What are genetic diseases?

Causes and Symptoms

Hereditary units called genes determine the majority of the physical and biochemical characteristics of an organism. Genes are composed of a chemical compound called
deoxyribonucleic acid (DNA) and are organized into rod-shaped structures called
chromosomes that reside in each cell of the body. Each human cell carries forty-six chromosomes organized as twenty-three pairs, each composed of several thousand genes. Twenty-two of the chromosome pairs are homologous pairs; that is, similar genes are located at similar sites on each chromosome. The remaining chromosomes are the sex chromosomes. Human females bear two X chromosomes, and human males possess one X and one Y chromosome.

During the formation of the reproductive cells, the chromosome pairs separate, and one copy of each pair is randomly included in the egg or sperm. Each egg will contain twenty-two autosomes (non-sex chromosomes) and one X chromosome. Each sperm will contain twenty-two autosomes and either one X or one Y chromosome. The egg and sperm fuse at fertilization, which restores the proper number of chromosomes, and the genes inherited from the baby’s parents will determine its sex and much of its physical appearance and future health and well-being.

Genetic diseases are inherited as a result of the presence of abnormal genes in the reproductive cells of one or both parents of an affected individual. There are two broad classifications of genetic disease: those caused by defects in chromosome number or structure and those resulting from a much smaller flaw within a gene. Within the latter category, there are four predominant mechanisms by which the disorders can be transmitted from generation to generation: autosomal dominant inheritance, in which the defective gene is inherited from one parent; autosomal recessive inheritance, in which defective genes are inherited from both parents, who themselves may show no signs of the disorder; X-linked chromosomal inheritance (often called sex-linked), in which the flawed gene has been determined to reside on the X chromosome; and multifactorial inheritance, in which genes interact with each other and/or environmental factors.

Errors in chromosome number include extra and missing chromosomes. The most common chromosomal defect observed in humans is
Down syndrome, which is caused by the presence of three copies of chromosome 21, instead of the usual two. Down syndrome occurs at a frequency of about one in eight hundred live births, this frequency increasing with increasing maternal age. The symptoms of this disorder include intellectual disability, short stature, and numerous other medical problems. The most common form of Down syndrome results from the failure of the two copies of chromosome 21 to separate during reproductive cell formation, which upon fusion with a normal reproductive cell at fertilization produces an embryo containing three copies of chromosome 21.

Gross defects in chromosome structure include duplicated and deleted portions of chromosomes and broken and rearranged chromosome fragments.
Prader-Willi syndrome results from the deletion of a small portion of chromosome 15. Children affected with this disorder are prone to intellectual disability, obesity, and diabetes. Cri du chat (literally, “cat cry”) syndrome is associated with a large deletion in chromosome 5. Affected infants exhibit facial abnormalities, are severely intellectually disabled, and produce a high-pitched, catlike wail.

Genetic diseases caused by defects in individual genes result when defective genes are propagated through many generations or a new genetic flaw develops in a reproductive cell. New genetic defects arise from a variety of causes, including environmental assaults such as radiation, toxins, or drugs. More than four thousand such gene disorders have been identified.

Manifestation of an autosomal dominant disorder requires the inheritance of only one defective gene from one parent who is afflicted with the disease. Inheritance of two dominant defective genes, one from each parent, is possible but generally creates such severe consequences that the child dies while still in the womb or shortly after birth. An individual who bears one copy of the gene has a 50 percent chance of transmitting that gene and the disease to his or her offspring.

Among the most common autosomal dominant diseases are
hyperlipidemia and hypercholesterolemia. These disorders result in elevated levels of lipids and cholesterol in the blood, respectively, which contribute to artery and heart disease. Onset of the symptoms is usually in adulthood, frequently after the affected individual has had children and potentially transmitted the faulty gene to them.

Huntington’s chorea causes untreatable neurological deterioration and death, and symptoms do not appear until affected individuals are at least in their forties. Children of parents afflicted with Huntington’s chorea may have already made reproductive decisions without the knowledge that they might carry the defective gene. They risk a 50 percent chance of transmitting the disease to their offspring.

Autosomal recessive genetic diseases require that an affected individual bear two copies of a defective gene, inheriting one from each parent. Usually the parents are simply carriers of the defective gene; their one normal copy masks the effect of the one flawed copy. If two carriers have offspring, those children have a 25 percent chance of receiving two copies of the flawed gene and inheriting the disease and a 50 percent chance of being asymptomatic carriers.

Cystic fibrosis
is an autosomal recessive disease that occurs at a rate of about one in two thousand live births among Caucasians. The defective gene product causes improper chloride transport in cells and results in thick mucous secretions in lungs and other organs.
Sickle cell disease, another autosomal recessive disorder, is the most common genetic disease among African Americans in the United States. Abnormality in the protein hemoglobin, the component of red blood cells that carries oxygen to all the body’s tissues, leads to deformed blood cells that are fragile and easily destroyed.

