Genetic Diseases

Genetic diseases result from chromosome abnormalities or mutant genes showing a specific pattern of inheritance. In addition, genetic factors are involved in susceptibility to some nongenetic DISEASES. As progress has been made in eliminating infectious diseases, genetic disease has come to represent an increasingly larger proportion of all disease. Genetic diseases among animals, particularly domestic species, have sometimes provided useful information about human counterpart disorders.

In Canada the earliest studies of human genetic disease were carried out by Norma Ford WALKER (Toronto), Madge Macklin (London, Ontario) and F. Clarke FRASER (Montréal). Recent advances in the study of DNA, the chemical basis of genes, are making possible the identification of the basic defect in many diseases and will increase the possibility for understanding and controlling human genetic disease.

A complete knowledge of disease at the gene level may make possible the replacement of faulty genes through GENETIC ENGINEERING. Information on specific diseases is available through genetic counselling services associated with medical schools and affiliated hospitals. Prenatal testing, frequently using DNA technology, is available for a number of genetic disorders.

Chromosome Abnormalities

Humans have 46 chromosomes, ie, 22 pairs of autosomes and one pair of sex chromosomes (responsible, among other features, for reproduction - XX in females, XY in males). Extra or missing chromosomal material usually results in pregnancy loss. About 15% of pregnancies end in spontaneous abortion (miscarriage) during the first 3 months; 40-50% of spontaneously aborted fetuses have a chromosome abnormality.

The most common type of chromosome abnormality among live-born infants is Down's syndrome, also called trisomy 21, in which affected individuals have 3 (instead of 2) of the chromosome designated 21. This condition occurs in about 1 in 700 pregnancies (1 in about 40 for mothers over 40 years of age). Affected individuals have multiple physical abnormalities and mental retardation.

Abnormalities of a single sex chromosome are usually less severe than those in autosomes. Loss of an X chromosome results in Turner's syndrome, found in approximately 20% of all spontaneously aborted fetuses and 0.0005% of newborns; normal mental development, short stature and infertility are characteristic. In Kleinfelter's syndrome (XXY), affected individuals are tall, often mentally retarded and have poorly developed secondary sexual characteristics. Chromosome abnormalities are rarely inherited.

Single Gene Disorders

Most genetic diseases result from inheritance of a single disease-controlling gene.

Autosomal Recessive Inheritance
Disease is inherited in a recessive manner when the clinically recognized characteristic is hidden in heterozygotes, ie, individuals who inherited the disease gene from only one parent. Only homozygotes, ie, individuals who have received the disease gene from each parent, are clinically affected. Partial abnormalities frequently can be found in heterozygotes. Often the gene involved normally produces an enzyme which is absent in an affected homozygote. These enzyme defects, termed inborn errors of metabolism, can occur in a wide range of biochemical pathways.

Typically, specific genetic diseases occur in all racial groups, although the frequencies are markedly different between groups. Cystic fibrosis is the most common autosomal recessive disease in white children. Affected individuals suffer abnormalities of secretion of pancreatic and digestive tract enzymes; thick mucous can block the small airways of the lung. In phenylketonuria, affected infants lack an enzyme that metabolizes the amino acid phenylalanine (present in milk). The result is an accumulation of abnormal toxic products that cause mental retardation. Many provinces have screening tests so that those affected (about 1 in 10 000 newborns) can be diagnosed and immediately placed on a diet with low levels of phenylalanine.

Tay-Sachs disease occurs more frequently (1 in 1600 births) in Ashkenazi Jews than in other racial groups. The absence of an enzyme leads to neurological deterioration and eventual death (at 2-4 years). Recessively inherited anemias can be caused by one of a number of abnormal hemoglobins. Sickle-cell hemoglobin, the most common abnormal type, produces sickle-cell disease in homozygotes; about 1 in 400 North American Blacks are affected. Affected individuals are severely anemic and suffer from arthritislike pain in joints and muscles.

Autosomal Dominant Inheritance
Individuals can be clinically affected, regardless of sex, when they carry one normal and one disease gene. Affected individuals pass the disease to 50% of their offspring. Typically, dominant conditions show variable penetrance, ie, some individuals are severely affected while others show few or no effects. Variable penetrance is typical in osteogenesis imperfecta, which results in abnormally brittle bones. Variable age of onset (from about 16 to over 50 years) is characteristic of Huntington's disease, which leads to jerking movements of limbs, mental illness and death.

X-Linked Inheritance
A disease gene on the X chromosome can be recessive or dominant; however, as for autosomal traits, recessive conditions are more common. Females, having a normal gene on the other X chromosome, do not express the disease; males are affected. Hemophilia, a bleeding disorder that occurs in 1 in 10 000 males, is such a trait. Queen Victoria was a carrier and some of her male descendants were affected. Muscular dystrophy, which involves the progressive deterioration of muscle, is another such disease.

Multifactorial Diseases

Many of the common congenital abnormalities (ie, those present at birth) are multifactorial traits for which both environment and genetic factors are responsible. Cleft lip and palate, pyloric stenosis (blockage of the stomach) and neural tube defects (spina bifida and anencephaly) are common abnormalities of this type. Risks for recurrence in brothers, sisters or offspring are usually about 3-5%, varying with sex of the affected child. Neural tube defects can be detected prenatally.

For most such abnormalities, the specific environmental and genetic factors have not been identified; however, it is known that HLA types (ie, markers on the surface of human white blood cells), which can now be identified by DNA methods, influence the susceptibility to diseases involving the immune system.


The Molecular Basis of Human Disease

Recombinant DNA techniques (see GENETICS) have made possible a rapid increase in our knowledge of human diseases. Random fragments of DNA that show high variability among individuals have been useful in mapping human diseases. Particularly useful are the DNA fragments called microsatellites, long strings of repeated series of bases that occur at frequent intervals along the human chromosomes. This allows the region containing a specific gene to be identified.

Canadian researchers have been particularly active in the cloning of genes by locating their position on the chromosome. This includes genes for muscular dystrophy on the X chromosome (Ronald Worton), cystic fibrosis (Lap-Chee TSUI), Wilms tumor (Brian Williams), Fanconi anemia (Manuel Buchwald) and Wilson disease (Diane Cox).

Once a disease gene has been identified, the specific changes or mutations causing disease can be identified. Even before the gene is cloned, markers close to the gene can be used to trace the gene within the family to diagnose presymptomatic individuals. This method is now being used for many diseases, including Huntington's disease and polycystic kidney.

The Human Genome Project, with the goal of sequencing the complete human genetic complement, has already provided useful information on marker and gene location. As this project advances, more and more normal genes will be identified and mapped. It will make the search for disease genes much easier, since candidate genes will be available once the position of a disease is identified on the chromosome. We will continue to see rapid advances in our knowledge of human genetic disease.


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