Sarita Agarwal

Profiling β-thalassaemia mutations in India at state and regional levels: implications for genetic education, screening and counselling programmes

Thalassaemia and sickle cell disease have been recognized by the World Health Organization as important inherited disorders principally impacting on the populations of low income countries. To create a national and regional profile of β-thalassaemia mutations in the population of India, a meta-analysis was conducted on 17 selected studies comprising 8,505 alleles and offering near-national coverage for the disease. At the national level 52 mutations accounted for 97.5% of all β-thalassaemia alleles, with IVSI-5(G>C) the most common disease allele (54.7%). Population stratification was apparent in the mutation profiles at regional level with, for example, the prevalence of IVSI-5(G>C) varying from 44.8% in the North to 71.4% in the East. A number of major mutations, such as Poly A(T>C), were apparently restricted to a particular region of the country, although these findings may in part reflect the variant test protocols adopted by different centres. Given the size and genetic complexity of the Indian population, and with specific mutations for β-thalassaemia known to be strongly associated with individual communities, comprehensive disease registries need to be compiled at state, district and community levels to ensure the efficacy of genetic education, screening and counselling programmes. At the same, time appropriately designed community-based studies are required as a health priority to correct earlier sampling inequities which resulted in the under-representation of many communities, in particular rural and socioeconomically under-privileged groups.

Prevention of homozygous beta thalassemia by premarital screening and prenatal diagnosis in India

To determine the feasibility and acceptability of premarital screening for beta thalassemia/related hemoglobinopathies followed by prenatal diagnosis in India.

Huntington's disease: An update of therapeutic strategies

Huntingtons disease (HD) is an autosomal dominant triplet repeat genetic disease, which results in progressive neuronal degeneration in the neostriatum and neocortex, and associated functional impairments in motor, cognitive, and psychiatric domains. Although the genetic mutation caused by abnormal CAG expansion within the htt gene on chromosome 4p16.3 is identified, the mechanism by which this leads to neuronal cell death and the question of why striatal neurones are targeted both remain unknown. Patients manifest a typical phenotype of sporadic, rapid, involuntary control of limb movement, stiffness of limbs, impaired cognition and severe psychiatric disturbances. There have been a number of therapeutic advances in the treatment of HD, such as fetal neural transplantation, RNA interference (RNAi) and transglutaminase inhibitors (Tgasei). Although there is intensive research into HD and recent findings seem promising, effective therapeutic strategies may not be developed until the next few decades.

Genetic insight of schizophrenia: past and future perspectives.

Schizophrenia (SCZ) has a heritability of about 80%, and the search for the genetic basis of this disease has been frustrating. Because schizophrenia has no distinguishing pathology or diagnostic criteria, it is difficult to relate gene changes to discrete physiological or biochemical changes associated with the disease. Schizophrenia fits the profile of a complex disorder in which multiple genes interact along with environmental influences to produce a range of phenotypes. There is accumulating evidence that both common genetic variants with small effects and rare genetic lesions with large effects determine risk of SCZ. As recently shown, thousands of common single nucleotide polymorphisms (SNPs), each with small effect, cumulatively could explain about 30% of the underlying genetic risk of SCZ. The ability of positional genetics to implicate novel genes and pathways will open up new vistas for neurobiological research, and all the signs are that genetic research is poised to deliver crucial insights into the nature of schizophrenia. In this review, we outline a general theoretical background of genetic mechanisms involved in SCZ.

Preeclampsia in North Indian women: the contribution of genetic polymorphisms.

Aim:  To find association of angiotensin‐converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen (AGT) T704C, methylenetetrahydrofolate reductase (MTHFR) C677T and factor V Leiden (FVL) G1691A polymorphisms with pre‐eclampsia (PE) in North Indian women.

Geographic and Ethnic Distribution of β-Thalassemia Mutations in Uttar Pradesh, India

We have studied the geographic and ethinic distribution of mutations in 376 subjects who were carriers of β-thalassemia, and identified the mutations in 365 chromosomes. The majority of the β-thalassemia carriers were of Uttar Pradesh (India) origin. Their pattern of mutations differed from the other states of India and from those families who had migrated from Pakistan. The frequency of the NS-I-5 (G→C) and 619 bp deletion mutations were 64.3 and 2.5%, respectively, among families originating from Uttar Pradesh, compared to a prevalence of 37.5 and 27.5%, respectively in the population of Pakistani immigrants. Of the 10 common Asian Indian mutations, only eight were observed in subjects studied from different parts of India. By use of the amplification refractory mutation system along with DNA sequencing techniques, the mutations were successfully identified in 97.1% of subjects, while 11 cases (2.9%) still remain to be characterized by single strand conformation polymorphism and sequencing analyses. The application of this knowledge has facilitated the successful implementation of the program of genetic counseling and prenatal diagnosis of β-tbalassemia, thus helping to avoid the birth of an affected child in India.

