What are hereditary diseases? |

Causes and Impact of Hereditary Diseases

Twentieth-century medicine was hugely successful in conquering infectious diseases. Elimination, control, and treatment of diseases such as smallpox, measles, diphtheria, and plague have greatly decreased infant and adult mortality. Improved prenatal and postnatal care have also decreased childhood mortality. Shortly after the rediscovery of Mendelism in the early 1900s, reports of genetic determination of human traits began to appear in medical and biological literature. For the first half of the twentieth century, most of these reports were regarded as interesting scientific reports of isolated clinical diseases that were incidental to the practice of medicine. The field of medical genetics is considered to have begun in 1956 with the first description of the correct number of chromosomes in humans (forty-six). Between 1900 and 1956, findings were accumulating in cytogenetics, Mendelian genetics, biochemical genetics, and other fields that began to draw medicine and genetics together.

The causes of hereditary diseases fall into four major categories:

single-gene defects or Mendelian disorders, such as cystic fibrosis, Huntington’s disease (Huntington’s chorea), color blindness, and phenylketonuria




chromosomal defects involving changes in the number or alterations in the structure of chromosomes, such as Down syndrome, Klinefelter syndrome, and Turner syndrome




multifactorial disorders caused by a combination of genetic and environmental factors, such as congenital hip dislocation, cleft palate, and cardiovascular disease




mitochondrial disorders caused by mutations in mitochondrial genes, such as Leber hereditary optic neuropathy

These four categories are relatively clear-cut. It is likely that genetic factors also play a less well-defined role in all human diseases, including susceptibility to many common diseases and degenerative disorders. Genetic factors may affect a person’s health from the time before birth to the time of death.

Congenital defects are birth defects and may be caused by genetic factors, environmental factors (such as trauma, radiation, alcohol, infection, and drugs), or the interaction of genes and environmental agents. Alan Emery and David Rimoin noted that the proportion of childhood deaths attributed to nongenetic causes was estimated to be 83.5 percent in London in 1914 but had declined to 50 percent in Edinburgh by 1976, whereas childhood deaths attributed to genetic causes went from 16.5 percent in 1914 to 50 percent in 1976. These changes reflect society’s increased ability to treat environmental causes of disease, resulting in a larger proportion of the remaining diseases being caused by genetic defects. Rimoin, J. Michael Connor, and Reed Pyeritz estimate that single-gene disorders have a lifetime frequency of 20 in 1,000, chromosomal disorders have a frequency of 3.8 in 1000, and multifactorial disorders have a frequency of 646 in 1,000. It is evident that hereditary diseases are and will be of major concern for some time.

Single-Gene Defects

Single-gene defects result from a change or mutation in a single gene and are referred to as Mendelian disorders or inborn errors of metabolism. In 1865, Gregor Mendel
described the first examples of monohybrid inheritance. In a trait governed by a single locus with two alleles, individuals inherit one allele from each parent. If the alleles are identical, the individual is said to be homozygous. If the alleles are different, the individual is said to be heterozygous.

Single-gene defects are typically recessive. A single copy of a dominant allele will be expressed the same in homozygous and heterozygous individuals, while a recessive allele is expressed only in homozygous individuals (often called homozygotes). In heterozygotes, the dominant allele masks the expression of the recessive allele. This helps explain why recessive single-gene defects predominate. Dominant single-gene defects are always expressed when present and never remain hidden. As a result, natural selection quickly removes these defects from the population.

Genes can be found either on sex chromosomes or nonsex chromosomes (called autosomes). One pair of chromosomes (two chromosomes of the forty-six in humans) have been designated sex chromosomes because the combination of these two chromosomes determines the sex of the individual. Human males have an unlike pair of sex chromosomes, one called the X chromosome and a smaller one called the Y chromosome. Females have two X chromosomes. Genes on the X or Y chromosomes are considered sex-linked. However, since Y chromosomes contain few genes, “sex-linked” usually refers to genes on the X chromosome; when greater precision is required, genes on the X chromosome are referred to as “X-linked.” Inheritance patterns for X-linked traits are different than for autosomal traits. Because males only have one X chromosome, any allele, whether normally recessive or dominant, will be expressed. Therefore, recessive X-linked traits are typically much more common in men than in women, who must have two recessive alleles to express a recessive trait. Additionally, a male inherits X-linked alleles from his mother, because he only gets a Y chromosome from his father.

Chromosomal Disorders

Chromosomal disorders are a major cause of birth defects, some types of cancer, infertility, intellectual disabilities, and other abnormalities. They are also the leading cause of spontaneous abortions.
Structural changes or deviations from the normal number of forty-six chromosomes usually result in abnormalities. Variations in the number of chromosomes may involve just one or a few chromosomes, a condition called aneuploidy, or complete sets of chromosomes, called polyploidy. Polyploidy among live newborns is very rare, and the few polyploid babies who are born usually die within a few days of birth as a result of severe malformations. The vast majority of embryos and fetuses with polyploidy are spontaneously aborted.