X-linked genetic diseases are transmitted by faulty genes located on the X chromosome. In the case of X-linked recessive diseases, which are by far the more common, females need two copies of the defective gene to acquire such a disease, and in general women carry only one flawed copy, making them asymptomatic carriers of the disorder. Males, having only a single X chromosome, need only one copy of the defective gene to express an X-linked disease. Males with X-linked disorders inherit the defective gene from their mothers, since fathers must contribute a Y chromosome to male offspring. All male offspring of a carrier female will have a 50 percent chance of inheriting the defective gene and developing the disease. In the rare case of a female with two defective X-linked genes, 100 percent of her male offspring will inherit the disease gene and, assuming that the father does not carry the defective gene, her female offspring will be carriers. There are more than 250 X-linked disorders, some of the more common being Duchenne
muscular dystrophy, which results in progressive muscle deterioration and early death; hemophilia; and
red-green color blindness, which affects about 8 percent of Caucasian males.

Multifactorial inheritance, which accounts for a number of genetic diseases, is caused by the complex interaction of one or more genes with each other and with environmental factors. This group of diseases includes many disorders that, anecdotally, “run in families.” Representative disorders include cleft palate, spina bifida, anencephaly, and some inherited heart abnormalities. Other diseases appear to have a genetic component predisposing an individual to be susceptible to environmental stimuli that trigger the disease. These include cancer, hypertension, diabetes, schizophrenia, alcoholism, depression, and obesity.

Diagnosis and Detection

Most, but not all, genetic diseases manifest their symptoms immediately or soon after the birth of an affected child. Rapid recognition of such a medical condition and its accurate diagnosis are essential for the proper treatment and management of the disease by parents and medical personnel. Medical technology has developed swift and accurate diagnostic methods, in many cases allowing testing of the fetus prior to birth. In addition, tests are available that determine the carrier status of an individual for many autosomal recessive and X-linked diseases. These test results are used in conjunction with genetic counseling of individuals and couples who are at risk of transmitting a genetic disease to their offspring so that they can make informed decisions about their reproductive futures.

Errors in chromosome number and structure are detected in an individual by analyzing his or her chromosomes. A small piece of skin or a blood sample is taken, the cells in the sample are grown to a sufficient number, and the chromosomes within each cell are stained with special dyes so that they may be viewed with a microscope. A picture of the chromosomes, called a karyotype, is taken, and the patient’s chromosome array is compared with that of a normal individual. Extra or missing chromosomes or alterations in chromosome structure indicate the presence of a genetic disease. The analysis of karyotypes is the method used to detect Down, Prader-Willi, and cri du chat syndromes, among others.

Defects in chromosome number and structure can also be identified in the fetus prior to birth. Samples may be collected from the fetus by
amniocentesis or by
chorionic villus sampling. In amniocentesis, a needle is inserted through the pregnant woman’s abdomen and uterus, into the fluid-filled sac surrounding the fetus. A sample of this fluid, the amniotic fluid, is withdrawn. The amniotic fluid contains fetal cells sloughed off by the fetus. The cells are grown for several weeks until there are enough to perform chromosome analysis. This procedure is performed only after sixteen weeks’ gestation, in order to ensure adequate amniotic fluid for sampling.

Chorionic villus sampling relies on a biopsy of the fetal chorion, a membrane surrounding the fetus that is composed of cells that have the same genetic constitution as the fetus. A catheter is inserted through the pregnant woman’s vagina and into the uterus until it is in contact with the chorion. The small sample of this tissue that is removed contains enough cells to perform karyotyping immediately, permitting diagnosis by the next day. Chorionic villus sampling can be performed as early as the eighth or ninth week of pregnancy. This earlier testing gives the procedure an advantage over amniocentesis, since the earlier determination of whether a fetus is carrying a genetic disease allows safer pregnancy termination if the parents choose this course.

Karyotype analysis is limited to the diagnosis of genetic diseases caused by very large chromosome abnormalities. The majority of hereditary disorders are caused by gene flaws that are too small to see microscopically. For many of these diseases, diagnosis is possible through either biochemical testing or DNA analysis.

Many genetic disorders cause a lack of a specific biochemical necessary for normal
metabolism. These types of disorders are frequently referred to as “inborn errors of metabolism.” Many of these errors can be detected by the chemical analysis of fetal tissue. For example,
galactosemia is a disease that results from the lack of galactose-1-phosphate uridyl transferase. Infants with this disorder cannot break down galactose, one of the major sugars in milk. If left untreated, galactosemia can lead to developmental disabilities, cataracts, kidney and liver failure, and death. By analyzing fetal cells obtained from amniocentesis or chorionic villus sampling, the level of this important chemical can be assessed, and, if necessary, the infant can be placed on a galactose-free diet immediately after birth.

