Publications by authors named "Saraswati Nashi"

27 Publications

  • Page 1 of 1

Comparison of The Carrier Frequency of Pathogenic Variants of DMD Gene in an Indian Cohort.

J Neuromuscul Dis 2021 Apr 2. Epub 2021 Apr 2.

Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India.

Background: Duchenne muscular dystrophy (DMD) is an X-linked disorder caused due to large deletions, duplications,and small pathogenic variants. This article compares the carrier frequency of different pathogenic variants in the DMD gene for the first time in an Indian cohort.

Methods: Ninety-one mothers of genetically confirmed DMD probands are included in this study. Pathogenic variants in the DMD gene in probands were detected by multiplex ligation-dependent probe amplification (MLPA) or next-generation sequencing (NGS). Maternal blood samples were evaluated either by MLPA or Sanger sequencing. The demographic and clinical details for screening of muscle weakness and cardiomyopathy were collected from the confirmed carriers.

Results: Out of 91 probands, large deletions and duplications were identified in 46 and 6 respectively, while 39 had small variants. Among the small variants, substitutions predicted to cause nonsense mutations were the most common (61.5%), followed by frameshift causing small insertion/deletions (25.6%) and splice affecting intronic variants (12.8%). Notably, 19 novel small variants predicted to be disease-causing were identified. Of the 91 mothers, 53 (58.7%) were confirmed to be carriers. Exonic deletions had a significantly lower carrier frequency of 47.8% as compared to small variants (64.1%). The mean age of the carriers at evaluation was 30 years. Among the carriers, two were symptomatic with onset in the 4th decade, manifesting with progressive proximal muscle weakness and dilated cardiomyopathy.

Conclusion: Carrier frequency of small pathogenic variants differs significantly from large deletions. Small pathogenic variants are more commonly inherited, whereas large deletions arise de novo.
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http://dx.doi.org/10.3233/JND-210658DOI Listing
April 2021

Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome.

J Hum Genet 2021 Mar 12. Epub 2021 Mar 12.

Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India.

Megaconial congenital muscular dystrophy (CMD)(OMIM #602541), related to CHKB mutation, is a rare autosomal recessive disorder. To date, only 35 confirmed patients are recorded. We present a detailed description of the clinical, histopathological, imaging, and genetic findings of five children from four Indian families. The children had moderate-to-severe autistic behavior, hand stereotypies, and global developmental delay mimicking atypical Rett syndrome. In addition, generalized hypotonia was a common initial finding. The progression of muscle weakness was variable, with two patients having a milder phenotype and three having a severe form. Interestingly, the majority did not attain sphincter control. Only patient 1 had classical ichthyotic skin changes. Muscle biopsy in two patients showed a myopathic pattern with characteristic peripherally placed enlarged mitochondria on modified Gomori trichrome stain and electron microscopy. Genetic analysis in these patients identified three novel null mutations in CHKB [c.1027dupA (p.Ser343LysfsTer86);c.224 + 1G > T (5' splice site); c.1123C > T (p.Gln375Ter)] and one reported missense mutation, c.581G > A (p.Arg194Gln), all in the homozygous state. Megaconial CMD, although rare, forms an important group with a complex phenotypic presentation and accounted for 5.5% of our genetically confirmed CMD patients. Atypical Rett syndrome-like presentation may be a clue towards CHKB-related disorder.
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http://dx.doi.org/10.1038/s10038-021-00913-1DOI Listing
March 2021

Recessive VAMP1 mutations associated with severe congenital myasthenic syndromes - A recognizable clinical phenotype.

Eur J Paediatr Neurol 2021 Mar 16;31:54-60. Epub 2021 Feb 16.

Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India. Electronic address:

Three unrelated girls, all born to consanguineous parents had respiratory distress, severe hypotonia at birth along with prominent fatigable muscle weakness and characteristic myopathic facies. In addition, patient 1 had fatigable ptosis, ophthalmoparesis and profound bulbar weakness and required nasogastric feeding from birth. A feeding gastrostomy was inserted at 9 months of age. She continued to have severe bulbar and limb weakness with dropped head at 5 years of age. Patient 2 and 3 did not have ocular signs at the time of initial presentation during infancy and at 2 years of age respectively. None of the patients attained independent walking. Patient 3, currently aged 16 years continues to be wheelchair bound and has only mild non-progressive bulbar weakness with normal cognitive development. Muscle biopsy in patient 1 and 3 showed predominant myopathic features admixed with small sized (atrophic/hypoplastic) fibres. Next generation sequencing confirmed the presence of a homozygous loss of function VAMP1 mutations in all three patients: A single nucleotide deletion resulting in frameshift: c.66delT (p.Gly23AlafsTer6) in patient 1 and nonsense mutations c.202C>T (pArg68Ter) and c.97C>T (p.Arg33Ter) in patient 2 and 3 respectively. Minimal but definite improvement in muscle power with pyridostigmine was reported in patients 1 and 2. This is the first report of VAMP1 mutations causing CMS from the Indian subcontinent, describing a clinically recognizable severe form of VAMP1-related CMS and highlighting the need for a strong index of suspicion for early genetic diagnosis of potentially treatable CMS phenotypes.
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http://dx.doi.org/10.1016/j.ejpn.2021.02.005DOI Listing
March 2021

Altered REM sleep architecture in patients with Myotonic dystrophy type 1: is related to sleep apnea?

