NR283 Ch.21

X-Linked Recessive Disorders

Alleles for sex-linked recessive disorders are usually carried by the X chromosome. (The Y chromosome does not carry the same genes as does the X.) The genes for X-linked disorders are recessive but are manifested in heterozygous males who lack the matching normal gene on the Y chromosome. Females are carriers (without clinical signs) when they are heterozygous. Examples of X-linked recessive disorders include hemophilia A and Duchenne's muscular dystrophy. Carrier females have a 50% chance of producing an affected male child and an equal chance of producing a carrier female child in each pregnancy. An affected male will transmit the defect to all his daughters, who become carriers, whereas his sons will neither be affected, nor be carriers. (The male passes only the normal Y chromosome to his sons.)

Genetic disorders

Autosomal Dominant Disorders Adult polycystic kidney disease Huntington's chorea Familial hypercholesterolemia Marfan syndrome Autosomal Recessive Disorders Cystic fibrosis Phenylketonuria Sickle cell anemia Tay-Sachs disease X-Linked Dominant Disorders Fragile X syndrome X-Linked Recessive Disorders Color blindness Duchenne muscular dystrophy Hemophilia A Multifactorial Disorders Anencephaly Cleft lip and palate Clubfoot Congenital heart disease Myelomeningocele Schizophrenia Chromosomal Disorders Down syndrome Monosomy X (Turner syndrome) Polysomy X (Klinefelter syndrome) Trisomy 18 (Edwards syndrome)

Autosomal Recessive Disorders

Autosomal recessive disorders include a variety of conditions, such as cystic fibrosis, which affects the exocrine glands, primarily the lungs and pancreas; sickle cell disease, which involves defective hemoglobin; and phenylketonuria (PKU), in which a metabolic enzyme is missing. In recessive disorders, both parents must pass on the defective gene (see Fig. 21-4A) to produce an affected (homozygous) child. Male and female children are affected equally. If the child is heterozygous (that is, if one normal gene and one disease gene are present in the pair), then that child is a carrier and shows no clinical signs of disease. In this case, the genotypes of the parents determine the risk of transmitting the defect to the child. In each pregnancy, in which each parent is heterozygous for the recessive disease trait, the probability of inheritance is: •25% that the child will be born with the unaffected genotype •50% that the child will be born with the carrier genotype •25% that the child will be born with the affected or disease genotype. Many of these recessive gene disorders involve an enzyme defect that causes toxic metabolites to accumulate inside cells or in the blood and tissues, interfering with cell function and possibly causing death. These disorders may also be called storage disease or inborn errors of metabolism.

Diagnostic Tools

Diagnostic tests that can detect some disease-causing genes or chromosomal abnormalities in carriers, during the prenatal period, immediately after birth, or later in life when a disorder is suspected are available. Prenatal diagnosis may offer reassurance to high-risk families; early diagnosis also provides time to plan for the special needs of an affected child or time to make an informed decision about an abortion. Birth defects that may be minor or severe occur in 1 : 28 live births. xamples of prenatal testing include ultrasonography, which can visualize structural anomalies and maternal blood tests such as the triple screen, performed at 16 to 18 weeks. This test measures levels of alpha-fetoprotein (AFP), the beta subunit of human chorionic gonadotropin (hCG), and unconjugated estriol (uE3). In some areas a quadruple screen is used, which also checks levels of inhibin-A. Abnormal levels indicate a high risk of conditions such as spina bifida or Down syndrome. Follow-up amniocentesis or chorionic villus sampling may confirm the abnormality. Methods of prenatal diagnosis include amniocentesis, or extraction of amniotic fluid from the uterus, and extraction of a sample of the chorionic villus of the fetus so as to examine a sample of fetal tissue. hromosomal abnormalities can then be detected by growing fetal cells, harvesting them, and then examining the chromosomes or karyotype One other drawback of prenatal diagnosis is that some tests may not show conclusive results for 4 to 6 weeks and are often not done until approximately 16 to 18 weeks into the pregnancy, leaving a long period of uncertainty. Neonates can be tested approximately 48 hours after birth, using blood from a heel prick. Most babies do not show signs of metabolic disorders at birth because the maternal kidney and liver have been active up to that time, but permanent damage to tissues can occur quickly thereafter. Tests for cystic fibrosis include a check for a pancreatic immunoreactive trypsinogen (IRT), which, if positive, is followed by a DNA test and additional tests.

