A novel missense mutation in glucose-6-phosphate dehydrogenase gene causing chronic nonspherocytic hemolytic anemia in an Indian family.
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Anemia, Hemolytic, Congenital Nonspherocytic↗
Biomedical subjects
Mammen Chandy
Publications and source records attributed to Mammen Chandy.
Molecular diversity of Glanzmann thrombasthenia in southern India: new insights into mRNA splicing and structure-function correlations of alphaIIbbeta3 integrin (ITGA2B, ITGB3).
The molecular basis of Glanzmann thrombasthenia (GT) was studied in 40 families from southern India. Of 23 identified mutations (13 in the alphaIIb (ITGA2B) gene and 10 in the beta3 (ITGB3) gene), 20 were novel and three were described previously. Three mutations in the beta3 gene-p.Leu143Trp (Leu117Trp), p.Tyr307Stop (Tyr281Stop), and p.Arg119Gln (Arg93Gln)-were detected in 12, three, and two families, respectively, with definite founder effects observed for the first two mutations. Alternative splicing was predicted in silico for the normal variant and a missense variant of the beta3 gene, and for 10/11 frameshift or nonsense mutations in alphaIIb or beta3. The prediction was confirmed experimentally for a c.2898_2902dupCCCCT mutation in exon 28 of the alphaIIb gene that induced exon skipping. Seven out of nine missense mutations substituted highly conserved amino acids buried in the proteins' cores, predicting structural abnormalities. Among these, a beta3 substitution, p.Cys39Gly (Cys13Gly) was found to cause intracellular degradation of the beta3 subunit, in contrast to previous findings that mutations at Cys435, the partner of Cys13 in a disulfide bond, cause constitutive activation of alphaIIbbeta3. The two patients with a beta3 Arg93Gln mutation had normal clot retraction, consistent with a recent finding that this substitution is associated with normal surface expression of alphaIIbbeta3. In conclusion, this study demonstrates that a variety of mutations account for GT in southern Indian patients, provides new insights into mRNA splicing, and highlights the role of specific amino acids in structure-function correlations of alphaIIbbeta3.
Alternative Splicing↗
Infections in children undergoing allogeneic bone marrow transplantation in India.
We studied the clinical profile of infections among 221 pediatric patients who underwent 230 allogeneic transplants between 1986 and June 2004. All patients developed febrile neutropenia. There were 283 documented infections, which included bacterial (36.9%), viral (45.7%), fungal (11.1%) and other infections (6.3%) including tuberculosis. Bacterial and fungal infections were more common in the first 30 days following BMT, while viral infections were more common >30 days after BMT. Bacterial pathogens were predominantly gram-negative organisms (72.7%), when compared with gram-positive organisms (27.3%). Common gram-negative organisms included NFGNB, Pseudomonas, Escherichia coli and Klebsiella while coagulase negative Staphylococci was the main gram-positive organism. Bacteremia (61.2%) was the main source positive cultures and was mainly because of gram-negative organisms (81%), predominantly NFGNB and Pseudomonas. Exactly 103/221(43.7%) transplants had 128 documented viral infections commonly because of Cytomegalovirus, Herpes group of viruses and transfusion related hepatitis. Thirty of 221 (13.5%) of transplants had 30 documented fungal infections with the majority being because of aspergillus (90%). Tuberculosis was seen in 1.7% of transplants while catheter infections were seen in 21 patients (9.1%). Infection related mortality was seen in 12% predominantly because of CMV or fungal infections. A sub group analysis (pre-1998 vs. post-1998) revealed higher incidences of gram-negative infections, bacteremia and bacterial infection related mortality in the pre-1998 era when compared with the recent times. The profile and mortality of infections in this series from India is not significantly different from reports from the West.
Adolescent↗
Mutations in coagulation factor XIII A gene in eight unrelated Indians. Five novel mutations identified by a novel PCR-CSGE approach.