Sleep Med 2021 Mar 1;79:48-54. Epub 2021 Jan 1.

Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India. Electronic address:

Objective: To determine the sleep architecture and sleep respiratory abnormalities and to correlate with sleep symptoms in patients with Myotonic dystrophy type 1 (DM1).

Methods: We recruited a cohort of genetically confirmed patients with DM1, who attended the Neuromuscular clinic between July 2016 and December 2019. Clinical, sleep and whole night polysomnography data were collected. The analysis of sleep architecture, sleep respiratory parameters and comparison with healthy controls (HC) was performed in our sleep laboratory.

Results: A total of 59 patients with DM1 underwent sleep evaluation. Hypersomnolence in 42 (77.8%), ESS>10 in 23 (39%), and PSQI>5 in 18 (30.5%) were found in patients with DM1. Thirty-one (68.89%) patients with DM1 and 22 (95.65%) HC had more than 4-h of total sleep time (TST). More than 4 h of TST was taken to compare respiratory and sleep architecture parameters. Patients with DM1 had reduced sleep efficiency, reduced N2 sleep, and increase in N1 sleep, wake index, stage shift index, nocturnal sleep-onset REM periods compared to HC. AHI>15 was found in 16 (51.61%) DM1 and in 3 HC (13.64%). AHI had positive correlation with BMI, but not with age, ESS or disease progression (MIRS). All DM1 with AHI>15; 8(80%) and 1(33.33%) in AHI5to15, and AHI<5 groups, respectively had hypersomnolence.

Conclusion: In this first study on Indian cohort, daytime hypersomnolence, poor nocturnal sleep quality, sleep architecture irregularities are identified to be common in patients with DM1. These abnormalities may be explained by sleep-related breathing disorders that are highly prevalent in these patients.
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http://dx.doi.org/10.1016/j.sleep.2020.12.036DOI Listing
March 2021

Whole-exome analyses of congenital muscular dystrophy and congenital myopathy patients from India reveal a wide spectrum of known and novel mutations.

Eur J Neurol 2021 Mar 26;28(3):992-1003. Epub 2020 Nov 26.

National Institute of Biomedical Genomics, Kalyani, India.

Background And Purpose: Congenital muscular dystrophies (CMDs) and congenital myopathies (CMs) are a group of genetically and clinically heterogeneous degenerative primary muscle disorders with onset at birth or during infancy. Due to vast heterogeneity, clinical examination and protein-based analyses often fail to identify the genetic causes of these diseases. The aim of this study was to genetically diagnose a cohort of 36 difficult-to-diagnose CMD and CM cases of Indian origin using next-generation sequencing methods.

Methods: Whole-exome sequencing (WES) was performed to identify pathogenic mutations in previously reported CMD and CM-related genes using variant calling and stringent variant filtration process. Subsequently, in silico homology modelling and molecular dynamics simulations (MDS) studies were undertaken for a number of novel and missense variants.

Results: A total of 33 and 21 rare and deleterious mutations were identified in 28 genes previously reported in CMD and CM based on OMIM, ClinVar and Orphanet, respectively. We could accurately diagnose 54% patients (n = 12/22) in the CMD group and 35% patients (n = 5/14) in the CM group. Furthermore, MDS studies for mutations located in LMNA, LAMA2 and RYR1 suggest that the wild-type proteins are more stable than their mutant counterparts, implying a potential mechanism of pathogenesis.

Conclusion: The WES findings led us to identify reported as well as novel variants for the first time in Indian patients with CMD and CM. This allowed us to achieve an accurate genetic diagnosis, which was difficult using conventional diagnostic tools. Transferring these WES findings to clinical practice will help guide clinical care of the affected patients and inform genetic counselling.
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http://dx.doi.org/10.1111/ene.14616DOI Listing
March 2021

Chitotriosidase, a biomarker of amyotrophic lateral sclerosis, accentuates neurodegeneration in spinal motor neurons through neuroinflammation.

J Neuroinflammation 2020 Aug 6;17(1):232. Epub 2020 Aug 6.

Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru, 560 029, India.

Background: Cerebrospinal fluid from amyotrophic lateral sclerosis patients (ALS-CSF) induces neurodegenerative changes in motor neurons and gliosis in sporadic ALS models. Search for identification of toxic factor(s) in CSF revealed an enhancement in the level and enzyme activity of chitotriosidase (CHIT-1). Here, we have investigated its upregulation in a large cohort of samples and more importantly its role in ALS pathogenesis in a rat model.

Methods: CHIT-1 level in CSF samples from ALS (n = 158), non-ALS (n = 12) and normal (n = 48) subjects were measured using ELISA. Enzyme activity was also assessed (ALS, n = 56; non-ALS, n = 10 and normal-CSF, n = 45). Recombinant CHIT-1 was intrathecally injected into Wistar rat neonates. Lumbar spinal cord sections were stained for Iba1, glial fibrillary acidic protein and choline acetyl transferase to identify microglia, astrocytes and motor neurons respectively after 48 h of injection. Levels of tumour necrosis factor-α and interleukin-6 were measured by ELISA.

