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Background: Leucine-rich repeat and fibronectin type 2 gene (LRFN2) variant rs2494938 has recently been found associated with esophageal cancer in a genome-wide association study in an Asian population. However, this association has not been replicated in any Indian population despite high incidence of the disease.Materials and Methods: In the present case-control study, 166 cases and 459 controls were included. Taqman assay technique using real-time PCR was employed to investigate the association of the variant with esophageal cancer in the population of Jammu and Kashmir (J&K). The Hardy-Weinberg equilibrium for rs2494938 was assessed using the Chi-square test. The allele- and genotype-specific risk was estimated by odds ratio (OR) with 95% confidence interval (CI).Results: Variant rs2494938 was observed to be significantly associated with esophageal cancer with an allelic OR of 1.59 (1.23-2.04 at 95% CI, P = 0.0003).Conclusion: The study highlights LRFN2 as a candidate gene for esophageal cancer susceptibility in the population of J&K and calls for a detailed study with a large sample size and involving more ethnic groups of India. [ABSTRACT FROM AUTHOR]

Genetic association studies have identified KIAA0319 gene as a possible susceptibility locus for reading disorder; however, very few studies are available from India. The study was planned to investigate the familial pattern and association of KIAA0319 polymorphisms among children with reading disorder visiting a tertiary centre in North India. This is a case-control, familial, and genetic association study on 30 children diagnosed with reading disorder (ICD-10) and 30 matched healthy controls and their families. The Aggregate Neurobehavioral Student Health and Educational Review System was administered on parents of probands and controls for reading problems in their siblings, and Adult Reading Questionnaire was administered for parents of both groups. The blood sample was taken from probands, and DNA was isolated. Four KIAA0319 coding sequence single nucleotide polymorphisms (SNPs; rs4504469, rs6935076, rs2038137, and rs2179515) were genotyped using SNaPshot single nucleotide extension. The incidence of reading problem was significantly higher in families of probands as compared with families of controls. There were no significant differences in both groups regarding the frequency of alleles of four SNPs. The reading disorder showed a significant familial pattern, but KIAA0319 gene did not appear to be a susceptibility factor. Future replications with larger samples and whole genome studies are warranted. [ABSTRACT FROM AUTHOR]

Introduction: There is a great deal of heterogeneity, both phenotypically and genotypically among the autosomal dominant cerebellar ataxias (ADCA). Their prevalence also varies in different populations. Trinucleotide repeat expansions (CTG/CAG) have been shown predominantly to cause a number of ADCAs.Aim: The present study describes the frequency of spinocerebellar ataxias (SCA) and the CAG repeat sizes among the different regions of India.Settings and Design: Molecular data from our central reference laboratory were retrospectively analyzed for SCAs 1, 2, 3, 6, 7, 10, 12, 17 and DRPLA. Correlation between age at diagnosis and the CAG repeats of the expanded and the normal alleles were tested with the Spearman correlation test.Results: The presence of SCAs vary according to geographical regions and ethnicities; SCA 12 was detected with the highest frequency (229/901), but was restricted to a specific ethnic population, followed by SCA 2 with a positivity of 12% (101/845). SCA 3 previously known as Machado-Joseph Disease had a prevalence of 4.05% (32/789), whereas SCA 1 was diagnosed in 30/773 (3.88%). No positivity was seen for SCA 10 from the 103 samples tested and for SCA 17 from the 131 samples tested either as a part of an extended panel or stand-alone.Conclusion: In this report, we are able to expand the portrait of SCAs in India by presenting the largest ever molecular data from a central reference laboratory. [ABSTRACT FROM AUTHOR]

