Genetic disorders are conditions that can be traced to an individual's heredity. Many of these disorders are inherited and are governed by the same genetic rules that determine dimples and red hair. However, some genetic disorders result from a spontaneous mutation during embryonic development. If one parent can transmit the genetic information (in genes) that causes a child's disorder, then the disorder is said to be genetically dominant. However, if both parents lack the disorder and pass the disorder's gene to a child, then the genetic disorder is said to be recessive. But not all genetic diseases are completely determined by genes alone; some are promoted by environmental factors such as diet. Disorders that result from both genes and environment are called multi-factorial genetic diseases. In addition, some genetic disorders occur predominantly in males or females, due to the nature of the sex chromosomes, X and Y. Although many genetic diseases, such as cystic fibrosis and sickle cell anemia , do not occur often, some more common genetic diseases include hypertension, diabetes , and certain forms of cancer.
The principles of genetic inheritance can seem complicated to non-scientists. Basically, genetic information is organized into chromosomes in the cellular nucleus. Human cells have 46 chromosomes each--except for sperm and eggs (reproductive cells), which each have 23 chromosomes. Each person receives 23 chromosomes from their mother's egg and 23 chromosomes from their father's sperm. All but one of the 23 chromosomes are called autosomes, or non-sex chromosomes. These 22 chromosomes do not determine gender. The remaining chromosome is the sex chromosome and is either an X or a Y. Females have two Xs (XX), and males have one of each (XY). Females can only pass an X to their offspring, and males can pass either an X or a Y. Hence, the male sperm is responsible for gender selection. Because of their two X chromosomes, females can carry a disease gene on one X chromosome but not exhibit the disease since they have another X chromosome to compensate. However, males only have one X chromosome and can be affected by the same disease. Such genetic disorders are called X-linked.
The 44 autosomes have parallel coded information on each of the two sets of 22 autosomes, numbered 1 through 22, called homologous pairs. This coding is organized into genes. Individual genes are made of deoxyribonucleic acid (DNA), and code for particular proteins. Proteins play numerous critical structural and functional roles in the body. Each gene has a set locus, or position, on a particular chromosome. The genes with the same locus on corresponding chromosomes are called alleles. So, conventional terminology would describe one person as having two alleles of the same gene. Humans are called diploid organisms, because we have two alleles of each autosomal gene.
A shorthand is used to portray alleles that make up a person's genotype for a single locus. Genotypes are usually written as lower or upper case letters of the alphabet (such as AA, aa or Aa), where capital letters define dominant genes and lower case letters define recessive genes. When an allele can be one of many types, several letters can represent the same gene. Genotypes are either homozygous or heterozygous. Having two identical alleles, such as AA or aa, makes a person homozygous for that locus. Having different alleles (for example, Aa) at a locus makes someone heterozygous. The actual trait observed in a person is called the phenotype . Examples of phenotypes include dimples, brown eyes, and tongue-curling. Some traits are dictated by a single gene; whereas other are the result of multiple genes (multi-genic). This is true whether the trait is disease-related or not.
Genetic dominance describes the ability of a single allele to control phenotype. However, this concept does not explain all genetic observations. For example, sickle-cell anemia is a genetic recessive disease characterized by abnormal hemoglobin production. However, sickle-cell heterozygous people also produce some abnormal hemoglobin, although they usually do not experience illness, due to their normal hemoglobin. The production of both allelically encoded forms is an example of codominance. Therefore, this phenotype is said to be codominant. Incomplete dominance also occurs. Height is a example of this type of dominance, where the offspring can have a height between the heights of their parents (which is not the same height as either parent). Height, however, is also determined by a number of other factors such as diet (environment) and hormonal regulation (genetic). Thus, it is apparent that several factors can contribute to final phenotype in a number of traits; this is also true for various diseases.