Findings: CHIT-1 level in ALS-CSF samples was increased by 20-fold and it can distinguish ALS patients with a sensitivity of 87% and specificity of 83.3% at a cut off level of 1405.43 pg/ml. Enzyme activity of CHIT-1 was also 15-fold higher in ALS-CSF and has a sensitivity of 80.4% and specificity of 80% at cut off value of 0.1077989 μmol/μl/min. Combining CHIT-1 level and activity together gave a positive predictive value of 97.78% and negative predictive value of 100%. Administration of CHIT-1 increased microglial numbers and astrogliosis in the ventral horn with a concomitant increase in the levels of pro-inflammatory cytokines. Amoeboid-shaped microglial and astroglial cells were also present around the central canal. CHIT-1 administration also resulted in the reduction of motor neurons.

Conclusions: CHIT-1, an early diagnostic biomarker of sporadic ALS, activates glia priming them to attain a toxic phenotype resulting in neuroinflammation leading to motor neuronal death.
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http://dx.doi.org/10.1186/s12974-020-01909-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412641PMC
August 2020

Appropriately Selected Nerve in Suspected Leprous Neuropathy Yields High Positive Results for DNA by Polymerase Chain Reaction Method.

Am J Trop Med Hyg 2020 07 9;103(1):209-213. Epub 2020 Apr 9.

Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India.

Identification of DNA by polymerase chain reaction (PCR) is a reliable and an affordable method to confirm leprosy. DNA from 87 nerve samples (61 from paraffin blocks and 26 fresh samples) was extracted. DNA was amplified by PCR from 80/87 (92%) specimens. Patients were seen over a period of 11 years (2007-2019), and leprosy was diagnosed based on clinical and characteristic histopathology findings. The clinical diagnostic possibilities were as follows: leprous neuropathy in 73/80 (91.3%), mononeuritis multiplex of unknown etiology in four (5.0%), vasculitic neuropathy in two (2.5%), and distal symmetric sensory motor neuropathy in one (1.3%). The biopsied nerves were as follows: superficial radial = 34 (42.6%), dorsal cutaneous branch of ulnar = 19 (23.8%), sural = 18 (22.5%), and superficial peroneal = 9 (11.3%), and corresponding neurological deficits were recorded in 77 (96.3%) cases. The histopathological diagnoses in total group were as follows: (borderline tuberculoid (BT) = 52, tuberculoid (TT) = 8, borderline lepromatous (BL) = 8, borderline borderline (BB) = 3, nonspecific inflammation = 3, healed/fibrosed = 4, and axonopathy = 2). Acid fast bacilli (AFB) was demonstrated in 11 (13.7%) samples. For comparison, 31 clinically and histopathologically defined non-leprous disease control nerves (inherited neuropathy = 20, vasculitis = 8, and nutritional neuropathy = 3) subjected to PCR were negative for DNA. In most instances, there are multiple thickened peripheral nerves in suspected cases of leprosy, but neurological deficits pertaining to the thickened nerve are not as widespread. The current findings emphasize the importance of selecting the most appropriate nerve for biopsy to obtain a positive PCR result. We infer that clinical, histopathological, and PCR tests complement each other to help achieve a definitive diagnosis of leprosy particularly in pure neuritic leprosy and in leprous neuropathy with negative skin smears/biopsy.
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http://dx.doi.org/10.4269/ajtmh.19-0746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356419PMC
July 2020

Lived Experience of Spouses of Persons with Motor Neuron Disease: Preliminary Findings through Interpretative Phenomenological Analysis.

Indian J Palliat Care 2020 Jan-Mar;26(1):60-65. Epub 2020 Jan 28.

Department of Psychiatric Social Work, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India.

Introduction: Motor neuron disease (MND) is a progressive neuromuscular disorder that can have significant and debilitating impact on the affected patient and families. Spouses are the primary carers for persons with MND in India, and the life of the person with MND and their spouse is never the same after the diagnosis.

Aim: The objective was to explore the lived experience of spouses of persons diagnosed with MND.

Methods: A qualitative exploratory study with three-point interviews was conducted with spouse caregivers of two persons diagnosed with MND who were receiving treatment from a national tertiary referral care center for neurological disorders. All the patients were diagnosed as definite MND according to the modified El Escorial criteria. With the spouses, in-depth interviews were conducted at their home, lasting on an average of 1 hour using a semi-structured interview guide (prompts). Interpretative phenomenological analysis was used to derive themes from the interviews.

Results: The major themes emerged from the analysis were meaning of MND which contained the subthemes of , relationship with the subthemes of ; adaptation with the subthemes of and life without the loved one.

Conclusion: The changes in the lives of spouses and in strategies for caring the partner with deterioration of symptoms in the illness trajectory are explained in this study. The palliative approach in the management of MND has to take into account, the experiences and needs of carers since care happens at home.
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http://dx.doi.org/10.4103/IJPC.IJPC_123_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017690PMC
January 2020

C9orf72 hexanucleotide repeat expansion in Indian patients with ALS: a common founder and its geographical predilection.

Neurobiol Aging 2020 04 3;88:156.e1-156.e9. Epub 2020 Jan 3.

