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Alagille syndrome (NORD)
Familial adenomatous polyposis
Multiple endocrine neoplasia
Polycystic kidney disease
Treacher Collins syndrome
von Hippel-Lindau disease
Gaucher disease (NORD)
Glycogen storage disease type I
Glycogen storage disease type II (NORD)
Glycogen storage disease type III
Glycogen storage disease type IV
Glycogen storage disease type V
Mucopolysaccharide storage disease type 1 (Hurler syndrome) (NORD)
Niemann-Pick disease type C
Niemann-Pick disease types A and B (NORD)
Polycystic kidney disease
Primary ciliary dyskinesia
Sickle cell disease (NORD)
Tay-Sachs disease (NORD)
Cri du chat syndrome
Fragile X syndrome
Down syndrome (Trisomy 21)
Edwards syndrome (Trisomy 18)
Patau syndrome (Trisomy 13)
Fragile X syndrome
Fabry disease (NORD)
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Mucopolysaccharide storage disease type 2 (Hunter syndrome) (NORD)
Ornithine transcarbamylase deficiency
Autosomal trisomies: Pathology review
Miscellaneous genetic disorders: Pathology review
Muscular dystrophies and mitochondrial myopathies: Pathology review
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Alpha-thalassemia is a genetic disorder where there’s a deficiency in production of the alpha globin chains of hemoglobin, which is the oxygen-carrying protein in red blood cells.
Normally, hemoglobin is made up of four globin chains, each bound to a heme group. There are four major types of globin chains- alpha (α), beta (β), gamma (γ), and delta (δ). These four globin chains combine in different ways to give rise different kinds of hemoglobin. First, there’s hemoglobin F (or HbF), where F stands for fetal hemoglobin, and it’s made up of two α-globin and two γ-globin chains. Hemoglobin A (or HbA) is the major form of adult hemoglobin, made up of two α-globin and two β-globin chains. Finally, hemoglobin A2 (or HbA2) amounts for a small fraction of adult hemoglobin in the blood, and it’s made up of two α-globin and two δ-globin chains. Alpha chain synthesis is controlled by four alpha genes, two on each copy of chromosome 16. And alpha thalassemia is caused by mutations in the alpha genes, most commonly a gene deletion. The mutations are inherited in an autosomal recessive pattern, which means that you need mutated genes from both parents to get the disease. If a person has one defective alpha gene, they’re called a silent carrier, because they don’t have symptoms, but can still pass the gene to their children. If a person has two defective alpha genes, the person has alpha thalassemia minor, which causes mild symptoms. This can either be caused by a ‘cis’ deletion, where mutated genes are on the same chromosome; or a ‘trans’ deletion when the mutated genes are on two different chromosomes. Cis-deletion variants are more prevalent in Asian populations, whereas, trans-deletion variants are more prevalent in African populations.
If there are three defective alpha genes, there’s moderate disease, called hemoglobin H, or HbH, disease. This is caused by excess beta chains, which clump together within developing red blood cells to form tetramers (β4), and give rise to a form of hemoglobin called hemoglobin H. HbH molecules cause hypoxia in two ways. First, they damage the red blood cell membrane, resulting in intramedullary hemolysis, or red blood cell breakdown in the bone marrow; or extravascular hemolysis, when red blood cells are destroyed by macrophages in the spleen. Second, HbH has very high affinity for oxygen, and doesn’t release oxygen to the tissues. And a consequence of hypoxia is that it signals the bone marrow, as well as extramedullary tissues like the liver and spleen, to increase production of red blood cells. This may cause the bones that contain bone marrow, as well as the liver and spleen, to enlarge.
Alpha-thalassemia is an inherited blood disorder in which there is insufficient production of alpha globin chains of hemoglobin. Hemoglobin is the protein in red blood cells that carries oxygen from the lungs to all parts of the body. Symptoms will vary depending on the extent of the deficiency of the globin chains. Some people with alpha-thalassemia do not have symptoms, while others experience mild to moderate anemia.
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