management of conditions associated with muscular and glandular over-activity. Botulinum toxins act by preventing release of acetylcholine into the neuromuscular junction. While botulinum toxin type A is commonly available, different manufacturers produce specific products, which are not directly interchangeable and should not be considered as generically equivalent formulations. Type B is also available in the market. Each formulation of botulinum toxin is unique with distinct dosing, efficacy and safety profiles for each use to which it is applied. Botulinum toxin type A is the treatment of choice based on its depth of evidence in dystonias and most other conditions. Botulinum toxin type A is established as useful in the management of spasticity, tremors, headache prophylaxis and several other neurological conditions. Active research is underway to determine the parameters for which the type B toxin can be used in these conditions, as covered in this review. Botulinum toxin use has spread to several fields of medicine. [ABSTRACT FROM AUTHOR]

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., (© 2023 Denali Therapeutics and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

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.

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., Competing Interests: There are no conflicts of interest., (Copyright: © 2006 - 2021 Annals of Indian Academy of Neurology.)

Huntington's disease is characterized by choreic movements, psychiatric disorders, striatal atrophy with selective small neuronal loss, and autosomal dominant inheritance. The genetic abnormality is CAG expansion in Huntingtin gene. Newer therapeutic strategies are evolving to treat this progressive disorder. The neuroprotective agents are one such group of drugs being tried. Lithium has been used to treat Huntington's disease in the past due to its neuroprotective effects. Though the precise mechanism of action is not clear, Lithium can directly or indirectly modulate proteins involved in neuronal survival/differentiation which may account for its neuroprotective effects. We report three patients with Huntington's disease in whom Lithium prevented the progression of chorea and also helped stabilize mood.

Accumulating evidences suggest that dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc) during ageing and in Parkinson's disease (PD) is linked to neurodegenerative changes like exponential increase in alpha-synuclein expression and protein misfolding. Lewy body formation is also a quintessential observation in neurodegeneration and PD. In experimental models of PD, GRP78 a neuroprotective endoplasmic reticulum (ER) chaperone protein targets misfolded proteins for degradation and prevents release of caspase12 from the ER. Release of active caspase12 and its translocation to the nucleus induces ER mediated apoptosis. The effect of ageing on these proteins in human nigra is not known. We evaluated alpha-synuclein, caspase12, GRP78 and ubiquitin expression in the SNpc of Asian Indians, using immunohistochemistry and stereology. The number of alpha-synuclein and caspase12 immunoreactive neurons increased gradually with age whereas the number of GRP78-labeled neurons remained stable. In contrast, GRP78 protein expression was significantly upregulated with age, while alpha-synuclein and caspase12 increased slightly. An increase in the size and numbers of marinesco bodies was prominent after the sixth decade. The mild increase in alpha-synuclein expression and occurrence of marinesco bodies suggests ageing induced protein misfolding and GRP78 upregulation indicates presence of ER stress. The logarithmic upregulation of GRP78 could even be an indicator of neuroprotective or neuromodulatory response of ER to protein misfolding and initiation of unfolded protein response pathway. Since dopaminergic neurons are preserved in ageing Asian Indians, our study possibly signifies better proteasomal or ER response and partially explains the lower prevalence of PD in them., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Glial derived neurotrophic factor (GDNF) protects dopaminergic nigral neurons and may prevent the progression of age-related motor deficits and Parkinson's disease. The multi-component receptor complex which mediates the neuroprotective action of GDNF comprises of GDNF receptor alpha1 (GFRalpha1), a ligand binding cell surface component and RET receptor tyrosine kinase (RET) the signaling component. The expression of both these receptors in the normally aging human substantia nigra pars compacta (SNpc) needs to be studied since GDNF infusion is being considered for restoration of the lost nigrostriatal function. In the present study, we used unbiased stereology to quantify the number of GFRalpha1 and RET immunoreactive neurons in human SNpc from 28 weeks of gestation to 88 years (n=31). We further determined the levels of immunostaining intensity using densitometric image analysis to measure changes in levels of receptor expression. Here we report that human nigral dopaminergic neurons express GFRalpha1 and RET receptors at all ages. There was no reduction in the number of neurons expressing these receptors as a function of age. Moreover, there was no age-related decline in immunostaining intensity of both these receptors. It is likely that preservation of GDNF receptors in the nigral neurons is because these receptors are constitutively expressed in the human SNpc and thus it is GDNF responsive thru aging. The sustained receptor protein expression could also be another marker of preserved nigrostriatal function in Asian Indians. The latter possibility explains our earlier observation that the melanized nigral neurons are preserved with age in the Asian Indians., (2010 Elsevier B.V. All rights reserved.)

