Sickle Cell Disease (AP) PDF

Sickle Cell Disease Anna Derrick [email protected]  Quiz Test your knowledge from last lecture! (Royal Family) https://kahoot.it Also available on: ...

Sickle Cell Disease Anna Derrick [email protected]  Quiz Test your knowledge from last lecture! (Royal Family) https://kahoot.it Also available on: Learning Outcomes Describe what sickle cell disease is and the symptoms. Understand the types of sickle cell disease and the genes implicated. Outline which populations typically have increased prevalence of sickle cell disease and its link to malaria. Erythrocytes - Red Blood Cells Sickle Cell Disease (SCD) Sickle Cell Disease - Symptoms People with SCD may start to have signs of the disease during the first year of life. Symptoms can range from mild to severe. Hypoxia and infarction/ necrosis of organs Anemia Vaso-occlusive or sickle cell crisis Acute pain Hyposplenism Osteonecrosis Nephropathy Acute chest syndrome Increased risk of infection Delayed growth TIAs/Stroke Sickle Cell Disease - Life expectancy Sickle cell disease can cause premature death in early to mid adulthood. The average life expectancy in the developed world is 40 to 60 years of age. Most developing nations however, have yet to see such a change. Haemoglobin Form Polypeptide Chains Total Fraction HbA α2β2 96 - 98% HbA2 α2δ2 1.5 – 3.5% HbF α2γ2 0.5 - 0.8% Chromosome 11 α = Alpha β = Beta γ = Gamma δ = Delta ε = Epsilon Chromosome 16 ζ = Zeta  Sickle Cell Disease - Genetics Haemoglobin-Beta (HBB) gene located on chromosome 11p15.5 Wild-type HBB (HbA) Nucleotide CTG ACT CCT GAG GAG AAG TCT Amino Acid Leu Thr Pro Glu Glu Lys Ser 4 7 10 Mutant HBB (HbS) Nucleotide CTG ACT CCT GTG GAG AAG TCT NM_000518 c. A20T Amino Acid Leu Thr Pro Val Glu Lys Ser NP_000509.1 p.Glu7Val 4 7 910 Mutant HBB (HbC) Nucleotide CTG ACT CCT AAG GAG AAG TCT NM_000518 c. G19A Amino Acid Leu Thr Pro Lys Glu Lys Ser NP_000509.1 p.Glu7Lys 4 7 10 Sickle Cell Disease - Genetics Sickle Cell Disease - Types Type Name Genetics Severity Typically, the HbSS Sickle Cell Anemia One sickle cell gene (S) from each parent most severe A sickle cell gene (S) from one parent and HbSC - Milder an abnormal Hb (C) from other parent A sickle cell gene (S) from one parent and HbS β0 - thalassemia β- thalassemia Anemia Severe β0 thalassemia gene from other parent A sickle cell gene (S) from one parent and HbS β+ - thalassemia Milder β+ thalassemia gene from other parent A sickle cell gene (S) from one parent and HbSD, HbSE, HbSO - an abnormal Hb (D,E or O) from other Varies parent A normal gene (A) from one parent and a HbAS Sickel Cell Trait Very mild sickle cell gene (S) from other parent Thalassemia is a term for a group of disorders in which there is reduced levels of haemoglobin.  Sickle Cell Disease - Inheritance Autosomal recessive inheritance 100% 50% 50% 100% AA Normal Haemoglobin AS Sickle Cell Trait (Carrier) SS Sickle Cell Disease 25% 50% 25% 50% 50% Sickle Cell Trait (HbAS) The individual has one mutated HBB allele (HbS) and one normal HBB allele (HbA). These individuals do not have sickle cell disease but are carriers of the allele. Individuals with sickle cell trait are at increased risk of having a child with sickle cell disease. Typically, no symptoms. Sickle Cell Trait (HbAS) However, certain conditions can lead to sickling. Increased risk of sudden death associated with rhabdomyolosis, myocardial ischemia, arrythmias. Sickle Cell Disease - Diagnosis and Screening Blood tests for genetic screening can be carried out at any age for sickle cell disease or sickle cell trait. In the UK sickle cell disease is often detected during pregnancy or soon after birth. Screening for sickle cell disease is offered in pregnancy if there is a risk of a child being born with sickle cell disease. Screening for all babies as part of the newborn blood spot test (heel prick test). Sickle Cell Disease - Management and Treatment Sickle Cell Disease – Gene Therapy UK medicines regulator has approved a therapy that uses the CRISPR–Cas9 gene-editing tool as a treatment. Sickle Cell Disease – Gene Therapy Sickle Cell Disease - Epidemiologic Prevalence One of the most common monogenic disorders. UK prevalence of sickle cell disease = 1 in 4600 Sickle Cell Trait and Malaria HbS allele has a narrower distribution than malaria incidence because variant arose in Africa. Limited population migration restricted allele distribution.  Malaria Malaria symptoms: fever vomiting tiredness headaches Severe cases: jaundice seizures coma death Malaria is caused by single-celled microorganisms of the Plasmodium group which infect red blood cells. Mosquito injects parasites into a vertebrate host during a blood meal. Destruction of host red blood cells.  Sickle Cell Trait and Malaria Schizogonic Haemolysis cycle HbSS are highly susceptible to the lethal effects of malaria. HbAA HbAS does not provide protection but gives resistance for the progression. Plasmodium Precise mechanism for HbAS resistance is infecting red blood cell unknown. Experimental studies suggest main protective effects involve: 1) Enhanced immunity 2) Increased clearance of infected erythrocytes HbAS Selective 3) Reduced parasite growth phagocytosis Selective sickling of sickled of plasmodium plasmodium infected red infected red blood cell blood cell Heterozygote Selective Advantage The heterozygous genotype has a higher relative fitness than either the homozygous dominant or homozygous recessive genotype. An evolutionary trade off.