Aneuploidy typically involves the loss of one chromosome from a homologous pair, called monosomy, or possession of an extra chromosome, called trisomy. Monosomy involving a pair of autosomes usually leads to death during development. Individuals have survived to birth with forty-five chromosomes, but they suffered from multiple severe defects. Most embryos and fetuses that have autosomal trisomies abort early in pregnancy. Invariably, trisomics that are born have severe physical and mental abnormalities. The most common trisomy involves chromosome 21 (Down syndrome), with much rarer cases involving chromosome 13 (Patau syndrome) or chromosome 18 (Edwards syndrome). Infants with trisomy 13 or 18 have major deformities and invariably die at a very young age. Down syndrome is the most common, occurring in about one in seven hundred births, and is the best known of the chromosomal disorders. Individuals with Down syndrome are short and have slanting eyes, a nose with a low bridge, and stubby hands and feet. About one-third suffer severe intellectual disability. The risk of giving birth to a child with Down syndrome increases dramatically for women over thirty-five years of age.

Variations in the number of sex chromosomes are not as lethal as those involving autosomes. Turner syndrome is the only monosomy that survives in any number, although 98 percent of cases are spontaneously aborted. Patients with Turner syndrome have forty-five chromosomes consisting of twenty-two pairs of autosomes and only one X chromosome. They are short in stature, sterile, and have underdeveloped female characteristics but normal or near-normal intelligence. Other diseases caused by variations in the number of sex chromosomes include Klinefelter syndrome, caused by having forty-seven chromosomes, including two X chromosomes and one Y chromosome (affected individuals are male with small testes and are likely to have some female secondary sex characteristics, such as enlarged breasts and sparse body hair); and triple X syndrome, in which individuals have forty-seven chromosomes, including three X chromosomes (affected individuals are female with variable characteristics; some are sterile, have menstrual irregularities, or both).

Variations in the structure of chromosomes include added pieces (duplications), missing pieces (deletions), and transfer of a segment to a member of a different pair (translocation). Most deletions are likely to have severe effects on developing embryos, causing spontaneous abortion. Only those with small deletions are likely to survive and will have severe abnormalities. The cri du chat (“cry of the cat”) syndrome produces an infant whose cry sounds like a cat’s meow. There is also a form of Down syndrome, called familial Down syndrome, that is caused by a type of reciprocal translocation between two chromosomes.

Multifactorial Traits

Multifactorial traits, sometimes referred to as complex traits, result from an interaction of one or more genes with one or more environmental factors. Sometimes the term “polygenic” is used for traits that are determined by multiple genes with small effects. Multifactorial traits do not follow any simple pattern of inheritance and do not show distinct Mendelian ratios. Such diseases show an increased recurrence risk within families. “Recurrence risk” refers to the likelihood of the trait showing up multiple times in a family; in general, the more closely related someone is to an affected person, the higher the risk. Recurrence risk is often complicated by factors such as the degree of expression of the trait (penetrance), the sex of the affected individual, and the number of affected relatives. For example, pyloric stenosis, a disorder involving an overgrowth of muscle between the stomach and small intestine, is the most common cause of surgery among newborns. It has an incidence of about 0.2 percent in the general population. Males are five times more likely to be affected than females. For an affected male, there is a 5 percent chance his first child will be affected, whereas for a female, there is a 16 percent chance her first child will be affected.

It is necessary to develop separate risks of recurrence for each multifactorial disorder. Multifactorial disorders are thought to account for 50 percent of all congenital defects. In addition, they play a significant role in many adult disorders, including hypertension and other cardiovascular diseases, rheumatoid arthritis, psychosis, dyslexia, epilepsy, and intellectual disability. In total, multifactorial disorders account for more genetic diseases than do single-gene and chromosome disorders combined.

Impact and Applications

In 2003, the Human Genome Project achieved its goal of mapping the entire human genome. The complete specifications of the genetic material on each of the twenty-two autosomes and the X and Y chromosomes will improve the understanding of the biological and molecular bases of hereditary diseases. Once the location of a gene is known, it is possible to make a better prediction of how that gene is transmitted within a family and the probability that an individual will inherit a specific genetic disease.

For many hereditary diseases, the protein produced by the affected gene and its relation to the symptoms of the disease are not known. Locating a gene facilitates this knowledge. It becomes possible to develop new diagnostic tests and therapies. The number of hereditary disorders that can be tested prenatally and in newborns will increase dramatically. In the case of those single genes that do not produce clinical symptoms until later in life, many more of these disorders will be diagnosed before symptoms appear, opening the way for better treatments and even prevention. Possibilities will exist to develop a way to use gene therapy to repair or replace the disease-causing gene. The identification and mapping of single genes and those identified as having major effects on multifactorial disorders will greatly affect hereditary disease treatment and genetic counseling techniques. It is evident that knowledge of genes, both those that cause disease and those that govern normal functions, will begin to raise many questions about legal, ethical, and moral issues.

Key Terms



chromosomal defects

:

defects involving changes in the number or structure of chromosomes





congenital defects


:

birth defects that may be caused by genetic factors, environmental factors, or interactions between genes and environmental agents




hemizygous

:

characterized by being present only in a single copy, as in the case of genes on the single X chromosome in males




Mendelian defects

:

also called single-gene defects; traits controlled by a single gene pair





mitochondrial disorders


:

disorders caused by mutations in mitochondrial genes




mode of inheritance

:

the pattern by which a trait is passed from one generation to the next




multifactorial disorders

:

disorders determined by more than one gene, sometimes in combination with environmental factors





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