Genetic Disorders

views updated

Genetic disorders

Genetic disorders refer to medical conditions that develop as the result of abnormalities in an individuals genetic material, usually that is inherited. Inheriting or developing a genetic disorder leads to a collection of clinical manifestations known as a syndrome . These clinical manifestations can vary from person to person with the same genetic defect or have similar presentations.

Principles of genetic inheritance patterns

Genetic information is packaged into chromosomes that are found in thecells nucleus, or DNA containing organelle. Virtually every human cell has 46 chromosomes, except for the sperm and egg (reproductive cells) which each have 23 chromosomes. Fertilization of the egg by the sperm results in a newly formed cell called the zygote. Each zygote receives 23 chromosomes from the egg and 23 chromosomes from the sperm. All but one of the 23 chromosomes are called autosomes. The remaining chromosome is the sex chromosome and it is either an X or a Y. After these sex cells unite, gender is determined. Females have two X's (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. Therefore, the male sperm is responsible for gender selection .

The duplicated set of 22 autosomes, numbered 1 through 22, are called homologous pairs in that there are two chromosome number 1 with similar genes and genetic material. There are approximately 50,000 genes on all the chromosomes. Individual genes are made of deoxyribonucleic acid (DNA) , which makes up the genetic code or alphabet that produces specific proteins . Proteins can play important structural and functional roles in the body. Each gene has a set locus , or position, on a particular chromosome. Identical genes that are located on the same locus on corresponding chromosomes are called alleles .

A persons genotype represents the genes that they inherited. If is an autosomally inherited disease , the genotypes are written as a lower or an upper case letter A (such as AA, aa or Aa to represent both alleles known as the genotype), where capital letters define dominant genes and lower case letters define recessive genes. Genotypes are either homozygous or heterozygous. Having two identical alleles, such as AA or aa, makes the genotype homozygous for that locus. Having different alleles (for example, Aa) at a locus represents a heterozygous genotype. The observable features that characterize an individual are collectively called the phenotype. A phenotype can also extend to observable characteristics that can only be visualized with the help of a microscope or other equipment.

Types of genetic inheritance

There are many types of genetic disorders. Mendelian disorders are a group of disorders that are inherited either as an autosomal (through one of the 44 chromosomes, excluding the X or Y chromosome) or X-linked (through the X chromosome) defect in a dominant or recessive pattern. Although most of them are commonly associated with inherited defects, many of them can involve spontaneous or de novo alterations in an individuals genetic material. There are also genetic disorders that have an unknown etiology and the mechanisms for how a disease develops have not been clearly elucidated. Some genetic disorders can be induced by environmental factors and are collectively called multifactorial disorders. Mitochondrial disorders involve disorders in the mitochondrial genome and are inherited only from the mother. The mitochondria are tiny compartments found in almost every cell and has a distinct genome from the DNA found in the nucleus and is involved primarily in producing energy for all the tissues of the body. Finally, polygenic disorders mean that many genes act together to produce a genetic disease.

Dominant and recessive

A dominant gene means that a single allele can control whether the disease develops. If only one parents (usually affected) passes on an autosomal, defective gene which results in the child having a genetic disorder, then the disorder is called autosomal dominant. A recessive gene means that there is enough normal protein product to function properly from the normal gene and, therefore, two copies of the defective gene are necessary for the disease to develop. If both parents are unaffected and they each pass on a defective gene causing their child to be affected, then the genetic disorder is autosomal recessive. The parents are called carriers. For example, sickle-cell anemia is a recessive disorder characterized by abnormal hemoglobin production. The genetic defect involves a gene that produces hemoglobin. Although sickle-cell carriers produce, in part, abnormal hemoglobin, although they usually do not experience clinical manifestations since the normal hemoglobin produced from the normal gene is enough to function normally.

However, Many other genetic disorders are caused by defects related to the sex chromosomes, or the X and Y chromosomes. If a defective gene on the X-chromosome are inherited, it is called X-linked. Like autosomal disorders, X-linked genetic diseases also can be inherited by dominant and recessive mechanisms. X-linked dominant means that if the father passes on the defective gene on his only X chromosome, all his offspring (which will be females) will be affected. If he passes on his Y chromosome, none of these males will be affected. Therefore, there is no male-to-male transmission. If it is X-linked recessive, all daughters will be carriers. If the mother passes on a recessive X-linked gene, then all her sons will be affected and all her daughters will be carriers. Understanding the mechanisms by which genetic disorders are inherited are very important for interpreting recurrence risks.

A variation of Mendelian patterns of inheritance is called incomplete dominance. Incomplete dominance occurs when both alleles are expressed. An example of this is observed in Four-O-Clock flower color . A white and a red phenotype are neither dominant nor recessive. If a flower is heterozygous and carries genes that produce both the white color and the red color, the flower color results in pink. Another variation is codominance. In incomplete dominance, the phenotype is a blending of the two different gene effects. In codominance, both gene variants are expressed at the same time, representing a third phenotype. For example, a flower with alleles that can produce either white or red in the homozygote form will produce both colors in the heterozygote form expressed as spotted flowers.