Factor XIII deficiency is a rare autosomal (1:2,000,000) recessive disorder of blood coagulation usually attributed to mutations in the coagulation factor XIII (FXIII) A gene. We have studied the molecular basis of FXIII deficiency in eight unrelated South Indian patients. Their diagnosis was based on clinical history, normal plasma clotting times and increased solubility of fibrin clot in 5 mol/l urea. Genomic DNA was screened for FXIII A gene defects by a novel PCR and CSGE strategy. Mutations were identified in all these patients. Five of these were novel mutations occurring in four patients. These included a novel c.210T > G transversion in homozygosity in exon 3 predicting a Tyr69X in the beta-sandwich domain in one patient. Another patient was compound heterozygote for a novel c.791C > T transition predicting a Ser263Phe in the core domain and a novel c.2045-1G > A transition at the acceptor splice junction of intron 14. Two novel frame shifts were also identified in two patients in a homozygous condition. One of them resulted from a single base 'G' duplication (c.892_895dupG) at codons Ser290/Ala291fs affecting the core domain and the other was due to a single base 'A' duplication (c.1642_1644dupA) and at codonTyr547fs affecting barrel-1 domain. The remaining four patients had the previously reported Arg260His, Ser413Leu, and Val414Phe (n = 2) missense mutations in the core domain. The novel mutations identified were considered to be disease causative by studying the nature of mutation, the degree of conservation of the mutated aminoacid among transglutaminases of different species and by molecular modeling. Apart from describing a significant number of novel mutations, this report is the first study from Southern India to describe FXIII A gene mutations.
Adolescent↗
Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity.
Arsenic trioxide, as a single agent, has proven efficacy in inducing molecular remission in patients with acute promyelocytic leukemia (APL). There is limited long-term outcome data with single-agent As2O3 in the management of newly diagnosed cases of APL. Between January 1998 to December 2004, 72 newly diagnosed cases of APL were treated with a regimen of single-agent As2O3 at our center. Complete hematologic remission was achieved in 86.1%. At a median follow-up of 25 months (range: 8-92 months), the 3-year Kaplan-Meier estimate of EFS, DFS, and OS was 74.87% +/- 5.6%, 87.21% +/- 4.93%, and 86.11% +/- 4.08%, respectively. Patients presenting with a white blood cell (WBC) count lower than 5 x 10(9)/L and a platelet count higher than 20 x 10(9)/L at diagnosis (n = 22 [30.6%]) have an excellent prognosis with this regimen (EFS, OS, and DFS of 100%). The toxicity profile, in the majority, was mild and reversible. After remission induction, this regimen was administered on an outpatient basis. Single-agent As2O3, as used in this series, in the management of newly diagnosed cases of APL, is associated with responses comparable with conventional chemotherapy regimens. Additionally, this regimen has minimal toxicity and can be administered on an outpatient basis after remission induction.
Adolescent↗
Management of hemophilia with minimal factor replacement in developing countries: role of ancillary therapy.
Compared with developed countries, the care of hemophiliacs in still relatively poor in developing countries. There are three major factors that influence this problem: inadequate knowledge, lack of laboratories to diagnose the disorder, and inadequate supply of factor concentrates. It is important that healthcare providers and family members of these patients be adequately educated about all of the aspects of hemophilia. Basic laboratories could be established at a reasonable price, technical personnel could be trained, and quality-assurance programs could be initiated. Even in the absence of high-quality factor concentrates, which are expensive, there are affordable means to manage these patients, although certainly not optimally. To overcome these problems, hemophilia care services need to be established and integrated to facilitate the basic needs for these patients.
Blood Coagulation Factors↗
Surgery for hemophilia in developing countries.
Surgical interventions in patients with hemophilia (PWH) in the developing world are difficult in the setting of limited availability of factor concentrates. Although the adequacy of international guidelines for factor concentrate prophylaxis for PWH undergoing surgery has been established, frequently it is not practical in the developing world. These recommendations were not established based on large clinical trials and fail to define the safe lower limit of factor concentrate prophylaxis for surgery. The need to define these lower limits is essential in the developing world so that the limited resources may be used optimally for the cohort of PWH. There are limited data from the developing world with regard to PWH undergoing surgical procedures. In this article, we outline experience from our institution, a tertiary referral center for hemophilia care in India. We trace the basis on which our current factor concentrate prophylaxis regimen (which is lower than that recommended internationally) was established. In our experience our low-dose protocols are effective, reduce factor consumption by one third, and are not associated with a significantly increased risk of delayed hemorrhage. We hope that this experience will form a framework on which guidelines can be established for developing countries.
