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Pathology => Human Diseases => Genetic Disorders
Genetic Disorders
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.
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).
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.
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.
° 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.
° Chromosomal Disorders
Chromosomal disorders are caused by the presence of an extra or missing whole or partial chromosome. In some cases, whole chromosomes or pieces of chromosomes are attached to one another in abnormal ways, which cause a person or their offspring to have an incorrect amount of chromosomal material. Chromosomal disorders are sometimes caused by an error in a type of cell division called meiosis, which occurs during the formation of eggs and sperm. Chromosomal disorders disrupt the biological functions of many genes. They produce multiple problems in the affected individual, often including mild or severe mental retardation. More than 600 chromosomal syndromes have been identified.
Down syndrome is the most common chromosomal disorder, affecting about 1 in 800 newborns. People with Down syndrome characteristically have three copies of the autosomal chromosome known as number 21 instead of the normal pair of number 21 chromosomes. For this reason, Down syndrome is commonly called trisomy 21. People with Down syndrome usually have mild to severe learning disabilities and physical symptoms that include a small skull, an extra fold of skin at the inner corner of each eye, a flattened bridge of the nose, and a large, protruding tongue. They also may have heart defects and other serious health problems.
Some chromosomal disorders involve the sex chromosomes. In many instances, an extra or missing sex chromosome is less life threatening than an extra or missing autosome. A person with Klinefelter syndrome, which affects about 1 in 500 males, has two X chromosomes and one Y chromosome. Males with Klinefelter syndrome are typically tall, and they may have small testes and slight breast development. They also may have minor problems with learning and are usually infertile.
Another chromosomal disorder that affects the sex chromosomes is Turner syndrome, which affects 1 in 2,500 to 5,000 females. In this disorder, a female has one functioning X chromosome instead of two. Females with this condition are typically short, with a thick, webbed neck. They may have mild problems with learning, and they usually are infertile because they lack normal ovaries.
° Multifactorial Disorders
Multifactorial disorders are caused by several genes as well as the influence of a person's environment, such as diet or lifestyle. An example of a multifactorial disorder is a category of birth defects called neural tube defects. In a neural tube defect, a fetus's neural tube-the structure that develops into the spinal cord and brain-is damaged. The two most common types of neural tube defects are anencephaly and spina bifida. Anencephaly is a fatal condition in which a baby is born with only a partial brain or no brain at all. About 1000 to 2000 babies with anencephaly are born each year in the United States. Spina bifida results when a neural tube defect causes an opening in the spine. In the United States, about one infant in every 2,000 live births is born with spina bifida. These infants need surgery to close the opening in the spine, and they may develop problems with walking or with bowel or bladder control. Geneticists believe that certain genes may play a role in damage to the neural tube, but the mother's diet during pregnancy also plays a role. A woman's risk of giving birth to an infant with a neural tube defect significantly decreases if she consumes adequate amounts of folic acid, a vitamin in the B complex, during the first three months of pregnancy and one month before conception.
Some common diseases that run in families but do not display an obvious pattern of inheritance are also thought to be multifactorial. Two examples are coronary heart disease and diabetes mellitus. In both cases, genes may cause a person to be predisposed to develop the disease, but lifestyle choices can help to prevent the disease from developing or from worsening after it occurs.
° Mitochondrial Disorders
All cells contain tiny self-replicating structures called mitochondria located outside of the nucleus. Each mitochondrion contains about ten single copies of small, circular chromosomes. These chromosomes contain a type of DNA that is different from the DNA found in chromosomes inside the cell nucleus. Both sperm and eggs contain mitochondria, but at fertilization, a sperm contributes only the genetic material in its nucleus to the new life form. All of a person's mitochondria are genetic descendents of those mitochondria that were present in the egg before fertilization. Therefore, mitochondrial disorders are transmitted solely through the mother. Both males and females can be affected, but an affected male will not pass on the disorder to his children.