Genomics and Molecular Medicine Division, CSIR - Institute of Genomics and Integrative Biology, New Delhi, India. Electronic address:

Hexanucleotide repeat expansion in C9orf72 is defined as a major causative factor for familial amyotrophic lateral sclerosis (ALS). The mutation frequency varies dramatically among populations of different ethnicity; however, in most cases, C9orf72 mutant has been described on a common founder haplotype. We assessed its frequency in a study cohort involving 593 clinically and electrophysiologically defined ALS cases. We also investigated the presence of reported Finnish haplotype among the mutation carriers. The identified common haplotype region was further screened in 192 (carrying 2-6 G4C2 repeats) and 96 (≥7 repeats) control chromosomes. The G4C2 expansion was observed in 3.2% (19/593) of total cases where 9/19 (47.4%) positive cases belonged to the eastern region of India. Haplotype analysis revealed 11 G4C2-Ex carriers shared the common haplotype (haplo-A) background spanning a region of ∼90 kbp (rs895021-rs11789520) including rs3849942 (a well-known global at-risk loci with T allele for G4C2 expansion). The other 3 G4C2-Ex cases had a different haplotype (haplo-B) with core difference from haplo-A at G4C2-Ex flanking 31 kbp region between rs3849942 and rs11789520 SNPs (allele 'C' of rs3849942 which is a nonrisk allele). Out of other five G4C2-cases, four carried the risk allele T of rs3849942 while one harbored the non-risk allele. This study establishes the prevalence of C9orf72 expansion in Indian ALS cases providing further evidence for geographical predilection. The global core risk haplotype predominated C9orf72 expansion-positive ALS cases, yet the existence of a different haplotype suggests a second lineage (haplo B), which may have been derived from the Finnish core haplotype or may imply a unique haplotype among Asians. The association of risk haplotype with normal intermediate C9orf72 alleles reinforced its role in conferring instability to the C9orf72-G4C2 region. We thus present an effective support to interpret future burden of ALS cases in India.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.12.024DOI Listing
April 2020

Evidence for Drug Resistance in a Large Cohort of Leprous Neuropathy Patients from India.

Am J Trop Med Hyg 2020 03;102(3):547-552

Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India.

Resistance to anti-leprosy drugs is on the rise. Several studies have documented resistance to rifampicin, dapsone, and ofloxacin in patients with leprosy. We looked for point mutations within the folP1, rpoB, and gyrA gene regions of the genome predominantly in the neural form of leprosy. DNA samples from 77 nerve tissue samples were polymerase chain reaction (PCR)-amplified for DNA and sequenced for drug resistance-determining regions of genes rpoB, folP1, and gyrA. The mean age at presentation and onset was 38.2 ± 13.4 (range 14-71) years and 34.9 ± 12.6 years (range 10-63) years, respectively. The majority had borderline tuberculoid leprosy (53 [68.8%]). Mutations associated with resistance were identified in 6/77 (7.8%) specimens. Mutations seen were those associated with resistance to rifampicin, ofloxacin, and dapsone. All the six patients were drug-naive. The clinical and pathological manifestations in this group did not differ from the drug-sensitive group. This study highlights the occurrence of resistance to the standard multidrug therapy and ofloxacin in leprosy. Among the entire cohort, 1/77 (1.3%) showed resistance to rifampicin, 2/77 (2.6%) to dapsone, and 5/77 (6.4%) to ofloxacin. Six new patients showing infection by mutant strains indicated the emergence of primary resistance. Resistance to ofloxacin could be due to frequent use of quinolones for many bacterial infections. The results of the study indicate the need for development of a robust and strict surveillance system for detecting drug resistance in leprosy in India.
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http://dx.doi.org/10.4269/ajtmh.19-0390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056437PMC
March 2020

GNE myopathy - A cross-sectional study on spatio-temporal gait characteristics.

Neuromuscul Disord 2019 12 8;29(12):961-967. Epub 2019 Nov 8.

Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore 560029, India.

GNE myopathy is a rare, predominantly distal myopathy, involving mainly the lower limbs and presenting with gait disturbances. In this cross-sectional study gait evaluation of 23 (14 men) genetically confirmed GNE myopathy patients was done using Instrumented walkway analysis (GAITRite®) along with video gait capture. We recorded the topographical pattern of muscles involvement in lower limbs and correlated Functional Ambulation Profile-FAP and Medical Research council-MRC grading of lower limb scores with duration of illness. Early foot flat, foot drop gait with wider out-toed stance and higher perturbations with increased pressure at heel and decreased arm swing were noted. Muscle topography showed predominant weakness in ankle dorsi-flexors, flexor hallucis longus, extensor hallucis longus, hip adductors and knee flexors with stark sparing of quadriceps and relative sparing of hip- abductors, extensors, flexors and ankle plantar-flexors. Gait parameters in women were significantly more affected than men (p < 0.05) for the same duration of illness. FAP score and MRC grading of lower limb scores correlated significantly with duration of illness (p < 0.05). We observed that ankle dorsiflexors were affected earliest with sparing of quadriceps muscles in these patients.
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http://dx.doi.org/10.1016/j.nmd.2019.11.003DOI Listing
December 2019

Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant.