Blood Coagulation Factors↗
Hyperbilirubinemia in homozygous HbE disease is associated with the UGT1A1 gene polymorphism.
Homozygous HbE [beta26(B8)Glu-->Lys] is a clinically mild disorder with no significant symptoms. However, we have frequently noted hyperbilirubinemia among patients with homozygous HbE in the Indian population, with jaundice being the major complaint at presentation. A study of the UGT1A1 gene polymorphism shows that the variant TA7 in the promoter region of the UGT1A1 gene is associated with hyperbilirubinemia in homozygous HbE patients.
Female↗
Compound heterozygosity for Hb E and Hb Lepore-Hollandia in India; first report and potential diagnostic pitfalls.
A compound heterozygous state of Hb E [beta26(B8)Glu-->Lys] with Hb Lepore is rare with very few cases reported in the literature. This report describes the first such case from India. The clinical features and hemoglobin (Hb) analysis mimic Hb E-beta-thalassemia (thal) but with a mild phenotype. Detection was made possible in this case because DNA analysis gave discrepant results suggestive of homozygous Hb E. As this was inconsistent with the clinical phenotype and Hb analysis, further evaluation was undertaken that confirmed the presence of Hb Lepore. This study shows that cases of Hb E/Lepore may remain undetected unless family studies and/or detailed DNA analyses in patients diagnosed to have Hb E-beta-thal are performed.
Adolescent↗
Dapsone for chronic idiopathic thrombocytopenic purpura in children and adults--a report on 90 patients.
Data on 90 patients (55 adults and 35 children) with chronic idiopathic thrombocytopenic purpura (ITP) and a platelet count of <50 x 10(9)/L treated with dapsone at a dose of 1-2 mg/kg/d are presented. A response was observed in 57 (63.3%) patients. The average time for response was 3.5 months (range 1-9) and the average duration of treatment with dapsone was 10.4 months (range 4-14). Overall response rates of 65.7% and 61.8% were observed in children and adults respectively. Side effects requiring discontinuation of therapy were observed in three (2%) patients. These results demonstrate that dapsone is an effective, inexpensive and well-tolerated treatment for chronic ITP, in both children and adults and could be considered for patients who fail steroid therapy.
Adolescent↗
Hb Showa-Yakushiji [beta110(G12)Leu-->Pro] in four unrelated patients from west Bengal.
A T-->C mutation in the beta-globin gene at codon 110 that produces the hyper unstable variant Hb Showa-Yakushiji was identified in four unrelated individuals in India. It was found in a compound heterozygous state with other mutations producing beta-thalassemia (thal) or Hb E [beta26(B8)Glu-->Lys]. The mutation producing this abnormal hemoglobin (Hb) was found on the same haplotype in all these patients but differed from the Japanese haplotype, indicating its independent origin in India.
Adolescent↗
Molecular characterization of factor IX gene mutations in 53 patients with haemophilia B in India.
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Factor IX↗
Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation.
Hepatic venoocclusive disease (HVOD) in bone marrow transplantation (BMT) is attributed to toxicity of cytoreductive agents, especially busulfan and cyclophosphamide, in the conditioning therapy. Busulfan, as well as the metabolites of cyclophosphamide, are conjugated with glutathione (GSH), catalyzed by enzymes of the glutathione S-transferase (GST) family. To assess the impact of polymorphisms of the GST genes, GSTM1 and GSTT1, on the risk of HVOD, we evaluated 114 consecutive patients with beta-thalassemia major undergoing BMT. There was a significantly increased incidence of HVOD in patients with the GSTM1-null genotype compared with those with the GSTM1-positive genotype (46.5% vs 18.3%; P =.001). Pharmacokinetic analysis in these patients showed that the clearance of busulfan was higher and first-dose steady-state concentration was lower among those with HVOD (0.403 +/- 0.06 vs 0.33 +/- 0.071 L/h/kg, Student t test P value =.000 01; and 508 +/- 125 vs 656 +/- 255 ng/mL, t test P value =.001, respectively). We conclude that the GSTM1-null genotype predisposes to HVOD, and the sinusoidal endothelial cells and hepatocyte damage may be mediated by metabolites of busulfan through depletion of the cellular GSH pool.
