Hereditary diseases

Medical genetics has become an integral part of preventive medicine (that is, genetic counseling, including prenatal diagnostics). Hereditary diseases may be subdivided into three classes: chromosomal diseases; hereditary diseases with simple, mendelian modes of inheritance; and multifactorial diseases.

One out of 200 newborns suffers from an abnormality that is caused by a microscopically visible deviation in the number or structure of chromosomes. The most important clinical abnormality is Down syndrome—a condition due to trisomy of chromosome 21, one of the smallest human chromosomes. This chromosome is present not twice but three times; the entire chromosome complement therefore comprises 47, not 46, chromosomes. Down syndrome occurs one to two times in every 1000 births; its pattern of abnormalities derives from an imbalance of gene action during embryonic development. Down syndrome is a good example of a characteristic pattern of abnormalities that is produced by a single genetic defect. See Down syndrome

Other autosomal aberrations observed in living newborns that lead to characteristic syndromes include trisomies 13 and 18 (both very rare), and a variety of structural aberrations such as translocations (exchanges of chromosomal segments between different chromosomes) and deletions (losses of chromosome segments). Translocations normally have no influence on the health status of the individual if there is no gain or loss of chromosomal material (these are called balanced translocations). However, carriers of balanced translocations usually run a high risk of having children in whom the same translocation causes gain or loss of genetic material, and who suffer from a characteristic malformation syndrome.

Clinical syndromes caused by specific aberrations vary, but certain clinical signs are common: low birth weights (small for date); a peculiar face; delayed general, and especially mental, development, often leading to severe mental deficiency; and multiple malformations, including abnormal development of limbs, heart, and kidneys.

Less severe signs than those caused by autosomal aberrations are found in individuals with abnormalities in number (and, sometimes, structure) of sex chromosomes. This is because in individuals having more than one X chromosome, the additional X chromosomes are inactivated early in pregnancy. For example, in women, one of the two X chromosomes is always inactivated. Inactivation occurs at random so that every normal woman is a mosaic of cells in which either one or the other X chromosome is active. Additional X chromosomes that an individual may have received will also be inactivated; in trisomies, genetic imbalance is thus avoided to a certain degree. However, inactivation is not complete; therefore, individuals with trisomies—for example, XXY (Klinefelter syndrome), XXX (triple-X syndrome), or XYY—or monosomies (XO; Turner syndrome) often show abnormal sexual development, intelligence, or behavior.

In contrast to chromosomal aberrations, the genetic defects in hereditary diseases with simple, mendelian modes of inheritance cannot be recognized by microscopic examination; as a rule, they must be inferred more indirectly from the phenotype and the pattern of inheritance in pedigrees. The defects are found in the molecular structure of the DNA. Often, one base pair only is altered, although sometimes more complex molecular changes, such as deletions of some bases or abnormal recombination, are involved. Approximately 1% of all newborns have, or will develop during their lives, a hereditary disease showing a simple mendelian mode of inheritance.

In medical genetics, a condition is called dominant if the heterozygotes deviate in a clearly recognizable way from the normal homozygotes, in most cases by showing an abnormality. Since such dominant mutations are usually rare, almost no homozygotes are observed.

In some dominant conditions, the harmful phenotype may not be expressed in a gene carrier (this is called incomplete penetrance), or clinical signs may vary in severeness between carriers (called variable expressivity). Penetrance and expressivity may be influenced by other genetic factors; sometimes, for example, by the sex of the affected person, whereas in other instances, the constitution of the “normal” allele has been implicated. Environmental conditions may occasionally be important. In most cases, however, the reasons are unknown.

X-linked modes of inheritance occur when the mutant allele is located on the X chromosome. The most important X-linked mode of inheritance is the recessive one. Here, the males (referred to as hemizygotes since they have only one allele) are affected, since they have no normal allele. The female heterozygotes, on the other hand, will be unaffected, since the one normal allele is sufficient for maintaining function. A classical example is hemophilia A, in which one of the serum factors necessary for normal blood clotting is inactive or lacking. (The disease can now be controlled by repeated substitution of the deficient blood factor—a good example for phenotypic therapy of a hereditary disease by substitution of a deficient gene product.) Male family members are affected whereas their sisters and daughters, while being unaffected themselves, transmit the mutant gene to half their sons. Only in very rare instances, when a hemophilic patient marries a heterozygous carrier, are homozygous females observed. See Sex-linked inheritance

There are thousands of hereditary diseases with simple mendelian modes of inheritance, but most common anomalies and diseases are influenced by genetic variability at more than one gene locus. Most congenital malformations, such as congenital heart disease, cleft lip and palate, neural tube defects and many others, fall into this category, as do the constitutional diseases, such as diabetes mellitus, coronary heart disease, anomalies of the immune response and many mental diseases, such as schizophrenia or affective disorders. All of these conditions are common and often increase in frequency with advanced age.