Eur J Hum Genet 2020 03 16;28(3):373-377. Epub 2019 Sep 16.

Department of Neuropediatrics and Muscle Disorders, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany.

Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of disorders caused by mutations which lead to impaired neuromuscular transmission. SLC25A1 encodes a mitochondrial citrate carrier, associated mainly with the severe neurometabolic disease combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). We previously reported a single family with a homozygous missense variant in SLC25A1 with a phenotype restricted to relatively mild CMS with intellectual disability, but to date no additional cases of this CMS subtype had been reported. Here, we performed whole exome sequencing (WES) in three additional and unrelated families presenting with CMS and mild intellectual disability to identify the underlying causative gene. The WES analysis revealed the presence of a homozygous c.740G>A; p.(Arg247Gln) missense SLC25A1 variant, the same SLC25A1 variant as identified in the original family with this phenotype. Electron microscopy of muscle from two cases revealed enlarged and accumulated mitochondria. Haplotype analysis performed in two unrelated families suggested that this variant is a result of recurrent mutation and not a founder effect. This suggests that p.(Arg247Gln) is associated with a relatively mild CMS phenotype with subtle mitochondrial abnormalities, while other variants in this gene cause more severe neurometabolic disease. In conclusion, the p.(Arg247Gln) SLC25A1 variant should be considered in patients presenting with a presynaptic CMS phenotype, particularly with accompanying intellectual disability.
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http://dx.doi.org/10.1038/s41431-019-0506-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029005PMC
March 2020

Family Caregivers' Experiences with Dying and Bereavement of Individuals with Motor Neuron Disease in India.

J Soc Work End Life Palliat Care 2019 Apr-Jun;15(2-3):111-125. Epub 2019 Aug 2.

Department of Neurology, National Institute of Mental Health and Neuro Sciences , Bangalore , India.

Motor neuron disease (MND) is a progressive neurodegenerative disease. Ideal management plan in MND includes palliative care initiated from the time of diagnosis. At present, most of the neurodegenerative conditions are cared for at home. Neuropalliative care is an emerging concept in India and social workers are integral team members in this process. The primary aims of the study were to explore (a) the caregivers' experiences of the end-of-life stage, and (b) the sources of support for individuals and their caregivers with MND at the end-of-life stage. In-depth interviews were conducted with seven bereaved caregivers of individuals with MND from a national tertiary referral care center for neuropsychiatry in South India. Interviews were conducted either in person or by telephone. Thematic analysis was done using the constant comparative method. Major themes derived from the interviews were: (1) Transition from person to patient, (2) support, (3) death, and (4) impact on the caregivers. Mapping of themes identified "Support received during advanced stages" as the central theme influencing all other themes. The need for a care manager seems evident and is a role that can be effectively fulfilled by the care teams' social workers.
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http://dx.doi.org/10.1080/15524256.2019.1645081DOI Listing
February 2020

Mutation pattern in 606 Duchenne muscular dystrophy children with a comparison between familial and non-familial forms: a study in an Indian large single-center cohort.

J Neurol 2019 Sep 28;266(9):2177-2185. Epub 2019 May 28.

Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India.

Introduction: Duchenne muscular dystrophy (DMD) is induced by a wide spectrum of mutations such as exon deletions, duplications and small mutations in the dystrophin gene. This is the first study on the mutational spectrum in a cohort of DMD children from India, with an emphasis to compare the mutations in familial and sporadic forms.

Results: Multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS) identified 525 and 70 cases of DMD, respectively, while 11 cases showed absent dystrophin staining with no mutations detected. Families with two or more affected males contributed to 12% of the entire cohort. The mutations comprised of exonic deletions in 492/606 (81.2%), duplications in 33/606 (5.4%) and small mutations (point mutations and INDELs) in 70/606 (11.5%) cases. MLPA identified significantly more larger mutations in sporadic (88.2%) than in familial cases (75.3%). The mutations in NGS were: [nonsense = 40 (57.1%); frameshift = 17 (24.3%); splice variant = 12 (17.1%)]. Nonsense mutations were more common in familial than in sporadic cases: 17.8% vs 10.7%. The familial group reported an earlier onset of disease (2.8 ± 1.7 years) as compared to sporadic cases (3.8 ± 1.6 years).

Conclusion: MLPA could identify mutations in a high percentage of our DMD children. The preponderance of small mutations was noted to be distinctly higher in the familial group. Intriguingly, the familial form of DMD formed a small percentage of the entire cohort. The reasons could be increasing awareness among parents and physicians with early identification of DMD cases, genetic counseling and prenatal testing.
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http://dx.doi.org/10.1007/s00415-019-09380-3DOI Listing
September 2019

Brain and Spinal Cord Lesions in Leprosy: A Magnetic Resonance Imaging-Based Study.

Am J Trop Med Hyg 2019 04;100(4):921-931

Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India.

