Medical brain notes 42

  BASIC CONCEPTS IN GENETICS   Knowledge of the basic principles of genetics and an under-standing of their application are essential in current med-ical practice. These principles form the basis for screening, diagnosis, and management of genetic disorders. Genes: Definition and Function   Genes,  the basic units of heredity, are segments of deoxyri-bonucleic acid ( DNA ) that reside on  chromosomes  located in cell nuclei. DNA is a double-stranded helical molecule. Each strand is a polymer of nucleotides made up of three components: (1) a “base,” which is either a purine (adenine [A] or guanine [G]) or a pyrimidine (cytosine [C] or thymine [T]); (2) a 5-carbon sugar; and (3) a phospho-diester bond. The strands of the DNA helix run in an antiparallel fashion, adenine binding to thymine and cyto-sine binding to guanine. These base pairs, in their nearly limitless combinations, constitute the  genetic code.   The information in the DNA must be proc...

  Chromosomes   The genetic information in the human genome is packaged as  chromatin,  within which DNA binds with several chromosomal proteins to make  chromosomes.  A  karyo-type  reveals the morphology and number of chromo-somes.  Somatic cells  are all the cells in the human body that are not gametes (eggs or sperm).  Germ cells,  or gametes, contain a  single set  of chromosomes ( n =  23) and are described as  haploid  in number. Somatic cells contain  two sets of chromosomes,  for a total of 46 chromosomes.These cells are  diploid,  signifying that they have a 2n chro-mosome complement (2n  =  46). These chromosome pairs consist of 22 pairs of  autosomes,  which are similar in males and females. Each somatic cell also contains a pair of sex chromosomes. Females have two X sex chromosomes; males have an X and a Y chromosome.   CHROMOSOME REPLICATION AN...

  ABNORMALITIES IN CHROMOSOME NUMBER   Any alteration in the chromosome number is called  heteroploidy .Heteroploidy can occur in two forms: euploidy and ane-uploidy. In  euploidy,  the haploid number of 23 chromo-somes is altered. An example of euploidy is triploidy, in which the haploid number has been multiplied by 3. The karyotype is 69,XXX or 69,XXY. Triploidy results from double fertilization of a normal haploid egg or from fer-tilization by a diploid sperm. Such abnormalities usually  result in conceptions of partial hydatidiform moles and end spontaneously in the first trimester. In  aneuploidy,  the diploid number of 46 chromo-somes is altered. The  trisomies  are aneuploidies in which there are three copies of an autosome instead of two. Examples include  trisomy 21 (Down syndrome) trisomy18 (Edward syndrome) trisomy 13 (Patau syndrome),  and  trisomy 16.  Most trisomies result from maternal meiotic nondisju...

  ABNORMALITIES IN CHROMOSOME STRUCTURE   Structural alterations in chromosomes are less common than numerical alterations. Structural abnormalities that  affect reproduction occur in 0.2% of the population.   A  deletion  occurs when a portion of a chromosome seg-ment is lost (Table 7.2). In a  terminal deletion,  the miss-ing portion of the chromosome is appended to the end of the long or short arm. If the missing portion of the chro-mosome is appended to both the long and short arms of the same chromosome, a  ring chromosome  can result. An  interstitial deletion  occurs when the deleted portion lacks a centromere, or in cases involving chromosomal breakage.  Insertions  occur when the portion of an inter-stitially deleted segment is inserted into a nonhomologous chromosome.   An  inversion  is the result of faulty repair of a chro-mosomal breakage. The broken portion is inserted into the chromosome ...

  AUTOSOMAL DOMINANT   Each gene occupies a specific position, or  locus,  on a chro-mosome. At each locus, there are two possible variations of the genes, or two  alleles.  If the phenotype of a disease is based on one allele in a gene pair, the gene is  dominant.  If the gene is located on an autosomal cell, its pattern of inher-itance is described as  autosomal dominant.  Individuals with one dominant allele for a disorder (described as being  heterozygous  for the gene) will express disease and trans-mit the gene to 50% of their offspring (Box 7.1). Examples of genetic disorders with autosomal dominant inheritance include Marfan syndrome, achondroplasia, and Hunting-ton disease.   Phenotypic expression of autosomal dominant genes is not always straightforward and may vary depending on specific characteristics of the gene.  Variable expressivity  is the varying expression of a disease in an affected person. Fo...

  AUTOSOMAL RECESSIVE   An  autosomal recessive  disease is only expressed when the affected individual carries two copies of the gene (described as being  homozygous  for the gene)  (see Box 7.1).  Individuals who are  heterozygous  for the gene express a normal phenotype.  During pregnancy, unless a woman has been screened for a particular disease based on her risk factors (e.g., sickle cell disease or cystic fibrosis), carriers of a recessive gene will not know they are carriers until they have affected off-spring. Other examples of autosomal recessive disorders include Tay-Sachs disease and phenylketonuria.    

  X-LINKED INHERITANCE   In  X-linked diseases,  the affected gene is located on the X chromosome. Because males only have one X chromo-some, they will manifest disease if their X chromosome carries the affected gene. The male carrier status is con-sidered  hemizygous,  while the female is almost always heterozygous.   X-linked recessive diseases are much more common than X-linked dominant diseases (Box 7.2). Some examples of X-linked recessive diseases are hemophilia and color blindness. Hypophosphatemia is an example of an X-linked dominant disease.   Fragile X syndrome  is an X-linked disorder that causesmental retardation. It is caused by a repeat in the cytosine-guanine-guanine sequence in a specific gene located on the X chromosome. Transmission of the disease-producing genetic mutation to a fetus depends on the sex of the parent and the number of repeats in the parental gene. If the num-ber of repeats is between 61 and 200, the individ...

  RISK FACTORS FOR GENETIC DISORDERS   Several factors have been identified that increase the risk of having a child with a chromosomal abnormality, includ-ing maternal or paternal age and exposure to certain drugs. Other factors, such as ethnicity or a family history of a disease, may indicate that an individual carries a gene for a Mendelian disorder. The first step in assessing risk is to document information about the patient’s family and personal history (see Appendix 1, Antepartum Record). This record is an effective method for obtaining informa-tion concerning personal and family medical history, parental exposure to potentially harmful substances, or other issues that may have an impact on risk assessment and management. This information can be collected prior to conception during a preconception office visit, or dur-ing the first prenatal visit in the first trimester.   Some infectious diseases, including cytomegalovirus, rubella, and sexually transmitted disease...

  PRENATAL SCREENING   Obstetricians are responsible for determining if a woman is at increased risk for fetal abnormalities, and for describ-ing and offering appropriate prenatal screening or diag-nostic tests.  The purpose of prenatal genetic screening is todefine the risk for a genetic disease in a low-risk population. screening test  differs from a  diagnostic test  in that screening tests only assess the risk that a child will have a genetic disease; they cannot confirm or rule out the presence of the dis-ease. A diagnostic test is given if a screening test is positive, to assess whether the disease is present or absent in the developing fetus.  Genetic screening tests are routinely offered to allwomen to detect neural tube defects (NTDs), Down syn-drome, and trisomy 18. In addition, individuals of certain ethnic groups can be tested to detect whether they carry a gene for a particular disorder. First-Trimester Screening   First-trimester scr...