Genetic analysis

Chromosomal analysis can be performed on cell samples from an individual, a technique called karyotyping. A karyotype involves visualizing the chromosomes using a specific dye and a high-resolution microscope. The chromosomes can be distinguished from one another in size and staining pattern. Corresponding chromosomes 1 through 22 and the sex chromosomes can be lined up and visually inspected for abnormalities. Any obvious defect can indicate a diseased state. Sometimes it is apparent that a part of one chromosome was incorrectly combined with a different chromosome during cellular division. This is called a translocation and represents a structural abnormality. Numerical abnormalities occur when an extra chromosome is present. When more than 46 chromosomes are observed in chromosome, it is called aneuploidy. Most aneuploidies that occur are called trisomies which involve three homologous chromosomes, or the presence of extra chromosome. Numerical abnormalities are typically incompatible with life, with the exception of Trisomy 21 (Down Syndrome ) and a few other rare genetic disorders.

Dominant genetic disorders

If one parent has an autosomal dominant disease, then offspring have a 50% chance of inheriting that disease. There are roughly 2000 autosomal dominant disorders (ADDs) with effects that range from mild clinical manifestations to death. These diseases may develop early or late in life. ADDs include Huntington disease , Marfan syndrome (extra long limbs), achondroplasia (a type of dwarfism), some forms of glaucoma, most forms of porphyrias, and hypercholesterolemia (high blood cholesterol ).

Huntington Disease is a late onset nuerodegenerative disease. It is characterized by progressive chorea (involuntary, rapid, jerky motions) and mental deterioration that often develop after the fourth decade of life, eventually leading to death approximately 15 years later. The Huntington disease gene locus is on chromosome 4, and can be identified.

Marfan syndrome is an ADD characterized by long arms, legs, and fingers. People with Marfan syndrome also have a blue sclera that represents a hallmark clinical feature that can be detected when observing the eyes. In addition, these individuals have a high incidence of eye and aortic heart problems. The elasticity of the vessels in the aorta are susceptible to rupture, which can cause death. Not all people with Marfan syndrome inherit it from a parent, about 15% of Marfan syndrome cases are caused by a spontaneous mutation .

Recessive genetic disorders

Recessive genetic disorders (RGD) result from inheriting two defective recessive alleles of a gene, one from each parent. RGD often require careful molecular or biochemical genetic analyses to determine carrier status. Hence, the birth of a child with a recessive disorder may surprise unknowing parents. The probability of two carrier or 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. More than 1,000 RGDs have been identified and include: cystic fibrosis , phenylketonuria (PKU), galactosemia, retinoblastoma (Rb), albinism , sickle-cell anemia, thalassemia, Tay-Sachs disease , autism , growth hormone deficiency, adenosine deaminase deficiency, and Werner's syndrome (juvenile muscular dystrophy).

A number of eye disorders are RGDs and are often associated with a mutant gene on chromosome 13. The Retinoblastoma (Rb) gene was the first human gene found to cause cancer and the first human cancer gene in which its location on a chromosome was determined. Rb is a gene that can cause a tumor in the retina, called a retinoblastoma. Most retinoblastomas are inherited; however, in some cases, inheriting a mutation on one allele combined with a spontaneous mutation on the other allele can result in retinoblastoma. Environmental carcinogens (cancer causing agents) can induce a spontaneous mutation. Other recessive eye disorders include myopia (nearsightedness), albinism, day blindness, displaced pupils, and dry eyes.

Some RGDs affect people having a particular ethnic background. For example, cystic fibrosis (CF), sicklecell anemia (SCA), and Tay-Sachs disease (TSD) all have specific mutations in the gene that causes each disorder that are preferentially found in individuals of a certain ethnic background. CF is a common autosomal recessive disease in individuals of Northern European decent and one in every 25 people in this population are carriers. SCA usually is most common in black and Hispanic
populations; however, some mutations in the gene that causes SCA are also found in Italian, Greek, Arabian, Maltese, Southern Asian, and Turkish populations. About 1 in 12 blacks are carriers for SCA gene mutations in one of the 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 and cannot transport oxygen efficiently. TSD gene mutation carriers are commonly found in Ashkenazi Jewish populations and approximately 1 in 30 are carriers of a mutation.

Galactosemia and PKU are examples of metabolic RGDs and are commonly called biochemical disorders. Both these disorders result from mutations in two different genes, both of which produce dysfunctional enzymes that are important in metabolism . Enzymes speed up chemical reactions and are essential for many cellular processes. People with galactosemia are enzyme deficient for Galactose-1-phosphate uridyl transferase, without which they can not metabolize galactose, a sugar found in milk. If milk and other galactose-containing food items are consumed, these individual cannot digest this compound properly and the result is severe developmental delay. Individuals that inherit PKU are deficient in the enzyme Phenylalanine hydroxylase, which is responsible for converting phenylalanine (an amino acid , a building block of protein) to tyrosine. The build-up of phenylalanine leads to severe developmental delay, and preventing clinical manifestations can be achieved by dietary modification. A phenylalanine-free diet containing sufficient amino acids is available for people diagnosed with PKU. Both of these metabolic disorders result from mutations in two different genes. Carriers are detected through a nationwide newborn screening programs, which differ in testing services from state to state.

