Inherited Anemias PDF

Genetic Basis of Inherited Anemias (Inherited aplastic anemia/bone Marrow Failure and G6PD Deficiency) Rozhgar A. Khailani Medical Geneticist, PhD...

Genetic Basis of Inherited Anemias (Inherited aplastic anemia/bone Marrow Failure and G6PD Deficiency) Rozhgar A. Khailani Medical Geneticist, PhD Lecturer at College of Medicine Hawler Medical University What is Anemia? Anemia is a medical condition in which the body lacks enough healthy red blood cells (RBCs) to carry adequate oxygen to tissues. This can lead to symptoms like fatigue, weakness, shortness of breath, and pale skin.. Aspect Inherited Anemia Acquired Anemia Cause Genetic mutations passed down Environmental, nutritional, through inheritance. autoimmune or disease-related factors. Examples Hereditary spherocytosis, G6PD Iron Deficiency, Folate deficiency, Deficiency, Sickle Cell Anemia Aplastic Anemia. Inheritance Pattern - Autosomal dominant (e.g., hereditary Not inherited. However, some acquired spherocytosis). anemias may have a genetic - Autosomal recessive (e.g., sickle cell). predisposition (e.g., autoimmunity, - X-linked (e.g., G6PD deficiency). cancer). Classification of Anemia Anemia Hemolytic Iron-Deficiency Folate Deficiency Aplastic Anemia Anemia Anemia Anemia Hemolytic Anemia Anaemias that result from an increase in the rate of red cell destruction. Compensated haemolytic disease: Because of erythropoietic hyperplasia and anatomical extension of bone marrow, red cell destruction may be increased several‐fold before the patient becomes anaemic. The normal adult marrow, after full expansion, is able to produce red cells at 6–8 times the normal rate provided this is ‘effective’. It leads to a marked reticulocytosis. Therefore, anaemia due to haemolysis may not be seen until the red cell lifespan is less than 30 days. Hereditary haemolytic anaemias are the result of ‘intrinsic’ red cell defects. Hereditary Hemolytic Anemia Acquired  Classification of Hereditary Haemolytic Anaemias Result from intrinsic red cell defects, including: Haemolytic Anaemias Membrane Metabolism Haemoglobin Defects Defects Defects Hereditary Hereditary Pyruvate kinase Genetic abnormalities G6PD deficiency (Hb S, Hb C) spherocytosis elliptocytosis deficiency Membrane Defects: Hereditary Spherocytosis What is Hereditary Spherocytosis?  Hereditary spherocytosis (HS) is a genetic disorder affecting red blood cells (RBCs), characterized by: Loss of the normal biconcave shape, forming spherical RBCs. Reduced RBC deformability, leading to premature destruction (hemolysis) in the spleen.  Forms of Hereditary Spherocytosis: Mild, Moderate, Moderate/Severe, and Severe forms.  Prevalence: Mild Form: 20–30% of cases. Moderate Form: 60–70% of cases. Moderate/Severe Form: 10% of cases. Severe Form: 3–5% of cases.  Severity: Forms differ in the intensity of symptoms, ranging from mild anemia to severe hemolysis and complications. Genetic Basis of Hereditary Spherocytosis  Cause: Mutations in genes encoding RBC membrane proteins responsible for maintaining shape and stability.  Affected Genes: ANK1: Encodes ankyrin, most common mutation. SPTA1 and SPTB: Encode alpha and beta spectrin. EPB42: Encodes protein 4.2. SLC4A1: Encodes band 3 protein.  Inheritance Pattern: Autosomal dominant: Most cases Autosomal recessive: Rare cases Membrane Defects: Hereditary Elliptocytosis What is Hereditary Elliptocytosis (HE)?  Hereditary Elliptocytosis is a genetic blood disorder characterized by abnormally shaped red blood cells (elliptical or oval), characterized by: Red blood cells (RBCs) are less flexible and prone to destruction (hemolysis). May range from asymptomatic to severe hemolytic anemia. Genetic mutations result in weakness of the cytoskeleton of the cell, leading to deformation of the cell. The abnormally shaped RBCs are taken up and destroyed by the spleen. Hemolysis is usually absent or slight, with little or no anemia except in some patients who are homozygous (hereditary pyropoikilocytosis). Genetic Basis of Hereditary Elliptocytosis  Cause: By mutations in genes encoding cytoskeletal proteins essential for RBC membrane stability.  Affected Genes: SPTA1 (Spectrin alpha chain) SPTB (Spectrin beta chain) EPB41 (Protein 4.1) GYPC (glycophorin C)  Inheritance Pattern: Autosomal dominant in most cases. Rarely, recessive inheritance with severe phenotypes. Hereditary pyropoikilocytosis is a related condition with more serious symptoms, and is inherited in an autosomal recessive pattern.  Severity: The severity of HE depends on the specific mutation and its impact on membrane stability. Metabolism Defect: Glucose‐6‐phosphate dehydrogenase deficiency (G6PD) What is Glucose‐6‐phosphate dehydrogenase deficiency (G6PD) ? G6PD deficiency is a genetic disorder where the enzyme glucose-6-phosphate dehydrogenase (G6PD) is deficient or absent in red blood cells (RBCs). This enzyme is crucial for protecting RBCs from oxidative damage.  