Abstract
This chapter focuses on genetic disorders affecting the human circulatory system. Genetic disorders can occur due to a defect in a single gene or in a set of genes. The body's circulatory system is made up of the heart and blood vessels (arteries, arterioles, veins, venules, and capillaries). The system carries both blood and lymphatic fluid in two circuits: pulmonary circulation (blood through the lungs for oxygenation) and systemic circuits (from the heart to all body parts). Fourteen disorders are presented in this chapter including sickle cell disease, Gaucher Disease, chronic myeloid leukaemia, Niemann-Pick Disease, haemophilia, atherosclerosis, ataxia telangiectasia, haemoglobinuria, thalassemia, William's syndrome, porphyria, long QT syndrome, and alpha-I-antitrypsin deficiency.
TopChapter Outline
13.1 Overview of the Circulatory System
13.2 Sickle-Cell Anemia
13.3 Burkitt Lymphoma
13.4 Gaucher Disease
13.5 Chronic Myeloid Leukemia
13.6 Niemann-Pick Disease
13.7 Hemoglobinuria
13.8 Hemophilia
13.9 Thalassemia
13.10 Atherosclerosis
13.11 William’s Syndrome
13.12 Ataxia Telangiectasia
13.13 Porphyria
13.14 Long QT Syndrome
13.15 Alpha-I-Antitrypsin Deficiency
Chapter Summary
TopLearning Outcomes
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Identify each genetic disorder affecting the circulatory system
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Outline the symptoms of each disorder
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Explain the genetic basis of each disorder
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Summarize the therapies available to treat each disorder
Top13.1 Overview Of The Circulatory System
The body’s circulatory system can be compared to the major road networks that connect many states in the United States (often called “freeways”). Interstate-80 connecting New York state in the eastern US to California in the west coast is a major conduit likened to the body’s major artery: the aorta—which directs freshly oxygenated blood to all parts of the body. The circulatory system is made of the heart and blood vessels (arteries, arterioles, veins, venules, and capillaries).
The circulatory system carries both blood and lymphatic fluid. Blood is composed of plasma (water, nutrients and wastes) and cells (erythrocytes, leukocytes and thrombocytes) (Figure 1).
Figure 1. Components of blood. Note that blood plasma comprises 50% or more of blood. The most abundant blood cells are red blood cells.
Blood also carries a variety of substances like hormones, antibodies, gases, and enzymes and frequently also infectious agents like bacteria, viruses, etc. In the heart, blood is separated in two chambers: oxygenated blood in one chamber; and de-oxygenated blood in the other (Figure 2). Deoxygenated blood enters the right side of the heart from tissues through two major veins superior vena cava (from upper body) and inferior vena cava (lower body). It enters the right atrium, passes through the tricuspid valve to the left ventricle; then pumped to the lungs for oxygenation through the pulmonary valve in the pulmonary artery (the only artery carrying de-oxygenated blood). In the lungs, the high partial pressure of oxygen breathed in from the air favours dissociation of the carboxyhaemoglobin releasing carbon dioxide to form oxyhaemoglobin. Carbon dioxide is released to the air through the nostrils. Once oxygenated, blood returns to the heart through the pulmonary vein (the only vein carrying oxygenated blood) to the left atrium, then passes through the mitral valve to the left ventricle. The left ventricle then pumps the blood through the aortic valve to the aorta and then to all parts of the body. The passage of blood from the heart to the lungs is often referred to as pulmonary circulation; while blood passing through the aorta to all parts of the body is referred to as systemic circulation (Figure 2).
Figure 2. Blood circulation in the human body
Key Terms in this Chapter
Enzyme Replacement Therapy (ERT): The process of intravenously replacing enzymes that are deficient in the body.
Coronary Angioplasty: A procedure in which a small balloon is inflated to open blocked or narrowed coronary arteries.
Radiation Therapy: A type of cancer treatment that uses beams of high energy to kill cancer cells and shrink tumours.
Genome-Wide Association Studies (GWAS): An observational study that examines if there is an association between genetic variants and traits in different individuals.
