Hemoglobinopathies - Radhika Sawh

Hemoglobinopathies Radhika Sawh, MS, CGC Genetic Counselor | Educator | Rare Disease Advocate Learning Objectives Review the most common and medically significant hemoglobinopathies Examine the pathophysiology of these conditions Identify at risk populations Recognize the clinical i...

Hemoglobinopathies Radhika Sawh, MS, CGC Genetic Counselor | Educator | Rare Disease Advocate Learning Objectives Review the most common and medically significant hemoglobinopathies Examine the pathophysiology of these conditions Identify at risk populations Recognize the clinical implications when two forms of hemoglobinopathies are co-inherited Describe current management and therapeutic options Global Distribution  Main function: reversible binding and transport of oxygen Hemoglobin is a tetramer, composed of 2 pairs of globin chains Each chain is attached to a heme group composed of a porphyrin attached to an iron atom Different types of hemoglobin are present in RBCs in varying concentrations during different stages in life and Hemoglobin with different conditions Fetal Switch 3 major types of hemoglobin Hb A αα/ββ Hb A2 αα/δδ Hb F αα/γγ Hemoglobinopathies Thalassemias Hemoglobin Variants Disorders of decreased synthesis of one Disorders that produce structurally or more globin chains abnormal globin proteins Alpha thalassemia Hb S Beta thalassemia Hb C Hb E The Thalassemias Alpha Thalassemia: Genetics Most often results from deletions of one or more of the alpha globin genes (HBA1, HBA2) located on chromosome 16p13.3. Can result also from non-deletion pathogenic variants Affects all 3 types of hemoglobin: Hb A αα/ββ Hb A2 αα/δδ Hb F αα/γγ Alpha Thalassemia: Forms Phenotype depends upon how many of the four genes are deleted. 1 2 1 X 2 1 X 2 X 1 2 1 2 1 2 Normal Silent Carrier Trait (CIS) 1 X 2 1 X  X2 1 X 2 X 1 X 2  X1 2  X1  X2 Trait (TRANS) Hemoglobin H disease Alpha Thalassemia Major (a.k.a. Hydrops Fetalis) Alpha Thalassemia Trait Silent Carriers One  globin gene deleted Normal CBC with no hematological abnormalities Normal Hb Elect Alpha Thalassemia Trait (CIS or TRANS) Two  globin genes deleted Mild anemia On CBC: Microcytic-Hypochromic RBCs (low MCV) Normal Hb elect!! Alpha Thalassemia Trait: At-risk Populations CIS Form TRANS Form East/Southeast Asia Europe Southern Asia Middle East Oceania Africa  Three  globin genes deleted On Hb elect: Hb H present Clinical heterogeneity Hemoglobin H Mild to moderate anemia Disease May require intermittent transfusions Complications can include splenomegaly, growth failure, bony deformities  Two cis  globin genes deleted plus the Constant spring (CS) termination codon variant (α142 STOP→Gln; TAA→CAA) in the third  globin gene On Hb elect: Hb H present Hemoglobin More severe clinical course than deletional Hemoglobin H disease H-Constant More likely to require transfusions Spring Susceptibility to severe anemia during illness Splenomegaly (moderate to severe) leading to splenectomy in >50% Growth delay Alpha Thalassemia Major (a.k.a. Hemoglobin Bart’s or Hydrops Fetalis) Four  globin gene deleted Death in utero Serious maternal complications can occur Survival is possible through intrauterine intervention Following birth, Alpha Thalassemia Major patients require regular transfusion therapy and chelation to prevent iron accumulation https://vimeo.com/251336395 Intrauterine SCT for Alpha https://vimeo.com/295220171 Thalassemia Major Beta Thalassemia: Genetics Results from single nucleotide pathogenic variants or less commonly, deletions of the beta globin gene (HBB) found on chromosome 11p15.4. Pathogenic variants affect the production of beta chains ß0 – complete absence of beta globin production ß+ – decreased beta globin production Only Hb A (αα/ββ) affected Phenotypes seen: Thalassemia “Trait” a.k.a. “Minor” Thalassemia “Major” a.k.a. ”Cooley’s Anemia” Thalassemia “Intermedia” Beta Thalassemia Trait: At-risk Populations