The autosomes can be distinguished from one another in size and staining patterns. Chromosomal analysis can be performed on cell samples from one person. Corresponding chromosomes 1 through 22 and the sex chromosomes can be lined up and visually inspected for abnormalities. Any obvious flaw can indicate or explain a diseased state. Sometimes it is apparent that a part of one chromosome was incorrectly combined with a different chromosome during cellular division. When other than two autosomes 1 through 22 are present, the aberrant result is called aneuploidy. Most aneuploidies are trisomies (three homologous autosomes), or the presence of extra sex chromosomes.
Dominant genetic disorders
If one parent has an autosomal dominant disease, then offspring have a 50% chance of inheriting that disease. There are roughly 2,000 autosomal dominant disorders (ADDs) with effects that range from inconvenience to death. These diseases may manifest early or late in life. ADDs include Huntington's disease (HD), polydactyly (extra toes or fingers), Marfan's syndrome (extra long limbs), achondroplasia (a type of dwarfism ), some forms of glaucoma, most forms of porphyrias, and hypercholesterolemia (high blood cholesterol). In most ADDs, the homozygous genotype elicits a more severe disorder; however, this is not true for Huntington's disease.
HD is one of the most debilitating ADDs. It is characterized by progressive chorea (involuntary, rapid, jerky motions) and mental deterioration. HD usually appears in affected individuals between the ages of 30 and 50, and leads to dementia and eventual death in about 15 years.
Marfan's syndrome, or arachnodactyly, is an ADD characterized by long, thin arms, legs, and fingers. People with Marfan's also tend to be stoop-shouldered and have blue sclera of the eyes. In addition, these individuals have a high incidence of eye and aortic heart problems. Statistics show some correlation between older fathers and offspring with Marfan's. Not all people with Marfan's inherit it from a parent; about 15% of Marfan's cases are caused by a fresh mutation in the same locus. Abraham Lincoln is believed to have been afflicted with Marfan's.
Recessive genetic disorders
Recessive genetic disorders (RGD) result from the acquisition of two recessive alleles of a gene--one from each parent. When both parents carry a harmful, recessive trait, one or both of them may be unaware that they are carriers. Hence, the birth of a child with the recessive disease may be a shock to the healthy parents. The probability of two heterozygous parents having an affected child is 25% each time they conceive. The chance that they will have a heterozygous (carrier) child is 50% for each conception, and the chance of having an unaffected homozygous child is also 25% for each pregnancy. About 1,000 confirmed RGDs exist with the better known diseases, including cystic fibrosis, phenylketonuria (PKU, galactosemia, retinoblastoma (Rb), albinism, sickle-cell anemia, thalassemia, Tay Sachs disease, autism , growth hormone deficiency, adenosine deaminase deficiency (ADD), and Werner's syndrome (juvenile muscular dystrophy).
A number of eye disorders are RGDs, and are usually associated with a mutant gene on chromosome 13. The Rb gene was the first human gene to be located and identified as causing retinoblastoma, cancer of the retina. Most retinoblastomas are hereditarily transmitted; however, in some case, a heterozygous person develops a mutation of one gene, which makes them homozygous for the disease. Other recessive eye disorders include myopia (nearsightedness), albino eyes, day blindness, displaced pupils, and dry eyes. Some RGDs affect people of one particular ethnic background more than the rest of the population. Three such RGDs are cystic fibrosis (CF), sickle-cell anemia (SCA), and Tay-Sachs disease (TSD). CF is one of the most common autosomal recessive diseases in caucasian children in the U.S. About 4-5% of caucasians carry this recessive gene on chromosome 7, which causes exocrine mucus-producing glands to secrete an unusually thick mucus that clogs ducts and collects in lungs and other body areas. CF patients usually die before the age of 20, while some individuals live to the age of 30. SCA usually appears in the world's black and Hispanic populations; however, some cases also occur in Italian, Greek, Arabian, Maltese, southern Asian, and Turkish people. About 1 in 12 blacks carry the SCA gene. SCA is caused by mutations in two hemoglobin genes. Hemoglobin carries oxygen in red blood cells to tissues and organs throughout the body. SCA patients have red blood cells that live only a fraction of the normal life span of 120 days. The abnormal blood cells have a sickled appearance, which led to the disease's name. SCA patients also die early, before the age of 30. The TSD gene is carried by 1 in 30 Ashkenazi Jews. Children born with TSD seem normal for the first 5 months, but eventual cerebral degeneration progresses to blindness and death before the age of four.
