1. Genetic diseases like thalassemia, sickle cell trait, and G6PD deficiency can provide resistance to certain infectious diseases like malaria.
2. For example, individuals with sickle cell trait have some protection against malaria, as the infected red blood cells tend to sickle and be removed from the body, preventing the parasite from spreading.
3. Similarly, those with thalassemia or G6PD deficiency may have enhanced immune responses that kill the malaria parasite. This has led scientists to study these genetic mechanisms of disease resistance to inform new therapies.
Congenital dyserythropoietic anemia (CDA) is a rare blood disorder characterized by ineffective red blood cell production. There are four main types of CDA, each caused by mutations in different genes. CDA Type I is caused by mutations in the CDAN1 gene and results in moderate to severe anemia diagnosed in childhood. CDA Type II is caused by mutations in the SEC23B gene and can range from mild to severe anemia diagnosed in adolescence. CDA Type III is dominantly inherited and caused by mutations in the KIF23 gene, resulting in milder anemia than other types. CDA Type IV is dominantly inherited and caused by mutations in the KLF1 gene
Dr. Mary Ann Anderson presented on hemoglobinopathies at a scientific meeting. She discussed the genetics, classification, and laboratory features of different hemoglobinopathies including thalassemias and variant hemoglobins. Key points included that hemoglobinopathies are inherited abnormalities of globin chain synthesis that range in severity from asymptomatic to death. Thalassemias result from imbalanced alpha and beta globin chain production and are typically microcytic anemias, while variant hemoglobins have normal globin ratios but structural globin abnormalities. Laboratory testing can help differentiate thalassemias from iron deficiency anemia based on red blood cell indices and iron studies.
(Hematology) alpha and beta thalassemias in english by dr. kalimullah wardakKalimullah Wardak
The document discusses alpha thalassemia and provides details on its classifications, causes, clinical syndromes, and diagnostic workup. It describes the four types of alpha thalassemia (silent carrier state, trait, hemoglobin H disease, and Bart's Hydrops Fetalis) based on the number of defective alpha globin genes. The diagnostic workup involves examination of blood counts, peripheral smear, bilirubin, iron studies, and globin chain or DNA testing to identify the genetic defect. Management depends on severity but may include folic acid, transfusions, splenectomy, or stem cell transplantation.
Hemoglobinopathies and thalassemia are genetic blood disorders that result in abnormal hemoglobin. Hemoglobinopathies are caused by mutations in the globin chains of hemoglobin molecules, while thalassemias are caused by reduced or absent globin chain production. Sickle cell disease is a hemoglobinopathy caused by a mutation in the beta globin chain that results in sickle-shaped red blood cells. Thalassemias include alpha and beta thalassemia, which are characterized by decreased alpha or beta globin chain production leading to anemia. Management involves blood transfusions, iron chelation therapy, and in some cases stem cell transplantation.
The document discusses thalassemia in pregnancy according to 2014 guidelines from the Royal College of Obstetricians and Gynaecologists (RCOG). It defines thalassemia as a quantitative disorder of globin chain production affecting either the alpha or beta globin chain. It describes the epidemiology, genetics, types (alpha and beta thalassemia), complications, and management both outside and during pregnancy. The RCOG guidelines provide recommendations for preconception care, antenatal care, intrapartum care, postpartum care, booking appointments, and schedule of antenatal appointments for women with thalassemia.
The document discusses haemoglobin disorders and haemoglobinopathies. It provides details on the molecular basis, inheritance patterns, clinical presentation and diagnosis of conditions like thalassaemia, sickle cell disease and other haemoglobin variants. Key points include that haemoglobin disorders are globally common due to ancestral mutations, are usually inherited in an autosomal recessive pattern, and can be diagnosed through blood tests, family history and molecular genetic analysis. Screening programs have helped identify carriers and provide prenatal diagnosis services.
Hemoglobinopathies are a group of inherited disorders involving abnormal hemoglobin. They are classified into quantitative disorders affecting globin chain synthesis (thalassemias) and qualitative disorders altering globin structure (sickle cell disease). Thalassemias include β-thalassemia resulting from reduced β-chain production and α-thalassemia from reduced α-chain production. Sickle cell disease is caused by a mutation substituting valine for glutamic acid on the β-chain, causing hemoglobin S which polymerizes and sickles red blood cells under low oxygen conditions.
Hemoglobinopathies are genetic disorders that result in abnormalities in the structure or synthesis of hemoglobin. There are two main types: qualitative abnormalities that change the structure of the globin chains, and quantitative abnormalities that reduce globin chain production (thalassemias). Thalassemias are caused by mutations that decrease or eliminate alpha or beta globin chain synthesis. This leads to imbalanced globin chain production and severe anemia. The most severe form is beta thalassemia major, which requires lifelong blood transfusions if untreated. Beta thalassemia trait is a milder form with microcytic anemia and elevated hemoglobin A2 levels.
Congenital dyserythropoietic anemia (CDA) is a rare blood disorder characterized by ineffective red blood cell production. There are four main types of CDA, each caused by mutations in different genes. CDA Type I is caused by mutations in the CDAN1 gene and results in moderate to severe anemia diagnosed in childhood. CDA Type II is caused by mutations in the SEC23B gene and can range from mild to severe anemia diagnosed in adolescence. CDA Type III is dominantly inherited and caused by mutations in the KIF23 gene, resulting in milder anemia than other types. CDA Type IV is dominantly inherited and caused by mutations in the KLF1 gene
Dr. Mary Ann Anderson presented on hemoglobinopathies at a scientific meeting. She discussed the genetics, classification, and laboratory features of different hemoglobinopathies including thalassemias and variant hemoglobins. Key points included that hemoglobinopathies are inherited abnormalities of globin chain synthesis that range in severity from asymptomatic to death. Thalassemias result from imbalanced alpha and beta globin chain production and are typically microcytic anemias, while variant hemoglobins have normal globin ratios but structural globin abnormalities. Laboratory testing can help differentiate thalassemias from iron deficiency anemia based on red blood cell indices and iron studies.
(Hematology) alpha and beta thalassemias in english by dr. kalimullah wardakKalimullah Wardak
The document discusses alpha thalassemia and provides details on its classifications, causes, clinical syndromes, and diagnostic workup. It describes the four types of alpha thalassemia (silent carrier state, trait, hemoglobin H disease, and Bart's Hydrops Fetalis) based on the number of defective alpha globin genes. The diagnostic workup involves examination of blood counts, peripheral smear, bilirubin, iron studies, and globin chain or DNA testing to identify the genetic defect. Management depends on severity but may include folic acid, transfusions, splenectomy, or stem cell transplantation.
Hemoglobinopathies and thalassemia are genetic blood disorders that result in abnormal hemoglobin. Hemoglobinopathies are caused by mutations in the globin chains of hemoglobin molecules, while thalassemias are caused by reduced or absent globin chain production. Sickle cell disease is a hemoglobinopathy caused by a mutation in the beta globin chain that results in sickle-shaped red blood cells. Thalassemias include alpha and beta thalassemia, which are characterized by decreased alpha or beta globin chain production leading to anemia. Management involves blood transfusions, iron chelation therapy, and in some cases stem cell transplantation.
The document discusses thalassemia in pregnancy according to 2014 guidelines from the Royal College of Obstetricians and Gynaecologists (RCOG). It defines thalassemia as a quantitative disorder of globin chain production affecting either the alpha or beta globin chain. It describes the epidemiology, genetics, types (alpha and beta thalassemia), complications, and management both outside and during pregnancy. The RCOG guidelines provide recommendations for preconception care, antenatal care, intrapartum care, postpartum care, booking appointments, and schedule of antenatal appointments for women with thalassemia.
The document discusses haemoglobin disorders and haemoglobinopathies. It provides details on the molecular basis, inheritance patterns, clinical presentation and diagnosis of conditions like thalassaemia, sickle cell disease and other haemoglobin variants. Key points include that haemoglobin disorders are globally common due to ancestral mutations, are usually inherited in an autosomal recessive pattern, and can be diagnosed through blood tests, family history and molecular genetic analysis. Screening programs have helped identify carriers and provide prenatal diagnosis services.
Hemoglobinopathies are a group of inherited disorders involving abnormal hemoglobin. They are classified into quantitative disorders affecting globin chain synthesis (thalassemias) and qualitative disorders altering globin structure (sickle cell disease). Thalassemias include β-thalassemia resulting from reduced β-chain production and α-thalassemia from reduced α-chain production. Sickle cell disease is caused by a mutation substituting valine for glutamic acid on the β-chain, causing hemoglobin S which polymerizes and sickles red blood cells under low oxygen conditions.
Hemoglobinopathies are genetic disorders that result in abnormalities in the structure or synthesis of hemoglobin. There are two main types: qualitative abnormalities that change the structure of the globin chains, and quantitative abnormalities that reduce globin chain production (thalassemias). Thalassemias are caused by mutations that decrease or eliminate alpha or beta globin chain synthesis. This leads to imbalanced globin chain production and severe anemia. The most severe form is beta thalassemia major, which requires lifelong blood transfusions if untreated. Beta thalassemia trait is a milder form with microcytic anemia and elevated hemoglobin A2 levels.