Mediterranean countries & islands Middle East North Africa Eastern Europe Indian Subcontinent Southeast Asia Melanesia Pacific Islands Beta Thalassemia Trait Heterozygous for pathogenic variant (+ or 0 ) Mild anemia, no disease Microcytosis (low MCV) On Hb elect: mildly elevated Hb A2 (> 3.5%)**, possible increased Hb F Thalassemia Major (“Transfusion Dependent Thalassemia”) Results from +/0 or 0/0 variants Diagnosis usually made before 2 years of age Severe anemia – fatal if untreated Secondary iron overload (hemochromatosis) causes organ damage if untreated Management: Chronic transfusions Chelation therapy Monitoring for complications Pathophysiology Cold Spring Harb Perspect Med. Dec 2012; 2(12): a011726. Thalassemia Major: Untreated Without transfusions Severely anemic Bone marrow hyperplasia Results in classic “thal facies” - maxillary and frontal bossing Splenomegaly Growth Retardation Cardiac failure Death Treating the Anemia: Hypertransfusion Regimens Hemoglobin levels maintained above 10 g/l Bone marrow (ineffective erythropoiesis) is suppressed Allows for normal levels of growth Proper transfusion regimens can prevent bone marrow hyperplasia, osteopenia of long bones, cardiomegaly, hepatomegaly and splenomegaly Iron Overload (Secondary Hemochromatosis) Results from transfusion therapy AND ineffective erythropoiesis Patients treated with transfusion therapy alone die in their late teens/early twenties Chelation therapy Reduces organ damage from iron overload Proven to prolong life expectancy Several chelators now available Compliance is an issue Complications  Shows genetic heterogeneity, but usually results Thalassemia from +/+ variants Intermedia Lesser clinical severity than thalassemia major Onset usually after 2 years of age, up to age 7 Moderate anemia (“Transfusion Splenomegaly Independent Moderate to severe hepatomegaly Bony changes Thalassemia”) Delayed puberty Thalassemia Intermedia: Management Transfusions Chelation Not usually required to survive, but Iron overload develops due to rather to improve quality of life Ineffective erythropoiesis May be regularly required due to: Peripheral RBC breakdown Poor growth and development Increased intestinal iron during childhood absorption Skeletal deformity Iron loading is less accelerated than Prevention/Management of seen with transfusion-dependent complications thalassemia Chelation therapy may be required Alternative Treatment Options: Hematopoietic Cell Transplantation Fetal Hemoglobin Stimulation Gene Therapy Gene Editing Reblozyl® (Luspatercept) Hemoglobin Variants Hemoglobin S Most common hemoglobin variant Results from the substitution of valine for glutamic acid in the sixth position of the beta globin gene RBCs containing Hemoglobin S “sickle” with deoxygenation Hemoglobin S: At-risk Populations Africa Countries around the Caribbean Sea Puerto Rico Cuba Haiti Jamaica Mediterranean countries Italy Greece Turkey Syria Saudi Arabia South India Normal vs. Sickle Cells Normal Disc-Shaped Flexible Easily flows through small blood vessels Lifespan = 120 days Sickle Sickle-Shaped Rigid, sticky Often gets stuck in small blood vessels Lifespan = 20 days or less  Red cell sickling and polymerization Consequences of Sickling Reduced lifespan of RBCs Vaso-occlusion Ischemia Infarction Hypercoagulable state Sickle Cell Trait Minimal clinical issues with normal overall life expectancy Episodes of hematuria possible May have more urinary tract infections In rare instances, extreme lack of oxygen can cause pain episodes or splenic infarctions Thi s Photo by Unknown Author i s l icensed under CC BY-SA-NC  (a.k.a. Sickle Cell Disease / Hb SS Disease) Onset in early childhood Moderate to severe hemolytic anemia Sickle Cell Recurrent pain episodes ** Anemia Increased incidence and severity of certain infections Tissue infarction leading to organ damage and failure Complications Sickle Cell Disease: Management Accurate, early diagnosis