Genetic diseases result from single-gene (Mendelian) alterations, chromosomal abnormalities, or multifactorial errors. Well over 6,000 such abnormalities have been identified in humans, ranging from mild differences (as in certain hemoglobin abnormalities) to fatal or overwhelmingly disabling conditions, such as trisomy 18 (Edwards') syndrome and trisomy 13 (Patau's) syndrome. The risk of single gene disorders is estimated at 1 in 200 births.
Although genetic disorders are determined primarily by genetic makeup, they can and do interact with environmental factors. For example, albinism (an inherited inability to generate the protective pigment melanin) greatly increases susceptibility to skin cancer after excessive exposure to sunlight.
Genetics, the study of heredity, analyzes defects in chromosomal reproduction or disease processes that can be passed from one generation to the next. It uses various tests to unravel the effects of altered genes and the patterns of inheritance. As heredity becomes better understood, genetic influences are likely to assume greater importance in health care delivery.
The essential ingredient of heredity is deoxyribonucleic acid (DNA), which makes up genes, basic units of hereditary material that are arranged into threadlike organelles called chromosomes in the cell nucleus. (See DNA and how it works, and DNA replication.) Together, these elements contribute to a person's genotype (gene composition) and phenotype (outward appearance). In humans, each body cell (except ova and sperm) has 46 chromosomes consisting of 22 pairs of autosomes and 1 pair of sex chromosomes. Females have a matched (homologous) pair of X sex chromosomes; males have an unmatched (heterologous) pair of sex chromosomes — an X and a Y. Thus, the normal human chromosome complement is 46,XX in females and 46,XY in males. The 22 autosomes are all homologous. Each chromosome has a short arm (p) and a long arm (q) joined at the centromere.
The position that the gene for a given trait occupies on a chromosome is called a locus. Different loci exist for hair color, blood group, and so on. The number and arrangement of the loci on homologous chromosomes are the same. When the two genes are identical, the individual is homozygous at that locus. When the genes aren't identical, the individual is heterozygous at that locus. A different form of the same gene that occupies a corresponding locus on a homologous chromosome is called an allele; it determines alternative (and inheritable) forms of the same characteristic. Some alleles control normal trait variation such as hair color; other defective alleles may cause a congenital defect or even induce a spontaneous abortion. Both heterologous (codominant) alleles may express their own effects, or one (the dominant allele) may be expressed and the other (the recessive) suppressed.
A mutation is a permanent, inheritable change in a DNA sequence. When a mutation occurs in a gene's DNA sequence it may cause serious, even lethal defects, or it may be relatively benign. Mutations can occur spontaneously or can be caused by exposure to teratogenic agents, such as radiation, drugs, viruses, and synthetic chemicals.
Genetic disorders occur in several different forms. (See Patterns of transmission in genetic disorders)
❑ Mendelian or single-gene disorders are inherited in clearly identifiable patterns.
❑ Chromosomal aberrations or abnormalities include structural defects within a chromosome, such as deletion and translocation, plus absence or addition of complete chromosomes.
❑ Multifactorial disorders reflect the interaction of at least two abnormal genes and environmental factors to produce a defect.
Single-gene disorders may be autosomal (resulting from a single altered gene or a pair of altered genes on one of the 22 pairs of autosomes) or X-linked (resulting from an altered gene on the X chromosome). Single-gene disorders may be further classified as dominant or recessive, depending on whether the altered gene is a dominant or a recessive allele.
A dominant allele produces its effect in heterozygotes (people who also carry a normal gene for the same trait) because the dominant allele masks the effects of the normal paired gene (autosomal dominant inheritance). Because a person with an autosomal dominant disease is usually a heterozygote and carries one dominant gene as well as one normal gene, his children have a 50% chance of inheriting the dominant gene and the disease. This probability remains the same for each pregnancy. Unaffected people (homozygote for the normal gene) don't carry the altered gene and therefore can't transmit it, except as a new mutation. (See Inheritance patterns.)