Conditions involving mitochondrial inheritance are rare, and they have been recognized only since the 1980s. One example is Leber's hereditary optic neuropathy, a vision disorder characterized by shrinking of the optic nerve, which transmits visual images from the eye to the brain.
GENETIC SCREENING
Clinical geneticists and other health professionals use several screening tests and procedures to determine whether a person has a genetic disorder or is at risk of having a child with a disorder. These tests may be performed at various times in a person's life. Some genetic screening tests are routinely performed on newborns. Among adults, genetic screening is always voluntary.
° Preimplantation Diagnosis
A test that can be performed at the earliest possible stage of life is called preimplantation diagnosis. This test is used in conjunction with in vitro fertilization, a procedure for uniting an egg and sperm in a laboratory rather than in a woman's body.
Before an embryo created using in vitro fertilization is surgically implanted into the mother's uterus, physicians remove a cell from the developing embryo and analyze its DNA to learn if abnormalities associated with a specific genetic disorder are present. Although in vitro fertilization is a standard medical practice, removing cells from a developing embryo and preimplantation diagnosis are considered experimental procedures.
° Prenatal Screening
Prenatal screening-genetic screening performed during a pregnancy-is used to identify fetuses at risk for certain genetic disorders. Usually, a multiple marker screen analyzes a pregnant woman's blood for the presence of three substances-alpha fetoprotein, estriol, and human chorionic gonadotropin-that may signal certain problems in the fetus. This test is a screening test to identify fetuses with an extra chromosome or fetuses with a neural tube defect.
Chorionic villus sampling is a prenatal screening test performed at about the tenth week of pregnancy. A thin hollow tube called a catheter is inserted through the vagina and cervix into the uterus and is used to withdraw small amounts of the chorionic villus, which is part of the developing placenta. In some instances a sample of the chorionic villus is obtained through a needle inserted through the abdomen. Doctors isolate fetal cells from the chorionic villus and analyze them in the laboratory to determine if certain genetic abnormalities are present.
Amniocentesis is a prenatal screening test that is offered primarily to women who are 35 years or older at the time of pregnancy. This test is performed between the 14th and 20th weeks of pregnancy. Doctors insert a thin needle through the abdomen and into a woman's uterus, away from the fetus, to remove a few tablespoons of amniotic fluid. This fluid contains fetal urine and fetal cells, which can be used to prepare a karyotype-a photographic image that depicts all of the embryo's chromosomes in a cell. A karyotype reveals whether a fetus has extra chromosomes, missing chromosomes, or chromosomes that have attached to one another in unusual ways. The cells in the amniotic fluid can also be used to check for the presence of certain DNA mutations and to determine whether enzymes present in the fluid are characteristic of certain genetic disorders.
° Newborn Screening
Genetic screening of newborns is necessary to identify those genetic disorders that would harm an infant if not treated immediately. Newborns with sickle-cell anemia are at risk of dying from severe infections; these infants are given antibiotics immediately after being diagnosed with this disease. Newborns with phenylketonuria lack the enzyme needed to convert phenylalanine, an amino acid present in food, into a different amino acid called tyrosine. As a result, phenylalanine can build up to toxic levels in the bloodstream, resulting in severe mental retardation. For infants diagnosed with this disease, doctors prescribe a special diet that lacks phenylalanine to prevent this damaging buildup. Similarly, infants with galactosemia require a diet that is low in the sugar galactose to prevent the buildup of this substance to levels that produce seizures, mental retardation, and early death. In the United States and Canada, hospitals commonly screen newborns for phenylketonuria and galactosemia. Screening for sickle-cell anemia is performed for all infants in the United States and for infants of parents from at-risk groups in Canada.