Adolescent↗
Molecular remission with arsenic trioxide in patients with newly diagnosed acute promyelocytic leukemia.
Thirty six APML patients achieving hematological remission with As2O3 were serially monitored using RT-PCR. Though only 5.5% achieved molecular remission at induction remission, 94.5% became negative during consolidation. At 20 months follow-up, 85% remain in remission but longer follow up studies are needed to monitor late relapses.
Adolescent↗
Hb Lepore in the Indian population.
A study of the spectrum of beta-thalassemia mutations in 230 patients with thalassemia major and 90 patients with thalassemia intermedia revealed mutations producing Hb Lepore in four patients. Two were homozygous and two were compound heterozygous for Hb Lepore and beta-thalassemia. Among the six delta beta fusion genes found in these four patients five were those producing Hb Lepore-Hollandia and one producing Hb Lepore-Washington-Boston. We also describe a possible misdiagnosis in the heterozygous state of Hb Lepore, as Hb Lepore and Hb A2 are not distinctly separated by cation exchange high performance liquid chromatography.
Base Sequence↗
Rapid detection of beta-globin gene mutations and polymorphisms by temporal temperature gradient gel electrophoresis.
BACKGROUND: Inherited hemoglobin disorders represent the most common Mendelian disease worldwide. Prevention programs based on molecular diagnosis of heterozygous carriers and/or patients require the use of reliable mutation scanning methods in at-risk populations. METHODS: We developed a rapid and highly specific mutation-screening test based on temporal temperature gradient gel electrophoresis (TTGE). We analyzed 889 beta-thalassemia genes from homozygous beta-thalassemia patients and unrelated individuals with heterozygous beta-thalassemia. Previously reported common mutations were screened by reverse dot blots using allele-specific probes. The rare mutations were analyzed by TTGE. RESULTS: We found common mutations in 753 beta-thalassemia genes. TTGE analysis in the rest of the genes showed the presence of mutations in different regions of the beta-globin gene in 134 of them, and these mutations were characterized by DNA sequencing. In the two genes in which mutations were not identified, large deletions spanning beta-globin gene were suspected. CONCLUSIONS: Compared with other approaches for comprehensive mutation screening, the reported method is rapid, highly sensitive, cost-effective, and suitable for high-throughput screening of a large number of samples.
Electrophoresis, Polyacrylamide Gel↗
Asymptomatic constitutional macrothrombocytopenia among West Bengal blood donors.
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Bernard-Soulier Syndrome↗
Etiology of diarrhea in patients undergoing allogeneic bone marrow transplantation in South India.
BACKGROUND: No studies so far have examined enteric infections in patients undergoing bone marrow transplantation (BMT) in developing countries where asymptomatic carriage and colonization with enteric pathogens is frequent. METHODS: A prospective study followed 65 patients who underwent BMT in South India between 1995 and 1998. Patients were screened for enteric pathogens before transplantation, weekly during the first 4 weeks after transplantation, and during all episodes of diarrhea. RESULTS: Enteric pathogens were found in 60% of patients before or after transplantation. Pretransplantation screening revealed asymptomatic excretion of enteric pathogens in 29% (19/65). Forty-eight percent of patients undergoing BMT developed diarrhea. Diarrhea was mainly of noninfectious origin in the first 20 days after transplantation. More than 20 days after transplantation, the major causes of diarrhea were graft-versus-host disease and infection. Parasitic infections other than Cryptosporidium did not contribute significantly to morbidity in the pre- and posttransplantation period. Rotavirus and adenoviruses were found in approximately 12% and 5% of subjects, respectively. Bacterial infections in the posttransplantation period were found to be more common in India than in developed countries. Clostridium difficile-associated diarrhea was seen in the posttransplantation period but not before transplantation. Enterotoxigenic and enterohemorrhagic Escherichia coli caused symptomatic infections in the posttransplantation period, but the association of other classes of diarrheogenic E. coli with diarrhea was doubtful. CONCLUSIONS: There was significantly higher mortality (P<0.01) in patients with symptomatic or asymptomatic gastrointestinal infections caused by bacteria than in patients with parasitic or viral infections or without enteric infections.
Adult↗