Cost-effective Whole Exome Sequencing discovers pathogenic variant causing Neurofibromatosis type 1 in a family from Jammu and Kashmir, India.

Neurofibromatosis type 1 (NF1) is a multisystemic hereditary disorder associated with an increased risk of benign and malignant tumor formation predominantly on the skin, bone, and peripheral nervous system. It has been reported that out of all the NF1 cases, more than 95% cases develop the disease due to heterozygous loss-of-function variants in Neurofibromin (NF1) gene. However, identification of NF1 causative variants by presently recommended method of gene-targeted Sanger sequencing is challenging and cost-intensive due to the large size of the NF1gene with 60 exons spanning about 350 kb. Further, conducting the genetic studies is difficult in low resource regions and among families with the limited financial capabilities, restricting them from availing diagnostic as well as proper disease management measures. Here, we studied a three-generation family from Jammu and Kashmir state in India, with multiple affected family members showing clinical indications of NF1. We combinedly used two applications, Whole Exome Sequencing (WES) and Sanger sequencing, for this study and discovered a nonsense variant NM_000267.3:c.2041C>T (NP_000258.1:p.Arg681Ter*) in exon 18 of NF1 gene in a cost effective manner. In silico analyses further substantiated the pathogenicity of this novel variant. The study also emphasized on the role of Next Generation Sequencing (NGS) as a cost-effective method for the discovery of pathogenic variants in disorders with known phenotypes found in large sized candidate genes. The current study is the first study based on the genetic characterization of NF1 from Jammu and Kashmir-India, highlighting the importance of the described methodology adopted for the identification and understanding of the disease in low resource region. The early diagnosis of genetic disorders would open the door to appropriate genetic counseling, reducing the disease burden in the affected families and the general population at large.

Evaluation of one-year effectiveness of clobazam as an add-on therapy to anticonvulsant monotherapy in participants with epilepsy having uncontrolled seizure episodes: An Indian experience.

OBJECTIVES: To prospectively study the effectiveness and safety of clobazam as an add-on therapy in patients with epilepsy whose seizures are not adequately controlled with antiseizure medicine (ASM) monotherapy. METHODS: We conducted a prospective, observational study at 28 neurology outpatient clinics in India from June 2017 to October 2019. Consecutive patients with epilepsy (older than 3 years) with inadequate seizure control with ASM monotherapy were initiated on clobazam. Patients were followed up at 1, 3, 6, 9, and 12 months. Seizure control and adverse events were assessed through personal interviews and seizure diaries. RESULTS: Out of 475 eligible patients, data of 429 patients (men: 65.5%) were evaluated (46 excluded due to protocol deviations). The median age was 25 (range, 3-80 years) years and the median duration of epilepsy was 3 (0.1-30) years. The majority of patients had focal epilepsy (55.0%) and genetic generalized epilepsy (40.1%). The one-year follow-up was completed by 380 (88.5%) patients. At one-year follow-up, 317 (83.4%; N = 380) patients in the study remained seizure free. These 317 patients who were seizure free at 12 months comprised 73.9% of the evaluable population (N = 429). In 98.8% of patients, the primary reason for adding clobazam was inadequate control of seizures with treatment. During one-year follow-up, a total of 113 (22.6%) patients experienced at least one adverse event which included 103 (20.6%) patients who experienced 386 episodes of seizures. CONCLUSION: The study provides preliminary evidence that clobazam is effective and well-tolerated as add-on therapy for a period of one year among patients with epilepsy inadequately stabilized with monotherapy. TRIAL REGISTRATION NUMBER: CTRI/2017/12/010906.

A case report on a novel MT-ATP6 gene variation in atypical mitochondrial Leigh syndrome associated with bilateral basal ganglia calcifications.

Leigh Syndrome (LS) is a rare, hereditary progressive neurodegenerative disorder of infancy or early childhood associated with a highly variable clinical presentation even among siblings. Further, genetic heterogeneity makes its diagnosis complicated. Its causative genetic variations are notified in some of the mitochondrial and nuclear genes. Here, we report an atypical case of LS in a 9-year-old boy associated with a novel variation in MT-ATP6 gene. The atypical findings were Bilateral Basal Ganglia Calcification (BGC) and late survival age in the patient. Analyses of the Whole Mitochondrial Genome Sequencing (WMGS) results of the recruited patient and his mother at different read coverage, first at 100× and later repeated at 500×, revealed a novel disease-associated variation in the already known disease-associated MT-ATP6 gene. In conclusion, the present study indicates amalgamation of both neuro-imaging and Next Generation Sequencing (NGS) Technologies aiding the proper diagnosis of LS in atypical cases.

