III.

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.

A.

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.

B.

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, and a flattened bridge of the nose. 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 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.

C.

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 1,000 to 2,000 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.

D.

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.