Background: The elderly population in developing countries is likely to increase by 200-280%. Age related diseases like Parkinsonism are also likely to increase in ageing population. The prevalence and awareness of Parkinsonism (and possible PD) amongst them are unknown., Methods and Material: The objective was to know the awareness and occurrence of Parkinsonism (and possible PD) in Old Age Homes in Bangalore, South India. The study design was prospective, direct clinical evaluation, and it was old age homes in Bangalore, South India setting. There were six hundred and twelve residents of the old age homes in Bangalore. A movement disorder neurologist examined 612 elderly residents living in Old age Homes in Bangalore city, India., Results: Parkinsonism was diagnosed in 109 (17.8%) of 612 residents. Possible PD was diagnosed in 9 (1.5% of 612) while in 100 (16.3% of 612) definite PD was diagnosed.94 (86.2%) had bilateral Parkinsonian signs (Stage > or = 2 of Hoehn & Yahr), only 4 (3.7%) of them or the caregivers knew they had PD., Conclusions: Knowledge about the disease was very low in the elderly residents although the occurrence of Parkinsonism was very high. Improving awareness of PD amongst the elderly and their caregivers might reduce their disability and improve their quality of life.

Improving economy and health in developing countries like India, has increased the life span and changed the emphasis from communicable to noncommunicable diseases. This is likely to increase the prevalence of movement disorders and, age-related diseases like Parkinson's disease (PD). We review Indian epidemiological studies to describe: a) Prevalence of movement disorders, b) methodological issues and c) potential of epidemiological research in a country with multiple ethnic races and environmental risks for PD. Most Indian epidemiological studies do not specifically assess PD and figures are from studies evaluating all neurological diseases. Well-designed Indian studies on PD and essential tremors estimate prevalence rates in Parsis who are ethnically different from Indians. We compare Indian prevalence studies with other parts of the world to examine the role of ethnicity in PD. Lack of accurate epidemiological data on PD and movement disorders creates an urgent need for properly designed and conducted epidemiological studies in India. This will help find out their load, identify areas of focus, create public health policies for elderly Indians and, possibly, provide etiological clues to the pathogenesis of PD.

DNA damage has been postulated as a mechanism of neuronal death in Parkinson's disease (PD). In the present study, genomic DNA was isolated from eight brain regions (frontal, temporal, and occipital cortex, hippocampus, caudate/putamen, thalamus, cerebellum, and midbrain) from five neuropathologically confirmed cases of Parkinson's disease and six control brains and analyzed for the presence of single and double strand breaks, melting temperature, EtBr intercalation, DNAse digestion pattern, and DNA conformations. The results showed that DNA from midbrain in PD accumulated significantly higher number of strand breaks than age-matched controls. Caudate nucleus/putamen, thalamus, and hippocampus also showed more DNA fragmentation compared to control brains. Circular dichroism studies showed that DNA conformation was altered with imprecise base stacking in midbrain, caudate nucleus/putamen, thalamus, and hippocampus in PD. However, DNA from frontal, temporal, and occipital cortex, and cerebellum was not affected significantly in PD group as compared to controls. This study provides a comprehensive database on stability, damage, and conformations of DNA in different regions in brains of PD patients.

Deficiency of enzyme acid beta-galactosidase causes GM1 gangliosidosis. Patients with adult GM1 gangliosidosis typically present with generalized dystonia. We describe clinical, bone marrow, and radiological features of adult GM1 gangliosidosis to help improve its recognition. We report 3 Indian patients and review of reports between 1981 and October 2002. The disease frequently is reported in the Japanese literature (75%). Patients are normal at birth and have normal early motor and mental development. Onset is within the first decade with abnormal gait, or worsening of speech is an initial symptom. Dystonia occurs in 97% of patients. Facial dystonia described as "facial grimacing" observed in approximately 90% could be an important clinical clue. Dysarthria/anarthria (97%) is frequent, and eye movements are normal. Bone marrow examination may show Gaucher-like foam cells (39%). Magnetic resonance imaging (MRI) frequently (90.9%) shows bilateral symmetrical putamenal hyperintensities on T2-weighted and proton density images. Diagnosis is confirmed by demonstrating deficiency of beta-galactosidase. Adult (Type 3) GM1 Gangliosidosis commonly presents with generalized dystonia with prominent facial dystonia, severe speech disturbances, and normal eye movements. Bone marrow frequently shows Gaucher-like foam cells. MRI shows typical lesions in the putamen. Deficiency of beta-galactosidase in fibroblasts confirms the diagnosis.

Task-specific dystonia significantly impairs the performance of approximately 8% of musicians [Lederman RJ. Muscle Nerve 2003;27:549-561]. We describe hand dystonia in two professional musicians experienced while playing tabla, a percussion instrument., ((c) 2004 Movement Disorder Society.)