A variation in PANK2 gene is causing Pantothenate kinase-associated Neurodegeneration in a family from Jammu and Kashmir - India.

Pantothenate kinase-associated neurodegeneration is a rare hereditary neurodegenerative disorder associated with nucleotide variation(s) in mitochondrial human Pantothenate kinase 2 (hPanK2) protein encoding PANK2 gene, and is characterized by symptoms of extra-pyramidal dysfunction and accumulation of non-heme iron predominantly in the basal ganglia of the brain. In this study, we describe a familial case of PKAN from the State of Jammu and Kashmir (J&K), India based on the clinical findings and genetic screening of two affected siblings born to consanguineous normal parents. The patients present with early-onset, progressive extrapyramidal dysfunction, and brain Magnetic Resonance imaging (MRI) suggestive of symmetrical iron deposition in the globus pallidi. Screening the PANK2 gene in the patients as well as their unaffected family members revealed a functional single nucleotide variation, perfectly segregating in the patient's family in an autosomal recessive mode of inheritance. We also provide the results of in-silico analyses, predicting the functional consequence of the identified PANK2 variant.

LoCa LoPa myelopathy: is prevention better than cure?

Manifestations of primary hypoparathyroidism are produced by neuromuscular irritability or by extraosseous calcifications. We present a patient of primary hypoparathyroidism who had extensive calcification of brain parenchyma, and was suffering from chronic, generalised and progressive stiffness of body due to cervical compressive myelopathy, caused by calcification of posterior longitudinal ligament and ligamentum flavum. By presenting this case we wanted to emphasize the usefulness of meticulous clinical examination to differentiate the stiffness caused by myelopathy from that which is caused by possible coexisting extrapyramidal disorder. This case presentation also builds the hypothesis that early diagnosis and institution of early and appropriate treatment has potential to prevent the complications arising from extraosseous calcifications in patients with primary hypoparathyroidism.

Celiac Neuropathy: A Case Report from Kashmir (India).

Celiac disease is considered to be rare in parts of the world where rice is a staple cereal. Kashmir is one of such places. We present an adult Kashmiri man, who had peripheral neuropathy, which turned out to be associated with celiac disease and improved remarkably with total elimination of gluten containing foods. This is probably the first case of celiac neuropathy reported from India.

Whole Exome Screening Identifies Novel and Recurrent WISP3 Mutations Causing Progressive Pseudorheumatoid Dysplasia in Jammu and Kashmir-India.

We report identification and genetic characterization of a rare skeletal disorder that remained unidentified for decades in a village of Jammu and Kashmir, India. The population residing in this region is highly consanguineous and a lack of understanding of the disorder has hindered clinical management and genetic counseling for the many affected individuals in the region. We collected familial information and identified two large extended multiplex pedigrees displaying apparent autosomal recessive inheritance of an uncharacterized skeletal dysplasia. Whole exome sequencing (WES) in members of one pedigree revealed a rare mutation in WISP3:c.156C > A (NP_003871.1:p.Cys52Ter), that perfectly segregated with the disease in the family. To our surprise, Sanger sequencing the WISP3 gene in the second family identified a distinct, novel splice site mutation c.643 + 1G > A, that perfectly segregated with the disease. Combining our next generation sequencing data with careful clinical documentation (familial histories, genetic data, clinical and radiological findings), we have diagnosed the families with Progressive Pseudorheumatoid Dysplasia (PPD). Our results underscore the utility of WES in arriving at definitive diagnoses for rare skeletal dysplasias. This genetic characterization will aid in genetic counseling and management, critically required to curb this rare disorder in the families.

"Peripheral neuropathy crippling bronchial asthma": two rare case reports of churg-strauss syndrome.

