Are we near the cure of genetic diseases and possibly cancers, in the advanced CRISPAR era??

A frozen bag of genetically engineered blood or a bag of cells can change the life of persons forever; this is the new era of precision gene medicine. Many debilitating diseases can be completely cured with some financial toxicity, but in front of a lifetime suffering this financial toxicity is bearable and manageable. Sickle cells disease (SCD), a blood disorder which damages multiple organs and excruciating pains leads to multiple morbidities. SCD occurs because of the defect in HBB gene, single mutation in this gene leads to formation of haemoglobin S, which leads to sickling, sticky and crescent-shaped red blood cells in slight hypoxic conditions. Leading to strokes, heart attacks and other critical organs damages in multiple ways in multiple times over period of time. This increases morbidity and early mortality. As this is disease is recessively heritable from parents and high degrees of penetrance in off springs. This disease thought to have originated in Africa and have protective effects against endemic malaria.

High mannose N-glycans on red blood cells as phagocytic ligands, mediating both sickle cell anaemia and resistance to malaria

In both sickle cell disease (SCD) and malaria, red blood cells (RBCs) are phagocytosed in the spleen, but receptor-ligand pairs mediating uptake have not been identified. Here, we report that patches of high mannose N-glycans (Man5-9GlcNAc2), expressed on diseased or oxidized RBC surfaces, bind the mannose receptor (CD206) on phagocytes to mediate clearance. Extravascular haemolysis in SCD correlates with high mannose glycan levels on RBCs. Infection of RBCs with Plasmodium falciparum expose surface mannose N-glycans on healthy RBCs, which occurred at significantly higher levels on RBCs from subjects with sickle cell trait compared to those lacking haemoglobin S. The glycans were associated with high molecular weight complexes and protease-resistant, lower molecular weight fragments containing spectrin. Recognition of surface N-linked high mannose glycans, a novel response to cellular stress, is the first molecular mechanism common to both the pathogenesis of SCD and resistance to severe malaria in sickle cell trait.

Effectiveness of a top up transfusion programme in preventing cerebrovascular damage in a birth cohort of sickle cell disease

Regular transfusions are effective in managing strokes in paediatric sickle cell patients. However, there are associated risks, including alloimmunisation and iron overload. This study evaluated the efficacy of top-up transfusions in primary and secondary stroke prevention in a single tertiary paediatric centre in Central London. Forty-seven children with sickle cell disease who received transfusions in the last decade were included. No patient on a primary stroke prevention transfusion programme had a cerebrovascular event during the study period but 9.5% on secondary stroke prevention programme did. Twenty-one per cent of patients in this cohort converted to exchange transfusions following transfer to adult services, of which 11% had subsequent strokes. Targeted pre-transfusion haemoglobin S % was not always met; 43% of HbS% readings in a 12- month period were above the set target of 30% and 37% were above the set target of 50%. About a third of patients had evidence of severe hepatic iron overload, but no significant cardiac iron. 25% of patients became alloimmunised, but not severe enough to warrant discontinuation of the transfusion programme. Although transfusions are effective for primary stroke prevention, iron overload remains a significant burden.

Retinal ultra-wide-field colour imaging versus dilated fundus examination to screen for sickle cell retinopathy

PurposeTo compare ultra-wide-field colour fundus imaging (UWFI) to dilated fundus examination (DFE) for the screening of sickle cell retinopathy (SCR).DesignThis study is a prospective, blinded, multicentre case series.ParticipantsThis study included two groups: an adult group (n=268 eyes) and a paediatric group (n=168 eyes). Sickle cell disease (SCD) types included haemoglobin S homozygous (HbSS), haemoglobin S and C (HbSC) and Hb S with β-thalassaemia (HbSß-Thal).MethodsParticipants underwent DFE and UWFI. Each eye received three independent grades (1–4), documented by three graders: clinical grader, image grader 1 and image grader 2. Three clinically relevant diagnostic thresholds were determined. Based on these thresholds, the sensitivity, specificity, positive predictive value and negative predictive value for all three graders were calculated relative to each other as reference tests.ResultsHbSC was associated with the most advanced SCR grades. When compared to the clinical grader, image grader 1 and image grader 2 consistently detected more SCR and higher SCR grades in both adult and paediatric groups. In both groups, image grader 1 and image grader 2 identified twice as many cases of capillary occlusion/anastomosis than clinical grader. To detect the presence of any proliferative SCR, image grader 1 and image grader 2 had a sensitivity of 82%, 71% in the paediatrics group and 90% and 72% in the adult group. The clinical grader sensitivity was 52% in the paediatrics group and 53% in the adult group.ConclusionThe UWFI is a sensitive tool to screen for SCR. It is superior to DFE in detecting capillary occlusion or anastomosis.

Partial recovery of vegetative state after a massive ischaemic stroke in a child with sickle cell anaemia

A 15-year-old patient with sickle cell disease with recessive homozygous haemoglobin S/HbSS suffered several crises developmentally after the last of which the patient fell into coma. CT scan then revealed a large infarct of the right cerebral hemisphere. Three weeks after the event, the patient began to demonstrate spontaneous eye opening and spastic quadriparesis with no evidence of command-following, gestural or verbal communication, visual pursuit or purposeful motor behaviour. Our case was in an ‘unresponsive wakefulness syndrome’ with atrophy of lateral and frontal regions of both hemispheres, demonstrated by MRI and preservation of circulation in the posterior arterial system, documented by MR angiography. Currently observed are spontaneous eye opening, preserved visual and auditory startle reflexes, normal brainstem reflexes, and grasp, palmomental and sucking reflexes. Our case demonstrates partial recovery of awareness with significant brain lesions, reflecting preserved brain activity as an indication of the modular nature of functional networks.