° Carrier Screening
Genetic screening detects carriers of genetic disorders-people who have a single copy of a mutated recessive gene but are otherwise healthy. These tests are usually intended to diagnose autosomal recessive disorders that are common in individuals of certain ethnic backgrounds. For example, people of Eastern European Jewish ancestry may be screened to see if they are carriers for Tay-Sachs disease, cystic fibrosis, and an inherited neurological disorder called Canavan disease. In the United States and Canada, African Americans are at high risk for developing sickle-cell anemia. A blood disorder called beta thalassemia is more common in individuals of Greek or Italian ancestry, and alpha thalassemia, a related condition, is more common in persons of Southeast Asian and Chinese ancestry.
Carrier testing identifies couples at risk of having an affected child so that they can make informed decisions about having children. Many couples choose to have children even if both partners are known to carry the same recessive gene. In such instances, some people undergo prenatal genetic testing to learn if a fetus has a disorder and decide at that time if they want to terminate the pregnancy (see Abortion). Others use prenatal genetic testing to learn in advance the health status of their child so that they can prepare for a specialized delivery or surgery, or other treatment the infant may need.
° Family History Screening
A medical family history helps identify healthy individuals at risk of developing a genetic disorder themselves, or of having a child with a genetic condition. In obtaining a family history, a health professional asks questions about the health of family members over a span of three or more generations. The information is recorded as a graphic image that incorporates symbols, such as squares, circles, triangles, and diamonds, to present a shorthand record of the medical family history. This image, called a pedigree, can reveal the multigenerational pattern of a genetic disorder. For example, a dominant disorder affects at least one family member in each generation, whereas a recessive disorder may cluster in a single generation.
TREATMENTS FOR GENETIC DISORDERS
Currently, there are no permanent cures for genetic disorders, but many treatments are available. A procedure called gene therapy is on the horizon; it may eventually provide permanent cures for at least some genetic disorders.
For a few genetic disorders caused by an enzyme malfunction, it is possible to replace the malfunctioning enzyme with a functioning enzyme. For example, Gaucher disease is an autosomal recessive disorder marked by a shortage of an enzyme called glucocerebrosidase. People with one type of Gaucher disease develop progressive bone disease and an enlarged spleen. They can be treated with enzyme replacement therapy, in which they receive regular intravenous infusions of synthetic enzymes that carry out the functions of glucocerebrosidase.
Most genetic disorders are treated using more than one type of treatment, in keeping with their complex and varied symptoms. For example, children with cystic fibrosis usually take pancreatic enzymes to help digest food and inhale medicines that are formulated to break up mucus in air passages. Parents of these children regularly clap their hand on the child's chest and back to loosen mucus in the lungs. In some instances, surgeons may perform a lung transplantation to save a patient's life.
People with sickle-cell anemia commonly require drugs to combat pain and anemia and to prevent infections. They may receive blood transfusions to increase the number of normal red blood cells in their bloodstream. Adults with severe sickle-cell anemia sometimes benefit from an anticancer drug called hydroxyurea, which reduces the frequency of cell sickling, and from erythropoietin, a hormone that stimulates red blood cell production. Some people with severe sickle-cell anemia benefit from bone marrow transplants.
An experimental procedure called gene therapy may have the potential to cure several fatal genetic disorders. Instead of treating symptoms of a disorder, gene therapy alters the genetic makeup of certain cells. Gene therapy was first used in 1990 to treat children with an autosomal recessive condition called adenosine deaminase (ADA) deficiency. In the absence of the enzyme adenosine deaminase, T lymphocytes, a type of immune system cell, cannot develop normally. Children with ADA lack the immunity to fight off infections and typically die within the first years of life. In experiments using gene therapy, a genetically modified virus was used to carry a normal ADA gene to the patient's immune cells. The inserted ADA gene then programmed the cells to produce the missing ADA enzyme, which led to normal immune function in those cells. Gene therapy has also produced promising results in treating a rare immunologic disorder called chronic granulomatous disease, and it is being investigated in the treatment of cystic fibrosis and hemophilia.
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