Papers by Manjunath Supriya
Journal of Neuroimmunology, Apr 1, 2023
Molecular Diagnosis & Therapy, Apr 22, 2020
Introduction Diagnosis of the rupture of an intracranial aneurysm (IA) relies on sophisticated ne... more Introduction Diagnosis of the rupture of an intracranial aneurysm (IA) relies on sophisticated neuro-imaging studies, and molecular biomarkers to identify an IA or predict its rupture are still unavailable. Objective Our objective was to determine the plasma microRNA (miRNA) expression profile in patients with ruptured IA presenting as aneurysmal subarachnoid hemorrhage (aSAH) and identify potential biomarkers of aneurysmal rupture. Methods Plasma miRNA profiling was carried out using quantitative real-time polymerase chain reaction (qRT-PCR) in 20 patients with aSAH and 20 age-and sex-matched healthy controls. Eight differentially expressed miRNAs were validated by qPCR in a larger cohort of 88 patients with aSAH and 110 healthy controls. A receiver operating characteristic (ROC) curve was constructed to evaluate the overall performance of the miRNA-based assay. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was used to determine the potential pathway of miRNA-target genes. Results The miRNA profiles were clearly distinct in patients compared with controls. Validation studies showed that three upregulated miRNAs (miR-15a-5p, miR-34a-5p, miR-374a-5p) and five downregulated miRNAs (miR-146a-5p, miR-376c-3p, miR-18b-5p, miR-24-3p, miR-27b-3p) could distinguish patients with aSAH from healthy controls with high predicted probability (0.865 and 0.995, respectively). Further, the expression levels of the eight candidate miRNAs were significantly dysregulated only in aSAH cases and not in patients with SAH due to other causes. Plasma miR-146a-5p and miR-27b-3p were associated with clinical outcomes in patients with aSAH. Functional analysis of the eight differentially expressed miRNA showed that the target genes involved in signaling pathways were related to inflammation. Conclusions Our study determined the plasma miRNA signature of ruptured IAs and identified eight candidate miRNAs that could be useful biomarkers for this condition. We hypothesize that these differentially expressed miRNAs may play pivotal roles in IA pathology.
Journal of the Neurological Sciences, Aug 1, 2018
Vitamin D receptor (VDR) gene polymorphism and vascular dementia due to cerebral small vessel dis... more Vitamin D receptor (VDR) gene polymorphism and vascular dementia due to cerebral small vessel disease in an Asian Indian cohort. Jns (2017),
Journal of neuromuscular diseases, Mar 1, 2022
Background: Late onset Pompe disease (LOPD) is rare and generally manifests predominantly as prog... more Background: Late onset Pompe disease (LOPD) is rare and generally manifests predominantly as progressive limb girdle muscle weakness. It is linked to the pathogenic mutations in GAA gene, which leads to glycogen accumulation in various tissues. Materials and methods: We describe the unusual clinical, biochemical, histopathological and genetic characteristics of 5 cases of LOPD. Results: The first case had progressive anterior horn cell like disease (AHCD) that evolved later to classical limb girdle syndrome and respiratory failure, the second patient had rigid spine syndrome with gastrointestinal manifestations, the third had limb girdle weakness superimposed with episodic prolonged worsening and respiratory failure, the fourth had large fibre sensory neuropathy without primary muscle involvement and the fifth presented with classical limb girdle muscle weakness. Two homozygous missense mutations c.1461C > A (p.Phe487Leu) and c.1082C > T (p.Pro361Leu) in the GAA gene were identified in case 1 and 2 respectively. Case 3 was compound heterozygous with inframe c.1935_1940del (p.Val646_Cys647del) and an intronic splice effecting variant c.-32-13T > G. Compound heterozygous missense variants c.971C > T (p.Pro324Leu) and c.794G > A (p.Ser265Asn) were identified in case 4. Case 5 had a frameshift insertion c.1396dupG (p.Val466GlyfsTer40) and a synonymous splice affecting variant c.546G > T(p.Thr182=). Conclusion: We are describing for the first time from India on LOPD with unusual phenotypes identified. A high degree of clinical suspicion and diagnosing rare phenotypes of Pompe disease is imperative to consider early initiation of Enzyme Replacement Therapy (ERT).
