The second edition of this already well-established reference provides an expanded encyclopedic source for a broad range of persons interested in biology. Although there is a vast amount of information presented in a well-organized fashion, the aim is not to create another comprehensive textbook of hematology, but rather to focus, in depth, on selected areas of knowledge that have been most advanced by the rapidly moving molecular revolution. The editors and other contributors are internationally recognized authorities in their respective areas of expertise. The book has seven sections: "Basic Concepts," "Red Cells and Erythropoiesis," "Lymphopoiesis," "White Cells," "Hemostasis," "Molecular Oncology," and "Viruses." The "Basic Concepts" section provides a necessary and complete introduction to the succeeding portions of the book. Definitions of terms, illustrations of methods, and discussion of the physiology of hematopoiesis make the rest of the book much more understandable to a wide audience. Most attention is paid to

The Molecular Basis of Blood Diseases

https://jmg.bmj.com/content/jmedgenet/25/11/789.2.full.pdf

The Molecular Basis of Blood Diseases.

Correction of β-thalassemia by CRISPR/Cas9 editing of the α-globin locus in human hematopoietic stem cells.

Rare diseases (RDs) affect a small percentage of the population but can be severely debilitating and life-threatening. Historically, patient groups (PGs) have been the prime movers in raising awareness about these diseases and advocating for national supportive policies. They have also driven relevant research programs. In India too, PGs have made significant contributions to the national RD ecosystem. To assess the contribution of various Indian RD PGs, we carried out an interview-based study of 19organizations. This study aims to highlight the origins and achievements of these groups and the challenges that they have faced. The study also helps to capture the changes in the RD ecosystem that have taken place in recent years. Of the 19 PGs, two are umbrella organizations, two are other organizations of national scope and 15 are disease specific groups. 14 interviewees were affected by an RD either directly or through a family member. Lack of awareness about RDs in the medical community was the biggest challenge, leading to a delay in diagnosis and subsequent management. Only two out of the 15 conditions have a definitive treatment. However, many of the diseases can be managed with replacement therapies administered for the patient’s entire life, or other supportive therapies. Most diagnostics and treatment regimens that are available globally are now available in India but are expensive and usually available only in a few major cities. These problems are compounded by a lack of medical insurance schemes and government policies to support these patients. The biggest achievement of the PGs was the passing of National Policy for Treatment of Rare Diseases in 2017, unfortunately since put in abeyance. If reinstated, and properly implemented, this policy could significantly improve RD management in the country. PGs have had a significant role in bringing diagnostics and treatments to India. They have also raised awareness about RDs and related issues such as newborn screening, prenatal diagnostics and genetic counselling. This study highlighted the recommendations of various PGs. The government should address these recommendations and institutionalize the participation of the PGs in formal decision making.

/pdf/the-role-of-patient-organizations-in-the-rare-disease-4zz8yi957s.pdf

The role of patient organizations in the rare disease ecosystem in India: an interview based study.

Transfusion-dependent E-Beta (EB) thalassemia is one of the major causes of hereditary hemoglobinopathies in India. Hydroxyurea has been tried for HbF induction and amelioration of the transfusion frequency in EB thalassemia. The primary objective of this retrospective study, conducted between January 2017 and December 2018, was to determine the efficacy of thalidomide in reducing transfusion frequency in patients with EB thalassemia who have failed a reasonable trial of hydroxyurea. Of the 21 patients studied, 15 (71.4%) attained transfusion independence (complete responders) and 1 (4.7%) attained partial response (50% decrease in transfusion requirement) while 5 (23.9%) were non-responders. 12 patients attained their response within 1 month, 2 patients achieved within 1–3 months, and 1 patient beyond 3 months. Median time to transfusion independence in complete responders was 1 month. The median time on thalidomide for the complete responders and partial responders was 16.48 months. No major grade 3/4 toxicities were documented. This approach needs larger randomised controlled studies. Thalidomide is a safe and effective strategy at reducing or abrogating transfusion requirement in patients with EB thalassemia. This approach requires further testing in systematic clinical trials.

Thalidomide in Patients with Transfusion-Dependent E-Beta Thalassemia Refractory to Hydroxyurea: A Single-Center Experience.