Biochemical genetics

Biochemical genetics began with the study of inborn errors of metabolism. These are diseases of the body chemistry in which a small molecule such as a sugar or amino acid accumulates in body fluids because an enzyme responsible for its metabolic breakdown is deficient. This molecular defect is the result of mutation in the gene coding for the enzyme protein. The accumulated molecule, dependent on its nature, is responsible for the causation of a highly specific pattern of disease.

The field of biochemical genetics expanded with the recognition that similar heritable defective enzymes interfere with the breakdown of very large molecules, such as mucopolysaccharides and the complex lipids that are such prominent components of brain substance. The resultant storage disorders present with extreme alterations in morphology and bony structure and with neurodegenerative disease.

The majority of hereditary disorders of metabolism are inherited in an autosomal recessive fashion. In these families, each parent carries a single mutant gene on one chromosome and a normal gene on the other. Most of these mutations are rare. In populations with genetic diversity, most affected individuals carry two different mutations in the same gene. Some metabolic diseases are coded for by genes on the X chromosome. Most of these disorders are fully recessive, and so affected individuals are all males, while females carrying the gene are clinically normal. The disorders that result from mutations in the mitochondrial genome are inherited in nonmendelian fashion because mitochondrial DNA is inherited only from the mother. Those that carry a mutation are heteroplasmic; that is, each carries a mixed population of mitochondria, some with the mutation and some without.

Phenylketonuria (PKU) is a prototypic biochemical genetic disorder. It is an autosomally recessive disorder in which mutations demonstrated in a sizable number of families lead, when present in the genes on both chromosomes, to defective activity of the enzyme that catalyzes the first step in the metabolism of phenylalanine. This results in accumulation of phenylalanine and a recognizable clinical disease whose most prominent feature is severe retardation of mental development.

The diseases that result from mutation in mitochondrial DNA have been recognized as such only since the 1990s. They result from point mutations, deletions, and other rearrangements. A majority of these disorders express themselves chemically in elevated concentrations of lactic acid in the blood or cerebrospinal fluid. Many of the disorders are known as mitochondrial myopathies (diseases of muscles) because skeletal myopathy or cardiomyopathy are characteristic features.

a branch of genetics closely related to anthropology and medicine. It is arbitrarily divided into two areas: anthropogenetics, which studies the heredity and variation of normal characters in man, and medical genetics, which studies hereditary pathology (diseases, defects, anomalies, and so forth). Human genetics is also related to evolutionary theory (in that it investigates the specific mechanisms of human evolution and man’s place in nature), psychology, philosophy, and sociology. Cytogenetics, biochemical genetics, immunogenetics, genetics of higher nervous activity, and physiological genetics are the most rapidly developing fields of human genetics.

Instead of the classical hybridological analysis, human genetics uses the genealogical method, which consists of analyzing the distribution of a particular character or anomaly in the families (more precisely, genealogies) of individuals who may or may not posses it in order to discover the type of inheritance, frequency, and intensity of expression of the character. Analysis of familial data also reveals the degree of empirical risk, that is, the probability of possessing a character in relation to the closeness of kinship with its carrier. The genealogical method has shown that more than 1,800 morphological, biochemical, and other kinds of human characters are inherited in accordance with Mendel’s laws. For example, dark skin and hair are dominant over light; and low level of activity or absence of certain enzymes is determined by recessive genes, whereas height, weight, intellectual capacity, and some other characters are determined by “polymeric” genes, or systems of many genes. Many sex-linked inherited human characters and diseases are caused by genes located in the X or Y chromosome. About 120 such genes are known. They include the genes of hemophilia A and B, deficiency of the enzyme glucose-6-phosphate-dehy-drogenase, and color blindness.