A 24-year-old female presented with wasting and weakness of both hands and fasciculations over the chin since 12 years, followed by imbalance while walking and speech changes since 10 years. Her 12-year-old sister also had a similar clinical presentation. There were fasciculations over the chin, tongue, hands, back, thighs with wasting and weakness in tongue, and C7, C8, T1 segments in both upper limbs along with bipyramidal signs. There was limb and gait ataxia. Magnetic resonance imaging brain showed pancerebellar atrophy, and electromyography was suggestive of anterior horn cell involvement in bulbar, cervical, thoracic, and lumbar segments. Next-generation sequencing identified a novel likely pathogenic deletion mutation: chr6:152527389_152527399del, c.22711_22721del, and p.Ala7571ArgfsTer4 in exon 125 of synaptic nuclear envelope protein 1 (SYNE1) gene. This mutation leads to frameshift and premature termination of the protein 'Nesprin 1'. Amyotrophic lateral sclerosis-like presentation followed by cerebellar ataxia have been described with SYNE1 ataxia. This unique phenotype and novel deletion mutation of SYNE1 gene is the first case reported from India. [ABSTRACT FROM AUTHOR]

Aging is a progressive process, and it may lead to the initiation of neurological diseases. In this study, we investigated the effects of wild Indian Curcuma longa using a Morris water maze paradigm on learning and spatial memory in adult and D-galactose-induced aged mice. In addition, the effects on cell proliferation and neuroblast differentiation were assessed by immunohistochemistry for Ki67 and doublecortin (DCX) respectively. The aging model in mice was induced through the subcutaneous administration of D-galactose (100 mg/kg) for 10 weeks. C. longa (300 mg/kg) or its vehicle (physiological saline) was administered orally to adult and D-galactose-treated mice for the last three weeks before sacrifice. The administration of C. longa significantly shortened the escape latency in both adult and D-galactose-induced aged mice and significantly ameliorated D-galactose-induced reduction of cell proliferation and neuroblast differentiation in the subgranular zone of hippocampal dentate gyrus. In addition, the administration of C. longa significantly increased the levels of phosphorylated CREB and brain-derived neurotrophic factor in the subgranular zone of dentate gyrus. These results indicate that C. longa mitigates D-galactose-induced cognitive impairment, associated with decreased cell proliferation and neuroblast differentiation, by activating CREB signaling in the hippocampal dentate gyrus. [ABSTRACT FROM AUTHOR]

Despite the devastating effect of suicide on numerous lives, there is still a lack of knowledge concerning its neurochemical aspects. There is increasing evidence that brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are involved in the pathophysiology and treatment of depression through binding and activating their cognate receptors TrkB and TrkA respectively. The present study was performed to examine whether the expression profiles of BDNF and/or TrkB as well as NGF and/or TrkA were altered in the hippocampus of postmortem brain of the participants, who had committed suicide and whether these alterations were associated with specific psychopathologic conditions. These studies were performed on the hippocampus of 21 suicide victims and 19 non-psychiatric control individuals. The protein and mRNA levels of BDNF, TrkB, NGF, and TrkA were determined by sandwich enzyme-linked immunosorbent assay, Western blot and reverse transcription-PCR. Given the importance of BDNF and NGF and their cognate receptors in mediating physiological functions, including cell survival and synaptic plasticity, our findings of reduced expression of BDNF, TrkB, NGF, and TrkA on both the protein and mRNA levels of postmortem brains of suicide victims suggest that these molecules may play an important role in the pathophysiological aspects of suicidal behavior. [ABSTRACT FROM AUTHOR]