Education / prompt recognition of complications Prevention / treatment of infections Management / aggressive treatment of acute vaso-occlusive events, chronic pain and hemolytic anemia Screening for early signs of organ damage Therapeutic intervention New Therapeutic Options Living with and Managing Sickle Cell https://youtu.be/qe59ar- GZmg Disease  Moderate to severe hemolytic anemia Recurrent pain episodes Hemoglobin S Splenomegaly Clinical severity depends on the type of beta Beta thalassemia variant inherited Hemoglobin S–+ thalassemia tends to be less severe Thalassemia than Hemoglobin S-0 thalassemia Often difficult to distinguish between sickle cell disease and Hemoglobin S-0 thalassemia on Hb elect Hemoglobin C Results from the substitution of lysine for glutamic acid in the sixth position of the Beta globin gene Hb C is less soluble than Hb A Crystallizes under conditions of dehydration and increased hemoglobin concentrations Hemoglobin C: At-risk Populations Western Africa Italy Greece Turkey Middle East Northern Africa Also reported in people of Hispanic and Sicilian ancestry Hemoglobin C Trait Clinically asymptomatic RBCs have normal lifespan Slightly low MCV On Hb elect: Hb A, approx. 35% Hb C  One of the most benign hemoglobinopathies Some cases may not be diagnosed until adulthood Mild, chronic hemolytic anemia Splenomegaly Hemoglobin C Sporadic episodes of joint and abdominal pain Potential complications can include pigmented Disease gallstones and jaundice Labs: Microcytosis Mild-to-moderate reduction in RBC lifespan Hb range = 10-12 g/dl On Hb elect: 100% Hb C  Usually milder than sickle cell disease Mild hemolytic anemia Occasional infarctive crises Hemoglobin Splenomegaly Increased viscosity of the blood causing: SC Disease Proliferative retinopathy Painful aseptic necrosis of the femoral head (more than in SS disease) Acute chest syndrome  With + variant Mild anemia Labs: Low MCV On Hb elect 65-70% Hb C, 20-30% Hb A Hemoglobin and increased Hb F C-Beta With 0 variant Moderately severe anemia Thalassemia Splenomegaly Possible bone changes Labs: On Hb elect: Hb C, no Hb A and increased Hb F Hemoglobin E Second most common hemoglobin variant Results from a substitution of lysine for glutamic acid at position 26 of the Beta globin gene Causes a + thalassemia phenotype Causes abnormal processing of pre- mRNA to functional mRNA Results in decreased synthesis of Hb E Hemoglobin E: At-risk Populations Extremely common in Southeast Asia: Vietnam Cambodia Laos Thailand Malaysia Indonesia India China Hemoglobin E trait Asymptomatic Normal hemoglobin level Microcytosis present without anemia Low MCV (average MCV 72 fl) On Hb elect: 30-45% Hb E  Similar to Hb CC disease Mild hemolytic anemia Mild splenomegaly Hemoglobin E No significant clinical problems Labs: Disease Normal or slightly low hemoglobin levels Low MCV (mean of 67 fl) On Hb elect: No HbA, Increased Hb F (10 - 15 %)  With 0 variant Treatment is similar to beta thalassemia major Severe anemia Splenomegaly Hemoglobin E Jaundice Beta Bone marrow expansion Labs: Thalassemia Microcytosis On Hb elect: Hb E present with significant increase in Hb F (30 - 60%), No Hb A  With + variant Moderate anemia Hemoglobin E Splenomegaly Jaundice Beta Labs: Thalassemia Microcytosis On Hb elect: ~40% Hb E, 1-30% Hb A and 30-50% Hb F My Story: Hemoglobin E Beta Thalassemia https://youtu.be/lsDINCVQWfA  Mild to moderate hemolytic anemia Clinical expression is variable: some patients have no symptoms, whereas others have sickle Hemoglobin E cell-related complications. Less severe as compared to more common Sickle Cell forms of sickle cell disease.  Characterized by persistent high levels of fetal hemoglobin (HbF) in adults. Range: 10-40% (Normal: 3.5%) May be normal if also iron deficient Possible Increased Hb F (> 2.0%) Thi s Photo by Unknown Author i s l icensed under CC BY  Hemoglobin A >95% Infants 10%-30% Hemoglobin A2 1.5%-3.5% Hemoglobin F