Neurotropism and infiltration by of peripheral nerves causing neuropathy are well established, but reports of central nervous system (CNS) damage are exceptional. We report CNS magnetic resonance imaging (MRI) abnormalities of the brain and spinal cord as well as lesions in nerve roots and plexus in leprosy patients. Eight patients aged between 17 and 41 years underwent detailed clinical, histopathological, and MRI evaluation. All had prominent sensory-motor deficits with hypopigmented and hypo/anesthetic skin patches and thickened peripheral nerves. All demonstrated DNA in affected peripheral nerve tissue. All received multidrug therapy (MDT). Two patients had brainstem lesions with enhancing facial nuclei and nerves, and one patient had a lesion in the nucleus ambiguus. Two patients had enhancing spinal cord lesions. Follow-up MRI performed in four cases showed resolution of brainstem and cord lesions after starting on MDT. Thickened brachial and lumbosacral plexus nerves were observed in six and two patients, respectively, which partially resolved on follow-up MRI in the two cases who had reimaging. The site and side of the MRI lesions corresponded with the location and side of neurological deficits. This precise clinico-radiological correlation of proximal lesions could be explained by an immune reaction in the gray matter corresponding to the involved peripheral nerves, retrograde axonal and gray matter changes, or infection of the CNS and plexus by lepra bacilli. Further study of the CNS in patients with leprous neuropathy is needed to establish the exact nature of these CNS MRI findings.
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http://dx.doi.org/10.4269/ajtmh.17-0945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447108PMC
April 2019

Caregiver burden and quality of life of patients with amyotrophic lateral sclerosis in India.

Amyotroph Lateral Scler Frontotemporal Degener 2018 11 24;19(7-8):606-610. Epub 2018 Jul 24.

b Department of Neurology , and.

Aim: Amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND) is a progressive degenerative disorder that can have significant debilitating impact. Few studies have explored living with ALS in the developing countries. The study aims to understand the relationship between functionality, quality of life, and caregiver burden in ALS in the sociocultural scenario in India.

Methods: A cross-sectional descriptive study was performed among 30 persons with ALS and their caregivers (men = 19; women = 11) receiving treatment from a national quaternary referral care center for Neurological disorders in Southern India. All patients were diagnosed as Definite ALS according to El Escorial Criteria. The mean age at onset of illness was 51.6 years and mean duration of illness at presenting to hospital was 11 months. The caregivers were spouses, offspring, or siblings. Variables were assessed with ALS Functional Rating Scale Revised (ALSFRS- R), ALS Specific Quality of Life Scale (ALSSQOL-R) with the patients and Zarit Burden Interview (ZBI) with the caregiver.

Results: Functionality and quality of life negatively correlated with caregiver burden. Caregiver burden was negatively associated with "negative emotional state" and "interaction of the patient with family and environment", sub domains in ALSQOL scale. No significant association was noted between caregiver burden and intimacy, religiosity as well as physical symptoms domains of quality of life.

Conclusion: ALS patients and caregivers would benefit from structured care plan that is sensitive to the impact of the illness on the specific domains of quality of life as well as the deterioration in the neurological functioning.
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http://dx.doi.org/10.1080/21678421.2018.1482353DOI Listing
November 2018

Hirayama disease/cervical flexion-induced myelopathy progressing to spastic paraparesis: A report on three cases with literature review.

Neurol India 2018 Jul-Aug;66(4):1094-1099

Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.

Hirayama disease (HD)/cervical flexion-induced myelopathy (CFIM) is a lower motor neuron disease conventionally affecting a single upper extremity. We describe three men progressing after a long stable period to develop severe spastic paraparesis and bladder disturbances as a protracted implication of HD. The age at onset was 20, 24, and 15 years, while the age at presentation was 27, 41, and 57 years, respectively. The second phase of disease progression occurred after 4, 13, and 28 years of stationary period. All had CFIM with characteristic magnetic resonance imaging features as observed during progressive stages. The anterior dural shift extended variably from C4 to D4 levels with a median value of 5 mm and was maximum at C6 to C7 levels, pushing the cord anteriorly causing compression. This study emphasizes the need to recognize this unusual subgroup of HD and mandates long-term follow-up with timely intervention in arresting the progression/improving the deficits.
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http://dx.doi.org/10.4103/0028-3886.236966DOI Listing
September 2019

Anti-AChR, MuSK, and LRP4 antibodies coexistence: A rare and distinct subtype of myasthenia gravis from Indian subcontinent.

Clin Chim Acta 2018 Nov 10;486:34-35. Epub 2018 Jul 10.

Department of Neuromicrobiology, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore, 560029, India. Electronic address:

Background: Myasthenia gravis is B-cell mediated autoimmune disease and is associated with antibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) and lipoprotein-related protein 4 (LRP4) in the postsynaptic membrane at the neuromuscular junction. There are few studies on the concurrent presence of two positive antibodies in the sera of patients with myasthenia gravis.

Case Description: A 32-year male admitted to the hospital with progressive neuromuscular weakness. He was diagnosed with Myasthenia gravis disorder mimicking Amyotrophic Lateral Sclerosis. We herein report a rare co-existence of three antibodies (anti-AChR, MuSK, and LRP4 antibodies) in the patient's serum.

Conclusion: We present a detailed clinical and laboratory analysis of the patient. This case report will emphasize the importance of evaluating anti-MuSK and anti-LRP4 antibodies even in patients with anti-AChR antibodies.
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http://dx.doi.org/10.1016/j.cca.2018.07.011DOI Listing
November 2018

Recessive variants of MuSK are associated with late onset CMS and predominant limb girdle weakness.

