Search

Background: Joubert syndrome and related disorders are a group of ciliopathies characterized by mid-hindbrain malformation, developmental delay, hypotonia, oculomotor apraxia, and breathing abnormalities. Molar tooth sign in brain imaging is the hallmark for diagnosis. Joubert syndrome is a clinically and genetically heterogeneous disorder involving mutations in 35 ciliopathy-related genes. We present a large cohort of 59 patients with Joubert syndrome from 55 families. Molecular analysis was performed in 35 families (trio).Methods: Clinical exome analysis was performed to identify causal mutations, and genotype-phenotype correlations were evaluated.Results: All of the cases were stratified into pure Joubert syndrome (62.7%), Joubert syndrome with retinal disease (22.0%), polydactyly (8.5%), and liver (1.7%) and kidney (1.7%) involvement. Joubert syndrome-related disorders include Meckel-Gruber syndrome in 5.1% cases and Leber congenital amaurosis (1.7%). Of the 35 Joubert syndrome-related genes, 11 were identified in these patients, i.e., CEP290, C5ORF, TCTN1, CC2D2A, RPGRP1L, TCTN3, AHI1, INPP5E, TCTN2, NPHP1, and TMEM237. For the first time, we identified a ciliopathy gene, CCDC28B, as a causal gene in Joubert syndrome in one family. CEP290 accounted for 37.8% cases of pure Joubert syndrome, Joubert syndrome with retinal and renal disease, and Meckel-Gruber syndrome. The p.G1890∗ allele in CEP290 is highly recurrent. Of the six families with Joubert syndrome who had a prenatal diagnosis, one fetus was normal, two were carriers, and three were affected.Conclusions: This is the largest study of Joubert syndrome from India. Although a high degree of locus and allelic heterogeneity was observed, CEP290 variants were the most common among these patients. [ABSTRACT FROM AUTHOR]

Objective: The primary objective was to evaluate the feasibility of setting up newborn screening in rural areas in India. Secondary objective was to enhance the knowledge and awareness towards early detection of diseases by newborn screening, management of the affected baby and to impart genetic counseling.Methods: Awareness programs were conducted at different mandals in the district for the medical practioners during the preparatory phase of the Task Force Project. Educative lectures and clinical meetings regarding the importance and relevance of newborn screening were held every 3 months initially and half yearly later. Families were counselled during antenatal check-ups.Results: Good co-operation was obtained from medical doctors and their willingness to participate in sample collection from the hospitals. Families accepted screening after an initial period of resistance. The fact that screening of this kind will help their babies made a positive impact. Many families started promoting newborn screening to their friends and relations. Confirmation of diagnosis, treatment, and follow-up were satisfactory with almost negligible number of cases lost to follow-up.Conclusions: With proper planning and commitment on the part of health authorities, it is possible to implement newborn screening in rural areas in India as well. [ABSTRACT FROM AUTHOR]

Abstract: Beta-ketothiolase deficiency, or mitochondrial acetoacetyl-CoA thiolase (T2) deficiency, is a rare autosomal recessive disorder affecting isoleucine catabolism and ketone body metabolism. A patient from South India presented with acute ketoacidosis at 11months of age. During the acute crisis the C5OH (2-methyl-3-hydroxybutyryl) carnitine and C5:1 (tiglyl) carnitine were elevated and large amounts of 2-methyl-3-hydroxybutyrate, tiglylglycine, and 2-methylacetoacetate were excreted. Brain CT showed bilateral basal ganglia lesions. Potassium ion-activated acetoacetyl-CoA thiolase activity was deficient in the patient’s fibroblasts. The patient is a homozygote for a novel c.578T>G (M193R) mutation. This is the first report of T2 deficiency confirmed by enzyme and molecular analysis from India. [Copyright &y& Elsevier]

In the current study, we report three cases of Asparagine Synthetase (ASNS) Deficiency from two consanguineous families. Family 1 had two early neonatal deaths due to a novel mutation in the ASNS gene c.788C > T (p.S263F) and both the children presented with microcephaly and one of them had severe intracranial haemorrhage. The proband from the second family was homozygous for c.146G > A (p.R49Q) and manifested myoclonic seizures, developmental delay, coarse hair and diffuse cortical atrophy. Molecular docking studies of both the mutations revealed alteration in the ligand binding site. Till date, 26 mutations were reported in ASNS gene in 29 affected children indicating high degree of genetic heterogeneity and high mortality. Although asparagine depletion is not of diagnostic utility, multiple linear regression model suggested that asparagine levels vary to the extent of 20.6% based on glutamine and aspartate levels and ASNS deficiency results in depletion of asparagine synthesis. ASNS deficiency should be suspected in any neonate with microcephaly and epileptic encephalopathy., (Copyright © 2019. Published by Elsevier B.V.)