Thalassemia is an inherited blood disorder caused by reduced or absent production of hemoglobin subunits (globin chains). There are two main types: alpha thalassemia involves a deficiency of alpha globin chains, while beta thalassemia involves a deficiency of beta globin chains. The severity of symptoms depends on how many globin genes are affected. Alpha thalassemia ranges from silent carrier state with no symptoms to hydrops fetalis, which is fatal if untreated.
The document discusses thalassemias, which are inherited autosomal recessive blood disorders caused by genetic defects that result in reduced synthesis of one of the globin chains. This causes anemia. It describes the prevalence of different types of thalassemias in various regions. It specifically discusses alpha and beta thalassemias, their genetic causes and effects, inheritance patterns, and treatment options such as blood transfusions, iron chelation therapy, and bone marrow transplantation.
Dr. Neela Ferdoushi presented on thalassemias and hemoglobinopathies. Thalassemias are genetic disorders caused by mutations that decrease the synthesis of the alpha or beta globin chains, resulting in imbalanced globin chain production and anemia. The clinical severity depends on the specific gene mutations inherited. Untreated homozygous forms can be fatal in childhood. Heterozygous carriers may be asymptomatic or have mild anemia. Laboratory tests can help identify abnormalities in hemoglobin type or amounts through hemograms and hemoglobin electrophoresis. Management involves blood transfusions and iron chelation therapy for severe forms.
Hemoglobin is a protein in red blood cells that carries oxygen throughout the body. It is composed of four polypeptide chains, two alpha chains and two beta chains, as well as an iron-containing heme group. Abnormalities in the hemoglobin protein chains or levels can result in hemoglobinopathies. Common hemoglobinopathies include sickle cell disease, where a mutation in the beta chain causes red blood cells to take on a sickle shape, and thalassemias, where reduced production of the alpha or beta chains causes anemia. Other clinically significant hemoglobin variants involve single amino acid substitutions that can alter oxygen affinity and cause issues like decreased oxygen delivery or increased red blood cell destruction.
This document summarizes different types of hemoglobinopathies and thalassemias. It describes normal adult hemoglobins and the two major disorders - qualitative hemoglobinopathies caused by structural mutations like sickle cell anemia, and quantitative hemoglobinopathies caused by reduced globin chain synthesis like thalassemias. Sickle cell disease results from a glutamic acid to valine substitution and causes polymerization of deoxygenated hemoglobin. Thalassemias are caused by alpha or beta globin chain deficiency. Beta thalassemia major involves homozygosity for beta thalassemia genes and requires frequent blood transfusions. Alpha thalassemia ranges from silent carrier state to Bart's hydrops
This document summarizes Alpha Thalassemia. It discusses the molecular pathology, pathophysiology, clinical presentations including Hydrops syndrome and Hb H disease, diagnosis using various PCR techniques, and prenatal screening. Alpha Thalassemia results from deletions or mutations affecting the alpha globin genes, leading to excess beta or gamma chains and anemia. Clinical severity depends on the number of functional alpha globin genes.
1) Hemoglobinopathies are inherited disorders affecting hemoglobin structure or production, ranging from asymptomatic to fatal. The most common types are sickle cell disease and thalassemias.
2) Thalassemias are caused by deficient production of globin chains, leading to imbalanced globin synthesis and red blood cell damage. Beta thalassemias result from low beta chain production while alpha thalassemias involve alpha chains.
3) Clinical features vary by specific disorder from mild anemia to transfusion-dependent anemia and organ damage. Management involves treatment of complications, transfusions, chelation therapy, and in severe cases, stem cell transplant.
This document summarizes the key points about thalassemia. Thalassemia is a genetic disorder where there is a reduction or absence in the production of hemoglobin subunits alpha and beta. There are two main types: alpha-thalassemia caused by deletion of alpha chains, and beta-thalassemia caused by mutations in beta chains. Beta-thalassemia is more common. Homozygous individuals are severely affected and can die in childhood without treatment, while heterozygous individuals are less severely affected and can live long lives. The document outlines the different genotypes and phenotypes of alpha and beta-thalassemia.
This document discusses thalassemia, a blood disorder characterized by reduced or absent globin chain synthesis. It was first described in 1925 and there are two main types: alpha and beta thalassemia. Alpha thalassemia is more common in Southeast Asia while beta is seen around the Mediterranean. Thalassemia is classified by genotype and clinical severity. Thalassemia major, the most severe form of beta thalassemia, presents in the first year of life with anemia, failure to thrive, and bone changes if untreated. The pathophysiology involves accumulation of unbound globin chains and hemolysis leading to complications like iron overload.
- Thalassemia is a genetic blood disorder caused by mutations in hemoglobin genes. It results in decreased or absent globin chains and abnormal hemoglobins.
- There are two main types - alpha and beta thalassemia. Beta thalassemia major requires lifelong blood transfusions and causes iron overload.
- India has a high burden of thalassemia with over 10,000 children born with thalassemia major each year. Carrier rates vary regionally from 1-15% in different parts of India.
- Management involves blood transfusions to prevent complications from anemia. Iron chelation therapy is also required to manage iron overload from frequent transfusions. Bone marrow
The HBA2 gene provides instructions for making the alpha-globin protein, which combines with other proteins to form hemoglobin. Mutations in the HBA2 gene can cause alpha thalassemia, a condition where there is a reduction in the production of alpha-globin, leading to abnormal hemoglobin molecules that cannot effectively carry oxygen. The severity of alpha thalassemia depends on how many of the four alpha-globin alleles a person is missing, ranging from the most severe Hb Bart syndrome where all alleles are lost to HbH disease where three alleles are lost.
The patient has beta-thalassemia based on his anemia, hepatosplenomegaly, and small size. Beta-thalassemia is a hereditary blood disorder caused by a defect in the gene responsible for producing the beta chain of hemoglobin. This leads to reduced hemoglobin and anemia. The document discusses the molecular basis, clinical features, epidemiology, and radiographic manifestations of beta-thalassemia.
Congenital dyserythropoietic anemia (CDA) is a rare blood disorder characterized by ineffective red blood cell production resulting in anemia. There are four main types of CDA which are inherited in an autosomal recessive pattern. Patients with CDA require frequent blood transfusions and iron chelation therapy to remove excess iron from the body. Bone marrow transplant and gene therapy may cure CDA but carry risks. Recent gene therapy trials have shown promise in curing beta-thalassemia.
Thalassemia refers to a group of inherited anemias caused by reduced or absent globin chain synthesis. There are two main types: alpha thalassemia results from alpha globin gene mutations and beta thalassemia from beta globin gene mutations. Symptoms range from none to severe anemia, bone abnormalities, organ enlargement, and other complications depending on severity. Treatment involves blood transfusions, iron chelation therapy, and in some cases bone marrow transplant or splenectomy.
Thalassemia is a genetic blood disorder caused by mutations in the genes that control globin production. There are two main types - alpha thalassemia affects alpha globin genes, while beta thalassemia affects beta globin genes. Thalassemia severity depends on the number of affected genes, ranging from no symptoms to severe anemia requiring chronic blood transfusions. The thalassemia gene is maintained in populations where malaria is common due to heterozygote resistance to the disease.
Etiology and pathogenesis of heredity and congenital diseases presentationMuhammad Faisal Mukhtar
This document discusses hereditary and congenital diseases. It defines hereditary disorders as being transmitted through generations in gametes from one's parents, while congenital diseases are present at birth but are not always genetic. It then covers Mendelian patterns of inheritance including autosomal dominant, recessive, and X-linked traits. Specific diseases are examined like Marfan syndrome, cystic fibrosis, familial hypercholesterolemia, phenylketonuria, and lysosomal storage diseases. The causes of these diseases are often traced to defects in structural proteins, enzymes, receptors, or channels due to mutations in single genes.
1• Define anemia and it's genetic bases.2• Describe thalassemia and it's genetic bases.3• What is the molecular defects and pathophysiology of thalassemia 4• Describe the diagnostic test that detect genetic mutation of thalassemia 5• Overview of pre-marital screening test.
This document summarizes haemoglobinopathies, genetic blood disorders caused by abnormal hemoglobin. It discusses sickle cell anemia and thalassemias. Sickle cell anemia is caused by a qualitative hemoglobin defect while thalassemias are quantitative defects. The document covers prevalence, pathophysiology, clinical manifestations, treatment including blood transfusions, and preventative measures for these conditions. Electrophoresis is described as a method to separate and identify hemoglobin variants.
This document summarizes beta thalassemia, a genetic blood disorder caused by a decreased production of the beta globin chain. It discusses the molecular defects that can cause beta thalassemia, resulting in reduced or unstable beta globin mRNA. It describes the clinical features of beta thalassemia major, also known as Cooley's anemia, which is characterized by severe anemia and other complications if not treated with regular blood transfusions. It provides information on some common lab findings in beta thalassemia and differences in hemoglobin levels between different types.