Susceptibility of glucose-6-phosphate dehydrogenase deficient red cells to primaquine enantiomers and two putative metabolites-I: effect on reduced glutathione, methemoglobin content and release of hemoglobin

The effects of the primaquine (PQ) enantiomers, (+)PQ and (-)PQ, and two putative metabolites [5-hydroxyprimaquine (5HPQ) and 6-desmethyl-5-hydroxyprimaquine (6D5HPQ)] on methemoglobin (Met Hb) and glutathione content and release of hemoglobin into plasma from glucose-6-phosphate dehydrogenase (G-6-PD) deficient red cells were studied in vitro. The results show that a 1.5 mM concentration of (-)PQ produced a significantly greater increase in Met Hb content and decrease in reduced glutathione (GSH) level than did (+)PQ. However, the release of plasma hemoglobin was greater with (+)PQ than with (-)PQ. The hydroxy derivatives of primaquine, 5HPQ and 6D5HPQ, were significantly more active than PQ. Their individual effects differed; whereas 5HPQ produced significantly greater reduction in GSH compared to 6D5HPQ, the effect of 6D5HPQ on Met Hb content and release of plasma hemoglobin was greater than that of 5HPQ. The qualitative effects of these compounds on normal, heterozygous and hemizygous G-6-PD deficient red cells were similar, but quantitatively the effects were greatest on hemizygous G-6-PD deficient cells and intermediate on heterozygous cells.

Is radiology a determinant of pain, stiffness, and functional disability in knee osteoarthritis? A cross-sectional study

Background and purposesDiscordance between clinical and radiological profiles in knee osteoarthritis has been reported. We hypothesized that the discordance could be due to limited radiological variables studied. This study essentially analyzed many more radiological features than previous studies in order to seek an association between clinical and radiographic features.MethodsOne hundred and eighty patients with knee osteoarthritis were enrolled as per the American College of Rheumatology (ACR) guidelines. Visual analog scale (VAS) for knee pain and the knee-specific Western Ontario Mac University (WOMAC) index for pain, stiffness, and disability were recorded. Five additional radiological features apart from those in the Kellgren-Lawrence (KL) classification grading system were recorded by two authors who were blinded to the clinical diagnosis. The variables significantly associated were analyzed by linear regression model.ResultsPain was significantly associated with increasing KL grades; physical function was nearly significant and stiffness was not. On analysis of individual radiological features, WOMAC pain was significant with subchondral sclerosis, joint space width, and tibiofemoral alignment although the correlation was week. VAS pain was significant with the latter two and with articular incongruity. Functional disability was associated with medial joint-space narrowing, tibiofemoral alignment, loose bodies, and juxta-articular osteopenia. However, in the linear regression model, pain and stiffness were significantly associated with articular incongruity and functional disability and total clinical scores with juxta-articular osteopenia.ConclusionWhen the radiological features were extended beyond those included in KL grades, pain, stiffness, and disability correlated well with radiography; articular incongruity with pain and stiffness; and juxta-articular osteopenia with physical disability and clinical severity.

MTHFR 677C→T and 1298A→C Polymorphisms: Evaluation of Maternal Genotypic Risk and Association with Level of Neural Tube Defect

Background: Neural tube defects (NTDs) are common birth defects (1 in 1,000) leading to significant morbidity and mortality. Periconceptional folic acid supplementation helps in prevention of 70% of NTDs. Recently, polymorphisms in genes encoding enzymes of the folate pathway have been implicated in causation of NTDs. Since the closure of neural tube occurs at multiple sites, the etiology of defect at different sites may be different – which explains the failure of folic acid supplementation to prevent all NTDs. Methods: Molecular analysis of methylenetetrahydrofolate reductase polymorphisms was carried out using polymerase chain reaction and restriction enzyme digestion. We studied the association of these polymorphisms in mothers with a previous child with NTD and further refined the risk by stratification based on level of defect. Results: The frequency of 677C→T homozygotes was higher in mothers with a previous child with NTD than the controls (OR = 1.6 (0.38–6.7), 95% CI, p = 0.72) but the difference was statistically insignificant. There was a significant difference in frequency of T alleles among mothers with a previous child with a ‘lower’ type of defect compared to controls (OR = 2.15 (1.13–4.1), 95% CI, p = 0.02). We did not find any significant association of 1298A→C polymorphism with the level of NTDs. Conclusions: We conclude that in the North Indian population, the 677C→T allele of the MTHFR gene may be associated with the occurrence of a lower type of NTD. This points towards the differential role of thermolabile MTHFR at different sites of neural tube closure.

Myotonic dystrophy type 1 (DM1): a triplet repeat expansion disorder.

Myotonic dystrophy is a progressive multisystem genetic disorder affecting about 1 in 8000 people worldwide. The unstable repeat expansions of (CTG)n or (CCTG)n in the DMPK and ZNF9 genes cause the two known subtypes of myotonic dystrophy: (i) myotonic dystrophy type 1 (DM1) and (ii) myotonic dystrophy type 2 (DM2) respectively. There is currently no cure but supportive management helps equally to reduce the morbidity and mortality and patients need close follow up to pay attention to their clinical problems. This review will focus on the clinical features, molecular view and genetics, diagnosis and management of DM1.