Akella Radha Rama Devi

Role of parental folate pathway single nucleotide polymorphisms in altering the susceptibility to neural tube defects in South India

Abstract Aim: To investigate the role of four parental folate pathway single nucleotide polymorphisms (SNPs) i.e., methylene tetrahydrofolate reductase (MTHFR) 677C>T, MTHFR 1298A>C, methionine synthase reductase (MTRR) 66A>G and glutamate carboxypeptidase (GCP) II 1561C>T on susceptibility to neural tube defects (NTDs) in 50 couples with NTD offspring and 80 couples with normal pregnancy outcome. Results: Maternal MTHFR 677C→T (odds ratio (OR): 2.69, 95% confidence interval (CI): 1.35–5.34) and parental GCP II 1561C→T (maternal: OR: 1.89, 95% CI: 1.12–3.21 and paternal: OR: 3.23, 95% CI: 1.76–5.93) were found to be risk factors for a NTD. Both paternal and maternal GCP II T-variant alleles were found to interact with MTHFR 677T- and MTRR G-variant alleles in increasing the risk for NTD. Segregation of data based on type of defect revealed an association between maternal 677T-allele and meningomyelocele (OR: 9.00, 95% CI: 3.77–21.55, P<0.0001) and an association between parental GCP II 1561T-allele and anencephaly (maternal: OR: 2.25, 95% CI: 1.12–4.50, P<0.05 and paternal: OR: 4.26, 95% CI: 2.01–9.09, P<0.001). Conclusions: Maternal MTHFR C677T and parental GCP II C1561T polymorphisms are associated with increased risk for NTDs. Apart from individual genetic effects, epistatic interactions were also observed.

Relationship between methionine synthase, methionine synthase reductase genetic polymorphisms and deep vein thrombosis among South Indians

Abstract Background: The rationale behind this study was to examine the relationship between polymorphisms in genes that regulate remethylation of homocysteine to methionine, i.e., methionine synthase (MTR A2756G) and methionine synthase reductase (MTRR A66G), and risk of deep vein thrombosis (DVT) in a South Indian cohort (163 DVT cases and 163 controls), as elevated homocysteine has been documented as an independent risk factor for DVT in the same cohort. Methods: Plasma homocysteine analysis was carried out by reverse phase HPLC. The MTR A2756G and MTRR A66G genetic polymorphisms were detected using PCR-restriction fragment length polymorphism method. For statistical analyses, Fishers exact test was used for categorical variables and Students t-test and analysis of variance were used for continuous variables. Results: The MTRR 66GG genotype was associated with a 2.74-fold [95% confidence interval (CI): 1.73, 4.34] risk of DVT. The MTR A2756G polymorphism was not a risk factor. MTRR GG/MTR AG and MTRR GG/MTR GG genotypes cumulatively were found to increase the risk of DVT by 2.38-fold (95% CI: 1.43, 3.96). A positive association was observed between plasma homocysteine and the MTRR G allele, and the MTR G allele was shown to have an additive effect. The risk associated with the MTRR 66GG genotype was further increased in subjects compound heterozygous for methylene tetrahydrofolate reductase (MTHFR) [odds ratio (OR): 3.46, 95% CI: 1.38, 8.63]. Conclusions: The MTRR 66GG genotype is a risk factor for DVT among South Indians. This risk is increased further in the presence of the MTHFR 677CT/1298AC genotype. Clin Chem Lab Med 2008;46:73–9.

Clinical utility of folate pathway genetic polymorphisms in the diagnosis of autism spectrum disorders.

Background The rationale of the current study was to test the clinical utility of the folate pathway genetic polymorphisms in predicting the risk for autism spectrum disorders (ASD) and to address the inconsistencies in the association of MTHFR C677T and hyperhomocysteinemia with ASD. Patients and methods An artificial neural network (ANN) model was developed from the data of 138 autistic and 138 nonautistic children using GCPII C1561T, SHMT1 C1420T, MTHFR C677T, MTR A2756G, and MTRR A66G as the predictors of autism risk. A neuro fuzzy model was developed to explore the genetic determinants of homocysteine. Meta-analyses were carried out on 1361 ASD children and 6591 nonautistic children to explore the association of MTHFR C677T and homocysteine with the risk for ASD. Results The ANN model showed 63.8% accuracy in predicting the risk of autism. Hyperhomocysteinemia was observed in autistic children (9.67±4.82 vs. 6.99±3.21 &mgr;mol/l). The neuro fuzzy model showed synergistic interactions between MTHFR C677T and MTRR A66G inflating homocysteine levels. The meta-analysis showed MTHFR to be a genetic risk factor for autism in both fixed-effects (odds ratio: 1.47, 95% confidence interval: 1.31–1.65) and random-effects (odds ratio: 1.57, 95% confidence interval: 1.16–2.11) models. The meta-analysis of nine studies showed hyperhomocysteinemia as a significant risk factor for autism in both fixed-effects (P<0.0001) and random-effects (P=0.026) models. Conclusion Genetic polymorphisms of the folate pathway were moderate predictors of autism risk. MTHFR C677T and hyperhomocysteinemia have been identified as risk factors for autism worldwide. Synergistic interactions between MTHFR C677T and MTRR A66G increase homocysteine.