Malaria resistance " Resistance to Malaria"Ahmed Zaahir
How The following factors contribute to malaria resistance
(1)Hemoglobin s
(2)Glucose 6 phosphate dehydrogenase deficiency
(3)Thalassemia
(4)Ovalocyte gene
This document discusses mutations and various genetic blood disorders including sickle cell anemia, thalassemia, and anemia. It begins by defining mutation as a change in genetic material that can be caused by errors in DNA replication or repair. It then describes different types of mutations like substitutions, insertions, deletions, and frameshifts. The document outlines the molecular basis and effects of mutations like loss or gain of function. Sickle cell anemia is presented as a case study where a single point mutation causes the disease. Thalassemia and the differences between alpha and beta thalassemia are also summarized. The signs, symptoms, and treatments of various types of anemia conclude the document.
Thalassemia is an inherited blood disorder caused by reduced or absent production of hemoglobin subunits (globin chains). There are two main types: alpha thalassemia involves a deficiency of alpha globin chains, while beta thalassemia involves a deficiency of beta globin chains. The severity of symptoms depends on how many globin genes are affected. Alpha thalassemia ranges from silent carrier state with no symptoms to hydrops fetalis, which is fatal if untreated.
The document discusses thalassemias, which are inherited autosomal recessive blood disorders caused by genetic defects that result in reduced synthesis of one of the globin chains. This causes anemia. It describes the prevalence of different types of thalassemias in various regions. It specifically discusses alpha and beta thalassemias, their genetic causes and effects, inheritance patterns, and treatment options such as blood transfusions, iron chelation therapy, and bone marrow transplantation.
Dr. Neela Ferdoushi presented on thalassemias and hemoglobinopathies. Thalassemias are genetic disorders caused by mutations that decrease the synthesis of the alpha or beta globin chains, resulting in imbalanced globin chain production and anemia. The clinical severity depends on the specific gene mutations inherited. Untreated homozygous forms can be fatal in childhood. Heterozygous carriers may be asymptomatic or have mild anemia. Laboratory tests can help identify abnormalities in hemoglobin type or amounts through hemograms and hemoglobin electrophoresis. Management involves blood transfusions and iron chelation therapy for severe forms.
Hemoglobin is a protein in red blood cells that carries oxygen throughout the body. It is composed of four polypeptide chains, two alpha chains and two beta chains, as well as an iron-containing heme group. Abnormalities in the hemoglobin protein chains or levels can result in hemoglobinopathies. Common hemoglobinopathies include sickle cell disease, where a mutation in the beta chain causes red blood cells to take on a sickle shape, and thalassemias, where reduced production of the alpha or beta chains causes anemia. Other clinically significant hemoglobin variants involve single amino acid substitutions that can alter oxygen affinity and cause issues like decreased oxygen delivery or increased red blood cell destruction.
This document summarizes different types of hemoglobinopathies and thalassemias. It describes normal adult hemoglobins and the two major disorders - qualitative hemoglobinopathies caused by structural mutations like sickle cell anemia, and quantitative hemoglobinopathies caused by reduced globin chain synthesis like thalassemias. Sickle cell disease results from a glutamic acid to valine substitution and causes polymerization of deoxygenated hemoglobin. Thalassemias are caused by alpha or beta globin chain deficiency. Beta thalassemia major involves homozygosity for beta thalassemia genes and requires frequent blood transfusions. Alpha thalassemia ranges from silent carrier state to Bart's hydrops
This document summarizes Alpha Thalassemia. It discusses the molecular pathology, pathophysiology, clinical presentations including Hydrops syndrome and Hb H disease, diagnosis using various PCR techniques, and prenatal screening. Alpha Thalassemia results from deletions or mutations affecting the alpha globin genes, leading to excess beta or gamma chains and anemia. Clinical severity depends on the number of functional alpha globin genes.
1) Hemoglobinopathies are inherited disorders affecting hemoglobin structure or production, ranging from asymptomatic to fatal. The most common types are sickle cell disease and thalassemias.
2) Thalassemias are caused by deficient production of globin chains, leading to imbalanced globin synthesis and red blood cell damage. Beta thalassemias result from low beta chain production while alpha thalassemias involve alpha chains.
3) Clinical features vary by specific disorder from mild anemia to transfusion-dependent anemia and organ damage. Management involves treatment of complications, transfusions, chelation therapy, and in severe cases, stem cell transplant.
This document summarizes the key points about thalassemia. Thalassemia is a genetic disorder where there is a reduction or absence in the production of hemoglobin subunits alpha and beta. There are two main types: alpha-thalassemia caused by deletion of alpha chains, and beta-thalassemia caused by mutations in beta chains. Beta-thalassemia is more common. Homozygous individuals are severely affected and can die in childhood without treatment, while heterozygous individuals are less severely affected and can live long lives. The document outlines the different genotypes and phenotypes of alpha and beta-thalassemia.
This document discusses thalassemia, a blood disorder characterized by reduced or absent globin chain synthesis. It was first described in 1925 and there are two main types: alpha and beta thalassemia. Alpha thalassemia is more common in Southeast Asia while beta is seen around the Mediterranean. Thalassemia is classified by genotype and clinical severity. Thalassemia major, the most severe form of beta thalassemia, presents in the first year of life with anemia, failure to thrive, and bone changes if untreated. The pathophysiology involves accumulation of unbound globin chains and hemolysis leading to complications like iron overload.
- Thalassemia is a genetic blood disorder caused by mutations in hemoglobin genes. It results in decreased or absent globin chains and abnormal hemoglobins.
- There are two main types - alpha and beta thalassemia. Beta thalassemia major requires lifelong blood transfusions and causes iron overload.
- India has a high burden of thalassemia with over 10,000 children born with thalassemia major each year. Carrier rates vary regionally from 1-15% in different parts of India.
- Management involves blood transfusions to prevent complications from anemia. Iron chelation therapy is also required to manage iron overload from frequent transfusions. Bone marrow
The HBA2 gene provides instructions for making the alpha-globin protein, which combines with other proteins to form hemoglobin. Mutations in the HBA2 gene can cause alpha thalassemia, a condition where there is a reduction in the production of alpha-globin, leading to abnormal hemoglobin molecules that cannot effectively carry oxygen. The severity of alpha thalassemia depends on how many of the four alpha-globin alleles a person is missing, ranging from the most severe Hb Bart syndrome where all alleles are lost to HbH disease where three alleles are lost.
The patient has beta-thalassemia based on his anemia, hepatosplenomegaly, and small size. Beta-thalassemia is a hereditary blood disorder caused by a defect in the gene responsible for producing the beta chain of hemoglobin. This leads to reduced hemoglobin and anemia. The document discusses the molecular basis, clinical features, epidemiology, and radiographic manifestations of beta-thalassemia.
Congenital dyserythropoietic anemia (CDA) is a rare blood disorder characterized by ineffective red blood cell production resulting in anemia. There are four main types of CDA which are inherited in an autosomal recessive pattern. Patients with CDA require frequent blood transfusions and iron chelation therapy to remove excess iron from the body. Bone marrow transplant and gene therapy may cure CDA but carry risks. Recent gene therapy trials have shown promise in curing beta-thalassemia.
Thalassemia refers to a group of inherited anemias caused by reduced or absent globin chain synthesis. There are two main types: alpha thalassemia results from alpha globin gene mutations and beta thalassemia from beta globin gene mutations. Symptoms range from none to severe anemia, bone abnormalities, organ enlargement, and other complications depending on severity. Treatment involves blood transfusions, iron chelation therapy, and in some cases bone marrow transplant or splenectomy.
Thalassemia is a genetic blood disorder caused by mutations in the genes that control globin production. There are two main types - alpha thalassemia affects alpha globin genes, while beta thalassemia affects beta globin genes. Thalassemia severity depends on the number of affected genes, ranging from no symptoms to severe anemia requiring chronic blood transfusions. The thalassemia gene is maintained in populations where malaria is common due to heterozygote resistance to the disease.
Etiology and pathogenesis of heredity and congenital diseases presentationMuhammad Faisal Mukhtar
This document discusses hereditary and congenital diseases. It defines hereditary disorders as being transmitted through generations in gametes from one's parents, while congenital diseases are present at birth but are not always genetic. It then covers Mendelian patterns of inheritance including autosomal dominant, recessive, and X-linked traits. Specific diseases are examined like Marfan syndrome, cystic fibrosis, familial hypercholesterolemia, phenylketonuria, and lysosomal storage diseases. The causes of these diseases are often traced to defects in structural proteins, enzymes, receptors, or channels due to mutations in single genes.
1• Define anemia and it's genetic bases.2• Describe thalassemia and it's genetic bases.3• What is the molecular defects and pathophysiology of thalassemia 4• Describe the diagnostic test that detect genetic mutation of thalassemia 5• Overview of pre-marital screening test.
