The development of gene therapy and the current advantageous method of clustered regularly interspaced short palindromic repeats (CRISPRs) has allowed the implementation of several clinical trials aimed at studying the possible efficacy of gene therapy for rare diseases. Rare diseases pose a global challenge, in that their collective impact on health systems is considerable, whereas their individually rare occurrence hinders research and development of efficient therapies. Despite the low prevalence of individual rare diseases, there are more than 7,000 defined rare diseases affecting 3.5–5.9% of the global population. Rare diseases are mostly chronic and approximately 80% are caused by genetic mutation with an early-life onset. In Italy, in 2021 were recorded more than 400,000 people with rare disease. Because of its location and history, Italy has an unfortunate statistic regarding the presence and prevalence of two rare genetic diseases, namely beta-thalassemia, of which there are about 90 million carriers worldwide, 400,000 of whom are actually affected, and sickle cell disease, with about 300 million carriers and 6.5 million people affected worldwide. Advancements in genomic studies allowed Italy to join clinical trials to study effective and resolving gene therapies for BT and SCD. This study reports on the impact of rare diseases in Italy, ongoing studies, and recent achievements in BT and SCD trials using the CRISPR method and remaining hurdles in the application of CRISPR technology to rare diseases, also taking a glimpse at the newest challenges and future opportunities in the genetic treatment for rare diseases.

A large number of studies have reported that the prevalence of beta thalassemia carriers in India varies by ethnic groups. The objective of this study was to conduct a systematic review of the published studies and conduct a meta-analysis to determine the prevalence of beta thalassaemia carriers in India. A PubMed database search using keywords \"beta thalassaemia AND India\" identified 1088 articles of which 69 articles were included in the review. Studies using diagnostic tests and methods recommended by the International Council for Standardization in Haematology were used for calculation of pooled prevalence. Pooled prevalence was calculated using a random effects model using Review Manager version 5.3. Studies had screened five categories of populations, that is, the general population; tribal groups, communities not belonging to tribal groups, persons with anemia, and persons referred with a suspicion of hemoglobinopathy. This heterogeneity contributed to a high pooled prevalence of beta thalassemia carriers of 8.23% (95% CI 7.36-9.10). Sub-group analysis however yielded 3.74% (95% CI 2.52-4.97) pooled prevalence of beta thalassemia carriers in the general population. It was 4.6% (95% CI 3.2-6.2) among tribal groups. Quality of prevalence studies was limited by methodological issues including non-random sampling methods, heterogeneity of population types screened, and lack of use of recommended diagnostic cut-offs. Prevalence of beta thalassemia carriers was similar in tribal populations and the general population, indicating the need to further investigate the prevalence of beta thalassemia carriers in tribal groups.

The objective of this study was to review the prevalence and features of the beta thalassaemia trait in Jamaican populations. Screening of 221,306 newborns over the last 46 years has given an indication of the distribution and prevalence of beta thalassaemia genes, and screening of 16,612 senior school students in Manchester parish, central Jamaica, has provided their haematological features. The prevalence of the beta thalassaemia trait predicted from double heterozygotes was 0.8% of 100,000 babies in Kingston, 0.9% of 121,306 newborns in southwest Jamaica, and 0.9% of school students in Manchester. Mild beta+ thalassaemia variants (-88 C>T, -29 A>G, -90 C>T, polyA T>C) accounted for 75% of Kingston newborns, 76% of newborns in southwest Jamaica, and 89% of Manchester students. Severe beta+ thalassaemia variants were uncommon. Betao thalassaemia variants occurred in 43 patients and resulted from 11 different variants of which the IVSII-849 A>G accounted for 25 (58%) subjects. Red cell indices in IVSII-781 C>G did not differ significantly from HbAA, and this is probably a harmless polymorphism rather than a form of beta+ thalassaemia; the removal of 6 cases in school screening had a minimal effect on the frequency of the beta thalassaemia trait. Red cell indices in the beta+ and betao thalassaemia traits followed established patterns, although both were associated with increased HbF levels. The benign nature of beta+ thalassaemia genes in Jamaica means that cases of sickle cell-beta+ thalassaemia are likely to be overlooked, and important clinical questions such as the role of pneumococcal prophylaxis remain to be answered.

Thalassaemia is one of the commonest inherited genetic disorders world-wide with around 25,000 births of the most severely affected transfusion dependent children annually. Patients with transfusion dependent thalassaemia require regular blood transfusions to maintain life but because of this will develop iron overload. To remove the excess iron, patients are required to take iron chelation therapy (ICT). ICT requires lifelong adherence to treatment to prevent end organ damage from developing. Many of these preventable complications make adherence to therapy more complex for patients. In this review, we focus on two commonly encountered patient scenarios and discuss how different psychological models and a relational theory can be used to understand and support adherence to treatment.

Pregnant women with iron deficiency and those who are carriers of haemoglobinopathies present with anaemia of varying severity. There is no antenatal screening for haemoglobinopathies in India. The objective of this study was to determine the prevalence of undiagnosed haemoglobinopathy carriers in a random sample of pregnant women attending antenatal care clinics in Pune city, India. Biobanked DNA of 360 randomly selected pregnant women was genotyped for six common mutations and two common haemoglobin variants, HbS and HbE. Odds ratios (OR) with 95% confidence intervals were computed to determine association of carrier status with socio-demographic, haematological and clinical characteristics. The prevalence of undiagnosed haemoglobinopathy carriers was 6.3% (95% CI 4.2-9.4%) of which 3.3% (95% CI 1.9-5.7%) were beta thalassaemia carriers. There was an increased odds that beta thalassaemia carriers had moderate anaemia (OR 10.59, 95% CI 1.15-96.90). This study reveals the high prevalence of undiagnosed haemoglobinopathy carriers among pregnant women, indicating the need to immediately implement carrier screening and genetic counselling services across the country.