Tropical tasar silkworm Antheraea mylitta Drury (Lepidoptera: Saturniidae) is one of the commercially exploited non-mulberry silkworm in tropical India. Since time immemorial the aboriginals of India use to rear the silkworms in their natural abode besides collecting bulk of cocoons from the forest area. The diapausing Daba bivoltine pupae remain in facultative pupal diapause state for 7 to 8 months (Nov.-June). During diapause period erratic emergence of moths takes place besides pupal mortality, unsynchronised emergence of male and female moths. It is estimated that tropical tasar silkworm industry is faced with the problem of loss of seed material due to pupal mortality (10-20 %) erratic (10-15 %), un-seasonal (10-20 %) and unsynchronised (10-20 %) emergence. This leads to the losses during seed production and overall production/ productivity. To understand the root cause of these the physiology of diapause needs to be studied at biochemical and molecular level in relation with environmental and nutritional factors responsible for induction and maintenance of diapause among population. Haemolymph is the only medium which caters to the energy reserves for any physiological mechanism in an insect. To explore the physiology of diapause to work out a temperature sensitive diapause termination state, the haemolymph biochemical parameters like glycerol, trehalose, glycogen, quantitative total proteins and free amino acids were estimated through out the pupal diapause period of Daba bivoltine ecorace. It was observed that the level of protein was high through out the diapause period. At the fag end of diapause at 190 to 200 days age of pupae, depletion in the level of protein was observed. The amino acids levels showed a fluctuating trend through out diapause development. Accumulation of glycogen was observed through out diapause period and it went down once pupae attained the age of 190 to 200 days. Resumption in the level of glycogen was observed once adult emergence was nearing by 215 to 220 days. Similarly, through out diapause period the accumulation of Glycerol in the haemolymph was observed which went down when pupae attained the age of 190 to 200 days. Contrary to this, the level of trehalose remained at low through diapause period and went up at 190 to 200 days of age of pupae. These findings indicate that when diapausing pupae of Daba bivoltine pupae attain the age of 195 to 200 days a shift is observed from deeper diapause state to diapause termination. This stage can be exploited for low temperature treatment to regulate the emergence of moths in grainages in order to have more couplings and enhanced egg production. Studies in this direction are under progress. Pupal diapause is mediated by the brain prothracicotropic complex and non-receipt of brain signals in the form PTTH leads to pupal diapause in adverse seasons in insects. Hence through SDS PAGE presence of brain proteins were also studied. It was found that in diapausing generation, in early diapause period (Day 0 to day 15) and mid diapause period (Day 30 to Day 150) and late diapause period (Day 150 to 165) and during termination period of diapause development period (day 180 to day 210) accumulation of four diapause specific proteins having molecular weight range of 80, 46, 38 (female specific), 31 and 18kDa was observed. These proteins were not present in non-diapausing generation. At the fag end of diapause period (after day 195 and at Day 210), the brain proteins profile was alike in both non-diapause and diapause destined generations. [ABSTRACT FROM AUTHOR]

Hereditary spastic paraplegias (HSPs), also known as spastic paraplegias (SPGs) are a heterogeneous group of inherited neurodegenerative diseases in which the patients present with gradually progressive spasticity and weakness that predominantly tends to affect the lower limbs.[1] SPGs are classified by the phenotype (pure or complicated), the trait of inheritance, and the mutated gene.[1] SPG12 is a pure SPG-type due to RTN2 gene mutation which encodes the reticulon 2 protein.[2] We are reporting a 46-year-old female with RTN2 gene mutation, who presented with spastic quadriparesis and features suggestive of anterior horn cell involvement. Overall psychiatric symptoms are rare in HSP, and SPG4-HSP patients are more likely to be associated with underlying psychosis.[5] To conclude, our patient extends the RTN2-gene associated SPG12 and provides evidence for anterior horn cell involvement. [Extracted from the article]

The neurogenic differentiation-1 (NEUROD1), neurogenin-3 (NEUROG3), and hepatic nuclear factor-1alpha (TCF1) genes are interacting transcription factors implicated in controlling islet cell development and insulin secretion. Polymorphisms of these genes (Ala45Thr [NEUROD1], Ser199Phe [NEUROG3], and Ala98Val [TCF1]) have been postulated to influence the development of type 2 diabetes. We have investigated the role and interaction between these variants using PCR/restriction fragment-length polymorphism assays in 454 subjects recruited as part of a population survey in South India. Additionally, 97 South Indian parent-offspring trios were studied. Polymorphisms of all three genes were associated with either fasting blood glucose (FBG) and/or 2-h blood glucose (BG) in either the total dataset or when restricted to a normoglycemic population. A monotonically increasing effect, dependent on the total number of risk-associated alleles carried, was observed across the whole population (P < 0.0001 for FBG and 2-h BG), raising FBG by a mean of 2.9 mmol/l and 2-h BG by a mean of 4.3 mmol/l. Similarly, an ascending number of the same risk alleles per subject increased the likelihood of type 2 diabetes (P = 0.002). In conclusion, we observed a combined effect of variations in NEUROD1, NEUROG3, and TCF1 in contributing to overall glucose intolerance in a South Indian population. [ABSTRACT FROM AUTHOR]