This document summarizes haemoglobinopathies, genetic blood disorders caused by abnormal hemoglobin. It discusses sickle cell anemia and thalassemias. Sickle cell anemia is caused by a qualitative hemoglobin defect while thalassemias are quantitative defects. The document covers prevalence, pathophysiology, clinical manifestations, treatment including blood transfusions, and preventative measures for these conditions. Electrophoresis is described as a method to separate and identify hemoglobin variants.
This document summarizes beta thalassemia, a genetic blood disorder caused by a decreased production of the beta globin chain. It discusses the molecular defects that can cause beta thalassemia, resulting in reduced or unstable beta globin mRNA. It describes the clinical features of beta thalassemia major, also known as Cooley's anemia, which is characterized by severe anemia and other complications if not treated with regular blood transfusions. It provides information on some common lab findings in beta thalassemia and differences in hemoglobin levels between different types.
Malaria resistance " Resistance to Malaria"Ahmed Zaahir
How The following factors contribute to malaria resistance
(1)Hemoglobin s
(2)Glucose 6 phosphate dehydrogenase deficiency
(3)Thalassemia
(4)Ovalocyte gene
This document discusses mutations and various genetic blood disorders including sickle cell anemia, thalassemia, and anemia. It begins by defining mutation as a change in genetic material that can be caused by errors in DNA replication or repair. It then describes different types of mutations like substitutions, insertions, deletions, and frameshifts. The document outlines the molecular basis and effects of mutations like loss or gain of function. Sickle cell anemia is presented as a case study where a single point mutation causes the disease. Thalassemia and the differences between alpha and beta thalassemia are also summarized. The signs, symptoms, and treatments of various types of anemia conclude the document.
Hereditary hemolytic anemias can be caused by defects in the red blood cell's hemoglobin, membrane, metabolic machinery or enzymes. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme defect causing hemolytic anemia. It results from a lack of the enzyme G6PD, which protects red blood cells from oxidative damage. Patients with G6PD deficiency typically present with neonatal jaundice or acute hemolytic anemia triggered by factors like fava beans, infections or drugs. An acute hemolytic episode is characterized by symptoms like jaundice and dark urine over hours to days, along with signs of intravascular and extravascular hemolysis on lab tests.
Hemoglobinopathies are disorders of hemoglobin structure or synthesis. The document discusses hemoglobin structure and function, as well as two main types of hemoglobinopathies: sickle cell anemia and thalassemia. Sickle cell anemia is a structural disorder caused by a mutation resulting in abnormal hemoglobin S, which causes red blood cells to sickle and break down early. Thalassemia is a disorder of hemoglobin synthesis, where there is reduced or absent alpha or beta globin chain production leading to anemia. Common symptoms, inheritance patterns, and treatments are described for both conditions.
Thalassemia is an inherited blood disorder characterized by reduced hemoglobin production. It is caused by mutations in genes that encode the alpha or beta globin chains that make up hemoglobin. There are different types of thalassemia depending on which chain is affected, including alpha-thalassemia affecting alpha chains and beta-thalassemia affecting beta chains. Symptoms range from none to severe anemia. Diagnosis involves blood tests like complete blood count and hemoglobin electrophoresis. Treatment depends on severity but may include blood transfusions, iron chelation therapy, and bone marrow transplantation.
This document discusses anaemia, defining it as a reduction in red blood cells or haemoglobin. It describes normal haemoglobin levels and the symptoms of anaemia. It then covers the different types of anaemia in more detail, including iron deficiency anaemia, megaloblastic anaemias, haemolytic anaemias like sickle cell anaemia and thalassaemia. For each type, it discusses causes, pathophysiology, diagnosis, management and treatment. Key points covered include the roles of iron, B12 and folate, and the genetic basis and management of conditions like sickle cell disease and thalassaemia through blood transfusions and other therapies.
Alpha thalassemia is caused by mutations in the genes responsible for producing alpha globin, resulting in excessive destruction of red blood cells and anemia. It is characterized by mild to severe anemia, enlargement of the liver and spleen, and other symptoms. Treatment involves regular blood transfusions, folic acid supplements, and iron chelation therapy. Bone marrow transplant may cure severe cases. Beta thalassemia is caused by mutations in the beta globin gene and is characterized by severe anemia and other symptoms from an early age. Treatment focuses on blood transfusions and iron chelation therapy.
GENETICS DISORDERS thelesemia.pptx from robbindr shahida
The document discusses the genetic disorders of thalassemia. It explains that thalassemia is caused by mutations that decrease the synthesis of the alpha or beta globin chains, leading to anemia. Specifically, it describes how beta thalassemia is caused by deficient beta chain synthesis and alpha thalassemia by deficient alpha chain synthesis. The clinical presentations of different forms of alpha and beta thalassemia are explained, ranging from mild anemia in trait forms to severe transfusion-dependent anemia or hydrops fetalis in major forms.
Introduction to Thalassemia power point..AllanIbnSuma
Thalassemia is a genetic blood disorder caused by defects in the production of hemoglobin. There are two main types: alpha thalassemia affects alpha chain production and beta thalassemia affects beta chain production. Symptoms range from mild to severe anemia depending on the number of affected genes. Beta thalassemia major is the most severe form requiring lifelong blood transfusions. Carriers can be identified through blood tests measuring specific hemoglobin levels. Treatment focuses on blood transfusions and iron chelation therapy to prevent organ damage from excess iron.
The document discusses genetic blood disorders that are common in Oman, including sickle cell disease, thalassemia, and glucose-6-phosphate dehydrogenase deficiency. It notes that 75% of the Omani population carries at least one type of genetic blood disease. The Ministry of Health has implemented premarital screening to detect carriers in order to reduce incidence of inherited blood disorders and educate the population. The screening process involves tests such as CBC, HPLC, and hemoglobin electrophoresis to identify trait carriers and diagnose conditions. Common genetic blood disorders found in Oman like sickle cell disease, thalassemia, and sickle cell trait are explained.
Single nucleotide polymorphisms (SNPs) are variations in single nucleotides that occur at specific positions in the genome. For example, the base C may appear in most individuals at a specific position, but in some individuals the position is occupied by base A, representing a SNP. SNPs can be classified as synonymous or nonsynonymous depending on whether they change the amino acid sequence. Common human diseases like sickle cell anemia and cystic fibrosis result from SNPs. SNPs can be identified and analyzed using methods like DNA sequencing, mass spectrometry, and primer extension.
A single mutation in the gene for the beta chain of hemoglobin causes sickle-cell anemia, replacing a glutamate residue with valine at position 6. This causes deoxygenated hemoglobin S molecules to associate abnormally, forming long fibrous aggregates that deform red blood cells into a sickle shape. Heterozygotes have a protective advantage against malaria, while homozygotes suffer from the painful and debilitating effects of sickle-cell anemia.
1. Thalassemias are genetic blood disorders caused by mutations in the globin genes that result in reduced or absent globin chain production and imbalanced hemoglobin synthesis.
2. There are two main types: alpha-thalassemia affects alpha chain production and beta-thalassemia affects beta chain production.
3. The clinical severity of thalassemias depends on the number of defective globin genes and ranges from asymptomatic carriers to severe anemias requiring lifelong blood transfusions. Laboratory tests can identify the type and severity through hemoglobin analysis and peripheral blood smears.
Thalassemia and sideroblastic anemia are inherited blood disorders characterized by reduced hemoglobin synthesis. Thalassemia results from a genetic mutation affecting either the alpha or beta globin chains, leading to imbalanced globin chain production and anemia. Sideroblastic anemia features iron accumulation in erythroblast mitochondria, causing ineffective red blood cell production. The document defines and compares the genetic causes and clinical manifestations of different types of thalassemia and sideroblastic anemia. Laboratory findings include abnormal hemoglobin levels, red blood cell morphology, and iron studies.
Hemoglobin is composed of four globin chains that each bind to a heme group. The genes that encode for the different types of globin chains are located on chromosomes 11 and 16. Mutations in these genes can result in disorders called thalassemias, where there is imbalanced production of the globin chains. In β-thalassemia major, there is little to no production of the β-globin chains. This causes unpaired α-globin chains to precipitate and destroy red blood cell precursors in the bone marrow. Patients with β-thalassemia major suffer severe anemia starting in infancy and require regular blood transfusions to survive, but this leads to iron overload in tissues
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Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
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2. GENETIC DISEASES: IS IT
SOMETIMES BENEFITS?
By
DR: Awad M. Elabd
Prof. Of Medical Biochemistry & Molecular Biology
Biochemical Endocrinology Unit (BEU) & Information
Technology Unit (IT) Founder & Manager
3. INTRODUCTION
Some genetic conditions can confer resistance to specific
infectious diseases.
It is theorized that these genotypes are preferentially
maintained in populations regularly exposed to certain infectious
agents, especially those with high virulence.
The protection afforded by these conditions has provided the
impetus for understanding these genetic mechanisms of
resistance that can potentially be exploited for developing novel
therapies or improving current therapies.
9. HEMOGLOBINOPATHY
It is a kind of genetic defect that results in abnormal structure of one of
the globin chains of the hemoglobin molecule.