Sex doesn't influence transmission of an autosomal dominant allele. However, in some autosomal dominant diseases (such as Huntington's disease) the severity of symptoms can vary in offspring, depending on which parent transmits the dominant allele. Unless the dominant allele has arisen as a new mutation or is nonpenetrant in an individual, every affected person has an affected parent. Thus, autosomal dominant traits don't skip generations. However, the severity of symptoms can range from very mild to severe among persons who inherit the allele. This variation of severity is known as expressivity.
Because a recessive allele can produce a disorder only when paired with another disease-causing allele (autosomal recessive inheritance), offspring must receive one copy of the disease causing allele from each parent to inherit the recessive trait. A carrier has a diseased gene, but is phenotypically normal. Autosomal recessive disorders affect males and females equally. Because both parents must be heterozygous carriers, autosomal recessive disorders are more common in children of consanguineous parents (blood relatives).
In X-linked recessive inheritance, nearly all affected persons are males because females have two X chromosomes and males have an X and a Y chromosome. There's very little DNA sequence in common between the X and the Y chromosomes. Therefore, recessive alleles on a male's X chromosome are expressed. Females who carry a disease-causing recessive allele on only one X chromosome are usually unaffected because they have two X chromosomes — one with the disease-causing allele and one with the normal dominant allele. However, every cell in the female, except the oocytes, undergoes a normal process called X inactivation where one X chromosome is turned off. This process is random. Therefore, females who carry only one copy of a disease-causing allele may have mild symptoms if a disproportionate number of cells have the X chromosome with the disease-causing allele turned on and the X chromosome with the normal allele turned off.
In X-linked dominant inheritance, which is rare, females are affected to varying degrees. These disorders tend to be lethal in males. A family history of multiple male miscarriages or stillbirths is usually a clue to an X-linked dominant disorder.
Sex does influence transmission of X-linked alleles. An affected male transmit's the disease-causing allele to all of his female offspring, but to none of his male offspring. This is because males have only one X chromosome. When a sperm containing an X chromosome joins an ovum (which can only have an X chromosome), a female offspring results. When the X chromosome contains a disease-causing recessive allele, female offspring are typically unaffected carriers. When the X chromosome contains a disease-causing dominant allele, all female offspring are affected. Male offspring receive a Y chromosome from their father, therefore not receiving the disease-causing allele.
During germ cell formation by meiosis, failure of chromosomes to divide (nondisjunction) results in a germ cell that contains fewer or more than the normal 23 pairs of chromosomes. Usually, such abnormal germ cells fail to unite at conception; if fertilization does take place, the embryo is usually miscarried early in the pregnancy. Experts believe that up to 60% of spontaneous abortions at less than 90 days' gestation result from an abnormal number of fetal chromosomes; offspring with some chromosomal abnormalities are probably never even implanted. Absence of an autosomal chromosome is incompatible with life, but absence of a sex chromosome, as in Turner's syndrome, is better tolerated. The presence of an extra chromosome ( trisomy), as in Down syndrome, commonly produces physical malformation, mental retardation, or both.
Chromosomal disorders may also result from structural changes within chromosomes. For instance, in deletion, loss of part of a chromosome during cell division produces varying effects in the offspring, depending on the type and amount of genetic material lost. An example is velocardiofacial syndrome, in which part of the long arm of chromosome 22 is missing.
In translocation, part of a chromosome attaches itself to another chromosome. If little or no genetic material is lost, the translocation is balanced (symmetrical) and the person displays no effects but may have reproductive problems, such as miscarriage, infertility, or children with malformations, cognitive effects, or both. The person may produce unaffected children, each of whom has a 50% chance of being a balanced translocation carrier, like the parent.
Another abnormality, ring chromosomes, results when a chromosome loses a section of genetic material from each end and the remaining stumps join together to form a ring. The effect varies, depending on the type of genetic material lost and on the specific chromosome that's involved.
In mosaicism, abnormal chromosomal division in the zygote results in two or more cell lines with different chromosomes. (One cell line may be normal and the other abnormal.) The patient's phenotype depends on the percentage of normal cells and on the varying effects of the abnormal cell line, which depend on the percentage of abnormal cells in each type of tissue.