DNA analysis can be used to determine whether a genetic disease has been inherited when either the chromosomal location of the gene, the chemical sequence of the DNA, or particular DNA sequences commonly associated with the gene in question (called markers) are known.

Genes are made up of sequences of four chemical elements of DNA: adenine (A), guanine (G), thymine (T), and cytosine (C). Sometimes the proper DNA sequence of a gene is known, as well as the changes in the sequence that cause disease. Direct analysis of the DNA of an individual suspected of carrying a certain genetic disorder is possible in these cases. For example, in sickle cell disease, it is known that a change in a single DNA chemical element leads to the disorder. To test for this disease, a tissue sample is obtained from the fetus, and the DNA is isolated from the cells and analyzed with highly specific probes that can detect the presence of the defective gene that will lead to sickle cell disease. Informed action may then be taken regarding the future of the fetus or the care of an affected child.

Occasionally a disease gene itself has not been precisely isolated or had its DNA sequence determined, but sequences very near the gene of interest have been analyzed. If specific variations within these neighboring sequences are always present when the gene of interest is flawed, these nearby sequences can then be used as markers for the presence of the defective gene. When the variant sequences are present, so is the disease gene. Prenatal testing for cystic fibrosis has been done by looking for such variant sequences.

Individuals who come from families in which genetic diseases tend to occur can be tested as carriers, so they will know the risk of passing a certain disease to their offspring. For example, individuals whose families have a history of cystic fibrosis, but who themselves are not affected, may be asymptomatic carriers. If they have children with individuals who are also cystic fibrosis carriers, they have a 25 percent chance of passing two copies of the defective gene to their offspring. DNA samples from the potential parents can be analyzed for the presence of a defective gene. If both partners are carriers, their decision about whether to have children will be made with knowledge of the possible risk to their offspring. If only one or neither of them is a carrier, their offspring will not be at risk of inheriting cystic fibrosis, as it is an autosomal recessive disease. Carrier testing is possible for many genetic diseases, as well as for disorders that appear late in life, such as Huntington’s chorea.

Many of the gene flaws of multifactorial diseases, those that interact with environmental factors to produce disease, have been identified and are testable. Individuals who know they have a gene that puts them at risk for certain disorders can incorporate preventive measures into their lifestyle, thus minimizing their chances of developing the disease. For example, certain cancers, such as colon and breast cancer, have a genetic component. Individuals who test positive for the genes that predispose them to develop cancer can modify their diets to include cancer-fighting foods and receive frequent medical checkups to detect cancer development at its earliest, most treatable stage. Those with genes that contribute to arteriosclerosis and heart disease can modify their diets and increase exercise, and those with a genetic predisposition for alcoholism can avoid the consumption of alcohol.

Perspective and Prospects

The scientific study of human
genetics and genetic disease is relatively new, having begun in the early twentieth century. However, there are many early historical records that recognize that certain traits are hereditarily transmitted. Ancient Greek literature is peppered with references to heredity, and the Jewish book of religious and civil laws, the Talmud, describes in detail the inheritance pattern of hemophilia and its ramifications for circumcision.

The Augustinian monk Gregor Mendel worked out many of the principles of heredity by manipulating the pollen and eggs of pea plants over many generations. His work was conducted from the 1860s to the 1870s but was unrecognized by the scientific community until 1900.

At about this time, many disorders were being recognized as genetic diseases. Pedigree analysis, a way to trace inheritance patterns through a family tree, has been used since the mid-nineteenth century to track the incidence of hemophilia in European royal families. This analysis indicates that the disease was transmitted through females (indeed, hemophilia is an X-linked disorder). In the early twentieth century, Archibald Garrod, a British physician, recognized certain biochemical disorders as genetic diseases and proposed accurate mechanisms for their transmission.

In 1953, Francis Crick and James D. Watson discovered the structure of DNA; thus began studies on the molecular biology of genes. This research resulted in the monumental discovery in 1973 that pieces of DNA from animals and bacteria could be cut and spliced together into a functional molecule. This recombinant DNA technology fostered a revolution in genetic analysis, in which pieces of human DNA can be removed and put into bacteria. The bacteria then replicate millions of copies of the human DNA, permitting detailed analysis. These recombinant molecules also produce human gene products, such as RNA and protein, thereby facilitating the analysis of normal and aberrant genes.

The recombinant DNA revolution spawned the development of DNA tests for genetic diseases and carrier status. Knowledge of what a normal gene product is and does is exceptionally helpful in the treatment of genetic diseases. For example, Duchenne muscular dystrophy is known to be caused by the lack of a protein called dystrophin. This suggests that one possible treatment is to provide functional dystrophin to an individual with this disease.

Ultimately, medical science seeks to treat genetic diseases by providing a functional copy of the flawed gene to the affected individual. While such gene therapy would not affect the reproductive cells—the introduced gene copy would not be passed down to future generations—the normal gene product would alleviate the genetic disorder in the individual.

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