Hemoglobinopathies are inherited single-gene disorders; in most cases,
they are inherited as autosomal co-dominant traits.
Common hemoglobinopathies include sickle-cell disease.
It is estimated that 7% of world's population (420 million) are carriers,
with 60% of total and 70% pathological being in Africa.
Hemoglobinopathies are most common in populations from Africa, the
Mediterranean basin and Southeast Asia.
10. THALASSEMIAS
Thalassemias are genetic disorders inherited from a person's
parents.
There are two main types, alpha thalassemia and beta
thalassemia.
The severity of alpha and beta thalassemia depends on how
many of the four genes for alpha globin or two genes for beta
globin are missing.
Diagnosis is typically by blood tests including a complete blood
count, special hemoglobin tests, and genetic tests.
Diagnosis may occur before birth through prenatal testing.
11. PATHOPHYSIOLOGY
The thalassemias are classified according to which chain of the hemoglobin molecule is
affected.
In α-thalassemias, production of the α globin chain is affected, while in β-thalassemia,
production of the β globin chain is affected.
The β globin chains are encoded by a single gene on chromosome 11; α globin chains are
encoded by two closely linked genes on chromosome 16.
Thus, in a normal person with two copies of each chromosome, two loci encode the β
chain, and four loci encode the α chain.
Deletion of one of the α loci has a high prevalence in people of African or Asian descent,
making them more likely to develop α-thalassemia.
β-Thalassemias are not only common in Africans, but also in Greeks and Italians.
12. α-THALASSEMIAS
The α-thalassemias involve the genes HBA1 and HBA2, inherited
in a Mendelian recessive fashion.
Two gene loci and so four alleles exist. It is also connected to the
deletion of the 16p chromosome.
α Thalassemias result in decreased alpha-globin production,
therefore fewer alpha-globin chains are produced, resulting in an
excess of β chains in adults and excess γ chains in newborns.
The excess β chains form unstable tetramers (called hemoglobin
H or HbH of 4 beta chains), which have abnormal oxygen
dissociation curves.
13. BETA THALASSEMIAS
Beta thalassemias are due to mutations in the HBB gene on
chromosome 11, also inherited in an autosomal, recessive fashion.
The severity of the disease depends on the nature of the mutation
and on the presence of mutations in one or both alleles.
Mutated alleles are called β+ when partial function is conserved
(either the protein has a reduced function, or it functions normally
but is produced in reduced quantity) or βo, when no functioning
protein is produced.
The situation of both alleles determines the clinical picture:
14. BETA THALASSEMIAS
β thalassemia major (Mediterranean anemia or Cooley anemia) is caused
by a βo/βo genotype. No functional β chains are produced, and thus no
hemoglobin A can be assembled. This is the most severe form of β-
thalassemia;
β thalassemia intermedia is caused by a β+/βo or β+/β+ genotype.
In this form, some hemoglobin A is produced.
β thalassemia minor is caused by a β/βo or β/β+ genotype.
Only one of the two β globin alleles contains a mutation, so β chain
production is not terribly compromised and patients may be relatively
asymptomatic.
16. • Sickle cell trait describes a condition in which a person has one abnormal
allele of the hemoglobin beta gene (is heterozygous), but does not display
the severe symptoms of sickle-cell disease that occur in a person who has
two copies of that allele (is homozygous).
• Those who are heterozygous for the sickle cell allele produce both normal
and abnormal hemoglobin (the two alleles are codominant with respect to
the actual concentration of hemoglobin in the circulating cells).
17. • Sickle cell disease is a blood disorder in which there is a single
amino acid substitution in the hemoglobin protein of the red
blood cells, which causes these cells to assume a sickle shape,
especially when under low oxygen tension.
• Sickling and sickle cell disease also confer some resistance to
malaria parasitization of red blood cells, so that individuals with
sickle-cell trait (heterozygotes) have a selective advantage in
environments where malaria is present.
18. HEMOGLOBIN GENETICS
Normally, a person inherits two copies of the gene that produces beta-
globin, a protein needed to produce normal hemoglobin (hemoglobin A,
genotype AA).
A person with sickle cell trait inherits one normal allele and one abnormal
allele encoding hemoglobin S (hemoglobin genotype AS).
The sickle cell trait can be used to demonstrate the concepts of co-
dominance and incomplete dominance. An individual with the sickle cell
trait shows incomplete dominance when the shape of the red blood cell is
considered.
19. • This is because the sickling happens only at low oxygen concentrations.
• With regards to the actual concentration of hemoglobin in the circulating
cells, the alleles demonstrate co-dominance as both 'normal' and mutant
forms co-exist in the blood stream.
• It is interesting to note that unlike the sickle-cell trait, sickle-cell disease is
passed on in a recessive manner.
• The sickle cell gene has five haplotypes, which are named after its core
geographical areas of distribution: Bantu, Benin, Cameroon, Senegalese and
Saudi-Indian.
20. Mechanism of resistance
of sickle patients
to
Malaria
This vein (4) shows the interaction between the malaria sporozoites (6) with sickle cells (3) and regular
cells (1). While malaria is still affecting the regular cells (2), the ratio of sickle to regular cells is 50/50 due
to sickle cell anemia being a heterozygous trait, so the malaria can’t affect enough cells with schizonts (5)
to harm the body.
21. • Sickle cell trait provides a survival advantage over people with normal hemoglobin in
regions where malaria is endemic.
• The trait is known to cause significantly fewer deaths due to malaria, especially when
Plasmodium falciparum is the causative organism.
Although the precise mechanism for this phenomenon is not known, a several factors
are believed to be responsible.
1. Infected erythrocytes (Red Blood cells) tend to have lower oxygen tension, because it
is significantly reduced by the parasite. This causes sickling of that particular
erythrocyte, signaling the phagocytes to get rid of the cell and hence the parasite
within.
2. Since the sickling of parasite infected cells is higher, these selectively get removed by
the reticulo-endothelial system, thus sparing the normal erythrocytes.
22. 3. Excessive vacuole formation occurs in those parasites
infecting sickle cells.
4. Sickle trait erythrocytes produce higher levels of the
superoxide anion and hydrogen peroxide than do normal
erythrocytes, both are toxic to malarial parasites.
The sickle cell trait was found to be 50% protective against
mild clinical malaria, 75% protective against admission to the
hospital for malaria, and almost 90% protective against
severe or complicated malaria.
24. Introduction
• G6PD deficiency is the most common disease producing enzyme
abnormalities in humans, affecting more than 200 million
individuals worldwide.
• The highest prevalence in the Middle East, tropical Africa & Asia.
• G6PD Deficiency is caused by 400 different mutations in gene
coding for G6PD, only few of them causes the clinical symptoms
of the disease.
25. What is G6PD?
• G6PD is an metabolic enzyme is involved in pentose
phosphate pathway, especially important in red blood cell
metabolism
• It also protects red blood cells from the effects of potentially
harmful molecules called REACTIVE OXYGEN SPECIES
26. G6PD Deficiency
• The G6PD gene is located on the telomeric region of the long arm of
X-chromosome (band Xq28).
• Mutation of the X-linked G6PD gene (approximately 127 have been
reported with a single base substitute leading to amino acid
replacements) results in many variants of protein with varying
enzyme activity that result in different patterns of clinical
manifestations.
27. Male to Female ratio
• Male cases are overrepresented compared with female cases.
• Males are hemizygous for the G6PD gene; therefore the expression is
either normal or deficient.
• In contrast, in females who have two copies of the gene on each
chromosome, the gene expression can be normal or heterozygous.
• Homozygous inheritance in females can occur; whereas, heterozygous
females have genetic mosaicism secondary to X-chromosome
inactivation and can have similar manifestation as male neonates.
31. G6PD variants can be classified into three categories
Class I Mutations
severe deficiency with
no or
minimal detected
enzyme activity
often associated with
chronic non-
spherocytic anemia
(occurs even in
absence of oxidative
stress)
Class II Mutations
(G6PD Mediterranean)
severe deficiency
with 1% to 10%
residual enzyme actiity
G6PD enzyme shows
normal stability but,
very low activity in all
RBCs
Class III
(G6PD Group A-)
moderate deficiency
with 10% to 60%
residual enzyme
activity,
RBCs contain unstable
G6PD enzyme, but
normal activity in
younger RBCs and
reticulocytes
Class IV
Normal enzyme
activity at 60% to 150%
Class V
increased
enzyme activity at
>150%
33. • Glucose-6-phosphate dehydrogenase (G6PD) deficiency
results in erythrocytes that are more prone to suffering
damage.
• The invasion of malarial parasites exacerbates this
condition, making the cells highly susceptible to
phagocytosis.
• Infected G6PD-deficient erythrocytes are
morphologically different compared to non-infected
ones and are thus hyper susceptible to phagocytosis.
34. • Another enzymopathy involves pyruvate kinase
deficiency leading to altered membrane rigidity of
erythrocytes, thus preventing Plasmodium invasion.
• Moreover, pyruvate kinase deficiency significantly
reduces the intracellular concentration of glucose, a vital
source of energy for the intra-cellular life cycle of
Plasmodium.
