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  • Genetic Diseases of the Blood

    Edwin M. Knights Jr.

    There are many genetic diseases affecting the blood, some of which were among the first to be recognized as being familial and even involving royal families. Linus Pauling is credited with recognizing the molecular nature of sickle cell anemia. Diagnosis can be complicated by the presence of more than one of these diseases in the patient, plus multiple genetic atypicalities, so detailed family medical history is particularly valuable. We've provided brief summaries and some pertinent references, but there's voluminous literature about each of these if you seek more details, and there are many web sites sponsored by charitable foundations anxiously waiting to provide you with every aspect of the disorder.

    SICKLE CELL ANEMIA
    It's appropriate to start with sickle cell anemia, as in 1949 it was the first illness to be defined as a molecular disease. It turned out to be so complex that scientists have been trying to explain it ever since. There are not only hundreds of genetic variations, but it can also be combined with other autosomal recessive disorders, such as beta-thalassemia or the with the presence of fetal hemoglobin. Like other autosomal recessive conditions, a person needs two copies of the abnormal hemoglobin present to be symptomatic. One possible combination consists of hemoglobin S plus hemoglobin C. Those who have one normal hemoglobin (Hb), such as Hb A and one of Hb S are sickle cell carriers and are said to have the "sickle cell trait."

    If you suspect one of your forebears had sickle cell anemia, look for symptoms resulting from chronic anemia (weakness and easy fatigue), chest pains or suffering a stroke at an early age. Lack of oxygen, as in high altitudes, can cause acute severe pain, or a "crisis." Childhood death usually results from bacterial infections or stroke. Sickle cell disease affects over 50,000 Americans and many of those afflicted are of African or Mediterranean origin. Birth prevalences in African-Americans of the more usual types of sickle cell anemia are listed in Table 1 and survival statistics in Table 2.



    Table 1.
    Birth Prevalences of Sickle Cell Variants, African-Americans
      Sickle cell anemia (Hb SS) 1/375 Hemoglobin SC 1/835 Hb S/beta thalassemia 1/1667 Sickle cell trait (Hb AS) 1/12


    Table 2.
    Median Survivals based on Genotype and Sex
      Males with Hb SS 42 years Females with Hb SS 48 years Males with Hb SC 60 years Females with Hb SC 68 years


    THALASSEMIA
    Thalassemia includes several inherited blood diseases and every year 100,000 babies are born who have severe types of these anemias. Greek, Italian, Middle Eastern, African and Southern Asian ancestry are common. A severe type of alpha thalassemia affects those of Southeast Asian, Chinese and Filipino ancestry, causing fetal or newborn death. Elsewhere, those with alpha thalassemia just suffer from anemias of varying severity.

    Beta thalassemia can also be in different forms, ranging from the most severe, thalassemia major (Cooley's anemia), to thalassemia intermedia and thalassemia minor. Cooley's anemia children may appear healthy when born but they soon become pale and weak, developing heart failure and infection. Frequent blood transfusions prolong life but lead to other complications, especially from iron deposits in the body. Rarely, cures have been obtained by bone marrow transplantation, but suitable donors are required and the procedure is risky.

    Thalassemia carriers have one normal and one thalassemia gene in their cells; when two carriers become parents, a child has one chance in four of either having a severe form of the disease or being completely free of thalassemia, and one chance in two he or she will be a carrier. Blood tests and DNA studies can determine whether someone has thalassemia or is a carrier. Diagnosis is possible in utero by genetic chorionic villus sampling or by amniocentesis. These procedures are not without risk and genetic counseling is important.

    The Cooley's Anemia Foundation, Inc. describes current efforts to perfect gene therapy for the disease.

    PERNICIOUS ANEMIA
    Also known as megaloblastic anemia, pernicious anemia (PA) is caused by impaired absorption of vitamin B(12) and cobalamine as the result of deficiency of two substances orinarily present in our stomach, intrinsic factor and hydrochloric acid. The congenital form is rare in comparison with the acquired adult onset type. It is autsomal recessive and follows the usual heritable pattern, present before the age of 2 years. It is a genetic problem which prevents infants from absorbing folic acid. Early intensive treatment is required to prevent long term problems, such as mental retardation related to B(12) deficiency. Symptoms can include pale skin, poor appetite, easy fatigue, diarrhea, difficulty in walking, and a smooth, tender tongue. As these symptoms can occur in other medical conditions, consultation with the child's pediatrician is important to confirm the diagnosis. The diagnostic criteria are well established and do not require DNA analyses, but involve blood and bone marrow studies plus the Schilling test, which compares results from isotope-labeled and unlabeled vitamin B(12). PA is considered an autoimmune disorder, related to genetic deficiencies.

    Adult PA is most common in Scandinavians, English and Irish, where up to .13 to .20 of the population are diseased. It involves all ethnic groups but is less common in Caucasians of Italian and Greek descent, rare in blacks and Asians, and it is often seen in females. The mean age of onset in whites is 60 years, in blacks 50 years.