Cellular and Molecular Neurobiology, Jun 29, 2021
The molecular mechanisms behind the rupture of intracranial aneurysms remain obscure. MiRNAs are ... more The molecular mechanisms behind the rupture of intracranial aneurysms remain obscure. MiRNAs are key regulators of a wide array of biological processes altering protein synthesis by binding to target mRNAs. However, variations in miRNA levels in ruptured aneurysmal wall have not been completely examined. We hypothesized that altered miRNA signature in aneurysmal tissues could potentially provide insight into aneurysm pathophysiology. Using a high-throughput miRNA microarray screening approach, we compared the miRNA expression pattern in aneurysm tissues obtained during surgery from patients with aneurysmal subarachnoid hemorrhage (aSAH) with control tissues (GEO accession number GSE161870). We found that the expression of 70 miRNAs was altered. Expressions of the top 10 miRNA were validated, by qRT-PCR and results were correlated with clinical characteristics of aSAH patients. The level of 10 miRNAs (miR-24-3p, miR-26b-5p, miR-27b-3p, miR-125b-5p, miR-143-3p, miR-145-5p, miR-193a-3p, miR-199a-5p, miR-365a-3p/365b-3p, and miR-497-5p) was signi cantly decreased in patients compared to controls. Expression of miR-125b-5p, miR-143-3p and miR-199a-5p was signi cantly decreased in patients with poor prognosis and vasospasm. The target genes of few miRNAs were enriched in Transforming growth factor-beta (TGF-β) and Mitogen-activated protein kinases (MAPK) pathways. We found signi cant negative correlation between the miRNA and mRNA expression (TGF-β1, TGF-β2, SMAD family member 2 (SMAD2), SMAD family member 4 (SMAD4), MAPK1 and MAPK3) in aneurysm tissues. We suggest that miR-26b, miR-199a, miR-497and miR-365, could target multiple genes in TGF-β and MAPK signaling cascades to in uence in ammatory processes, extracellular matrix and vascular smooth muscle cell degradation and apoptosis, and ultimately cause vessel wall degradation and rupture.
Clinical Biochemistry, Oct 1, 2017
The study aimed to establish age and gender-specific reference values for the activities of lysos... more The study aimed to establish age and gender-specific reference values for the activities of lysosomal enzymes (acid α-galactosidase [GLA], acid β-glucocerebrosidase [GBA], acid α-glucosidase [GAA], acid sphingomyelinase [ASM] and galactocerebrosidase [GALC]) in dried blood spots (DBS) of Indian population. A total of 3797 healthy Indian subjects (1456 females and 2341 males) aged from 2days to 60years were selected for the study. Activities of 5 lysosomal enzymes were determined by tandem mass spectrometry, for newborns (<30days), infants (>1month-1year), children (>1-5years) and (>5-18years) and adults (>18years).Variations in enzyme activities based on age and gender were studied. The reference interval was defined as the central 95% range, and was determined based on age and gender. Highly significant differences in activities were observed for GAA (p=0.001), GLA (p<0.0001), GBA (p<0.0001), ASM (p<0.0001) and GALC (p<0.0001), between different age groups. Comparison of activities between genders showed significant difference for ASM in children aged 1-5years (p=0.03) with higher activity in females, and for GLA in children aged 5-18years (p=0.004) where the activity was higher in males. Reference intervals decreased with age for all enzymes, except GAA. The ranges of GLA and GALC were higher in females, whereas GBA was higher in males. The study establishes age and gender-specific reference values for the screening and identification of lysosomal storage disorders in Indian population. Our data may facilitate establishment of mass screening programs for these disorders in India.
Journal of Neuroimmunology
Journal of Neuromuscular Diseases, 2021
Background: Late onset Pompe disease (LOPD) is rare and generally manifests predominantly as prog... more Background: Late onset Pompe disease (LOPD) is rare and generally manifests predominantly as progressive limb girdle muscle weakness. It is linked to the pathogenic mutations in GAA gene, which leads to glycogen accumulation in various tissues. Materials and methods: We describe the unusual clinical, biochemical, histopathological and genetic characteristics of 5 cases of LOPD. Results: The first case had progressive anterior horn cell like disease (AHCD) that evolved later to classical limb girdle syndrome and respiratory failure, the second patient had rigid spine syndrome with gastrointestinal manifestations, the third had limb girdle weakness superimposed with episodic prolonged worsening and respiratory failure, the fourth had large fibre sensory neuropathy without primary muscle involvement and the fifth presented with classical limb girdle muscle weakness. Two homozygous missense mutations c.1461C > A (p.Phe487Leu) and c.1082C > T (p.Pro361Leu) in the GAA gene were iden...