Am J Med Genet A 2018 07 28;176(7):1594-1601. Epub 2018 Apr 28.

Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.

Congenital myasthenic syndrome (CMS) is a heterogeneous disorder that causes fatigable muscle weakness. CMS has been associated with variants in the MuSK gene and, to date, 16 patients have been reported. MuSK-CMS patients present a different phenotypic pattern of limb girdle weakness. Here, we describe four additional patients and discuss the phenotypic and clinical relationship with those previously reported. Two novel damaging missense variants are described: c.1742T > A; p.I581N found in homozygosis, and c.1634T > C; p.L545P found in compound heterozygosis with p.R166*. The reported patients had predominant limb girdle weakness with symptom onset at 12, 17, 18, and 30 years of age, and the majority exhibited a good clinical response to Salbutamol therapy, but not to esterase inhibitors. Meta-analysis including previously reported variants revealed an increased likelihood of a severe, respiratory phenotype with null alleles. Missense variants exclusively affecting the kinase domain, but not the catalytic site, are associated with late onset. These data refine the phenotype associated with MuSK-related CMS.
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http://dx.doi.org/10.1002/ajmg.a.38707DOI Listing
July 2018

Case Report: Neurobrucellosis with Plastered Spinal Arachnoiditis: A Magnetic Resonance Imaging-Based Report.

Am J Trop Med Hyg 2018 03 11;98(3):800-802. Epub 2018 Jan 11.

Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India.

Diffuse spinal arachnoiditis in neurobrucellosis is a rare manifestation. We report a boy aged 17, presenting with hearing impairment and recurrent vomiting for 18 months, weight loss for 12 months, dysphagia, dysarthria, hypophonia for 6 months, and gait unsteadiness for 5 months. He had bilateral 5th (motor) to 12th cranial nerve palsy, wasting and weakness of limbs, fasciculations, absent tendon reflexes, and positive Babinski's sign. Cerebrospinal fluid (CSF) showed raised protein and pleocytosis. Magnetic resonance imaging (MRI) showed extensive enhancing exudates in cisterns and post-contrast enhancement of bilateral 5th, 6th, 7th, and 8th nerves. Spine showed clumping with contrast enhancement of the cauda equina roots and encasement of the cord with exudates. Serum and CSF were positive for anti- antibodies. He showed significant improvement with antibiotics. At 4 months follow-up, MRI demonstrated near complete resolution of cranial and spinal arachnoiditis. It is important to recognize such rare atypical presentations of neurobrucellosis.
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http://dx.doi.org/10.4269/ajtmh.17-0828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930921PMC
March 2018

Natural history of a cohort of Duchenne muscular dystrophy children seen between 1998 and 2014: An observational study from South India.

Neurol India 2018 Jan-Feb;66(1):77-82

Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.

Background: Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy. There are no large studies describing its natural course from India.

Materials And Methods: Immunohistochemically/genetically confirmed DMD patients diagnosed between 1998 and 2014 were ambispectively included. The main aim was to study the natural course of motor milestones, i.e., age at onset of wheelchair status, bedbound state, and age at death, which were considered as primary outcome measures. We also correlated the DMD genotype with the motor milestones and other phenotypic features.

Results: A total of 500 DMD patients were included and 275 participated in the study. The mean age at symptom onset was 3.7 ± 1.9 years, mean age at presentation was 8.1 ± 2.5 years, and mean duration of illness was 4.4 ± 2.6 years. On following them over 15 years, 155 (56.4%) had attained at least one of the primary outcome measures. Wheelchair status was attained in 124 (45.1%) [mean age: 10.4 ± 1.6 years] and bedbound state in 24 (8.7%; mean age: 11.8 ± 2.2 years) patients. Seven patients (2.6%) died during the follow-up period (mean age: 15.2 ± 2.4 years). There was no significant impact of the genotypic or phenotypic features on the primary outcome.

Conclusion: The pattern of major motor milestones (primary outcome measures) in this large cohort is comparable with that of the Western population despite variability in medical care. The genotypic pattern was also similar to other large studies, which suggests that DMD is a more homogeneous disorder with limited ethnic variability in its geno-phenotypic expression.
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http://dx.doi.org/10.4103/0028-3886.222881DOI Listing
September 2019

CARASIL families from India with 3 novel null mutations in the gene.

Neurology 2017 12 3;89(23):2392-2394. Epub 2017 Nov 3.

From the National Institute of Mental Health and Neurosciences (V.P.-K., S.T., S.V., M.B., C.P., S.D., J.S., S.N., K.P., A.N.), Bangalore, India; and Graduate School of Health Sciences (H.N.) and Clinical Neuroscience Branch, Brain Research Institute (H.N., O.O., M.U.), Niigata University, Niigata, Japan.

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http://dx.doi.org/10.1212/WNL.0000000000004710DOI Listing
December 2017

Intrafamilial phenotypic variations in familial cases of cervical flexion induced myelopathy/Hirayama disease.

Amyotroph Lateral Scler Frontotemporal Degener 2018 02 22;19(1-2):38-49. Epub 2017 Sep 22.

a Department of Neurology , National Institute of Mental Health and Neurosciences , Bengaluru , India.

