Genetic Disorders

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Introduction

Genetic Disorders, medical conditions caused by an error in a person’s genetic material. Some genetic disorders result in medical problems that are apparent at birth (see Birth Defects), while other genetic disorders do not become evident until childhood or adult life. Genetic disorders range in severity from those that cause death to those that produce only mild problems, such as color blindness. Scientists have identified more than 9,000 genetic disorders. Some of these disorders are extremely rare, while others are comparatively common.

Genetic disorders pose a medical challenge. Scientists have not yet developed cures or effective ways to treat many genetic conditions. Many genetic disorders are complex, involving several different parts of the body, making treatment difficult. For example, patients with cystic fibrosis require treatment for problems affecting the lungs, pancreas, intestines, and liver. In some instances, doctors must diagnose and treat affected newborns immediately to prevent them from developing complications that would cause impaired development or even death. In addition, genetic disorders have unique personal, family, and social consequences. Parents who have a child with a genetic disorder may blame themselves for having passed on the genetic condition. Healthy siblings or other members of an affected person’s family may feel guilty for having escaped the disorder. Some people with a genetic condition may feel different or stigmatized because they perceive their genes as flawed. People may alter their plans to have children because they do not want their children to develop the genetic condition.

Specially trained health professionals help people deal with the complex medical and social consequences of genetic disorders. Clinical geneticists are physicians who diagnose and treat individuals with genetic disorders. These professionals explain the medical facts related to the disorder, such as the factors that cause the disease and the diagnostic and treatment options available. Genetic counselors are health professionals with graduate training in human genetics. Genetic counselors work alone and with clinical geneticists to help couples understand their risks of having a child with a genetic disorder. Genetic counselors also help patients choose a course of action to deal with their disorder that is in harmony with their feelings about the medical risks, their family goals, and their ethical and religious values.

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Genes, Chromosomes, and Disease

All genetic disorders involve one or more genes found in the nuclei, or in some cases, the cytoplasm, of human cells. Genes are composed of deoxyribonucleic acid (DNA), a threadlike molecule whose structure provides instructions used by cells to direct the synthesis of proteins. Proteins regulate most of the biochemical reactions that occur within cells, and they are the building blocks of many substances in the body. Genes are precisely arranged on chromosomes, rodlike structures that each contain several thousand genes. Human cells contain 46 chromosomes arranged in 23 pairs. One of these chromosome pairs is called the sex chromosomes because they determine a person’s gender. Among females, the sex chromosomes consists of two chromosomes, both called X. The sex chromosomes in males are made up of one X chromosome and a smaller Y chromosome. The remaining 22 pairs of human chromosomes are called autosomes. These chromosomes are numbered 1 through 22, with 1 corresponding to the largest chromosome pair and 22 corresponding to the smallest (see Genetics).

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Most, but not all, of a person’s DNA is located within these 23 pairs of chromosomes, all of which are found within the nuclei of cells. In contrast, some DNA is found outside the nuclei of cells. This DNA is present in small, self-replicating structures called mitochondria and is called mitochondrial DNA.

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Types of Genetic Disorders

Scientists have identified certain categories of genetic disorders, some of which have characteristic inheritance patterns. One category consists of single-gene disorders—disorders that involve an error in the DNA that makes up an individual gene. A second category of genetic disorders involves abnormalities of chromosomes in which too much or too little chromosomal material is present. Some genetic disorders are said to be multifactorial, because they are caused by the combined effects of multiple genes and environmental factors, such as diet and exposure to certain chemicals. Still other genetic disorders are caused by mutations in mitochondrial DNA.

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Single-Gene Disorders

Single-gene disorders result from errors within an individual gene. Each gene contains information used by cells to manufacture a specific protein or a component of a protein. A tiny alteration, or mutation, in the DNA that makes up a gene may cause a person’s cells to either fail to produce sufficient quantities of a crucial protein or to synthesize a protein with an altered form. Such a protein cannot perform its normal role.

The impact of a single-gene disorder sometimes depends on whether a person has inherited a faulty version of a gene from only one parent or from both parents. The genes that are carried on each of the 22 pairs of autosomes always occur in pairs—one of which is inherited from the mother, and the other from the father. In some instances, a faulty gene has a dominant effect, in which the person who inherits one faulty gene and one normally working gene will eventually develop a disorder. In other instances, the faulty gene is recessive—it will not cause a disorder unless a person inherits two copies of the faulty gene, one from the mother and one from the father.