Molecular Diagnosis & Therapy, 2020
Introduction Diagnosis of the rupture of an intracranial aneurysm (IA) relies on sophisticated ne... more Introduction Diagnosis of the rupture of an intracranial aneurysm (IA) relies on sophisticated neuro-imaging studies, and molecular biomarkers to identify an IA or predict its rupture are still unavailable. Objective Our objective was to determine the plasma microRNA (miRNA) expression profile in patients with ruptured IA presenting as aneurysmal subarachnoid hemorrhage (aSAH) and identify potential biomarkers of aneurysmal rupture. Methods Plasma miRNA profiling was carried out using quantitative real-time polymerase chain reaction (qRT-PCR) in 20 patients with aSAH and 20 age- and sex-matched healthy controls. Eight differentially expressed miRNAs were validated by qPCR in a larger cohort of 88 patients with aSAH and 110 healthy controls. A receiver operating characteristic (ROC) curve was constructed to evaluate the overall performance of the miRNA-based assay. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was used to determine the potential pathway of miRNA-target genes. Results The miRNA profiles were clearly distinct in patients compared with controls. Validation studies showed that three upregulated miRNAs (miR-15a-5p, miR-34a-5p, miR-374a-5p) and five downregulated miRNAs (miR-146a-5p, miR-376c-3p, miR-18b-5p, miR-24-3p, miR-27b-3p) could distinguish patients with aSAH from healthy controls with high predicted probability (0.865 and 0.995, respectively). Further, the expression levels of the eight candidate miRNAs were significantly dysregulated only in aSAH cases and not in patients with SAH due to other causes. Plasma miR-146a-5p and miR-27b-3p were associated with clinical outcomes in patients with aSAH. Functional analysis of the eight differentially expressed miRNA showed that the target genes involved in signaling pathways were related to inflammation. Conclusions Our study determined the plasma miRNA signature of ruptured IAs and identified eight candidate miRNAs that could be useful biomarkers for this condition. We hypothesize that these differentially expressed miRNAs may play pivotal roles in IA pathology.
Meta Gene, 2018
Abstract Matrix metalloproteinases (MMPs), a family of zinc-dependent proteases, have been linked... more Abstract Matrix metalloproteinases (MMPs), a family of zinc-dependent proteases, have been linked with the pathogenesis of intracranial aneurysm (IA) formation and rupture. Patients with IA have elevated serum levels of MMP-2 and MMP-9 gene expression has been shown to be increased in aneurysm tissue. In this study, we have evaluated the association between MMP gene variants and aneurysmal subarachnoid hemorrhage (aSAH). The rs243865 in MMP-2 and rs17576 in MMP-9 genes were genotyped using Taqman allelic discrimination assay. Upon gender stratification, the presence of G allele of MMP-9 gene exon variant was found to increase the risk of aSAH by 1.4 fold (p = 0.032), in men. The GG genotype also showed a trend towards association with the risk of aSAH (OR: 1.785, CI: 0.971–3.283, p = 0.062) in men, after adjusting for the vascular risk factors. In women, no association was observed. The MMP-2 gene variants were not associated with aSAH in both genders. Further functional studies are required to describe the exact basis of the association between MMP-9 polymorphism and intracranial aneurysm in men.
Journal of the Neurological Sciences, 2018
Vitamin D receptor (VDR) and its ligand Vitamin D, play a crucial role in regulating multiple pat... more Vitamin D receptor (VDR) and its ligand Vitamin D, play a crucial role in regulating multiple pathways for maintaining vascular health. The present study aimed at evaluating whether single nucleotide polymorphisms in VDR gene were associated with susceptibility to vascular dementia (VaD) due to cerebral small vessel disease (SVD). A total of 644 subjects (302 patients diagnosed with cerebral SVD-associated VaD and 342, age- and gender-matched healthy controls) were genotyped for VDR gene variants, FokI, ApaI, TaqI and BsmI, by PCR-RFLP method. Among the 4 examined VDR variants, the presence of the minor allele (Ff+ff vs FF) of FokI variant increased the risk for cerebral SVD by 1.5-fold in men (p = 0.047). Serum 25-hydroxyvitamin D [25(OH)D] was lower in subjects having the FokI "ff" genotype compared to those with the "FF" genotype (p = 0.044). Moreover, in subjects with low serum 25(OH)D the presence of "ff" genotype increased the odds of SVD by 2.5 folds (p = 0.041). ApaI polymorphism decreased the risk of cerebral SVD in women. The distribution of TaqI and BsmI variants were not significantly different between patients and controls. Further studies in large cohorts are necessary to validate the role of FokI polymorphism in cerebral SVD and VaD etiopathogenesis.