Churg-Strauss syndrome (CSS) is a rare cause of vasculitic neuropathy. Although rare and potentially fatal, Churg-Strauss syndrome (CSS) is easily diagnosable and treatable. The presence of bronchial asthma with peripheral neuropathy in a patient alerts a physician to this diagnosis. This is vividly illustrated by the presented two cases who had neuropathy associated with bronchial asthma, eosinophilia, sinusitis, and positive perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) test, which improved with administration of steroids.

"Excess gooD can be Dangerous". A case series of iatrogenic symptomatic hypercalcemia due to hypervitaminosis D.

Vitamin D is increasingly recognized to have several beneficial effects. Its toxicity, causing hypercalcemia, is considered as extremely rare. We report case series of 15 patients (most of them being elderly subjects) with iatrogenic symptomatic hypercalcemia in whom toxicity occurred due to empirical excessive administration of vitamin D by oral and parenteral route.

Active epilepsy as indicator of neurocysticercosis in rural northwest India.

Objective. To determine the contribution of neurocysticercosis as a cause for active epilepsy and to establish Neurocysticercosis as major definable risk of epilepsy in our setup. Methods. We conducted a door-to-door survey of 2,209 individuals of Bhore Pind and Bhore Kullian villages in Chattah zone of district Jammu (Jumma and Kashmir, Northwest India) to identify patients with symptomatic epilepsy. Patients with active epilepsy were investigated with neuroimaging techniques to establish diagnosis of NCC (neurocysticercosis). Results. Among 25 patients with epilepsy 10(40%) had CT/MR evidence of past or recent NCC infection. This gave us the point prevalence of 4.5/1000 for Neurocysticercosis in our study population. Interpretation. The study shows a high prevalence of NCC accounting for symptomatic epilepsy in our part of India.

Inbreeding as a cause for deafness: Dadhkai study.

BACKGROUND: We report on the higher prevalence of deaf-mutes from a village in Jammu and Kashmir State of India. MATERIALS AND METHODS: A cross-sectional study among 79 deaf mutes using pedigree analysis, audiometry, imaging and molecular analysis. RESULTS: A high rate of hereditary deafness with 79 individuals diagnosed to be suffering from non-syndrome deafness in a total population of 2452 individuals residing in the village. INTERPRETATION: Flourishing of intermarriages led to a population with high prevalence of deafness.

Prevalence of mental retardation among children in RS Pura town of Jammu and Kashmir.

OBJECTIVE: To determine the Prevalence of mental retardation in children 3 to 10 years of age. MATERIALS AND METHODS: The study was conducted in the framework of a population based, single centre, cross-sectional study at R.S.Pura town, 22 kms south- west of Jammu city. RESULTS: A total of 61 (0.79 percent) of the 7,707 children surveyed had positive screening results on the Ten Questions instrument. 56 (0.72percent) children were diagnosed as suffering from mental retardation. Serious mental retardation was diagnosed in 48 children and mild mental retardation was diagnosed in 8 children. The combined prevalence estimates of mild and serious mental retardation were 7.2/1000. No notable sex differences were observed for either serious or mild retardation. INTERPRETATION: The prevalence rates of mental retardation among children less than 19 years of age in R. S. town compares favorably with studies from developed world.

New-onset headache in an elderly man with uremia that improved only after correction of hyperphosphatemia ("uremic headache"): a case report.

INTRODUCTION: New-onset headaches in the elderly are usually secondary and rarely primary. We present the case of an elderly man with recent-onset headache due to uremic hyperphosphatemia and hypocalcemia. To the best of our knowledge, this is the first case report of its kind in the literature. CASE PRESENTATION: We present the case of a 70-year-old Indian man with chronic kidney disease whose new-onset headache improved only when his hyperphosphatemia and hypocalcemia were corrected. He had diffuse, dense calcification of tentorium cerebelli and falx due to hyperphosphatemia. CONCLUSIONS: This case report reinforces the importance of identifying the cause of a new-onset headache, particularly in the elderly, and treating it before blaming a tension headache or primary headache as the cause.

Prevalence of cerebral palsy in children < 10 years of age in R.S. Pura town of Jammu and Kashmir.