Originally, Gregory Mendel's theories of heredity pointed to the understanding that an individual's phenotype is the same no matter which parent donates the allele. Now, it's known that this isn't always true. When a deletion on 15q11-13 is inherited from the father, the child will have Prader-Willi syndrome (obesity, short structure, hypogonadism). If the deletion is inherited from the mother, the child will have Angelman's syndrome (mental retardation, no verbal language, seizures). This indicates that different genes are active on chromosome 15 depending on which parent provided the chromosome.
Multifactorial disorders are abnormalities that result from the interaction of at least two inherited abnormal genes and environmental factors. They include common malformations, such as neural tube defects, cleft lip, and cleft palate, as well as disorders that may not appear until later in life such as diabetes mellitus. Such disorders don't follow the Mendelian patterns of inheritance, but the increased incidence of specific birth defects within families suggests familial transmission.
Genetic testing and counseling can help prevent genetic disorders and help patients and their families deal with them when they do develop. Genetic diagnosis relies primarily on pedigree (family tree) analysis, karyotype (chromosomal) analysis, and biochemical analysis of blood, urine, or body tissues (including tissues obtained by amniocentesis or chorionic villus sampling [CVS]) to detect abnormal gene products. Neonatal screening for inherited metabolic disorders such as phenylketon uria has become standard, and prompt treatment of such disorders can prevent or minimize their effects.
Simple blood tests can detect carriers of recessive-gene disorders, such as Tay-Sachs disease and sickle cell anemia. DNA testing can detect some autosomal recessive, autosomal dominant, and X-linked recessive disorders. This gives a couple at risk the option of prenatal diagnosis (by amniocentesis or possibly CVS) for some disorders, to detect affected offspring.
A pedigree, a diagram of family relationships and diseases and cause of death of individual family members, helps determine a disorder's inheritance pattern, including the probability of occurrence. The pedigree chart begins with the patient (proband, or index case) and traces all living and deceased blood relatives in order of their birth, listing:
❑ current age or age at death
❑ health status of all relatives, including miscarriages and stillbirths (and the reasons for them), the site and nature of congenital anomalies, and the presence of mental and growth retardation
❑ relationships (if the patient is a twin, involved in a consanguineous marriage, or divorced).
This information can be obtained from the patient's memory, autopsy and pathology reports, photographs, and medical records. The pedigree chart is analyzed in relation to the clinical features of the suspected genetic disorder and appropriate laboratory tests or medical records. In one such test, the karyotype, white blood cells obtained from a venous blood sample are grown in a special culture until a specific stage of mitosis, when chromosomes are most easily seen with a microscope. Then the cells are broken open and stained to show specific bands on the chromosomes. Staining techniques can be varied to help identify each chromosome and the bands it contains.
Amniocentesis, needle aspiration of amniotic fluid after transabdominal puncture of the uterus under ultrasound guidance, can now detect over 600 genetic disorders before birth by:
❑ karyotyping cultured amniocytes
❑ using a special technique called fluorescent in situ hybridization on cultured amniocytes to detect submicroscopic chromosome deletions, duplications, or translocations
❑ measuring enzyme levels or activity on cultured amniocytes
❑ performing DNA mutation or linkage analysis on cultured amniocytes
❑ measuring proteins (for example, alpha-fetoprotein) or biochemical substrates in amniotic fluid.
Amniocentesis allows parents to make informed decisions for a pregnancy before the birth of a child with a genetic disorder. It's recommended to patients with:
❑ maternal age over 34 at delivery
❑ family history of chromosomal abnormalities
❑ history of previous children or a first- or second-degree relative with an open or closed neural tube defect or scoliosis with spinal dysraphism
❑ history of multiple reproductive losses
❑ parents who are known carriers of a genetic disorder that's detectable by biochemical or DNA testing.