Background: The diagnostic workup for choreiform movement disorders including Huntington's disease (HD) and those mimicking HD like phenotype is complex., Objective: The aim of the present study was to genetically define HD and HD-like presentations in an Indian cohort. We also describe HTT-CAG expansion manifesting as neuroferritinopathy-like disorder in four families from Punjab in India., Materials and Methods: 159 patients clinically diagnosed as HD and HD-like presentations from various tertiary neurology clinics were referred to our centre (CSIR-IGIB) for genetic investigations. As a first tier test, CAG-TNR for HTT was performed and subsequently HD-negative samples were screened for JPH3 (HDL2), TBP (SCA17), ATN1 (DRPLA), PPP2R2B (SCA12) and GGGGCC expansion in C9orf72 gene. Four families presenting as neuroferritinopathy-like disorder were also investigated for HTT-CAG expansion., Results: 94 of 159 (59%) patients were found to have expanded HTT-CAG repeats. Pathogenic repeat expansion in JPH3, TBP, ATN1 and C9orf72 were not found in HD negative cases. Two patients were positive for SCA12-CAG expansion in pathogenic length, whereas 5 cases harboured TBP-CAG repeats falling in reduced penetrance range of 41- 48 repeats for SCA17. Four unrelated families, presented with atypical chorea and brain MRI findings suggestive of basal ganglia abnormalities mimicking neuroferritinopathy were found to harbour HTT-CAG expansion., Conclusion: We present SCA12 as a new reported phenocopy of HD which should be considered for diagnostic workout along with SCA17 for HD-like syndromes. This study also illustrates the necessity, to consider evolving HD like phenotype, as a clinical diagnosis for cases with initial manifestations depicting neuroferritinopathy.

The triple A or Allgrove's syndrome is an autosomal recessive disorder characterized by the triad of achalasia cardia, alacrima and ACTH resistant adrenocortical insufficiency. Mutations of the Achalasia-Addisonianism-Alacrima-Syndrome (AAAS) gene on chromosome 12q13 are associated with this syndrome. We report an Indian family where two siblings were homozygous for a known mutation of the AAAS gene and presented with the classical triad of symptoms. The mother and the brother were heterozygous and asymptomatic. The affected siblings had iron deficiency anemia and the younger sister had pes cavus and palmoplantar keratosis. Neurological symptoms were absent in both affected children. Recognition of this syndrome can lead to early treatment of adrenal insufficency and genetic counselling.

Objective: Spinocerebellar ataxia type 2 (SCA2) has been reported as the commonest dominant hereditary ataxia in India. However, India is an ethnically and religiously diverse population. Previous studies have not clearly indicated exact ethnic and religious origins, and must therefore be interpreted with caution. The purpose of this study was to determine the prevalence of different SCA mutations in a relatively homogeneous population from eastern India., Methods: We identified 28 families with autosomal dominant cerebellar ataxia from eastern India. Each underwent full clinical evaluation and were analysed for the presence of SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, and SCA17 mutations. In addition, haplotype analysis was carried out in seven of the 16 families with SCA2., Results: Seven patients from four (14%) families were positive for an expansion in SCA1 and 26 patients from 16 (57%) families were positive for an expansion in SCA2. No mutations were detected in the remaining eight families (29%). Most of the SCA1 and SCA2 families were Hindu from the state of Bihar. Five out of 26 SCA2 patients in this study did not have slow saccades. In addition, four of seven SCA1 patients had slow saccades. We found an association between the SCA2 CAG repeat expansion and the 285 base pair (bp) allele of microsatellite marker D12S1672, and also data supportive of the association between the expansion and the 225 bp allele of D12S1333, which has been previously described., Conclusions: We conclude that (1) although slow ocular saccades are highly suggestive of SCA2, that they are not universal, nor are they exclusive to this disorder and (2) SCA2 is likely to be the commonest dominant ataxia in eastern India, with further evidence for a founder effect.

