Objectives
: A. Discuss the genetics and occurrence of some common disorders: Huntington Chorea, neurofibromatosis, sickle cell anemia, Thalassemia, PKU, Tay-Sachs, Cystic Fibrosis, Down syndrome, Klinefelter syndrome, Turner syndrome, Cat-cry syndrome, retinoblastoma, Leukemia and the Philadelphia chromosome.
Approximate time: one week.
With the foregoing background information dealing with the genetic factors and patterns of inheritance, one can look at some of the disorders and birth defects that occur as a result of unusual or abnormal behavior of chromosomes or genes.
“Many genetic traits are determined by genes at a single locus, in either homozygous or heterozygous state. There are 2786 such conditions, most of which are abnormalities rather than normal variants; catalogued in a most useful reference:
Mendelian Inheritance in Man
by V.A. McKusick (5th ed., 1978). This is an appreciable amount of the estimated 30,000 human structural genes. Of the total, 1473 are autosomal dominant, 1108 are autosomal recessive and 205 X-linked.”
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Huntington Chorea described by Huntington in 1872 in Americans of English descent, is caused by an autosomal dominant gene. The disease is characterized by chorea (spasmodic movements and incoordination) and progressive mental deterioration. It occurs in 1 in 25,000 and can occur between 15-65 years of age. Anyone who is heterozygous will develop the disease if they live long enough.
Since carriers of the allele may reproduce before the allele reveals itself, their children live with the knowledge that they too may some day be stricken. This may be the situation with the children and grandchildren of the folk singer and composer Woodie Guthrie, who died of Huntington disease in 1967, as had his mother in 1930. However, the older the persons at risk become without showing the symptoms, the less likely they are to possess the gene.
Neurofibromatosis can be traced to an autosomal dominant gene. It is characterized by “ . . . multiple fibrous tumors of the skin and nervous tissue; scattered areas of brownish pigment in skin (known as cafe-au-lait spots). Biochemical defect unknown.”
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Several blood disorders, in addition to Hemophilia previously cited, are commonly found. Sickle cell anemia and beta-Thalassemia (Mediterranean anemia; Cooley anemia) are two such diseases. Both of these diseases are described in connection with hemoglobin defects and with certain ethnic groups of people.
Before proceeding with each of these blood disorders, a brief description of the structure and function of hemoglobin seems necessary. Hemoglobin is found in red blood cells and has the ability to combine with oxygen and transport it throughout the body. It is a molecule of 4 subunits; each has two parts-a polypeptide chain, globin, and a heme group which is an iron-containing pigment. The heme portion is the same in all hemoglobins but the globin portion is affected by genetic variation. There are two different types of polypeptide chains; in normal adult hemoglobin (HbA) these chains are designated as alpha a and beta b. The four chains are folded and each is attached to the heme portion. The alpha chain has 141 amino acids and the beta chain has 146 amino acids. Two separate genes code for the alpha and beta chains. Other genes code for the heme portion.
Looking at sickle cell anemia, the cause appears to be a mutant gene that substitutes the amino acid valine for glutamic acid in the sixth position of the beta chain. The valine distorts the shape of the molecules so that they tend to stack into narrow crystals thereby changing the shape of the red cells to form the sickling phenomenon. This happens only in venous blood after oxygen is lost to the capillaries. When re-oxygenated in the lungs, the sickled cells return to their normal rounded shape.
Because of this irregular shape of red blood cells, blood flow is impeded which lengthens the time of return to the lungs and increases sickling. This slows the blood even further and the cells are irreversibly distorted and have a life span of only a few weeks rather than the normal three months. Also, sickled cells block small vessels anywhere in the body reducing oxygen, causing tissue damage and painful crises. Death can result from damage to a vital organ.
The disease can be treated in that pain can be relieved, the frequency and duration of crises can be lessened by rest, and transfusions and drugs and antibiotics can be administered. Sickle cell anemia can be diagnosed with a blood test.
The disorder occurs predominantly in African blacks and American blacks with a frequency of about 1 in 500. The heterozygous state, known as sickle cell trait, is present in approximately 8% American blacks. Sickle cell trait is not a disease and causes no health problems. The sickle cell disease results from the homozygous state (recessive) of the mutant gene. Persons who are heterozygous for sickle cell are protected against malaria. Figure 8 illustrates some of the possibilities resulting from two types of matings. Other matings can be demonstrated in the classroom using a similar chart (see Appendix 1).
In the Thalassemias, the amino acid sequence of hemoglobin chains are normal, but their rate of synthesis is not. In alpha (a) Thalassemia, the alpha polypeptide is either absent or produced in much reduced quantity. Hemoglobin is produced by other chains during embryonic life or out of four beta chains later in fetal life; but these chains are not suitable as oxygen carriers. When alpha chain synthesis is totally suppressed, death occurs in utero with miscarriage late in pregnancy.
The beta (b) Thalassemias account for 100,000 childhood deaths per year. The disease state is known as Cooley or Mediterranean anemia. The synthesis of beta chains is very much reduced. Homozygotes with beta Thalassemia major (Cooley anemia) often die before age 10; heterozygotes who have Thalassemia minor usually have only a mild anemia. The alpha chains lacking a beta partner precipitate inside the red blood cells and shorten their life span.