We studied whether the occurrence of Parkinson's disease (PD) in the Anglo-Indians, an admixed population of European and Asian Indian origin, differs from Indians living in the same environment. Epidemiological studies show considerably higher prevalence of PD amongst white compared to non-white populations. Normal Indians contain a approximately 40% lower number of melanized nigral neurons compared to Caucasians from the UK. Anglo-Indians are an admixed population of European and Indian origin. We used the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria (steps 1 and 2) to diagnose PD in 84 of 493 residents (Indians, 409; Anglo-Indians, 84) living in elderly homes in Bangalore, India. Of these 84, 80 were Indians (19.5%) and 4 were Anglo-Indians (4.8%). Occurrence of PD is nearly five times higher amongst Indians compared to the Anglo-Indians (odds ratio, 3.9; 95% confidence interval, 1.3-12.9). We conclude that an admixture population of European and Indian origins, rather than averaging, might result in reduced occurrences of PD. Hence, studying an admixed population could provide crucial insights into understanding genetic mechanisms in the etiopathogenesis of PD., (Copyright 2003 Movement Disorder Society)

We describe a patient with an unusual clinical presentation of progressive multiple cranial nerve palsies, cerebellar ataxia, and palatal tremor (PT) resulting from an unknown etiology. Magnetic resonance imaging showed evidence of hypertrophy of the inferior olivary nuclei, brain stem atrophy, and marked cerebellar atrophy. This combination of progressive multiple cranial nerve palsies, cerebellar ataxia, and PT has never been reported in the literature. We have also reviewed the literature of PT secondary to neurodegenerative causes. In a total of 23 patients, the common causes are sporadic olivopontocerebellar atrophy (OPCA; 22%), Alexander's disease (22%), unknown etiology (43.4%), and occasionally progressive supranuclear palsy (4.3%) and spinocerebellar degeneration (4.3%). Most patients present with progressive cerebellar ataxia and approximately two thirds of them have rhythmic tremors elsewhere. Ear clicks are observed in 13% and evidence of hypertrophy of the inferior olivary nucleus in 25% of the patients. The common neurodegenerative causes of PT are OPCA/multiple system atrophy, Alexander's disease, and, in most of them, the result of an unknown cause.

The prevalence of Parkinson's disease (PD) is higher in whites than in nonwhites and it increases with advancing age. The pathological hallmarks of PD are loss of pigmented neurons in the substantia nigra pars compacta (SNpc) and presence of Lewy bodies. With increasing age, a similar loss of pigmented neurons in the SNpc has been reported. Hence, age and race possibly play a role in the pathogenesis of PD. The objectives of this study were to count the number of melanized neurons in the SNpc in normal human brains from India and study the change in neuronal count with advancing age and to compare the neuronal counts from this Indian population with counts reported in normal brains from the United Kingdom. Melanized neurons in the SNpc were counted in 84 normal human brains (age range, 5-84 years) in a single 7-microm section at the level of emergence of the oculomotor nerve. In the brains from India, there was no loss of melanized nigral neurons with advancing age. The absolute number of these melanized neurons was about 40% lower than the brains from UK. Despite a low number of melanized nigral neurons in the brains from India, individuals function normally and have dopamine levels comparable with their Western counterparts, suggesting that it is not the absolute number of melanized nigral neurons but the percent loss of nigral neurons that results in dopaminergic deficiency in PD. There is no significant loss of pigmented nigral neurons with age, suggesting that the loss seen in PD is exclusively due to the disease process itself. Indians have a lower prevalence of PD despite having a low count of melanized nigral neurons, suggesting that better protective mechanisms may be present in the Indians to prevent the loss of nigral neurons.

It is controversial if early onset Parkinson's disease (EOPD) (onset at < 41 years of age) is Parkinson's disease (PD) occurring at a younger age or a different disease. This controversy is due to some clinical and pathological differences between EOPD and PD. Within EOPD, there appear to be two groups namely: young onset Parkinson's disease (YOPD), with onset between 21 and 40 years, and juvenile parkinsonism (JP), with onset at < 20 years. The two major clinical differences between these groups are a higher familial occurrence of PD and dystonia in JP. In this study, we determine if the two groups have the classical features of PD, namely rest tremors, rigidity, bradykinesia, and postural instability, and have a meaningful response to levodopa. Furthermore, we compare their other clinical features, autonomic and cognitive functions, and levels of CSF monoamine metabolites to determine differences between these groups. We observe that all YOPD (100%) and JP (85%) patients had rest tremors. Most of these patients also had a meaningful response to levodopa (YOPD: 72%; JP: 100%). The prevalence of family history of PD was similar, whereas dystonia was more frequent in JP (43%) compared to YOPD (9%). Autonomic symptoms were twice as common in JP (42%) compared to YOPD (17%). However, bedside autonomic functions were abnormal in similar proportions and, like in PD, suggest involvement of parasympathetic nervous system. Cognitive dysfunction does occur but with no difference in severity between the two groups. The difference in number of patients between YOPD and JP groups makes statistical comparison of the occurrence of clinical features like dystonia and autonomic dysfunction difficult.(ABSTRACT TRUNCATED AT 250 WORDS)