• As such, both G6PD and pyruvate kinase have been
recognized as important drug targets against P.
falciparum.
36. DUFFY ANTIGEN SYSTEM
Duffy antigen/chemokine receptor (DARC), also known as Fy glycoprotein (FY) or
CD234 (Cluster of Differentiation 234), is a protein that in humans is encoded by the
DARC gene.
The Duffy antigen is located on the surface of red blood cells, and is named after the
patient in which it was discovered.
The protein encoded by this gene is a glycosylated membrane protein and a non-
specific receptor for several chemokines.
The protein is also the receptor for the human malarial parasites Plasmodium vivax
and Plasmodium knowlesi.
Polymorphisms in this gene are the basis of the Duffy blood group system.
37. • Duffy-binding-like domains are so named because
of their similarity to the Duffy-binding proteins of
P. vivax and P. knowlesi.
• There are six variant types of DBL, named DBLα,
DBLβ, DBLγ, DBLδ, DBLε and DBLζ. CIDR is also
divided into three classes: CIDRα, CIDRβ and CIDRγ.
• Both DBL and CIDR have an additional type called
PAM, so named because of their specific
involvement in pregnancy-associated malaria
(PAM).
38. • In spite of the diverse DBL and CIDR proteins, the
extracellular amino terminal region is partly
conserved, consisting of about 60 amino acids of
NTS, one each of DBLα and CIDR1 proteins in
tandem.
• This semi-conserved DBLα-CIDR1 region is called
the head structure.
• The last CIDR region joins the TMD, which is
embedded in the cell membrane. The TMD and ATS
are highly conserved among different PfEMP1s.
39. The Duffy antigen /chemokine receptor gene (gp-Fy;
CD234) is located on the long arm of chromosome 1
(1.q22-1.q23) and was cloned in 1993.
The gene was first localised to chromosome 1 in 1968,
and was the first blood system antigen to be localised. It
is a single copy gene spanning over 1500 bases and is in
two exons.
The gene encodes a 336 amino acid acidic glycoprotein.
40. It carries the antigenic determinants of the Duffy blood
group system which consist of four codominant alleles—
FY*A and FY*B—coding for the Fy-a and Fy-b antigens
respectively, FY*X and FY*Fy, five phenotypes (Fy-a, Fy-b,
Fy-o, Fy-x and Fy-y) and five antigens. Fy-x is a form of Fy-b
where the Fy-b gene is poorly expressed.
Fy-x is also known as Fy-b weak or Fy-bWk.
43. • In contrast to thalassemais and enzymopathies, the Duffy
antigen represents an extracellular-based resistance mechanism.
• The Duffy antigen, a receptor for chemokines, is present on the
surface of erythrocytes.
• This antigen is also an obligatory binding site for the malarial
toxin secreted by P. vivax.
• A point mutation in the Duffy gene leads to lack of expression of
the encoded receptor and thus negates P. vivax toxin
attachment.
• This innocuous polymorphism is the most common in Papua
New Guinea and Western Africa, which may explain why
infection of P.vivax is uncommon in these areas of the world.
47. NOTABLE HISTORY
1905
Austrian Karl Landsteiner
describes Meconium ileus
47
1938
Cystic fibrosis disease
identified by American
Dorothy H. Andersen
1838
Carl Von Rokitansky’s
autopsy of infant with
Meconium peritonitis
48. CYSTIC FIBROSIS TRANSMEMBRANE
CONDUCTANCE REGULATOR (CFTR) GENE
The CFTR gene is located on the long arm of
chromosome 7.
There are 1604 mutations in CFTR listed on
the CFTR mutation database
The most common mutation is
Δ F508---70% CF alleles in caucasians.
49. PROTEIN FUNCTION AND BIOCHEMISTRY
CFTR controls chloride
ion movement in and
out of the cell.
50. WHAT IS CYSTIC FIBROSIS (CF)?
A multisystem disease
Autosomal recessive inheritance
Cause: mutations in the cystic fibrosis
transmembrane conductance regulator (CFTR)
gene
chromosome 7
codes for a c-AMP regulated chloride
channel
CysticFibrosis
51. PATHOGENESIS
Defects in (CFTR), - encodes for a protein that functions as
chloride channel & regulated by (cAMP).
Abnormalities of cAMP-regulates chloride transport
Defective CFTR - decreased secretion of chloride and
increased re-absorption of sodium and water
Reduced height of epithelial lining fluid
Decreased hydration of mucus - that is stickier to bacteria
Result in viscid secretions
52. PRESENTATION : CF PANCREAS
C Chronic respiratory disease
F Failure to thrive
P Polyps
A Alkalosis, metabolic
N Neonatal intestinal obstruction
C Clubbing of fingers
R Rectal Prolapse
E Electrolyte in sweat
A Aspermia / absent vas deferens
S Sputum – S.aureus/P.aeruginosa
CysticFibrosis
53. HALLMARKS OF CF
Very salty-tasting skin
Appetite, but poor growth & weight
gain
Coughing, wheezing, at times with
phelgum & shortness of breath
Lung infections, e.g.
pneumonia/bronchitis
greasy, bulky stools or difficulty in
bowel movements
53
59. GENETICS
Tay–Sachs disease is inherited in the autosomal recessive pattern
The HEXA gene is located on the long (q) arm of human chromosome 15, between positions 23
and 24.
Tay–Sachs disease is an autosomal recessive genetic disorder, meaning that when both parents
are carriers, there is a 25% risk of giving birth to an affected child with each pregnancy. The
affected child would have received a mutated copy of the gene from each parent.
Tay–Sachs results from mutations in the HEXA gene on chromosome 15, which encodes the
alpha-subunit of beta-N-acetylhexosaminidase A, a lysosomal enzyme. By 2000, more than 100
different mutations had been identified in the human HEXA gene.
These mutations have included single base insertions and deletions, splice phase mutations,
missense mutations, and other more complex patterns. Each of these mutations alters the
gene's protein product (i.e., the enzyme), sometimes severely inhibiting its function.
60. THE HEXA GENE IS LOCATED ON THE LONG (Q) ARM OF
HUMAN CHROMOSOME 15, BETWEEN POSITIONS 23 AND 24
62. CHERRY RED SPOT AS SEEN IN TAY SACHS DISEASE.
THE CENTER OF THE FOVEA APPEARS BRIGHT RED BECAUSE IT IS
SURROUNDED BY A MILKY HALO.
63. Without this enzyme, gangliosides, particularly
ganglioside GM2, increases and degenerates
central nervous system.
64. PATHOPHYSIOLOGY
Tay–Sachs disease is caused by insufficient activity of the enzyme
hexosaminidase A.
Hexosaminidase A is a vital hydrolytic enzyme, found in the lysosomes,
that breaks down glycolipids.
When hexosaminidase A is no longer functioning properly, the lipids
accumulate in the brain and interfere with normal biological processes.
Hexosaminidase A specifically breaks down fatty acid derivatives called
gangliosides; these are made and biodegraded rapidly in early life as the
brain develops.
Patients with and carriers of Tay–Sachs can be identified by a simple
blood test that measures hexosaminidase A activity.
65. ISOZYMES AND GENES
Lysosomal A, B, and S isozymes.
Functional lysosomal β-hexosaminidase enzymes are dimeric in structure. Three
isozymes are produced through the combination of α and β subunits to form any
one of three active dimers:
hexosaminidase
isozyme
subunit composition function
A α/β heterodimer
only isozyme that can
hydrolyze GM2 ganglioside in
vivo
B β/β homodimer
exists in tissues but no known
physiological function
S α/α homodimer
exists in tissues but no known
physiological function
66. The α and β subunits are encoded by separate genes, HEXA
and HEXB respectively.
Beta-hexosaminidase and the cofactor GM2 activator
protein catalyze the degradation of the GM2 gangliosides
and other molecules containing terminal N-acetyl
hexosamines.
Gene mutations in HEXB often result in Sandhoff disease;
whereas, mutations in HEXA decrease the hydrolysis of
GM2 gangliosides, which is the main cause of Tay-Sachs
67. Signs or Symptoms
Tay–Sachs disease is classified in variant forms,
based on the time of onset of neurological
symptoms.
Infantile Juvenile Adult/Late Onset
3 to 10 months two and 10 years 20 and 30 years
Extremely rare usually non-fatal
68. Signs or Symptoms
-Loss of learned skills
-Loss of smile, crawl, grab.
-Blindness, Deafness, Paralysis.
-Dementia
-Unable to swallow
-Muscle atrophy
-Cherry-red spot in the back of their eyes
69. -Treatment
There is no treatment for Tay-Sachs
disease, nor there is any way to prevent
or reduce the progression of this
disorder.
70. Examination
Fund of eye: presence of bilateral pallor of papila
and cherry-red spot in the macula.
Biochemical profile:
Total Hexosaminidase 125.0 nM,
Hexosaminidase A: 0%.
Other blood tests without significant alterations.