Chromosomal Disorders

Down syndrome is an example of a trisomy, in which there are three chromosomes rather than two in the 21 position; it is called trisomy 21. Therefore an individual with Down syndrome has 47 chromosomes. A less common form of Down syndrome exists in which part of a chromosome 21 is attached to another chromosome (translocation). Monosomy X, or Turner syndrome (Fig. 21-6), occurs when only one sex chromosome, the X chromosome, is present. This person has only 45 chromosomes, resulting in a variety of physical abnormalities and lack of ovaries. In Klinefelter's syndrome or polysomy X, an extra X chromosome is present (XXY), resulting in a total of 47 chromosomes in each cell.

Down Syndrome

Down syndrome, or trisomy 21, is a common chromosomal disorder, resulting in numerous defects in physical and mental development. The risk of bearing a child with Down syndrome increases with maternal age. For example, a woman at age 30 has a risk of approximately 1 in 1000 of bearing a child with Down syndrome, whereas at age 35 the risk increases to approximately 1 in 500 and at age 40 to 1 in 100. Characteristics of individuals with Down syndrome include the following (Fig. 21-10): •The head is small and has a flat facial profile. •The eyes are slanted, and the irises contain Brushfield spots. •The mouth tends to hang open, revealing a large, protruding tongue and a high-arched palate. •The hands are small and have a single palmar (simian) crease. •The muscles tend to be hypotonic, the joints are loose, cervical abnormalities and instability are often evident, and stature is short. •Developmental stages are delayed. •All children are cognitively impaired, but the severity of impairment varies with the individual, and early stimulation programs are helpful. •Sexual development is often delayed or incomplete. •Many children have an assortment of other problems, including visual problems (cataracts, strabismus), hearing problems, obstructions in the digestive tract, celiac disease, congenital heart defects, decreased resistance to infection (immune deficit), and a high risk of developing leukemia.

Developmental Disorders

Exposure to negative environmental influences during pregnancy and even before pregnancy such as radiation may cause changes in the sperm or ova. Evidence has been gathered about the damaging effects on the fetus of alcohol (fetal alcohol syndrome), cigarette smoking (low birthweight and increased risk of stillbirth), radiation, pharmaceuticals, cocaine abuse, and maternal infections. TORCH is an acronym applied to routine prenatal screening tests for high-risk maternal infections: Toxoplasmosis, Other (hepatitis B, mumps, rubeola, varicella, gonorrhea, syphilis), Rubella, Cytomegalovirus, and Herpes. Exposure to harmful influences in the first 2 weeks of embryonic life usually results in the death of the embryo. The most critical time is the first 2 months of development, when the cells are dividing rapidly and differentiating, organogenesis is taking place, and the basic body structures are forming. Cerebral palsy is an example of the kind of brain damage that can occur before, during, or immediately after birth (see Chapter 14). The cause may be insufficient oxygen, the toxic effects of excessive bilirubin in the blood (jaundice), or trauma.

X-Linked Dominant Disorders

Fragile X syndrome is the most common cause of mental retardation, cognitive deficit, and learning disorders in North America. One in 4000 boys are affected and one in 8000 girls have been identified with the disorder. Social and behavioral problems are often present and may account for the higher identification in males. One-third of affected males exhibit autistic behaviors and one-sixth experience seizures. The mutation responsible for Fragile X syndrome is inherited as a dominant allele carried on the X chromosome, thus males and females can be affected. The mutation causes the affected X chromosome to appear constricted or broken.

Genetic Engineering and Gene Therapy

Genetic engineering refers to the laboratory practices of manipulating genes in living organisms, including microorganisms, plants and animals, and humans. Genes may be altered by changing the sequence of DNA by rearrangement, deletion, or substitution. The ultimate goal of gene manipulation is to remove a defective gene and supply a normal one so as to eliminate genetic defects. Recombinant DNA technology formed an early stepping stone toward this goal. A chain of DNA was split and either some of the components changed position or a new piece was added, and then the chain was joined together again. This altered DNA then produces identical specific molecules such as insulin or erythropoietin. Gene therapy can be effective, particularly in humans, where a single gene appears to be responsible for a disease, such as cystic fibrosis, polycystic kidney, or Huntington disease. Gene therapy involves the introduction of normal genes into living target cells, sometimes by means of a harmless virus or bacterium, thus changing the cell activity or replacing missing genes.