Adeno-Associated Viruses (AAV Vectors): These are small viruses widely spread throughout the human population, but do not cause infection. AAVs are often used by scientists as ideal delivery vehicles for gene therapy.
Hepatocytes: Liver cells.
?-Adrenergic Receptor Antagonists (?-Blockers): Drugs that inhibit the binding of norepinephrine and epinephrine by competitively binding to beta-adrenoreceptors.
Pluripotent Bone Marrow Stem Cells: The first step in the developmental process of red blood cells that results in cells that are able to transform into anything.
Augmentation Therapy: A treatment used to increase the level of alpha-1 antitrypsin (AAT) protein circulating in the blood and lungs by intravenously transferring AAT from the blood plasma of a healthy donor.
Palliative Treatments: Treatments focused on relieving symptoms and improving the quality of life for patients with serious illnesses.
Protein Replacement Therapy: The process of replacing proteins in the body that are deficient or absent.
Immunization: The process in which a person is made to become resistant to an infectious disease.
Health Disparities: Higher burden of illness, injury, mortality.
Ischaemic Cardiomyopathy: Heart muscle disease caused by a reduction in blood flow.
HapMap Project: A project aimed to creating a halotype map of the human genome in order to find genetic variants that affect human health and diseases.
Serum Serine Protease Inhibitor: Inactivates related proteases in order to regulate protease mediated activities.
Cirrhosis: A degenerative disease that occurs when there is scarring of liver tissue.
Non-Steroidal Anti-Inflammatory Agents (NSAIDS): One of the most common over-the-counter drug used to treat pain and inflammation by preventing an enzyme called cyclooxygenase from producing prostaglandins.
Bronchodilators: Substances used to dilate the bronchial tubes and relaxing the lung muscles.
Erythropoiesis: Production of red blood cells which is initiated by the decreasing levels of oxygen which cause erythropoietin hormone production in the kidneys.
Substrate Reduction Therapy (SRT): An oral medication that prevents the production of glucocerebroside.
Emphysema: Type A COPD caused by irreversible damage to alveolar walls or the enlargement of distal air sacs.
Antibiotics: A range of powerful drugs used to treat bacterial infections by killing or slowing down bacteria growth.
Congenital: A condition or trait present from birth.
Dementia: Disease characterized by mental instability, impaired memory, and possible personality changes.
Tachycardia: Term used to describe heart rate that is abnormally rapid.
Coronary Artery Bypass Grafting: A surgery that improves blood flow to the heart by creating more pathways for the blood to flow using arteries or veins from other areas of the body.
Chemotherapy: Therapy designed to treat cancerous diseases through the administration of cytotoxic drugs that aim to regulate and prevent further growth and division of cancerous cells.
Gene Therapy: The replacement of defective genes with functional genes or the introduction of new genes to prevent or treat diseases.
Blood Transfusion: The process in which donated blood is transferred to another patient through the veins.
Cardioverter-Defibrillators: A small battery powered device that is surgically placed under the skin below the collar bone and is used to detect heart rate abnormalities. If dangerous heart rate is detected, the device sends an electrical shock to correct the rhythm.
Physical Therapy: Therapy designed to restore, preserve, or improve physical function through exercise or the use of specially designed equipment.
Hemoglobinopathies: A group of disorders involving abnormal haemoglobins and anaemia which are caused by defects in the genes that produce haemoglobin.
Speech Therapy: A clinical program designed to improve speech and language related issues.
Angina: Chest pain.
Cardiogram: Produced by a cardiograph, this is a record of heart muscle activity.
Stent Insertion: Permanent placement of a wire mesh tube into a clogged artery in order to increase blood flow to the heart.
Necrosis: Irreversible cell injury characterized by cell rupture, inflammation, and leakage of contents into extracellular fluid.
Single Nucleotide Polymorphisms (SNPs): A genetic variant of a single nucleotide in a DNA sequence.
Stem Cell Transplantation: The process of replacing unhealthy blood forming cells (stem cells) with healthy cells donated by a healthy individual; also known as a bone marrow transplant.
Arteriosclerosis: Abnormal thickening or hardening of arteries.