The patient evolved with physical and
neurological progressive deterioration, being
diagnosed with TSD
Slide 39
72. • It is now known that carriers of the Tay-Sachs gene have
increased production of the b-subunit of hexosaminidase
and that the b-subunit is closely associated with increased
host defense against mycobacteria.
• Additionally, cell surface bactericidal activity declined in
the absence of b-hexosaminidase.
73. • It is therefore possible that b-hexosaminidase is cytotoxic
to Mycobacteria tuberculosis, making the organism more
susceptible to macrophage attack.
• In the advent of drug-resistant tuberculosis, developing
drugs that up-regulate or maintain b-hexosaminidase may
prove beneficial for the treatment of tuberculosis while
circumventing concerns of antibiotic resistance.
77. What is Phenylketonuria (PKU)?
an autosomal recessive metabolic genetic
disorder characterized by homozygous or compound
heterozygous mutations in the gene for the hepatic
enzyme phenylalanine hydroxylase (PAH), rendering it
nonfunctional.[ This enzyme is necessary to
metabolize the amino acid phenylalanine (Phe) to the
amino acid tyrosine (Tyr).
78. THE PAH GENE
The PAH gene is located on chromosome
12 in the bands 12q22-q24.1.
More than 400 disease-causing
mutations have been found in the PAH
gene.
This is an example of allelic genetic
heterogeneity.
81. PHENYLALANINE HYDROXYLASE (PAH)
Phenylalanine hydroxylase (PAH) is an enzyme that catalyzes the
hydroxylation of the aromatic side-chain of phenylalanine to generate
tyrosine.
PAH is one of three members of the biopterin-dependent aromatic amino
acid hydroxylases, a class of monooxygenase that uses tetrahydrobiopterin
(BH4, a pteridine cofactor) and a non-heme iron for catalysis.
During the reaction, molecular oxygen is heterolytically cleaved with
sequential incorporation of one oxygen atom into BH4 and phenylalanine
substrate.
83. LEVELS OF BLOOD PHENYLALANINE
• A normal blood phenylalanine level is about 1mg/dl.
• In cases of PKU, levels may range from 6-80mg/dl, but are
usually greater than 30mg/dl.
84. INCIDENCE OF PKU
• PKU affects about one out of every 10,000 to 20,000
Caucasian or oriental births. The incidence in African
Americans is far less.
• The PKU disorder is as frequent in men as it is in women.
85. What are the signs and symptoms of
phenylketonuria?
• A child with PKU may look normal and completely
healthy for the first few months of life.
• If left untreated, signs and symptoms may appear
between 3 to 6 months of age.
• Child may begin to be less active and do things
later than other children. He may lose interest or
not pay attention to things around him.
86. • Learning, speech, or behavior problems.
• More irritable, fussy, or restless than normal.
• Musty or mousy odor of his breath, hair, skin, or urine.
• Fair skin.
• Short stature (height) or small head.
• Skin may be dry or have rashes, such as eczema.
• Vomiting (throwing up), muscle stiffness, or seizures
(convulsions).
87. How is phenylketonuria diagnosed?
• Blood tests: A newborn
screening test is usually
done during your first days
of life. A sample of child's
blood is taken and sent to the
lab.
88. Guthrie test
• The Guthrie test, also known as the Guthrie bacterial
inhibition assay, is a medical test performed on newborn
infants to detect phenylketonuria, an inborn error of amino
acid metabolism.
89. • A drop of blood is usually obtained by pricking the heel of a
newborn infant in a hospital nursery on the sixth or seventh
day of life (end of the first week). The blood is collected on a
piece of filter paper and sent to a central laboratory.
90. • CT scan:. It may be used to look at child's bones,
muscles, brain, body organs, and blood vessels. child
may be given dye by mouth or in an IV before the
pictures are taken. The dye may help child's caregiver
see the pictures better. People who are allergic to
iodine or shellfish (lobster, crab, or shrimp) may be
allergic to some dyes. Tell the caregiver if child is
allergic to shellfish, or has other allergies or medical
conditions.
91. • Genetic tests: Genetic testing may be needed
to check child's genes. This test helps
caregivers learn how child's genes may affect
him. This may also help child's caregivers
decide on a treatment plan.
93. How is phenylketonuria treated?
• Diet: A special diet is needed to keep the amount
of phenylalanine in the body low.
This diet is different from one child
to another. It is started
as early as the first few days of life
or a few weeks after birth. This
special diet may need to be
followed for life.
94. • Medicines: child may be given medicines to
treat his symptoms. Medicines may be given to
treat his rash, vomiting, to control his seizures,
or to relax his muscles.
Special formulas or products: These are also
called protein substitutes that have little or no
phenylalanine. These formulas have the right
amino acids, calories, vitamins, and minerals
your child needs.
96. • Historically, physicians observed that women who were PKU carriers had a
much lower than average incidence of miscarriages.
• Woolf et al4 published data showing that women who were heterozygous
for the PKU disorder displayed a significantly reduced rate of spontaneous
abortions, when compared to wild-type homozygous individuals.
• This was the most prevalent in Scotland and Ireland, where the consistent
damp climate promotes the growth of mold and fungi on grains and beans.
• Aspergillus spp. produces a mycotoxin known as ochratoxin A which is
teratogenic at low doses and potentially lethal at high doses.
97. • In the case of pregnant women, ochratoxin A can cross the
placenta and cause spontaneous abortions.
• This toxin, being an N-acyl derivative of phenylalanine, is a
competitive inhibitor of phenylalanine in the phenylalanyl
tRNA synthetase-catalyzed reaction thus preventing protein
synthesis, which can be reversed by introducing phenylalanine
which is in excess in PKU individuals.
• The high frequency of the PKU gene present in women from
this particular section of Europe, as well as that observed in
Yemenite Jews, may help to protect against sudden
miscarriages, thus ensuring a normal pregnancy.
101. CONGENITAL DISORDER OF GLYCOSYLATION
A congenital disorder of glycosylation (previously called carbohydrate-deficient
glycoprotein syndrome) is one of several rare inborn errors of metabolism in
which glycosylation of a variety of tissue proteins and/or lipids is deficient or
defective.
Congenital disorders of glycosylation are sometimes known as CDG syndromes.
They often cause serious, sometimes fatal, malfunction of several different
organ systems (especially the nervous system, muscles, and intestines) in
affected infants.
The most common subtype is CDG-Ia (also referred to as PMM2-CDG) where
the genetic defect leads to the loss of phosphomannomutase 2, the enzyme
responsible for the conversion of mannose-6-phosphate into mannose-1-
phosphate.
102. CLASSIFICATION
Historically, CDGs are classified as Types I and II (CDG-I
and CDG-II), depending on the nature and location of the
biochemical defect in the metabolic pathway relative to
the action of oligosaccharyltransferase.
The most commonly used screening method for CDG,
analysis of transferrin glycosylation status by isoelectric
focusing, or other techniques, distinguish between these
subtypes in so called Type I and Type II patterns.
103. TYPE I
Type I disorders involve disrupted
synthesis of the lipid-linked
oligosaccharide precursor (LLO) or
its transfer to the protein.
104. TYPE II
Type II disorders involve malfunctioning
trimming/processing of the protein-bound
oligosaccharide chain.
There are many subtype including from a to l
106. • Resistance to glycosylation-dependent viral infections (e.g.,
HIV-1, dengue, herpes simplex 2, hepatitis C, and influenza)
has been linked to congenital disorder of CDGIIb.
• This condition is caused by defective
mannosyloligosaccaride
glucosidase (MOGS), which is the initial enzyme in the
processing phase of N-linked oligosaccharides.
• In this extremely rare condition, the process of attaching N-
glycans to proteins is disrupted, resulting in dysfunctional
glycoprotein synthesis.
107. • Due to the dependence of enveloped viruses on proper host cell
glycosylation for the assembly of their capsid proteins, it appears
that the defective glycosylation in patients with CDG-IIb hinders
cellular entry, cellular egress, and viral replication for
glycosylation-dependent enveloped viruses.
• Evidence to support the theory of lowered susceptibility in those
with defective glycosylation has been documented through a case
study of two siblings with CDGIIb.
• These individuals had appropriate immune responses to non-
replicating viruses, but failed to mount a humoral response to live
glycosylation-dependent virus vaccinesMMR and varicella.5
108. • Furthermore, the MOGS inhibitors castanospermine, N-
butyldeoxynojirimycin, and deoxynojirimycin have been shown to lower
replication in cells infected with enveloped viruses such as HIV, dengue,
hepatitis B and C, and herpes simplex virus.
• These findings are additionally supported by the antiviral use of 2-
deoxyglucose and tunicamycin, both of which truncate glycan polymers
and attenuates the replication of certain viruses.
In summary
The antiviral effects of defective glycosylation provide a strong basis for
continued researchon the next generation of MOGS inhibitors.
