Medical brain notes 30

  GENETIC DISEASES INTRODUCTION Genes  are the fundamental units of heredity and encode specific functionalproducts, such as RNA molecules and polypeptides. They are encoded by sequences of bases in DNA molecules and are found at particular positions in chromosomes in the nucleus and also in the relatively small circular DNA molecules in the mitochondria. Only 37 of the approximately 22 000 human genes occur in mitochondria although mutations of these may become clinically significant as described. The genes constitute the blueprint or the set of instructions which affects hereditary characteristics, for example hair and eye color, height and the susceptibility to certain diseases. When a cell divides the genetic information needs to be replicated accurately so that these instructions pass on to the daughter cells. When changes occur in the base sequence of DNA, either as a result of incorrect replication or from random changes caused by physical or chemical agents, then the i...

  GENETICS AND DNA Genetics , from the Greek genno meaning ‘to give birth’, is that branch of biologyconcerned with heredity, genes and DNA ( Figure 15.3 ), the genetic material. It is also the scientific study of the variations in inherited characteristics, often called traits, and how these are transmitted from one generation to the next. Inherited characteristics include a number of clinical conditions and diseases that are described, for example sickle-cell anemia and hemophilia , the muscular dystrophies and cystic fibrosis . Others, such as phenylketonuria and Down syndrome, will be described. Genomics is the study of the full complement of bases in the DNA of an organism. Genes are the stretches of bases in DNA that carry the code for making RNA or proteins. The code is contained in sequences of the four nucleotide bases, adenine, cytosine, guanine and thymine (A, C, G and T, respectively). DNA normally occurs as the famous double helical molecule ( Figure 15.3 (A) ) that co...

  DNA REPLICATION AND THE CELL CYCLE When a cell divides the genetic information must be passed on to the two daughter cells. The series of biochemical and morphological events that occur in a population of reproducing cells is called the  cell cycle . This results in the replication of the genetic material (DNA molecules) and division of the cell into two daughter cells. The replication of DNA involves separating the two DNA strands of the double helix and aligning new bases according to the usual pairing rules; A with T and G with C. The new nucleotides are linked together to form two new strands, each of which is complementary to one of the original (parental) strands. This action forms two new double-stranded DNA molecules, each of which consists of one parental strand and one daughter strand ( Figure 15.5 ) and, for this reason, is often called semiconservative replication. This is a very simplified account of an extremely complex process, which is catalyzed by a range of...

  GENOTYPE AND PHENOTYPE The genetic or hereditary constitution of an individual, which is the whole complement of genes present, forms the  genotype . The term can also be applied to any particular pair of alleles that an individual possesses at a specific locus on a chromosome. In contrast, the visible or measurable characteristics of an individual constitute the  phenotype . A phenotype includes biochemical, physiological, morphological and behavioral characteristics or, indeed, any observable biological trait that is apparent throughout life, such as the total physical appearance and constitution of an individual or any specific trait, such as size, weight or eye color and, of course, includes characteristics of clinical importance and the presence of a disease. Some phenotypic traits, for example eye color, are directly observable but others, such as the blood group of a patient , may only become apparent following specific tests. Phenotypic traits do not necessarily...

  INHERITANCE AND MUTATIONS Genes occur as paired alleles. Each corresponding allele is carried by one of a pair of homologous chromosomes. If the two alleles are identical, the individual is homozygous  for that gene and, if they differ, the individual is said to be  heterozygous . In the heterozygous state, one allele may be  dominant  overthe other which is therefore  recessive . In this situation, only the characteristic encoded by the dominant trait will be expressed, as would also be the case if the individual was homozygous for both dominant alleles. The recessive trait will only become apparent in a homozygous recessive individual. Dominant genes are conventionally written as an upper case italic letter, for example  G , while its recessive counterpart is given the lower case form,  g .  Figure15.10 (A) illustrates the normal inheritance pattern first established byMendel (1822–1884). If one parent is homozygous for an autosomal domin...

  SEX-LINKED GENETIC DISEASES A number of genetic diseases are caused by defective alleles of genes of the sex (X and Y) chromosomes. The X chromosome contains many more genes than the Y, although they do have some genes in common, thus any defective (mutated) gene on the X chromosome is likely to be expressed in males (XY) but be masked in females (XX). Genetic diseases associated with the X chromosome are commonest and they are often referred to as X- or sex-linked genetic conditions. X-linked diseases can be recessive or dominant, although the former, for example hemophilia described, are the better known ( Table 15.1 ). Given that females have two X chromosomes but males only one together with a Y chromosome, then the expression of sex-linked genes differs between females and males because many genes on the Y chromosome lack a corresponding allele on the X chromosome. Thus X-linked recessive genes are only expressed in females if there are two copies of the gene; one on each of...

  INHERITED GENE DISORDERS Most inherited diseases are due to mutations in genes in the nuclear chromosomes although they can also occur as a result of mutations in mitochondrial genes as described. The mutation of a single gene may lead to the absence or modification of a specific protein, for example, the abnormal hemoglobin in sickle cell anemia . In some cases, the inherited disorder may result in defective receptor synthesis, such as in familial hypercholesterolemia where there is a defect in low density lipoprotein (LDL) receptors, or in defective carrier proteins, such as in cystinuria where renal reabsorption of cystine (formed by the oxidation of two cysteines) is impaired. If the defective or absent protein is an enzyme the result is a metabolic disorder. Most inherited metabolic disorders are autosomal recessive diseases, that is, symptoms are only seen in the homozygous condition and heterozygotes are phenotypically normal because sufficient amounts of the protein are p...

  CONSEQUENCES OF AN ENZYME DEFICIENCY In inherited metabolic disorders caused by a complete or partial deficiency of an enzyme that controls a particular reaction in a metabolic pathway, the clinical features are a consequence of the enzyme deficiency.  Figure 15.15  shows how this may occur. Symptoms arise from a lack of product D if this isan essential substance and alternative pathways for its synthesis do not exist. Moreover, an accumulation of precursor C will occur if the enzyme is absent and may produce clinical features if the substrate is toxic when it accumulates. Intermediates of the pathway may also accumulate especially since there will be no negative feedback effect as the final product of the pathway is absent and cannot inhibit the first enzyme of the pathway. Finally, accumulation of a product of a minor pathway, E, may occur and if this is toxic in excess it may produce clinical features. The treatment of inherited metabolic disorders aims at trying to ...

  NATIONAL SCREENING PROGRAMS FOR INHERITED DISEASES A number of factors need to be considered before a screening program for any inherited disease is instituted. These include:   ·              does the disease have a relatively high incidence;   ·              can the disease be detected within days of birth;   ·              can the disease be identified by a biochemical marker that is easily measured;   ·              will there be a failure in diagnosing the disease early and would this cause irreversible damage to the baby;   ·              can the disease be treated and will the result of any screening test be available before irreversible damage to the ba...