Galactosemia and phenylketoniuria (PKU) are examples of metabolic RGDs that are caused by a defective gene important in metabolism. People with galactosemia cannot metabolize galactose, the sugar found in milk, and mental retardation may result if normal milk is not avoided by people with this rare disease. People with PKU cannot convert phenylalanine to tyrosine. The build-up of phenylalanine leads to severe mental retardation. PKU is carried by 1 in 50 caucasians. It is one of the few severe genetic disorders that can be controlled by diet. A phenylalanine-free diet containing sufficient amino acids is available for people diagnosed with PKU. Since 1961, a test has been available to readily screen newborns for PKU from a blood test, and most states perform this test routinely.
ADD is one of few "curable" genetic diseases. ADD is caused by a single mutation on chromosome 20 in an enzyme important to the immune system. Not only are bone marrow transplants hopeful treatments, but now gene therapy has been successful at replacing these patients' defective gene with a healthy gene which enables their immune system to function effectively.
X-linked genetic disorders
X-linked genetic disorders (XLGDs) can be either dominant or recessive. Dominant XLGDs affect females, are usually lethal, and are severely expressed in those males that survive; a high percentage of male embryos with dominant XLGD will spontaneously abort in a miscarriage. Dominant XLGD's include: Albright's hereditary osteodystrophy (seizures, mental retardation, stunted growth), Goltz's syndrome (mental retardation), cylindromatosis (deafness and upper body tumors), oral-facial-digital syndrome (no teeth, cleft tongue, some mental retardation), and incontinentia pigmenti (abnormal swirled skin pigmentation).
Recessive XLGDs are passed to sons through their mothers, who are known or unknown carriers. Often, a carrier mother will have an affected male relative. Major XLGDs include: severe combined immune deficiency syndrome (SCID), color blindness, hemophilia, Duchenne's muscular dystrophy (DMD), some spinal ataxias, and Lesch-Nyhan syndrome. Roughly one third of these XLGDs result from a spontaneous mutation. Of these disorders, color blindness is the most benign.
Hemophilia is a more serious XLGD caused by failure of one of the clotting proteins that routinely prevent an injured person from bleeding to death. Hemophilia A, the most severe form of this disease, is characterized by extreme bleeding. It primarily affects males, although a few females have had hemophilia A (the offspring of a hemophiliac father and a carrier mother).
Other usually fatal XLGDs affect the immune, muscular, and nervous systems. SCID is an immune system disorder characterized by a very poor ability to combat infection. This illness is very rare, and its only likely cure is a near-match bone marrow transplant. DMD afflicts young boys and is apparent by age three or four; it is characterized by wasting leg and pelvic muscles. DMD victims are usually wheelchair bound by the age of 12, and die before the age of 20, often due to heart problems. Some spinal ataxias are XLGDs marked by degeneration of the brain and spinal chord.
Multifactorial genetic disorders
Statistics and studies of twins are often used to determine the genetic basis for multi-factorial genetic disorders (MFGDs). Because environment can play an important role in the development of these diseases, identical and fraternal twins who have been raised in different and identical homes are evaluated for these MFGDs. If fraternal twins have a higher than normal incidence and identical twins show an even higher rate of the disease, then genetic inheritance is believed to contribute to causing the disease. These disorders include some disorders associated with diet and metabolism, such as obesity, diabetes, alcoholism , rickets, and high blood pressure. Also included is the tendency to contract certain infections such as measles, scarlet fever, and tuberculosis. In addition, schizophrenia and some other psychological illnesses are strong MFGD candidates. Congenital hip, club foot, and cleft lip are also MFGDs. Various cancers are also correlated with genetic vulnerability.