We describe a consanguineous Indian family having spinocerebellar ataxia type 2 (SCA2) expansions with complex phenotypes (early-onset, dopa-responsive parkinsonism, ataxia and retinitis pigmentosa). The two probands having homozygous SCA2 mutations presenting with early-onset dopa-responsive parkinsonism without ataxia develop dyskinesias within a year of starting levodopa. Their siblings, heterozygous for SCA2 mutations, had retinitis pigmentosa with or without ataxia. Approximately 38% of family members with SCA2 mutations were asymptomatic.

Schizophrenia is a severe neuropsychiatric disorder with a polygenic mode of inheritance which is also governed by non-genetic factors. Candidate genes identified on the basis of biochemical and pharmacological evidence are being tested for linkage and association studies. Neurotransmitters, especially dopamine and serotonin have been widely implicated in its etiology. Genome scan of all human chromosomes with closely spaced polymorphic markers is being used for linkage studies. The completion and availability of the first draft of Human Genome Sequence has provided a treasure-trove that can be utilized to gain insight into the so far inaccessible regions of the human genome. Significant technological advances for identification of single nucleo-tide polymorphisms (SNPs) and use of microarrays have further strengthened research methodologies for genetic analysis of complex traits. In this review, we summarize the evolution of schizophrenia genetics from the past to the present, current trends and future direction of research.

A variable number tandem repeat (VNTR) polymorphism consisting of multiple copies of a 17-bp repeat in the second intron of the serotonin transporter gene (SERT) has been reported. Different alleles of this VNTR have been found to be associated with bipolar disorder and schizophrenia. These findings have been confirmed in some populations, but disconfirmed in others. Furthermore, significant ethnic variations in the distribution of these alleles both in normal and patient populations also have been reported. We analyzed the VNTR polymorphism in 50 Indian patients with bipolar disorder and in ethnically matched controls. Two alleles corresponding to 10 and 12 repeats of the VNTR were found in both groups. There were no significant differences either in allele frequency or genotype frequency between the two groups. The nine-repeat allele that has been reported in Japanese and Caucasian populations was absent in our sample. Although it will be important to extend the present study in a larger sample, our initial results do not suggest any large association with alleles of the VNTR in the SERT gene and bipolar disorder in Indian patients. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:170-172, 2000., (Copyright 2000 Wiley-Liss, Inc.)

The identification of a CAG trinucleotide repeat expansion, located within the coding sequence of the ataxin-2 gene, as the mutation underlying spinocerebellar ataxia 2 (SCA2) has facilitated direct investigation of pedigrees previously excluded from linkage analysis due to insufficient size or pedigree structure. We have previously described the identification of the ancestral disease haplotype segregating in the Cuban founder population used to assign the disease locus to chromosome 12q23-24.1. We now report evidence for the segregation of the identical core haplotype in pedigrees of diverse ethnic origin from India, Japan and England, established by the analysis of the loci D12S1672 and D12S1333 located 20kb proximal and 200 kb distal to the triplet repeat motif respectively. Interpretation of this data is suggestive that for these pedigrees at least, the mutation has arisen on a single ancestral or predisposing chromosome.

Fibrocalculous pancreatic diabetes (FCPD) is a form of diabetes associated with tropical chronic calcific pancreatitis, seen mostly in developing countries. FCPD is likely to be a multifactorial disease with both environmental and genetic components. The reg 1A gene encodes a protein associated with regeneration of pancreatic islets and has a sequence identical to that of pancreatic stone protein. Since FCPD is associated with both diabetes and pancreatitis, we tested the hypothesis that FCPD may be the result of mutations in the coding regions of the reg 1A gene. Restriction length polymorphisms (RFLPs) and possible sequence variants of the reg 1A gene were studied by RFLP analysis, looking for single-stranded conformational polymorphisms (SSCPs) and direct nucleotide sequencing. In 20 patients with FCPD and 20 control subjects, no RFLPs were detected using 10 restriction enzymes. In 50 patients with FCPD and 50 control subjects, no SSCP variants were detected. Finally, direct nucleotide sequencing of the reg 1A gene from 30 patients with FCPD did not show any differences from the published human reg 1A gene sequence. In conclusion, it seems unlikely that mutations in the coding region of the reg 1A gene are a common cause of FCPD.