Agents that may cause haemolytic anaemia in (G6PD) deficiency Without sufficient G6PD, RBCs are vulnerable to damage when exposed to oxidative stress like: Infections and other acute illnesses Drugs (Antimalarials , sulphonamides and sulphones , antibacterial agents and analgesics) Fava beans Genetic Basis of G6PD Deficiency  X-linked Inheritance:G6PD deficiency is inherited in an X-linked recessive pattern, meaning the gene causing the condition is located on the X chromosome. Males have one X chromosome and are typically more severely affected. Females have two X chromosomes, and the condition may be less severe or asymptomatic if only one X chromosome carries the mutated  X-Inactivation in Females: In females, one of the two X chromosomes is randomly inactivated early in embryonic development. Skewed X-inactivation occurs when one X chromosome is inactivated more than the other in a majority of cells. This can result in the X chromosome with the mutated G6PD gene being more frequently expressed. This leads to a deficiency in normal G6PD enzyme production Metabolism Defect: Pyruvate Kinase Deficiency What is Pyruvate Kinase Deficiency? Pyruvate Kinase Deficiency is a rare genetic disorder that affects red blood cell (RBC) metabolism. It results in chronic hemolytic anemia due to a deficiency of the enzyme pyruvate kinase (PK), which is crucial for the glycolytic pathway in RBCs.. Without PK, RBCs cannot produce sufficient ATP, leading to membrane instability and premature RBC destruction (hemolysis). Genetic Basis of Pyruvate Kinase Deficiency Inheritance Pattern: Autosomal recessive. Gene Involved: PKLR gene on chromosome 1, which encodes the pyruvate kinase enzyme. Mutations: Over 300 mutations in the PKLR gene have been identified, leading to varying degrees of enzyme deficiency. Haemoglobin Defect  Hemoglobinopathies Disorders affecting the structure or production of hemoglobin: Sickle Cell Disease (SCD): Caused by a mutation in the HBB gene (e.g., HbS variant). Inheritance: Autosomal recessive. HbC : Mutations in the HBB gene leading to abnormal hemoglobin structucture. Iron deficiency Anemia The body has limited ability to absorb iron, iron deficiency is the major cause of a microcytic, hypochromic anaemia  Causes: Dietary Deficiency Blood Loss Malabsorption Increased Demand  Iron-Refractory Iron Deficiency Anemia (IRIDA) Cause: Genetic mutations, primarily in the TMPRSS6 gene, affecting iron regulation through hepcidin overproduction. Features: Rare autosomal recessive disorder. Unresponsive to oral iron; requires intravenous iron. Aplastic Anemia and Bone Marrow Failure Syndromes Aplastic (hypoplastic) anaemia is defined as pancytopenia resulting from hypoplasia of the bone marrow. It’s rare but serious blood disorder, where the bone marrow doesn't make enough new blood cells. Aplastic Anemia Congenital Acquired External Factors Non-Fanconi Fanconi Anemia Idiopathic (Radiation, Chemicals Anemia Drugs, Viruses) Congenital Aplastic Anemia Congenital aplastic anemia is a rare genetic disorder where the bone marrow fails to produce adequate blood cells, leading to pancytopenia (low red blood cells, white blood cells, and platelets) from birth or early childhood. It is caused by inherited genetic mutations that affect bone marrow function. Congenital Aplastic Anemia Non-Fanconi Fanconi Anemia Anemia Fanconi Anemia Fanconi Anemia (FA) is a rare genetic disorder characterized by bone marrow failure, congenital abnormalities, and an increased risk of cancer, particularly leukemia. It results from defects in the DNA repair mechanism, causing an inability to repair DNA cross-links, which can lead to damage in the bone marrow and other tissues. Feature Details Bone Marrow Failure Pancytopenia (low red blood cells, white blood cells, and platelets), leading to anemia, infections, and bleeding problems. Congenital Abnormalities -Short stature, limb abnormalities -Skin pigmentation changes (café-au-lait spots) - Renal abnormalities, hearing loss, and eye defects Increased Cancer Risk Higher risk of acute myelogenous leukemia (AML) Growth and Development Growth retardation and potential developmental delays. Genetic Basis of Fanconi Anemia Fanconi Anemia (FA) is primarily caused by mutations in genes that are involved in the DNA repair pathway, specifically in the repair of DNA cross-links. These genes are responsible for maintaining genome stability by repairing damaged DNA, particularly when it is cross-linked, which can otherwise lead to chromosome breakage and cellular malfunction. Fanconi Anemia (FA) is a genetically heterogeneous disorder that follows an autosomal recessive inheritance pattern. This means an individual must inherit two defective copies of the gene (one from each parent) to develop the condition. The disorder is associated with growth retardation, congenital defects, and an increased risk of chromosomal instability and cancer. Genetic Basis of Fanconi Anemia Feature Details Autosomal Recessive Inheritance - FA is inherited in an autosomal recessive manner. - An individual must inherit two defective copies (one from each parent) to develop the disorder. - Carrier parents are typically asymptomatic. Genetic Heterogeneity - FA is caused by mutations in 16 different genes (FANCA to FANQ). - The most common mutation occurs in FANCA, but other genes like FANCB, FANCD2, and FANCD1 also contribute. FANCD1 Identical to BRCA2 - FANCD1 is identical to BRCA2, the breast cancer susceptibility gene. - Mutations in BRCA2/FANCD1 are linked to increased cancer risks, including breast and ovarian cancer. Chromosomal Instability - Cells from FA patients exhibit a high frequency of chromosomal breakage due to faulty DNA repair. - DEB test (diepoxybutane test) is used to detect elevated chromosomal breakage in FA patients. Non-Fanconi Anemia Bone Marrow Failure Syndromes Non-Fanconi Anemia Shwachman- Congenital Diamond-Blackfan Dyskeratosis Diamond Syndrome dyserythropoietic Anemia (DBA) Congenita (DC) (SDS) anaemia THANK YOU