The benefits of amniocentesis must be carefully weighed against the potential complications, which may include amni-otic fluid leakage, miscarriage, and (rarely) infection. The risk of complications is estimated to be 0.5% (1 in 200) or less. Genetic counseling is done to help the patient and family weigh the risks against the benefits so they can make an informed decision about testing. For some patients, CVS, another method of collecting genetic information from the fetus, may be an alternative. Using a vaginal or abdominal approach, with ultrasound as a guide, the physician collects a small amount of chorionic tissue, which is then analyzed in much the same way as the amniocentesis. Biochemical tests that are typically done on amniotic fluid can't be done on CVS tissue.
Researchers are currently studying new methods of earlier prenatal diagnosis, such as amniocyte filtration and karyotyping of fetal cells in maternal blood.
Prenatal diagnosis may be considered even when a couple would continue an affected pregnancy because knowing the diagnosis ahead of time can help the health care team provide the optimal timing and method of delivery, thus improving the neonate's outcome. It also gives the couple more time to look into financial, educational, and psychological support services to prepare for the birth of a child with special needs.
Health care providers may recommend genetic testing for selected children and adolescents; it's indicated for prevention, decreasing the need for surveillance, and examining treatment availability.
Genetic counseling helps a family to understand its risk for a particular genetic disorder and to cope with the disorder if that risk becomes reality. Counseling sessions make it easier for the family to comprehend:
❑ medical facts (diagnosis, prognosis, treatment)
❑ how heredity works (risks to other relatives)
❑ options for dealing with the problem
❑ consequences of their decision.
Psychological support to relieve stress and improve the child's or parents' self-concept is as important as obtaining the correct information. The birth of a child with a genetic defect may provoke parental feelings of guilt, anxiety, isolation, insecurity, and helplessness and may place undue stress on all members of the family. Family members may experience a period of shock and denial, followed by grief and mourning. Following acceptance of the diagnosis, parents may continue to experience periods of denial; guilt; and chronic sorrow, a phenomenon that manifests as episodes of sadness, particularly around developmental milestones. These feelings are a normal response to having a child with a disability.
When testing confirms a genetic disorder, here's how you can provide psychological support:
❑ Refer the family for genetic counseling. The following organizations can be contacted to obtain a list of qualified health professionals throughout the United States who can provide genetic evaluation, diagnosis, counseling, and management services:
– American College of Medical Genetics
– International Society of Nurses in Genetics
– March of Dimes Birth Defects Foundation
– National Society of Genetic Counselors.
❑ Find out the services that are offered by the counseling center so you can tell the family what to expect.
❑ Provide the genetic professional with pertinent medical records and information about the family's special concerns, such as religious beliefs and social preferences.
❑ After counseling sessions, make sure family members understand the new information presented to them, and reinforce the information provided. Communicate with them in an unhurried and nontechnical manner, and make sure your facts are accurate.
❑ Inform the family about community resources, agencies, and available support groups to help them deal with genetic disorders. If they're interested, help them get in touch with the families of other patients with the same disorder. The Alliance of Genetic Support Groups or the National Organization for Rare Disorders are valuable resources for locating support groups and parent networking opportunities.
❑ Coordinate the assistance needed from other members of the health care team, such as physicians, psychologists, and social workers.
❑ Recognize the parents' stresses in caring for their child, and allow them to express their feelings.
Review other book chapters online related to X-linked Genetic Diseases:
Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.
|
More About This Book:
Title: Professional Guide to Diseases (Eighth Edition) Authors: Springhouse Publisher: Lippincott Williams & Wilkins Copyright: 2005 ISBN: 1-58255-370-X 
|
|
What do you think about the features of this website? Take our user survey and have your say:
Next articles:
Tools & Services:
Medical Articles:
Search Specialists by State and City
By using this site you agree to our Terms of Use. Information provided on this site is for informational purposes only; it is not intended as a substitute for advice from your own medical team. The information on this site is not to be used for diagnosing or treating any health concerns you may have - please contact your physician or health care professional for all your medical needs. Please see our Terms of Use.
Copyright © 2009 Health Grades Inc. All rights reserved.