Journal of Clinical Laboratory Analysis, 2017
Journal of the Neurological Sciences, 2015
Vitamin D plays vital roles in human health and recent studies have shown its beneficial effect o... more Vitamin D plays vital roles in human health and recent studies have shown its beneficial effect on brain functioning. The present study was designed to evaluate the association of vitamin D with vascular dementia (VaD) due to cerebral small vessel disease (SVD) in Asian Indian population. 140 VaD patients aged ≥ 60 years with neuroimaging evidence of SVD, and 132 age and gender-matched controls, were investigated. Vitamin D status was estimated by measuring serum 25-hydroxy vitamin D. Logistic regression model revealed that deficient levels of vitamin D (<12 ng/ml) were associated with 2.2-fold increase in odds of VaD after adjustment with covariates. Hypertension was independently associated with 11.3-fold increased odds of VaD. In hypertensives with vitamin D deficiency and insufficiency (12-20 ng/ml), the odds were increased to 31.6-fold and 14.4-fold, respectively. However, in hypertensives with vitamin D sufficiency (>20 ng/ml), the odds of VaD were increased by 3.8-fold only. Pearson correlation showed that serum vitamin D was inversely associated with systolic and diastolic blood pressure (r=-0.401 and -0.411, p<0.01, respectively) in vitamin D-deficient subjects. Since the combined presence of hypertension and vitamin D deficiency increases the probability of developing VaD, screening for vitamin D status in addition to regular monitoring of blood pressure, could reduce the risk of VaD associated with cerebral SVD in the elderly Asian Indian subjects.
Indian Journal of Nephrology, 2010
Online Journal of Health and Allied Sciences, 2010
Cellular and Molecular Neurobiology, 2021
OBJECTIVES The study aimed to establish age and gender-specific reference values for the activiti... more OBJECTIVES The study aimed to establish age and gender-specific reference values for the activities of lysosomal enzymes (acid α-galactosidase [GLA], acid β-glucocerebrosidase [GBA], acid α-glucosidase [GAA], acid sphingomyelinase [ASM] and galactocerebrosidase [GALC]) in dried blood spots (DBS) of Indian population. DESIGN AND METHODS A total of 3797 healthy Indian subjects (1456 females and 2341 males) aged from 2days to 60years were selected for the study. Activities of 5 lysosomal enzymes were determined by tandem mass spectrometry, for newborns (<30days), infants (>1month-1year), children (>1-5years) and (>5-18years) and adults (>18years).Variations in enzyme activities based on age and gender were studied. The reference interval was defined as the central 95% range, and was determined based on age and gender. RESULTS Highly significant differences in activities were observed for GAA (p=0.001), GLA (p<0.0001), GBA (p<0.0001), ASM (p<0.0001) and GALC (p&l...
Journal of the Neurological Sciences, 2015
Vitamin D plays vital roles in human health and recent studies have shown its beneficial effect o... more Vitamin D plays vital roles in human health and recent studies have shown its beneficial effect on brain functioning. The present study was designed to evaluate the association of vitamin D with vascular dementia (VaD) due to cerebral small vessel disease (SVD) in Asian Indian population. 140 VaD patients aged ≥ 60 years with neuroimaging evidence of SVD, and 132 age and gender-matched controls, were investigated. Vitamin D status was estimated by measuring serum 25-hydroxy vitamin D. Logistic regression model revealed that deficient levels of vitamin D (&amp;amp;amp;amp;lt;12 ng/ml) were associated with 2.2-fold increase in odds of VaD after adjustment with covariates. Hypertension was independently associated with 11.3-fold increased odds of VaD. In hypertensives with vitamin D deficiency and insufficiency (12-20 ng/ml), the odds were increased to 31.6-fold and 14.4-fold, respectively. However, in hypertensives with vitamin D sufficiency (&amp;amp;amp;amp;gt;20 ng/ml), the odds of VaD were increased by 3.8-fold only. Pearson correlation showed that serum vitamin D was inversely associated with systolic and diastolic blood pressure (r=-0.401 and -0.411, p&amp;amp;amp;amp;lt;0.01, respectively) in vitamin D-deficient subjects. Since the combined presence of hypertension and vitamin D deficiency increases the probability of developing VaD, screening for vitamin D status in addition to regular monitoring of blood pressure, could reduce the risk of VaD associated with cerebral SVD in the elderly Asian Indian subjects.
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Papers by Manjunath Supriya