Certain breast, colon, skin, and small-cell lung cancers have a genetic link. Familial breast cancer usually affects younger women, whereas some other types of breast cancer do not appear until later in life. Although familial breast cancer shows a very high degree of genetic dominance, it does not target every female relative and is thought to have another environmental or other unknown factor contribution. Familial colon cancer is attributed to polyposis--colon polyps that become cancerous. Some malignant melanomas of the skin are also highly heritable.
The tendency of some people to be more susceptible to a particular MFGD and not another is characteristic of human genetics. Although all healthy humans have a similar body form with very similar physiological functions, there is a tremendous diversity among humans that results from a diverse gene pool, which explains why certain groups of people with some genotypes in common would be more prone to a particular disease, while others would have resistance to the same disease. This diversity buffers the human race from being annihilated by a single agent.
Other genetic-linked disorders
The two most common aneuploidies, trisomies and extra sex chromosomes, can be due to maternal or paternal factors, including advanced age. A number of aneuploidies can be attributed to dispermy--where two sperm fertilized one egg. The resulting genetic disorders can occur due to a spontaneous mutation, and a familial tendency towards these disorders cannot always be found. Trisomies make up to 52% of chromosomal abnormalities, with trisomies 14, 15, 16, 18, 21, and 22 being the most frequent. Live-born children with autosomal aneuploidies have trisomy 13, 18, or 21, and all have some mental retardation. Trisomy 13 (Patau's syndrome) is characterized by retarded growth, cleft lip and palate , small head and chin, and often polydactyly. Trisomy 18 (Edward's syndrome) is marked by severe, variable abnormalities of the head, thumbs, ears, mouth, and feet. Trisomy 21 (Down syndrome ) occurs equally in all ethnic groups, and is closely related to increased maternal age. Children with Down syndrome can have poor muscle tone, a flattened face, extra folds of skin at the eyes, low-set ears, visible (Brushfield) spots on the iris of their eyes, and a single crease along the palm of their hands.
Aneuploidy of the sex chromosomes can cause abnormal genital development, sterility, and other growth problems. The most common such aberration are multiple X syndromes. Triple X females can bear normal children. Males with an XXY aneuploidy are afflicted with Klinefelter's syndrome , have small testes and cannot produce sperm. Men with XYY aneuploidy are born more frequently (about 1 in every 200-1,000 males) than most aneuploidies, and controversy exists as to whether these individuals have a higher criminal tendency than the rest of the male population.
Genetic testing and counseling
Tests exist that reveal varying degrees of genetic information. Most of these tests are performed by isolating chromosomes from cellular nuclei, or by measuring a detectable product linked with a known genetic disorder. These tests can be used prior to conception, to determine a couple's risk of having an affected child; during pregnancy, to identify possible genetic disorders; and at birth or later in life, to assess an individual's probability of developing a disorder.
The most successful widespread test for a genetic disorder is newborn testing for PKU, a condition treatable with a special diet. Newborn screening for hypothyroidism and galactosemia is also done in several states. Prenatal tests in embryos and fetuses include chorionic villus sampling (CVS), amniocentesis , and ultrasound. CVS can detect Down syndrome, hemophilia, DMD, CF, SCA, and sex chromosomal aberrations. Amniocentesis can detect Tay-Sachs disease, Down syndrome, hemophilia, spina bifida, and other abnormalities. Ultrasound is used to visualize the developing baby; it can detect spina bifida, anencephaly (no brain), and limb deformities.
Genetic counseling and testing can help people find out if they carry the gene for some disorders, or whether they will develop a late-onset genetic disorder themselves. Genetic probes can identify the genes for Huntington's disease, cystic fibrosis, Tay-Sachs, sickle-cell anemia, thalassemia, and abnormalities associated with growth hormones. Genetic testing capabilities increase each year as additional genetic disorder loci are found. Genetic disorders that are determined by multiple loci are more difficult to pin down for testing.
For Your Information
- Plomin, R. Nature and Nurture . Pacific Grove, CA: Brooks/Cole Publishing, 1990.
- Stine, G., ed. The New Human Genetics . Dubuque, IA: Wm. C. Brown, 1989.
Gale Encyclopedia of Childhood & Adolescence. Gale Research, 1998.