The rationale of the current study was to elucidate the contributing factors for the gender-based differences in total plasma homocysteine levels. A total of 413 subjects comprising of 293 men and 120 women were enrolled for the study. Chemiluminescence technology for vitamin B 12 , folate and total plasma homocysteine; ELISA for estradiol and 8-oxo-2-deoxyguanosine; Ellman's method for total glutathione; and PCR-RFLP analysis for the detection of methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism were employed. No statistically significant differences were observed between the men and women in the distribution of age (p = 0.82), vitamin B 12 (p = 0.23), folate (p = 0.36) and MTHFR C677T polymorphism (p = 0.35). However, the total plasma homocysteine levels were higher in men compared to women (28.4 ± 17.9 vs. 20.6 ± 13.6 μmol/L, p < 0.0001). In order to explain this gender differences in homocysteine, adaptive neuro-fuzzy inference systems (ANFIS) were developed to understand trivariate interactions among estradiol, glutathione and homocysteine. In the presence of adequate estradiol levels, inverse association was observed between glutathione and homocysteine. This association is lost when estradiol levels were inadequate. Estradiol was found to quench homocysteine mediated oxidative DNA damage. Irrespective of gender, combined deficiency of vitamin B 12 and folate showed positive association with hyperhomocysteinemia and vice versa. Homocysteine reduction in response to vitamin status varied according to gender with men responding to folate and women responding to B 12 . To conclude, gender-differences in homocysteine are attributable estradiol mediated lowering of homocysteine that prevents inactivation of glutathione mediated oxidative defense in women., (Copyright © 2017 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Glutaric aciduria type I is an autosomal recessive organic acid disorder. The primary defect is the deficiency of Glutaryl-CoA dehydrogenase (EC number 1.3.99.7) enzyme that is involved in the catabolic pathways of the amino acids l-lysine, l-hydroxylysine, and l-tryptophan. It is a treatable neuro-metabolic disorder. Early diagnosis and treatment helps in preventing brain damage., Methods: The Glutaryl-CoA dehydrogenase gene (GCDH) gene was sequenced to identify disease causing mutations by direct sequencing of all the exons in twelve patients who were biochemically confirmed with GA I., Results: We identified eleven mutations of which nine are homozygous mutations, one heterozygous and two synonymous mutations. Among the eleven mutations, four mutations p.Q162R, p.P286S, p.W225X in two families and p.V410M are novel. A milder clinical presentation is observed in those families who are either heterozygous or with a benign synonymous SNP. Multiple sequence alignment (MSA) of GCDH with its homologues revealed that the observed novel mutations are not tolerated by protein structure and function., Conclusions: The present study indicates genetic heterogeneity in GCDH gene mutations among South Indian population. Genetic analysis is useful in prenatal diagnosis and prevention. Mutation analysis is a useful tool in the absence of non-availability of enzyme assay in GA I., (Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: To estimate total plasma homocysteine levels in Indian newborns by modifying the existing SBD-F based High performance liquid chromotography (HPLC) method in order to enable analysis in newborn heel-prick samples and assess the prevalence of hyperhomocysteinemia in Indian newborns who are exclusively breast-fed., Methods: Reverse-phase HPLC with fluorescence detection for plasma homocysteine estimation and statistical analysis using student t-test., Results: SBD-F based HPLC method was modified and Bland and Altman analysis was carried out to assess agreement between original and modified methods. The correlation co-efficient was 0.994. The limits of agreement (-5.9, 6.3) were small enough to apply new method in place of the old for heel-prick sample analysis. Total plasma homocysteine analysis was carried out on heel-prick samples of 607 randomly selected newborns (331 males and 276 females). The mean plasma homocysteine estimated by this method in Indian newborns was 6.99 (95% CI: 6.48-7.49) with no appreciable gender effect (P=0.74). Elevated homocysteine levels were observed in 31 males and 21 females., Conclusions: Modified HPLC method is validated and can be used for homocysteine analysis on newborn heel-prick samples. Using this method, the prevalence of hyperhomocysteinemia in Indian newborns is 8.6%.