About half of all single-gene disorders are said to be autosomal dominant, meaning that the faulty gene is carried on an autosomal chromosome and exerts its effects even when only one copy is present. A person with an autosomal dominant disorder has a 50 percent chance of producing a child with the disorder each time he or she has a child. An example of an autosomal dominant disorder is Huntington’s disease. In this condition, which affects about 1 in 10,000 people, a person usually does not experience symptoms until they are at least 30 to 40 years old. At that time, or even later in life, a person with Huntington’s disease develops uncontrolled movements called chorea and may also have problems with coordination, thinking, and judgment. These symptoms are due to the degeneration of nerve cells in a part of the brain called the basal ganglia in the cerebrum. This degeneration typically progresses until it results in the person’s death.

In contrast to Huntington’s disease, many other single-gene disorders are autosomal recessive. These disorders only occur when a person inherits two faulty copies of the same gene. In such cases, the parents are not affected themselves but they each carry one copy of the problematic gene, in which case they are known as carriers. If both parents are carriers of the same flawed gene, they have a 25 percent risk that they will produce a child with a genetic disorder each time they have a child.

An example of an autosomal recessive single-gene disorder is cystic fibrosis. This disease involves a gene that produces a protein that helps transport chloride molecules across cell membranes. This protein is typically present in specialized cells called epithelial cells, which line the inner surface of the lungs. If a person inherits two mutated forms of this gene, symptoms develop, including the potential build up of thick, suffocating mucus in the lungs. In some people with cystic fibrosis, pancreatic enzymes are secreted that interfere with the digestion of food. Abnormal mucus also interferes with the digestion of food. About 1 in 29 people of northern European ancestry carry a cystic fibrosis gene alteration, and about 1 in every 3,300 Caucasians in North America has the disease.

Another disorder that follows this inheritance pattern is Tay-Sachs disease. People who inherit two copies of the faulty Tay-Sachs gene lack a crucial enzyme called hexosaminidase A, which is needed to break down certain fatty substances in brain and nerve cells. As a result, these substances build up in such large quantities that the central nervous system gradually stops functioning and the person dies. Symptoms of Tay-Sachs typically become evident within the first six months of life, and most affected individuals die before reaching four years of age. Among people of eastern European Jewish ancestry, about 1 in 30 people carry a Tay-Sachs gene, and the incidence of Tay-Sachs disease for this population is 1 out of 3,600 people.

Some single-gene disorders are not entirely dominant or entirely recessive. In these disorders, each member of a pair of genes has a distinct effect. This is sometimes referred to as co-dominant, semi-dominant, or intermediate expression. An example of such a disorder is sickle-cell anemia, caused by a mutated gene that produces an abnormal form of hemoglobin, a protein in red blood cells that transports oxygen from the lungs to the tissues. In people who have two copies of the faulty gene, this abnormal hemoglobin molecule causes red blood cells to assume a distorted shape after releasing oxygen. The distorted cells resemble a sickle—a crescent-shaped tool used in harvesting crops. The sickled shape prevents the cells from passing easily through tiny blood vessels, resulting in painful blockages. Among people who inherit two faulty sickle-cell genes, the abnormal form of hemoglobin is predominant; these people are said to have sickle-cell disease. People who have a single faulty sickle-cell gene are said to have sickle-cell trait. These individuals have mainly the normal form of hemoglobin, but they have small amounts of the abnormal form and their cells may sickle on rare occasions. Sickle-cell anemia is most common among people who have ancestors from Africa, the Mediterranean, India, and the Middle East. In North America, about 10 percent of African Americans carry a faulty sickle-cell gene. In the United States, about 72,000 people have sickle-cell anemia.

A category of single-gene disorders known as X-linked disorders involves genes located on the X chromosome, one of the two sex chromosomes. Males are at greater risk for X-linked genetic disorders than females, because if a male inherits an X chromosome with a mutated recessive gene, he lacks a second X chromosome that might provide the normal, dominant form of the gene. The Y chromosome contains only a small number of genes that are mostly involved in determining male characteristics. Alterations to genes on the Y chromosome are a factor in some instances of male infertility.

An example of an X-linked disorder is hemophilia. People with hemophilia usually lack 1 of the 14 or more proteins called clotting factors that repair a cut or torn blood vessel. Consequently, their bodies are sometimes unable to stop bleeding after an injury. The clotting factor that is absent in hemophilia A, the most common form of hemophilia, is called factor VIII and is encoded by a gene on the X chromosome. Most people with hemophilia are males who have inherited an X chromosome with the faulty gene from their mother. It is rare for females to have hemophilia, because this would require inheriting the faulty gene from the X chromosome of both parents. About 1 in 10,000 men have hemophilia A.

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