117. WHAT IS FAVISM?
Favism is formally defined as hemolytic response to the
consumption of broad beans
Favism is disorder characterized by hemolytic reaction to the
consumption of broad beans
• All individual with favism show
G6PD deficiency
• However not all individuals with
G6PD deficiency show favism
118. DECREASED AMOUNTS OF GLUTATHIONE
DUE TO DECREASED PRODUCTION OF NADPH
Reduction of amounts of NADPH in RBCs in G6PD deficiency causes
reduction of oxidized glutathione .
Role of reduced glutathione in RBCs:
Reduced glutathione gets rid of Reactive oxygen species including
hydrogen peroxide.
Reduced Glutathione helps to keep sulfhydryl groups of
haemoglobin protein in the reduced state.
119. Reduced production of reduced glutathione results in:
1- A decrease in detoxication of peroxides. This causes damage to
RBCs membrane and hemolysis (ending in hemolytic anemia).
2- Hemoglobin protein is denatured forming insoluble masses (Heinz
bodies). Heinz bodies attach to red cell membranes.
Membrane proteins are also oxidized.
Accordingly, red cells become rigid and removed from the
circulation by macrophages in the spleen and liver ending in
anemia
120. Although Deficiency of G6PD occurs in all cells of affected individual. It is severe in RBCs
because the only pathway to form NADPH in RBCs is pentose phosphate pathway (using
G6PD).
Individuals who have inherited one of the many G6PD mutations do not show clinical
manifestation.
Some of patients with G6PD develop hemolytic anemia if they are exposed or ingest any
oxidizing drugs
121. G6PD VARIANTS
Most G6PD variants are caused by point mutations in the G6PD
gene.
Some of these point mutations do not disturb the structure of the
enzyme's active site and hence, do not affect enzyme activity.
Other point mutations may lead to production of mutant enzymes
with one or more of the following:
altered catalytic activity
decrease stability
an alteration of binding affinity for NADP+ or Glucose 6-phosphate.
122. Both G6PD Mediterranean and G6PD A- represent mutant enzymes that differ
from the normal variants by a single amino acid.
This change is due to DNA changes in the form of point mutations or missense
mutations.
Frame shift mutations or large deletions have not been identified indicating
that the complete absence of G6PD is lethal.
Mutation causing non spherocytic hemolytic anemia are clustered near the
carboxyl end of the enzyme, whereas mutations causing milder forms of the
disease tend to be located at the amino end of the enzyme.
123. CARE OF G6PD PATIENTS
The most important measure is prevention – avoidance of the drugs and foods that
cause hemolysis.
Vaccination against some common pathogens (e.g. hepatitis A and hepatitis B) may
prevent infection-induced attacks.
In the acute phase of hemolysis, blood transfusions might be necessary, or even dialysis
in acute renal failure.
Blood transfusion is an important symptomatic measure, as the transfused red cells are
generally not G6PD deficient and will live a normal lifespan in the recipient's circulation.
124. Some patients may benefit from splenectomy as this is an important site of
red cell destruction.
Folic acid should be used in any disorder featuring a high red cell turnover.
Although vitamin E and selenium have antioxidant properties, their use does
not decrease the severity of G6PD deficiency.
125. HEMOLYTIC ANEMIA
G6PD deficiency cause impraired red blood cells’ transport of oxygen
effectively throughout the body resulting in stress conditions and hence
leading to hemolysis.
There are other conditions that also caused by G6PD deficiency- neonatal
jaundice, abdominal back pain, dizziness, headache, irregular breathing,
and palpitations.
127. NEONATAL HYPERBILIRUBINEMIA IN G6PD
Newborns with G6PD deficiency have a 9% incidence of hyperbilirubinemias.
Estimated at 3.4% incidence, the condition ranges by infant race/ethnicity
(12.2% in African American male infants to nearly 0% in white female infants).
Oxidant stressors, sepsis, and delay in bilirubin elimination (such as co-
inheritance with Gilbert’s disease or persistent enterohepatic recirculation)
add to total plasma or serum bilirubin (TSB) rise, need for phototherapy, and
risk for exchange transfusion.
Vinod K. Bhutani, MD,jaundice due to glucose-6-phosphate dehydrogenase deifciency, NeoReviews Vol.13
No.3 March 2012
128. CLINICAL PATTERNS OF HYPERBILIRUBINEMIA IN G6PD DEFICIENT
NEONATES
Early-onset hyperbilirubinemia (ie, TSB >75th percentile and increased bilirubin production)
Pre-discharge TSB <75th percentile track exacerbated by starvation, unrecognized sepsis or
late prematurity;
Slow postnatal rise with natural decline
Slow postnatal rise with persistent prolonged unconjugated hyperbilirubinemia, >2 weeks age
Complicated by acute-onset, dramatic hyperbilirubinemia with TSB rise >1 mg/dL per hour
(“favism”).
Vinod K. Bhutani, MD,jaundice due to glucose-6-phosphate dehydrogenase deifciency, NeoReviews Vol.13
No.3 March 2012
129. ELEVATION OF COHB IN G6PD DEFICIENT NEONATES
Within the reticuloendothelial system, hemoglobin releases globin and heme,
which in turn undergo further degradation to release equimolar amounts of
bilirubin and CO.
The CO released then binds strongly to hemoglobin, forming
carboxyhemoglobin (COHb).
Cathy Hammerman, MD and Michael Kaplan, MB, ChB; Recent Developments in the
Management of Neonatal Hyperbilirubinemia.
130. Because endogenous CO production in the newborn occurs almost exclusively
by this pathway, hemolysis can be quantitated by determining blood COHb
levels.
Elevated COHb levels have been correlated with increased hemolysis in
fetuses and neonates suffering from immune hemolytic disease and even
with kernicterus and death in G6PD-deficient infants.
Cathy Hammerman, MD and Michael Kaplan, MB, ChB; Recent Developments in the
Management of Neonatal Hyperbilirubinemia.
131. RISK OF SEPSIS
Increased risk of sepsis has also been reported among preterm infants with
G6PD deficiency.
The prevalence of G6PD deficiency among 170 infants with birthweight <2.0
kg admitted to a neonatal intensive care nursery was 5.3%.
Stage 2 necrotizing enterocolitis was 6.9-fold higher (95% CI: 2–23.5)
compared with matched cohort.
Schutzman DL, Porat R. Glucose-6-phosphate dehydrogenase deficiency: another risk factor for necrotizing
enterocolitis? J Pediatr. 2007;151(4):435–437
132. NEONATAL SCREENING FOR G6PD DEFICIENCY
Newborn screening relies on the accurate (phenotypic) identification of deficient enzyme
activity.
However, variations due to partial genotypic manifestations, postnatal age, and population
of younger, high enzyme activity RBCs are significant confounding factors.
Vinod K. Bhutani, MD,jaundice due to glucose-6-phosphate dehydrogenase deifciency, NeoReviews Vol.13
No.3 March 2012
133. The definitive biochemical test is the spectrophotometric quantitative
enzyme assay based on rate of NADPH formation (mmoles/min/gHb) with
absorbance at 340 nm wavelength and expressed as IU/ gHb.
A useful semi-quantitative screening test, Fluorescent spot test (FST) relies on
the ability of NADPH to fluoresce intensely with exposure to long wave
ultraviolet light.
It lacks the sensitivity to diagnose infants with partial enzyme activity (20%–
60%) including female heterozygotes.
134.
135. Other tests that detect NADPH such as methylene blue reduction, cresyl blue
dye decolorization, cytochemical staining are also available.
Identification of specific mutations by DNA/polymerase chain reaction (PCR)
screening, ideal for identification of female heterozygotes, is limited by the
diversity of known mutations, time-intensive process and occasional
mismatch with phenotype expression of enzyme activity.
136. In patients with acute hemolysis, testing for G6PD deficiency may be falsely
negative because older erythrocytes with a higher enzyme deficiency have
been hemolyzed.
Female heterozygotes may be hard to diagnose because of X-chromosome
mosaicism leading to a partial deficiency that will not be detected reliably
with screening tests.
137. Thus, a two-step approach to measure enzyme functional assay with
concomitant DNA verification seems to be the most accurate and practical
approach to screen, monitor and diagnose neonatal G6PD deficiency.
143. • One proposed mechanism for an evolutionary advantage afforded by CFTR mutations relates to the virulence of
cholera in affected individuals.
• The etiologic agent, Vibrio cholerae, produces a toxin that constitutively activates guanine nucleotide-binding
proteins that in turn hyperactivate the same chloride channels affected by mutations in the CFTR gene.
• This hyperactivation causes a profound secretory diarrhea.
• In murine model studies, heterozygous mice were less susceptible to the cholera toxin and consequently did not
suffer from symptoms as severe as seen in mice with normal CFTR function.
• It is postulated that this result was due to heterozygous mice having only 50% of the functioning chloride channels
compared with a wild-type mouse.
• The decrease in functioning chloride channel is reduced the mass influx of ions, thus ameliorating diarrhea.
• Research concerning the CFTR chloride channel and its role in intestinal secretions resulted in potentially novel
therapies for cholera.
• The volume of fluid losses seen in cholera cases could be reduced by pharmacologic inhibition of CFTR and
chloride secretions.