    FANCONI ANEMIA
    Occurring in all ethnic groups, Fanconi anemia (FA) particularly affects the Ashkenazi Jewish population, with a carrier frequency of 1/87-89. FA is a recessively inherited aplastic anemia caused by bone marrow failure. As in other recessive disorders, if both parents carry the same defective FA gene, each child has a one in four chance of inheriting their genes for FA. The disease occurs equally in males and females.

    Individuals with FA are usually small, and may have missing bones in the thumbs and arms. All systems of the body can be affected, but the first signs may be easy bruising and nosebleeds. The skin becomes pigmented and many patients eventually develop leukemia. Those who live to adulthood are also prone to have head and neck, gynecological or gastrointestinal cancer. Mental retardation also occurs.

    The test currently used to confirm the diagnosis is a "chromosomal breakage" test, using chemically treated FA cells. During pregnancy, chorionic villus sampling or amniocentesis for genetic study are also available options, but not without risk. Genetic counseling is recommended.

    Treatment depends on the extent and severity of the disease, and so far there is no treatment that works consistently. Prevention is more effective than treatment, because up to 80 percent of carriers can be identified by genetic testing. An International Fanconi Anemia Registry is located in the Rockfeller University Hospital in New York City.

    HEMOPHILIA
    Hemophilia was recognized as far back as the 2nd century, described by an Arab physician as a familial disease in the 12th century and later traced through a family history from 1720 to 1830 by a Philadelphia physician who was obviously a talented genealogist. The severe hemorrhages, affecting males, became known as "The Royal Disease" in the 19th Century, because Queen Victoria of England was a carrier -- a story familiar to genealogists. Transmition by the female line became apparent when two of her daughters, Alice and Beatrice, passed on the disease to the Russian, Spanish and German royal families.

    Inheritance
    We now realize hemophilia is an inherited, sex-linked recessive trait with a defective gene located on the X chromosome. Females are carriers of the trait. Fifty percent of their male offspring will have the disease, and 50 percent of their female offspring will be carriers. All female offspring of a male with hemophilia will carry the trait.

    Recognizing a Carrier
    Female carriers can be identified by testing, but for the genealogist studying his or her family tree, the following information is helpful:

    A woman is is carrier if:
    1. she's the biological daughter of a man with hemophilia.
    2. she's the biological mother of more than one son with hemophilia.
    3. she's the biological mother of one hemophiliac son who has at least on other blood relative with hemophilia.
    A woman may or may not be a carrier if:
    1. she's the biological mother of one son with hemophilia.
    2. she's the sister of a man with hemophilia.
    3. she's an aunt, cousin or niece of an affected male related via maternal ties.
    4. she's the biological grandmother of one hemophilic grandson.
    Hemophilia can also occur when there is no family history of the disease. This is true about one-third of the cases and is the result of a genetic mutation.

    Pathologic features
    Until the 1930's, doctors were convinced that fragile blood vessels caused the disease, but in 1937 two physicians, Patek and Taylor, discovered "anti-hemophilic globulin" in normal blood plasma could correct the clotting problem. Seven years later, when it was discovered that blood from one hemophiliac could actually improve clotting in another, it was realized that these were two sex-linked recessive heritable diseases. These were eventually named Hemophilia A, with a deficiency of clotting Factor VIII, and Hemophilia B, with clotting Factor IX deficiency.

    The incidence of hemophilia A is one in 5,000 to 10,000 live male births. Approximately 12,000 Americans have it, almost all of whom are males.

    Diagnosis
    Hemophilia is diagnosed by a careful personal and family history supplmented by clotting activity tests of the blood. These tests measure:
      * How long the blood takes to clot.
      * If you have low levels of any clotting factor.
      * If any clotting factors are missing.
    Hemophilia A and B are not the only possible causes. Low levels of a protein known as Von Willebrand factor can also cause bleeding; this condition is called Von Willebrand's disease. From the results, hemophilia can be classified as to its type and rated as to its severity:
      * Mild 5-30 percent of normal
      * Moderate 1-5 percent of normal
      * Severe: Less than 1 percent of normal
    Severe hemophilia an result in severe bleeding in infants. Milder versions may not be apparent until adulthood. Persons with hemophilia need to avoid situations which might cause bleeding. Good dental hygiene is important to avoid the need for dental extractions. They should also avoid using drugs such as aspirin, heparin, wafarin and some of the non-steroidal anti-inflammatory medications which could contribute to bleeding problems.

    Pre-Natal Diagnosis
    Molecular testing isn't needed for routine diagnosis but is used in two methods which make it possible to determine whether a fetus is likely to have hemophilia:
      * Chorionic villus sampling. A small sample of placental tissue can be obtained from the uterus 9-12 weeks into pregnancy. DNA in fetal cells can show the sex of the fetus and whether the gene for hemophilia is present. There is a slight possibility that miscarriage can occur when this test is performed.