Thalassaemias are the most common inherited autosomal recessive single gene disorders characterised by chronic hereditary haemolytic anaemia due to absence or reduced synthesis of one or more of the globin chains. Haemoglobin E (HbE)-β-thalassaemia is the genotype responsible for approximately one-half of all cases of severe β-thalassaemia worldwide. This study proposes to evaluate response of hydroxyurea in reducing transfusion requirements of severe HbE-β-thalassaemia patients, and its correlation with foetal haemoglobin (HbF) level and α-mutation. Hydroxyurea was started at a baseline dose in 82 transfusion-dependent HbE-β-thalassaemia patients. HbF levels and %F-cells were measured. β-Thalassaemia mutations and α-globin gene deletions and triplications were detected by amplification refractory mutation system (ARMS)-polymerase chain reaction (PCR) and Gap-PCR, respectively. Patients were categorised as good (41.5%), moderate (31.7%), and poor responders (26.8%) based on their decrease in transfusion requirements. Nine patients were excellent responders who became transfusion independent. The mean increase in HbF levels and %F-cells after therapy was correlated with decrease in transfusion requirements. Patients having a deletion of the α-globin gene were better responders. The response was proportional to the number of α-globin gene deletions. We conclude that hydroxyurea treatment decreases transfusion requirements, and the response correlates with α-globin gene deletions.

Alpha Globin Gene Mutation: A Major Determinant of Hydroxyurea Response in Transfusion-Dependent HbE-β-Thalassaemia

Thalassaemia are the most common inherited autosomal recessive single gene disorders characterized by chronic hereditary haemolytic anaemia due to the absence or reduced synthesis of one or more of the globin chains. Haemoglobin E-β thalassaemia is the genotype responsible for approximately one half of all severe beta-thalassaemia worldwide. This study proposes to evaluate the effect of various molecular parameters on the response of hydroxyurea. Hydroxyurea was started at an initial dose of 10 mg/kg of body weight/day on 110 transfusion-dependent HbE-β thalassaemia patients. HbF level was measured by HPLC analysis. β-Thalassaemia mutations, XmnI and five other SNPs, and α-globin gene deletions and triplications were detected by ARMS-PCR, RFLP-PCR and Gap-PCR, respectively. Based on the factors for evaluating hydroxyurea-response, 42 patients were responders as they showed an increment of Hb from a mean baseline value of 6.45 g/dl (± 0.70) to 7.78 g/dl (± 0.72) post-therapy. Based on increase in HbF above the median value (14.72%) post-therapy, 78 patients were found to be responders. All the 78 responders showed mean decrease in transfusion of 74.26% (± 8.32) with a maximum decrease of 98.43%. There was a significant correlation between decrease in transfusion and increase in HbF level for all 78 responders. XmnI polymorphism showed the strongest association (p < 0.0001) with increase in HbF levels and Hb levels. Patients with α-globin gene deletions were better responders. It was concluded that hydroxyurea treatment is effective in transfusion-dependent HbE-β thalassaemia patients and the response is best in patients having both XmnI polymorphism and α-deletion.

Genetic determinants related to pharmacological induction of foetal haemoglobin in transfusion-dependent HbE-β thalassaemia.

In this study, we aimed to investigate the pattern and association of genetic mutations occurring within the alpha hemoglobin-stabilizing protein (AHSP) gene among HbE beta thalassemia patients with varying phenotypic expressions. Fifty-four diagnosed cases of HbE beta thalassemia (transfusion dependent and independent) were included in the study. Among them, 38 patients with similar genotypes (IVS 1-5, alpha gene deletion and triplication, Xmn polymorphism) were selected for further analysis. AHSP gene sequencing was done for these 38 samples to study associated mutations in AHSP gene. HbE beta thalassemia patients with similar genotypes but different phenotypic expressions were found to have mutations in the AHSP gene. There were five mutations found most prevalent among the samples analyzed for AHSP gene sequencing. Among these, two mutations were from intron 1 region of AHSP and three mutations were found in exon 3. The most prevalent mutation was found at the Oct binding site at intron 1 of AHSP. The mutations in exon 3 were more prevalent among the TDT groups. A mutation in exon 3 changing the amino acid (33rd) from serine to phenylalanine was found to be associated with only TDT group. This study documents that among the HbE beta thalassemia patients with varying severity, an exon mutation in AHSP is significantly prevalent only among the TDT group. Further understanding of the mechanism will shed light upon the impact of AHSP in modifying the disease severity in thalassemia.

Sujana Biswas

Papers

Alpha Globin Gene Mutation: A Major Determinant of Hydroxyurea Response in Transfusion-Dependent HbE-β-Thalassaemia

Genetic determinants related to pharmacological induction of foetal haemoglobin in transfusion-dependent HbE-β thalassaemia.

Association of alpha hemoglobin–stabilizing protein (AHSP) gene mutation and disease severity among HbE—beta thalassemia patients