Intermediate syndrome (IS) developed in 38 of 214 cases with organophosphorous compound poisoning (OPCP). Neck muscle weakness, motor cranial nerve palsy, respiratory muscle paralysis, proximal limb weakness were the chief neurological signs developed 16-120 hours after consumption of the insecticide. Two patients had pyramidal tract signs. Mean duration of IS was 9.26 (+/- 4.84) days. Electrophysiological study (EPS) was done in 21 patients. 18 patients showed decremental response to repetitive stimulation at 3Hz 5 pulses and absence of post tetanic facilitation. Motor conduction studies were abnormal in on (prolonged distal latency and reduced conduction velocity), 'F' responses were abnormal in, sensory nerve conduction was abnormal in two, and simple repetitive response were observed in 11 patients. 4 patients died. In IS neuromuscular junctional dysfunction is the predominant factor.

We report on a patient with acute intermittent porphyria (AIP) who, during treatment with hypertonic glucose, developed peripheral neuropathy. Once haeme-arginate was started, the progression of the neuropathy was attenuated. This suggests that hypertonic glucose may be inadequate in preventing the development of neuropathy in a patient with porphyria. However, haeme-arginate, if started early, can attenuate the progression of porphyric neuropathy.

Parkinson's disease (PD) is characterized mainly by a loss of nigrostriatal dopamine neurons. Thus far, the actual physiopathology of PD remains uncertain, although recent studies have found decreased activity of complex I, one of the enzymatic units of the mitochondrial respiratory chain, in various tissues of PD patients. Because most, if not all, of PD patients are treated chronically with levodopa, the precursor of dopamine, and because we have shown previously that catecholamines may alter mitochondrial respiration, we assessed the effects of chronic administration of levodopa on complex I activity in rat brain. We found that chronic administration of levodopa, at a dose used in PD patients, caused a significant reduction in complex I activity while it did not affect the activities of complex II, complex IV, and citrate synthase. Reduction in complex I activity correlated well with catecholamine innervation as the reduction was observed mainly in the striatum and substantia nigra and to a lesser extent in the frontal cortex but not in the cerebellum. Moreover, the levodopa-induced decrease of complex I activity was reversible since activities at 1, 3, and 7 days after the last injection showed a progressive return to control values. Incubation of whole brain mitochondria in vitro showed that both levodopa and dopamine inhibit complex I activity in a dose- and time-dependent manner. In contrast, other compounds such as homovanillic acid, 3,4-dihydroxyphenylacetic acid, and 3-O-methyl-dopa were minimally effective. Reduced glutathione, ascorbate, superoxide dismutase, and catalase prevented the effect of levodopa and dopamine on complex I. Various inhibitors of monoamine oxidase also prevented the effect of dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied visual (VEP) and brainstem auditory (BAEP) evoked potential changes in 23 patients with early onset Parkinson's disease (EOPD) to establish the nature of the changes as well as their relationship to dopaminergic (DA) and serotonergic (5-HT) disturbances, as determined by cerebrospinal fluid levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA). We also compared these parameters between the young onset (YOPD) and juvenile Parkinsonism (JP), the two subgroups of EOPD, to look for any possible differences between the two. In EOPD, the mean P100 latency of the VEP was significantly prolonged compared to controls (p < 0.001). However, within EOPD the evoked potential parameters were not significantly different between YOPD and the JP subgroups. P100 latency was abnormal in six patients (YOPD: 5, JP: 1) (26%). Six patients (YOPD: 3, JP:3) (26%) had abnormal BAEP. A significant negative correlation (r: -0.89, p < 1%) was observed between the P100 latency and CSF HVA levels. No correlation was observed between the BAEP interpeak latencies and either CSF HVA or 5-HIAA levels. This study suggests that VEP and BAEP abnormalities do occur in EOPD (in both YOPD and JP), and that the prolongation of P100 latency is secondary to DA deficiency as in PD. The cause of BAEP abnormalities is probably independent of DA and 5-HT disturbances. The only difference between EOPD and classical PD was the higher incidence of BAEP abnormalities in EOPD. There was no correlation between the VEP or BAEP changes to either the age at onset or duration of EOPD.