OBJECTIVE: To determine the prevalence of cerebral palsy in children aged <10 years. METHODS: The study was conducted in the framework of a population-based, single-centre, cross-sectional surveillance at R.S. Pura town, 22 km south-west of Jammu city. RESULTS: A total of 11 cases of cerebral palsy were ascertained yielding a crude prevalence rate of 2.27/1000 in the age group of <10 years. The proportion of cerebral palsy occurring in males was higher than that in females. INTERPRETATION: The prevalence rates of cerebral palsy among children <10 years of age in R.S. town compare favorably with studies from developed countries.

Prevalence of neurological disorders in children less than 10 years of age in RS Pura town of Jammu and Kashmir.

OBJECTIVE: To determine the prevalence of major neurological disorders in children less than 10 years of age. MATERIALS AND METHODS: The study was conducted in the framework of a population based, single centre, cross-sectional study at Ranbir Singh Pura town, 22 km south-west of Jammu city. RESULTS: Eight cases of active epilepsy with a crude prevalence rate of 202 (95% confidence interval [CI] 180-220), five cases of Febrile seizures with a crude prevalence of 126 (95% CI 110-140) and eleven cases of cerebral palsy with a crude prevalence rate of 277 (95% CI 245-309) per 100,000 were found. Very few cases of other major neurological disorders were found. The prevalence rate of these disorders is estimated at same level as for other disorders such as - Post-meningitic sequelae, Infantile hemiparesis, Spinal deformity and Tic disorder is at 25 (95% CI 15-34) per 100,000. INTERPRETATION: On the basis of the data obtained, the present study provides some valuable data on common neurological diseases among children in RS Pura town of Jammu district of Jammu and Kashmir.

Incidence of dementia in a Kashmiri migrant population.

BACKGROUND: Mishriwala is one of five exclusive clusters of Kashmiri migrants established in 1990 to accommodate Kashmiri Pandit families who left Kashmir valley in the wake of militancy. Mishriwala migrant camp has seen minimal immigration and out-migration since its establishment. In an earlier study we reported on the prevalence of dementia amongst a Kashmiri migrant population. That study was conducted in the migrant camp at Mishriwala, 12 km west of Jammu city, the winter capital of Jammu and Kashmir State. We have developed standardized study methods and instruments for use in the Kashmiri-speaking population, which we used for screening for dementia during the prevalence study. We now report the results of a 1-year prospective study carried out to find out the incidence of dementia in the same population. AIM: To ascertain the incidence of dementiain the Kashmiri Pandit population aged 60 years and above. MATERIALS AND METHODS: A 1-year, prospective, epidemiological study of 186 subjects aged 60 years and above, using cognitive and functional ability screening and clinical evaluation. RESULTS: The incidence of dementia in this population was 5.34 cases per 1000 person-years.

Prevalence of dementia among Kashmiri migrants.

BACKGROUND: Neurological diseases are common disorders resulting in the loss of productive life and disability. Dementia is becoming a major public health problem in the developing world also. AIM: To ascertain the prevalence of dementia among Kashmiri Pandit population aged 60 years and above. MATERIALS AND METHODS: A cross-sectional survey was conducted among the elderly population of the Kashmiris living in a migrant camp. We developed and used a Kashmiri version of the Mini-Mental State Examination as the test instrument, and a score below 24 was considered indicative of dementia. A functional ability questionnaire was also administered to the subjects. A neurologist carried out the examinations. RESULTS: A sample comprising 200 subjects (95 males and 105 females) were evaluated. The prevalence of dementia is 6.5% among the Kashmiri Pandit population aged 60 years and above, which is higher than that reported from other parts of India.

Diagnosis of intraventricular cysticercosis by magnetic resonance imaging: improved detection with three-dimensional spoiled gradient recalled echo sequences.

Neurocysticercosis (NCC) is caused when the cysticercus larvae of Taenia solium infect the central nervous system. The larvae usually land in the parenchymal tissue, but quite rarely can lodge in the ventricles and cisterns of the brain. Unlike parenchymal NCC, it is not easy to demonstrate the cysticercus cysts within the cerebrospinal fluid spaces. Computed tomography and even conventional MR sequences can fail to detect such cysts. However, obtaining three-dimensional spoiled gradient recalled echo imaging sequences can help in improving the detection of intraventricular NCC, as is borne out by a case described in the present report. The use of such special MR sequences is therefore strongly advocated in suspected cases of intraventricular NCC.