Autosomal Dominant Disorders

In autosomal dominant disorders, the presence of the defect in only one of the alleles produces clinical expression of the disease. An affected parent has a 50% probability of passing the disorder on to each child regardless of the gender of the child (see Fig. 21-4B). There are no carriers, and unaffected persons do not transmit the disorder. Some of these conditions do not become evident clinically until mid-life, and because diagnostic tests are not always available, the defective gene may already have been passed on to the next generation before the disease is diagnosed. A screening program is available to detect the presence of the gene for Huntington's disease, a condition in which brain degeneration does not develop until mid-life

Genetic Disorders Single-Gene Disorders

More than 6000 abnormalities are known, with a single-gene disorder occurring in 1 : 200 live births. Many disorders present few if any signs and may not be diagnosed; serious defects usually cause spontaneous miscarriage. Single-gene disorders are commonly classified by inheritance pattern, the major groups being recessive, dominant, and X-linked recessive.

Multifactorial Disorders

Multifactorial disorders are involving a number of genes or genetic influences combined with environmental factors. Common examples include cleft palate, congenital hip dislocation, congenital heart disease, type 2 diabetes mellitus, anencephaly, and hydrocephalus. These disorders tend to be limited to a single localized area. The same defect is likely to recur in siblings, but there is no increased risk of occurrence of other defects. If the presence of the mutated gene can be documented, avoidance of certain environmental factors or close monitoring of the individual may minimize the risk of development of the disease. For example, genetic.

Homozygous

having two identical alleles at corresponding points on a chromosome pair.

Proteomic Research and Designer Drugs

Research has recently turned from identification of base pairs in the DNA of specific genes to the proteins that are elaborated when the gene is activated. This study is termed proteomics and strives to characterize all of the proteins that are significant in the metabolic pathway for expression of a particular allele. Proteomic research is being funded to determine the shape and chemical activity of these crucial proteins so as to develop drugs specific to the metabolic pathway.

Mutation

a change in the genetic makeup (DNA) of a cell, which will be inherited.

Mitosis

a process of cell reproduction resulting in two daughter cells with the same DNA as the parent cell.

Karyotype

a visual demonstration of the pairs of cell chromosomes arranged in order of size.

Anomaly

an abnormal structure, often congenital.

Heterozygous

having two different alleles at corresponding points on a chromosome pair.

Neonate

newborn child.

Allele

one of two forms of a gene at corresponding sites on a chromosome pair; the code for phenotype or characteristic manifested in an individual.

Amniocentesis

removal of a small amount of amniotic fluid from around the fetus for examination and diagnosis.

Phenotype

the characteristics manifested by a person depending on genetic and environmental factors.

Organogenesis

the formation and differentiation of organs and systems during embryonic development.

Genotype

the genetic makeup of a cell or individual.

Congenital Anomalies

•Genetic disorders may result from a single-gene trait or from a chromosomal defect, or they may be multifactorial. •Single-gene disorders are caused by a change in one gene within the reproductive cells (ova or sperm); this mutant gene is then transmitted to subsequent generations following the specific inheritance pattern for that gene. •Chromosomal anomalies usually result from an error during meiosis, when the DNA fragments are displaced or lost, thus altering genetic information (e.g., Down syndrome). •Other congenital or developmental disorders result from premature birth, a difficult labor and delivery, or exposure to a damaging agent during fetal development. The defect may be limited to one organ, or it may affect the functions of many organs. •Teratogenic agents—agents that cause damage during embryonic or fetal development—are often difficult to define. Many reports must be collated before a cause is identified. For example, the effects of the drug thalidomide were not realized for a long time, and during this time many children were born with missing limbs. Since then, women have been advised to refrain from using any drugs or chemicals during the childbearing years unless recommended by a physician. •Multifactorial disorders, affecting approximately 10% of the population, are more complex. They may be polygenic (caused by multiple genes), or they may be the result of an inherited tendency toward a disorder that is expressed following exposure to certain environmental factors.