Hirayama disease is generally considered to be a sporadic disorder, except for a few reports of familial occurrence. In this study, we describe eight patients from four families with cervical flexion induced myelopathy (CFIM)/Hirayama disease (HD) and intra-familial phenotypic variations. All underwent clinical and electrophysiological evaluation, while seven of them had contrast MR imaging of cervical spine in flexion. There was significant intra-familial variability: distal bimelic form in four patients, classical monomelic form in three and proximo-distal form in one. Irrespective of the clinical phenotype, MRI showed characteristic dynamic changes of posterior dural detachment with prominent epidural enhancement extending variably from C3 vertebral level to dorsal spine in six patients. One patient with 28 years of illness, had only lower cervical cord atrophy without dynamic changes while another patient demonstrated forward dural displacement with epidural enhancement even after 38 years of disease duration.
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http://dx.doi.org/10.1080/21678421.2017.1374977DOI Listing
February 2018

Fatty acid oxidation defects presenting as primary myopathy and prominent dropped head syndrome.

Neuromuscul Disord 2017 Nov 24;27(11):986-996. Epub 2017 Aug 24.

Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore 560029, India. Electronic address:

Fatty acid oxidation disorders presenting as primary myopathy is relatively rare and also diagnostically challenging. Its association with "dropped head syndrome" is reported till date in single cases of carnitine deficiency and multiple acyl CoA dehydrogenase deficiency (MADD).We studied nineteen cases of primary progressive myopathy confirmed to have fatty acid oxidation defects by Tandem Mass Spectrometry. The detailed clinical, muscle histopathology, tandem mass spectrometry and muscle magnetic resonance imaging (MRI) findings are presented here. The fatty acid oxidation defects identified were sub-grouped into: medium chain acyl CoA dehydrogenase deficiency (MCAD) = 4; very long chain acyl CoA dehydrogenase deficiency (VLCAD) = 7; MADD = 6; carnitine uptake defect and short chain acyl CoA dehydrogenase (SCAD) deficiency = 1 each. The age at onset for MCAD, VLCAD and MADD ranged from 11.5 to 15, 8 to 17 and 10 to 38 years respectively. The patients with carnitine uptake defect and SCAD had onset at 29 and 15 years of age. The dominant symptoms were exertion induced myalgia and progressive proximal limb weakness in all. 12/19 (63.2%) had classical dropped head syndrome. Ptosis and bulbar weakness were present in a few cases. This study emphasizes that fatty acid oxidation disorders presenting as primary myopathy are probably under diagnosed and should be entertained in the differential diagnosis of acute or chronic limb girdle syndromes. Hitherto, unreported we describe "dropped head syndrome" as a prominent phenomenon in MCAD and VLCAD. The presence of ptosis and bulbar weakness in fatty acid oxidation defects expands the clinical spectrum.
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http://dx.doi.org/10.1016/j.nmd.2017.08.004DOI Listing
November 2017

Comparing sleep profiles between patients with juvenile myoclonic epilepsy and symptomatic partial epilepsy: Sleep questionnaire-based study.

Epilepsy Behav 2017 01 22;66:34-38. Epub 2016 Dec 22.

Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), India.

Objectives: Patients with epilepsy commonly report excessive daytime sleepiness and daytime fatigue, which may be attributed to the direct effect of seizures, a side effect of antiepileptic drugs or a combination of the two. The aim of the study was to compare sleep profiles in patients with juvenile myoclonic epilepsy (JME) and symptomatic partial epilepsy (PE) in drug naïve and treated patients using standardized sleep questionnaires.

Methods: Three study groups: - 1) juvenile myoclonic epilepsy (N=40) [drug naïve (N=20); On sodium valproate (SVA) (N=20)]; 2) symptomatic partial epilepsy (N=40) [drug naïve (N=20); On carbamazepine (CBZ) (N=20)]; 3) healthy controls (N=40) completed 3 standardized sleep questionnaires - Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, and NIMHANS Comprehensive Sleep Disorders Questionnaire. Scores were compared using t-test and Chi-squared tests (P≤0.005).

Results: The mean PSQI scores as well as the proportion of subjects with abnormal PSQI scores were higher in patients with JME and PE compared to controls. Although the mean ESS scores were comparable between patients with epilepsy and controls, the percentage of patients with partial epilepsy having abnormal ESS scores was higher. No significant differences were present between drug naïve and treatment monotherapy groups. Excessive daytime somnolence was reported more often by patients with JME compared to patients with partial epilepsy and controls.

Conclusion: This study found that patients with epilepsy have a higher prevalence of poor sleep quality compared to controls. Moreover, a significantly higher percentage of patients with partial epilepsy had higher ESS scores compared to healthy controls. However, there was no difference between ESS and PSQI scores between drug naïve and treated patients with JME or PE.

Significance: Poor sleep quality is more prevalent in patients with epilepsy irrespective of the use of antiepileptic medications. Excessive daytime somnolence is more commonly seen in patients with partial epilepsy when compared to the general population.
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http://dx.doi.org/10.1016/j.yebeh.2016.10.009DOI Listing
January 2017