There is overwhelming evidence implicating Haemoglobin Subunit Beta (HBB) protein in the onset of beta thalassaemia. In this study for the first time, we used a combined SNP informatics and computer algorithms such as Neural network, Bayesian network, and Support Vector Machine to identify deleterious non-synonymous Single Nucleotide Polymorphisms (nsSNPs) present in the HBB gene. Our findings highlight three major mutation points (R31G, W38S, and Q128P) within the HBB gene sequence that have significant statistical and computational associations with the onset of beta thalassaemia. The dynamic simulation study revealed that R31G, W38S, and Q128P elicited high structural perturbation and instability, however, the wild type protein was considerably stable. Ten compounds with therapeutic potential against HBB were also predicted by structure-based virtual screening. Interestingly, the instability caused by the mutations was reversed upon binding to a ligand. This study has been able to predict potential deleterious mutants that can be further explored in the understanding of the pathological basis of beta thalassaemia and the design of tailored inhibitors.

Sitagliptin, a modern antidiabetic agent which is weight neutral and associated with low rate of hypoglycaemias, is being increasingly used in type 2 diabetes mellitus (DM). However, there is a paucity of data about its efficacy and safety in beta-thalassaemia major (β-TM). This retrospective case series of five patients (mean age of 45 years) is the first study evaluating the use of sitagliptin in patients with β-TM and DM. Four patients responded well to sitagliptin, as evidenced by a decrease in fructosamine by 77 and 96μmol/L (equivalent reduction in HbA1c of 1.5% and 1.9%) observed in two patients and reduction in the frequency of hypoglycaemia without worsening glycaemic control in two others. One patient did not respond to sitagliptin. No patients reported significant side effects. This study provides evidence that sitagliptin may be considered, with caution, for use in patients with β-TM and DM, under the close monitoring of a Diabetologist.

OBJECTIVE: Inherited disorders of haemoglobin are the world\'s most common genetic diseases, resulting in significant morbidity and mortality. The large number of mutations associated with the haemoglobin beta gene (HBB) makes gene scanning by High Resolution Melting (HRM) PCR an attractive diagnostic approach. However, existing HRM-PCR assays are not able to detect all common point mutations and have only a very limited ability to detect larger gene rearrangements. The aim of the current study was to develop a HBB assay, which can be used as a screening test in highly heterogeneous populations, for detection of both point mutations and larger gene rearrangements.
METHODS: The assay is based on a combination of conventional HRM-PCR and a novel Gene Ratio Analysis Copy Enumeration (GRACE) PCR method. HRM-PCR was extensively optimised, which included the use of an unlabelled probe and incorporation of universal bases into primers to prevent interference from common non-pathological polymorphisms. GRACE-PCR was employed to determine HBB gene copy numbers relative to a reference gene using melt curve analysis to detect rearrangements in the HBB gene. The performance of the assay was evaluated by analysing 410 samples.
RESULTS: A total of 44 distinct pathological genotypes were detected. In comparison with reference methods, the assay has a sensitivity of 100 % and a specificity of 98 %.
CONCLUSIONS: We have developed an assay that detects both point mutations and larger rearrangements of the HBB gene. This assay is quick, sensitive, specific and cost effective making it suitable as an initial screening test that can be used for highly heterogeneous cohorts.

Beta thalassaemia is an autosomal recessive inherited blood disorder which results in abnormal formation of Haemoglobin molecule and ineffective erythropoiesis. Patients need to be dependent on habitual blood transfusion and on unaffordable exorbitant therapies for continued existence. It has been hypothesized that if the level of foetal Haemoglobin increases, it compensates the need of adult Haemoglobin and hence, ameliorates clinical symptoms associated with beta thalassaemia major. Illation from previous studies has proved that reactivation of foetal Haemoglobin with the aid of natural compounds is a better alternative therapy for patients of beta thalassaemia because of its cost effectiveness and occurrence in natural eatables. Piceatannol, a naturally occurring stilbene, is less studied compound in comparison to resveratrol, but it shows a wide range of biological activities. This article has mainly focused on piceatannol and its application as a foetal Haemoglobin inducer in future.

OBJECTIVE: There are limited published data on the performance of the percentage of haemoglobin A (Hb A) as a screening test for beta thalassaemia major in the newborn period. This paper aims to analyse data derived from a national newborn bloodspot screening programme for sickle cell disease on the performance of haemoglobin A (Hb A) as a screening test for beta thalassaemia major in the newborn period.
METHODS: Newborn bloodspot sickle cell screening data from 2,288,008 babies were analysed. Data reported to the NHS Sickle Cell and Thalassaemia Screening Programme in England for the period 2005 to 2012 were also reviewed to identify any missed cases (4,599,849 babies).
RESULTS: Within the cohort of 2,288,008 births, 170 babies were identified as screen positive for beta thalassaemia major using a cut-point of 1.5% HbA. There were 51 identified through look-back methods and 119 prospectively identified from 4 screening laboratories. Among 119 babies with prospective data, 7 were lost to follow up and 15 were false positive results. Using a cut-off value of 1.5% Hb A as a percentage of the total haemoglobin as a screening test for beta thalassaemia major in the newborn provides an estimated sensitivity of 99% (from the look back arm of the study) with a positive predictive value of 87% (from the prospective arm of the study). Excluding infants born before 32 weeks gestation, the positive predictive value rose to 95%.
CONCLUSIONS: A haemoglobin A value of less than 1.5% is a reliable screening test for beta thalassaemia major in the newborn period.