The nature of the mutations responsible for the Thalassemia syndromes is complex and only partially understood. Some are simple deletions of the Hb or Hb ; others appear to be mutations of nearby control genes. The Thalassemias occur in Canada and United States, Mediterranean, Middle East and parts of Africa. Like sickle cell, the heterozygote is resistant to malaria.
Three other disorders that are produced as autosomal recessives are PKU (phenylketonuria), Tay-Sachs and Cystic Fibrosis.
In PKU, “The metabolic defect is an inability to convert the amino acid phenylalanine to tyrosine, owing to the absence of a liver enzyme called phenylalanine hydrogen; ase.”
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Some of the phenylalanine is converted to phenylpyruvic acid which is changed to several other compounds. Since there is a deficiency of tyrosine so too is its derivative pigment melanin deficient and people tend to be fair-skinned with blond hair and blue eyes.
SICKLE CELL ANEMIA
(figure available in print form)
Figure 8
Infants show motor and mental retardation when untreated. Babies are hyperactive but uncoordinated and have nervous system disorders. Dietary restrictions of phenylalanine and providing a protein substitute are used in treating the disorder. The child can eat almost all fruits and vegetables. Infants must be identified in the first few weeks of life and probably must continue the diet throughout their lives in some way or other.
Pregnant women with PKU, who have high levels of serum phenylalanine as adults but were treated as children may produce children of their own with brain damage even though the children are heterozygous. Their brains can be harmed by the high phenylalanine during fetal life. These mothers should go back on a more restricted diet during pregnancy.
Tay-Sachs is caused by a missing hexosaminidase enzyme (Hex A) that assists in the synthesis of a ganglioside, a lipid-sugar molecule in the brain.
The disorder is common among the Ashkenazi Jews from Eastern and Central Europe. Among American and Canadian Jews the occurrence is 1 in 4000, in non-Jews 1 in 550,000. One in 30 Jews is heterozygous, 1 in 300-400 non-Jews.
The disease is recognized about four months of age. Affected children become blind and regress mentally and physically with enlargement of the head. A “cherry-red” spot in the fundus of the eye is a striking diagnostic sign. The disease is usually fatal in early childhood.
“The most frequent autosomal recessive disorder in white (Caucasian) children is cystic fibrosis a condition in which there are abnormalities of several exocrine secretions, including pancreatic and duodenal enzymes, sweat chlorides and bronchial secretions.”
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The Tel-Med tape listed in the bibliography describes the incidence in the United States and symptoms and treatment.
Males are infertile as a secondary consequence of abnormal mucous secretion in the vas deferens. Loss of salt in sweat can cause heat prostration. In whites it affects 1 in 2000 births; about 1 in 22 is a heterozygous carrier. The disease is much less common in Orientals.
Down syndrome can usually be diagnosed at birth or shortly thereafter by its phenotypic features. The eyes may be close set with narrow slanting eyelids. Also, all parts of the body are shortened. Defects of major organs are common and moderate retardation is present. Almost all cases are recognized within a few weeks of birth. The risk of having a Down syndrome child appears to increase with the mother’s age.
Sex chromosome abnormalities include Klinefelter syndrome and Turner syndrome. Klinefelter syndrome produces an XXY male with Barr bodies (sex chromatin seen only in female somatic cells) in his cells. Maternal age is advanced in XXY patients. There are some variants of this condition: XXYY, XXXY, XXXXY. The chief characteristics are defects in sexual development and subnormal mentality.
An early observation that males with a second Y chromosome, XYY were found in excess numbers in a maximum security prison was greatly overinterpreted. Most boys and men with a second Y are normal. The origin of the XYY is paternal nondisjunction at the second meiotic division which produces YY sperm.
In Turner syndrome, the XO condition exixts. This is a female with lack of sexual development. Physical features include webbed neck and short stature. The chromosome loss may occur during early cleavage of the zygote.
Females with XXX have been reported. Generally they are normal although a few show some degree of mental retardation or mental illness.
“Homosexuality, transvestitism and other sexual psychological variations do not as a rule have their basis in either chromosomal aberrations or single gene defects.”
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Deletions or the loss of part of a chromosome may also be responsible for abnormal development. One such example is the deletion of the short arm of chromosome 5 (5p) which causes among newborns a high-mewing cry like a kitten known as the cat-cry syndrome. Other characteristics include a small head with round face and slow growth. Most survive beyond childhood, albeit with severe mental retardation.
Deletion in the long arm of chromosome 13 (13q) are found in some cases of retinoblastoma (tumor of the retina of the eye).
The Philadelphia chromosome, a deleted chromosome 22 with translocation of the deleted part to Chromosome 9 is seen in marrow cells of patients with chronic myelogenous leukemia. Other chromosomal changes occur as the disease progresses.
“Although most malignant cancers have abnormal karyotypes, the relation between cancer karyotypes and phenotypes is poorly understood. Most cancers probably develop from a single mutant cell, followed by clonal evolution and selection for the cell line that grows most successfully. The process is usually irreversible.”
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Researchers are now at work on what causes cells to become cancers. One study has demonstrated that there are genes with two components, one called “onc” and the other a control element working in tandem”
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that could turn normal DNA into cancerous cells.
The table below summarizes all of these disorders and defects and the genetic factors for each.