Adenoside deaminase deficiency another autosomal recessive genetic disorder that is also called severe combined immunodeficiency. It is caused by a single mutation on chromosome 20 in a gene that encodes an enzyme important for proper functioning of the immune system . Adenosine deaminase converts breaksdown a small molecule called adenosine. Gene therapy has been successful in delivering a normal gene and prevents the damaging effects of adenosine on specific cells important for immune system function.

X-Linked genetic disorders

X-Linked genetic disorders (XLGDs) can be either dominant or recessive. Dominant XLGDs affect females and males. Dominant XLGD's include: Albright's hereditary osteodystrophy (seizures, mental retardation, stunted growth), Goltz's syndrome (mental retardation), cylindromatosis (deafness and upper body tumors), oralfacial-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 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, which serves to prevent an injured person from bleeding to death. Hemophilia A is the most severe form of this disease, and is characterized by extreme bleeding. It primarily affects males, although a few females can develop symptoms. This disease has been associated with royalty, as England's queen Victoria was a carrier and her descendants became rulers in several European countries.

Multi-factorial genetic disorders

Statistics and twin studies 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 homes are ideally studied. MFGD include some disorders associated with diet and metabolism, such as obesity , diabetes, alcoholism , rickets, and high blood pressure . And the tendency of contracting certain infections such as measles, scarlet fever , and tuberculosis can be considered MFGDs. In addition, schizophrenia and some other psychological illnesses represent as well as congenital hip, club foot, and cleft lip are also inherited in this manner. Cancer, where the risk is associated with the environmental exposure also falls into this class of disorders. Certain breast, colon, skin, and small-cell lung cancers have been shown to have a genetic link. Certain genes predisposed people to a certain type of cancer and this risk is enhanced when there is a specific environmental exposure. This susceptibility is influenced by inherited variations in genes, which encode proteins that may be more or less functional. For example, if the protein is involved in the metabolism of a carcer causing substance and an individual inherits a variation in the gene sequence, this might affect the function of the protein it encodes. If it reduced its function, this might lead to more damaging effects of the cancer causing substance.

Aneuploidy

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, or when two sperm fertilizes one egg. The resulting genetic disorders can result in a spontaneous mutation. Live-born children with autosomal aneuploidies can have trisomy 13, 18, or 21, and all have some form of developmental delay, while trisomy of any other chromosome is usually always fatal. Trisomy 13 (Patau's syndrome) is characterized by retarded growth, cleft lip, 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's syndrome) occurs equally in all ethnic groups, and is closely related to increased maternal age.

Aneuploidy of the sex chromosomes can cause abnormal genital development, sterility, and other growth problems. The most common aberrations involve multiple X chromosome syndromes. Males with an XXY aneuploidy have Klinefelter's syndrome, and have small testes and typically no sperm. Hermaphrodites are individuals that have both male and female genitals, are extremely rare, and result from cell lines that have two different chromosome patterns with both XX and XY cells.

Genetic screening

Genetic tests are available and can reveal varying degrees of genetic information depending on the test. Most of these tests are performed by isolating chromosomes or by measuring a protein product that is excreted in the urine to test for biochemical defects. These tests can be used prior to conception to determine a couple's risk for having an affected child, during pregnancy, at birth or later in life.

The most successful wide-spread test for genetic disorders is the newborn program that tests for diseases such as PKU. Newborn screening for hypothyroidism and galactosemia are also performed in several states. Prenatal testing 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, thalassemia, and abnormalities associated with growth hormone. Genetic testing capabilities increase each year as additional genetic disorders are better characterized and the gene localization and protein function is determined.

Resources

books

Lodish, J., D. Baltimore, A. Berk, S. L. Zipursky, P. Matsudaira, and J. Darnell. Molecular Cell Biology. New York: Scientific American Books, Inc., 1995.

Nussbaum, Robert L., Roderick R. McInnes, and Huntington F. Willard. Genetics in Medicine. Philadelphia: Saunders, 2001.

David L. Rimoin Emery and Rimoin's Principles and Practice of Medical Genetics. London; New York: Churchill Livingstone, 2002.

Louise Dickerson
Bryan Cobb

KEY TERMS

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Allele: —Any of two or more alternative forms of a gene that occupy the same location on a chromosome.
Chromosomes: —he structures that carry genetic information in the form of DNA. Chromosomes are located within every cell and are responsible for directing the development and functioning of all the cells in the body.
Dominant trait: —A trait which can manifest when inherited from one parent.
Gene: —A discrete unit of inheritance, represented by a portion of DNA located on a chromosome. The gene is a code for the production of a specific kind of protein or RNA molecule, and therefore for a specific inherited characteristic.
Heterozygote: —A person possessing two non-identical alleles.
Homozygote: —A person possessing two identical alleles.
Multifactorial trait: —A trait which results from both genetic and environmental influences.
Recessive trait: —A trait which is not expressed in heterozygotes but is expressed if two defective genes are inherited by carrier parents.
Sclera: —White of the eye.
X-Linked trait: —A trait that is inherited due to mutations in genes on the X-chromosome.