The twin method is also used in human genetics. Identical twins develop from a single egg fertilized by a single sperm; hence, the set of genes (genotype) in identical twins is identical. Fraternal twins develop from two or more eggs fertilized by different sperm; hence, their genotypes differ as much as those of siblings do. A comparison of the differences in pairs between identical and fraternal twins reveals the relative significance of heredity and the environment in determining the properties of the human organism. Of particular importance in research on twins is the index of concordance, which expresses (in percentages) the probability of one identical or fraternal twin having some character if the other twin possesses it. If the character is determined chiefly by hereditary factors, the percentage of concordance is much higher in identical twins than in fraternal twins. For example, concordance in blood groups, which are determined only genetically, is 100 percent in identical twins. For schizophrenia, concordance is 67 percent in identical twins and 12.1 percent in fraternal twins. In congenital feeblemindedness (oligophrenia), the figures are 94.5 and 42.6 percent, respectively. Similar comparisons have been made for a number of diseases. Thus, research on twins shows that heredity and the environment differ in their contributions to the development of a great variety of characters, and that these characters develop as a result of the interaction of the genotype and the external environment. Some characters depend mainly on the genotype, with the genotype acting as a predisposing factor in the formation of other characters (that is, a factor limiting the standard reaction of the body to an environmental action).

The human genome contains several million genes capable of influencing the development of characters in different ways. Gene mutation and recombination give rise to a wide variety of characters in man. Human genes mutate at the rate of one per 100,000 to one per 10,000,000 gametes per generation. Population genetics studies the distribution of mutations among large groups of people so that charts can be made to show the distribution of genes responsible for the development of normal characters and hereditary diseases. Of particular interest to population genetics are isolates, groups of people that are endogamous for geographic, economic, social, or religious reasons. Endogamy increases the frequency of consanguinity between married people; it makes it probable that recessive genes will become homozygous. The phenomenon is quite apparent when the isolates are few in number.

Research has proved the existence of natural selection in human populations. However, human selection has specific features; it is strongly active only in the embryonic stage. (So-called spontaneous abortions are a reflection of such selection.) Selection in human society is achieved by means of differences in forms of marriage and in fertility, that is, as a result of the interaction of social and biological factors. Mutation and selection are responsible for the great variety of some characters (polymorphism), which makes man an extraordinarily flexible and adaptive species from a biological point of view.

The extensive use of cytological methods in human genetics helped to develop cytogenetics, in which the main object investigated is the chromosome, a structure of the cell nucleus containing the genes. The chromosome set in human body, or somatic, cells was discovered in 1946 to consist of 46 chromosomes, with the female sex determined by the presence of two X chromosomes and the male sex by an X chromosome and a Y chromosome. Mature gametes (haploids) contain half the number of chromosomes. Mitosis, meiosis, and fertilization maintain the continuity and constancy of the chromosome set throughout both the series of cell generations and the generations of organisms. Disruptions of these processes may give rise to anomalies in the chromosome set and change the number and structure of the chromosomes, causing the so-called chromosomal diseases. The latter are often manifested by feeblemindness, severe congenital abnormalities, and anomalies of sex differentiation; they may also cause spontaneous abortions.

Advances in human genetics have made it possible to prevent and treat hereditary diseases. One of the effective methods of preventing them is medicogenetic consultation, with a prediction of the risk that an offspring of individuals suffering from such a disease or having relatives with the disease will develop it. Biochemical human genetics has discovered the ultimate cause (molecular mechanism) of many hereditary defects and metabolic anomalies and thereby has helped to devise rapid diagnostic methods that permit prompt and early detection and treatment of individuals suffering from many hitherto incurable hereditary diseases. Therapy generally consists of introducing into the body substances that are not produced there because of genetic defects, or using special diets that exclude substances having a toxic effect because of a hereditarily determined inability to break them down. Many genetic defects are corrected by timely surgery or training.

Practical means of maintaining human hereditary health and preserving the gene pool are made available through a plan of medicogenetic consultations. Their principal purpose is to inform those who are interested about the probable risk of a disease developing in the offspring. Another medicogenetic measure is the dissemination of genetic knowledge among the population in that it promotes a more responsible attitude toward parturition. Medicogenetic consultation abstains from recommendations aimed at compelling or encouraging parturition or marriage and limits itself solely to providing information. Actions aimed at creating ideal conditions for the manifestation of positive hereditary tendencies and at preventing injurious environmental factors from impairing human heredity are very important.

Human genetics is the natural scientific basis for the struggle against racism. It has conclusively shown that races are forms of human adaptation to specific environmental conditions (climatic and other) and that they differ from one another not in the presence of “good” or “bad” genes but in the distribution of the ordinary genes common to all races. Human genetics has shown that all races are equal in value (but not identical) from the biological standpoint and that they are all equal in their capacity for development, which is determined by sociohistoric and not genetic conditions. The existence of biological or hereditary differences between individual persons or races cannot be used as a basis for drawing conclusions of a moral, juridical, or social nature that restrict the rights of these persons or races.