Disorders of the synthesis or function of haemoglobin

The inherited disorders of haemoglobin are the commonest single-gene disorders in the world. Disorders of haemoglobin can be genetic or acquired and due to disordered production of one or more globin chains or structural change in the globin chain. The most important disorders are the genetic conditions thalassaemia and sickle cell disease. Thalassaemia—a heterogeneous group of genetic disorders, all resulting from a reduced rate of production of one or more of the globin chains of haemoglobin and inherited in a simple Mendelian fashion. They are clinically classified according to their severity into major (a severe transfusion-dependent disorder), intermediate (characterized by anaemia and splenomegaly), and minor (a symptomless carrier state) forms. The β‎ thalassaemias are the most important types of thalassaemia because they are very common and produce severe anaemia in their homozygous and compound heterozygous states. Most countries in which the disease is common are putting a major effort into programmes for its prevention (population screening and prenatal diagnosis). Symptomatic management of severe disease requires regular blood transfusion, judicious use of splenectomy if hypersplenism develops, and chelating agents to reduce iron overload. Sickle cell disease—haemoglobin S differs from haemoglobin A by the substitution of valine for glutamic acid at position 6 in the β‎ globin chain, and homozygosity for haemoglobin S produces the state of sickle cell disease. This occurs very frequently in African populations and, sporadically, throughout the Mediterranean region and the Middle East, with extensive pockets in India. Management of both acute and chronic complications remains largely supportive, with hydroxycarbamide being the only clinically proven effective treatment to date.

The Influence of Blood Groups on Diseases Pattern Globally: A Review of Literature

The present survey reports the influence of blood groups on disease pattern in worldwide basis. Genetic factors have been associated with vulnerability or resistance to certain disease. For example, individuals who are heterozygous to haemoglobin S and haemoglobin E are resistant to infection with Plasmodium falciparum. The manifestation of metabolic syndrome, a sickness characterized by multiple risk factors like obesity, hypertension and glucose intolerance is also influenced by genetic and environmental factors. Several studies have established a relationship between ABO blood type and incidences of Plasmodium falciparum infection. This review brought to the fore the relationship between blood groups and susceptibility or resistance to disease. There is need for more studies to be carried out to unravel the exact mechanism how blood groups affect disease. It is recommended that individuals of various blood groups should know the different disease that they are prone to and avoid the predisposing factors to such diseases.

Clinical phenotypes and outcomes of precapillary pulmonary hypertension of sickle cell disease

RationalePrecapillary pulmonary hypertension (PH) is a devastating complication of sickle cell disease (SCD). Little is known about the influence of the SCD genotype on PH characteristics.ObjectivesTo describe clinical phenotypes and outcomes of precapillary PH due to SCD according to disease genotype.MethodsA nationwide multicentre retrospective study including all patients with SCD-related precapillary PH from the French PH Registry was conducted. Clinical characteristics and outcomes according to SCD genotype were analysed.Results58 consecutive SCD patients with precapillary PH were identified, of whom 41 had homozygous for haemoglobin S (SS) SCD, three had S-β0 thalassaemia (S-β0 thal) and 14 had haemoglobin SC disease (SC). Compared to SC patients, SS/S-β0 thal patients were characterised by lower 6-min walk distance (p=0.01) and lower pulmonary vascular resistance (p=0.04). Mismatched segmental perfusion defects on lung scintigraphy were detected in 85% of SC patients and 9% of SS/S-β0 thal patients, respectively, and 50% of SS/S-β0 thal patients had heterogeneous lung perfusion without segmental defects. After PH diagnosis, 31 patients (53%) received medical therapies approved for pulmonary arterial hypertension, and chronic red blood cell exchange was initiated in 23 patients (40%). Four patients were managed for chronic thromboembolic PH by pulmonary endarterectomy (n=1) or balloon pulmonary angioplasty (n=3). Overall survival was 91%, 80% and 60% at 1, 3 and 5 years, respectively, without influence of genotype on prognosis.ConclusionsPatients with precapillary PH related to SCD have a poor prognosis. Thrombotic lesions appear as a major component of PH related to SCD, more frequently in SC patients.

In vitro-Modulation of HbS Erythrocyte Parameters By Prednisolone Testing For Fe2+/Fe3+ Ratio, HbS Gelation and Osmotic Fragility

Aim: The study is targeted at the sickle cell disease. It has been discovered that some drugs or medications taken for certain ailments are either pro-sickling or anti-sickling in nature. In this study, acorticosteroid by the name of prednisolone was investigated to determineits possible effects on human haemoglobin-S gelation, erythrocyte fragility and Fe2+ and Fe3+ concentrations. Materials and Method: The blood sample of 5ml was collected from adult male and female donors by vein puncture using a 5 ml syringe and needle. The blood samples were confirmed as HbSS using standard haemoglobin electrophoresis. Various concentrations of the drug (0.05, 0.1, 0.3, 0.5 and 1 mg/ml) were used to determine the effects on human haemoglobin-S, gelation rate, erythrocyte fragility, Fe2+& Fe3+ concentrations. Absorbance reading was taken at 540 nm using a spectrophotometer. Results: The results showed that Prednisolone increased haemoglobin S gelation at all concentrations (p< 0.05) when compared to the control. The Fe2+/Fe3+ ratio showed a reduction in haemoglobin values at 0.3, 0.5 and 1.0 mg/ml concentrations when compared to the control and a slight increase at 0.05 and 0.1 mg/ml. For Erythrocyte Fragility, there was destabilization of red cell in all concentrations. Conclusion: This study suggests that this drug could have some undesirable effects on sickle cell subjects.