FOXN1 Italian founder mutation in Indian family: Implications in prenatal diagnosis

The Forkhead box N1 (FOXN1) is a transcriptional factor regulating the development, differentiation and function of thymic epithelial cells; maintaining T-lineage progenitors in bone marrow; promoting terminal differentiation of epithelial cells of hair follicles. Mutation in FOXN1 was reported to cause a rare disorder characterized by rudimentary thymus gland, T-cell immunodeficiency, congenital alopecia and nail dystrophy within an Italian community. This is the first report of FOXN1 p.R255X mutation from India, outside this endogamous Italian community. Out of the two affected children, only one was alive during the genetic evaluation and had all the clinical manifestations such as alopecia totalis and nail dystrophy. The proband was homozygous for FOXN1 p.R255X Italian founder mutation. The carrier status of both the parents was established. Immunological study of the proband revealed total absence of T-cells confirming T-cell immunodeficiency. Prenatal diagnosis during third pregnancy revealed absence of FOXN1 mutation. To conclude, this is the first report of FOXN1 mutation from India highlighting that diseases once confined to certain geographical areas are spreading across the globe probably due to human migrations.

Targeted exome sequencing for the identification of complementation groups in methylmalonic aciduria: A south Indian experience

OBJECTIVES In view of high incidence of methylmalonic aciduria (MMA) among South Indians, we have performed clinical, biochemical and molecular genetic evaluation of fifteen patients. DESIGN AND METHODS Targeted exome sequencing was performed for a panel of MMA causing genes i.e. MUT, ABCD4, ACSF3, CD320, LMBRD1, MCEE, MMAA, MMAB, MMACHC, MMADHC. RESULTS Methylmalonyl-CoA mutase (MUT), MMAB and MMAA genetic variants were found to contribute towards 40%, 33.3% and 6.6% etiology, respectively. Early onset of the disease (during the neonatal period) and presence of MUT and MMAB genetic variants was shown to be associated with higher mortality. The patients with MMAA variants had a milder disease. Among the identified mutations, 66% were already known. Three novel mutations, i.e.MUTp.Ala376Serfs, MMAB p.Glu112* and MMAA p.Tyr24* were identified. We also report three novel variants with predicted pathogenicity, MMAA intron 3 c.562+1_562+2insT, p.Ala668Pro in exon 12 of one of the alleles of the MUT gene and c.519+1G>A in intron 6 of one of the alleles in MMAB gene. We performed prenatal diagnosis in five of these families. CONCLUSIONS MMA among South Indian patients is genetically heterogeneous, caused by different complementation groups. Both B12-responsive and non-responsive patients were diagnosed. In biochemically diagnosed patients, targeted exome sequencing is cost effective to identify different MMA causing mutations and facilitate genetic counseling.

Identification of Two Novel Mutations in Aminomethyltransferase Gene in Cases of Glycine Encephalopathy

In this study, we report three cases of nonketotic hyperglycinemia (NKHG) diagnosed biochemically and molecularly. Clinical exome analysis in two families revealed two novel mutations in the aminomethyltransferase (AMT) gene, that is, c.14_15insT (p.Ser6LysfsTer22) and c.259-2A > T, both of them adversely affecting the protein. This is the first report of AMT gene mutations in NKHG from India. Prenatal diagnosis in the first family showed an unaffected fetus in the third pregnancy. The role of AMT protein is pivotal for the synthesis of 5,10-methylene tetrahydrofolate, the first metabolite in one-carbon metabolism that regulates DNA synthesis, repair, and methylation.

SLC25A13 c.1610_1612delinsAT mutation in an Indian patient and literature review of 79 cases of citrin deficiency for genotype-phenotype associations

Here, we report SLC25A13 c.1610_1612delinsAT mutation from India in a 13-year old boy who presented with recurrent episodes of delirium and hyperammonemia. This is the second case with this mutation; the first case was of Pakistani origin. The boy responded to diet modification, sodium benzoate and arginine supplementation. Furthermore, we have aimed to establish genotype-phenotype correlation of 79 cases of citrin deficiency (46 males and 33 females) reported in 24 studies from all over the world. Inverse association was observed between age of onset and jaundice (r = -0.73). Late age of onset was associated with delirium (r = 0.61), aggressive behaviour (r = 0.67), altered sensorium (r = 0.67) and tremors (r = 0.65). The most common mutations associated with citrin deficiency were c.851_854del4, IVS16ins3kb, 1638-1660dup with a frequency of 42.41%, 16.46% and 6.33%, respectively. The c.851_854del4 mutation showed positive association with alpha feto protein (r = 0.40), ammonia (r = 0.50) and tyrosine (r = 0.40) while showing inverse association with threonine (r = -0.55). The IVS16ins3kb mutation was associated with high total (r = 0.65) and conjugated bilirubin (r = 0.54) along with high aspartate transaminase (r = 0.49) while citrulline levels are lower (r = -0.36). To conclude, all cases of intrahepatic cholestasis and neuropsychiatric abnormalities should be evaluated for citrin deficiency. However, the ethnic group-specific mutation frequencies should be considered in implementing screening.

Neuro-fuzzy model of homocysteine metabolism

In view of well-documented association of hyperhomocysteinaemia with a wide spectrum of diseases and higher incidence of vitamin deficiencies in Indians, we proposed a mathematical model to forecast the role of demographic and genetic variables in influencing homocysteine metabolism and investigated the influence of life style modulations in controlling homocysteine levels. Total plasma homocysteine levels were measured in fasting samples using reverse phase HPLC. Multiple linear regression (MLR) and neuro-fuzzy models were developed. The MLR model explained 64% variability in homocysteine, while the neuro-fuzzy model showed higher accuracy in predicting homocysteine with a mean absolute error of 0.00002

Adaptive developmental plasticity in methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism limits its frequency in South Indians

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