      * The other method is by amniocentesis. This is done somewhat later in pregnancy, around 16 weeks. A small amount of amniotic fluid is collected and fetal cells are allowed to grow. The DNA in these cells is analyzed for the sex of the fetus and the presence of the hemophilia gene. Miscarriage occurs in about 1 of 200 women using this test.
    In either test, it may be necessary to obtain a blood sample from a hemophiliac family member. As these intra-uterine tests require some medical decisions and are not without risks, medical advice and sometimes genetic counseling are indicated. The patients will need information concerning carrier testing, prental diagnosis, possible termination of a pregnancy, plus hemophilia and its treatment.

    Molecular analysis of DNA is also used to check familiy members who might be at risk. Carrier females have a 50 percent chance of transmitting mutation to each child; sons will have the disease, daughters are carriers. Hemophilia A is one of the first diseases where genetic therapy has already been successful.

    From 15-20 percent of hemophiliacs have hemophilia B, also known as Christmas disease, in which a genetic defect causes blood Factor IX deficiency. It is also sex-linked, recessive and transmitted by females. In severe cases bleeding begins in the newborn, sometimes after injections or circumcisions. By the end of the first year there is obvious bleeding in 90 percent of severe hemophilia B patients. There are also moderate and mild forms of the disease. Bleeding in the elbows, knees and ankles is typical, but it can occur in many other sites. Genetically engineered recombinant Factor IX was introduced in 1997.

    A variant of hemophilia B is hemophilia B Leyden, a form of inherited Factor IX deficiency first described in families of Dutch origin. This disease can present early in childhood in the severe, moderate or mild forms but there is a gradual increase in Factor IX levels beginning at puberty. The disease is inherited as an X-linked recessive in a pattern similar to that of hemophiia B. Adults usually have minimal problems with bleeding because Factor IX levels have increased to 40 percent or considerably higher.

    Treatment
    Minor cuts and scrapes respond to the usual first-aid treatment. Deeper cuts or internal bleeding require replacement of the missing clotting factor, which is injected intravenosly. The National Hemophilia Foundation encourages use of recombinant clotting factor products for young children, as they do not contain human blood. Patients with severe hemophilia may benefit from regular prophylactic infusions of factor concentrate. Hemorrhage in joints may require orthopedic consultations. Acute intracerebral hemorrhage requires prompt treatment under professional supervision.

    Early treatments with whole blood or fresh plasma weren't effective because there just wasn't enough clotting factor present. The introduction of cryoprecipitate by Dr. Judith Pool made treatment far more efficient but unfortunately it was also introducing viruses causing hepatitis and other complications. About 60 percent of hemophiliac patients treated with concentrated plasma in the 1980's became infected with HIV. Later, the hazards of contracting HIV or hepatitis C were largely eliminated by use of screened blood, introduction of technologies to counter viruses, plus introduction of genetically engineered clotting factors. A process known as gene transfer is under intense investigation in animal models, using various viral vectors, and appears to offer useful treatments for hemophilia A and B. Also of interest in promoting hemostasis is a recombinant human coagulation Factor VII marketed as NovoSeven, which appears to be valuable in controlling acute intracerebral hemorrhage associated with hemophilia. Hemophilia gene therapy appears well on its way to success.

    THROMBOCYTOPENIC PURPURA (TP)
    This condition is really not one disease, but a collection of rather similar conditions having multiple causes. The condition previously known as idiopathic thrombocytopenic purpura because the cause wasn't known. TP can be acute or chronic, and it can appear in the neonatal stage or following blood transfusions. It can be drug-induced or associated with a number of connective tissue disorders or infections.

    At least one genetic cause seems to have been identified. It may be possible to treat this condition with a specific enzyme or eventually produce recombinant gene therapy. There are at least four closely related diseases which will also benefit from genetic research.

    THROMBOPHILIA
    The term thrombophilia is used when the body tends to form blood clots, and if these clots start blocking blood flow they can be life-threatening. There are multiple obvious causes, which can include surgery, obesity, pregnancy, prolonged immobility and use of oral contraceptives.

    Importance of Family History
    Persons who experience thrombophilia at a young age may have a definite family history of clotting problems, which could result in a stroke, clotting of deep leg veins or pulmonary embolism. In the latter condition, blood clots which might have formed in leg or pelvic veins break loose and are carried into the lungs. It can also cause recurrent fetal miscarriages. In these patients it may be well to see if recently identified genetic markers are present.

    THE LEUKOCYTES
    B-lymphocytes and T-lymphocytes have important defensive roles in the body, especially in the development of immunity. Immortalization techniques have provided abundant quantities of these cells for DNA research. There are other leukocyes in human blood with specific functions, undoubtedly many of which are genetically programmed. They also can form leukemias, in which the circulating cells reproduce in an uncontrolled fashion, or lymphomas, solid tumors consisting of expanding masses of these cells which can infiltrate surrounding organs.

    The most common leukemia in adults is B-cell chronic lymphocytic leukemia. It can produce death within a few months or be present for over 20 years. Staging systems have been devised to predict survival in chronic lymphocytic leukemia, but they are not very useful in the early stages when the disease is first recognized. Seeking better methods, scientists turned to fluorescence in situ hybridization (FISH) to look for genomic aberrations which might be of use in establishing the prognosis.

    In a study of 325 chronic lymphocytic leukemia cases, aberrations were found in 82 percent. A number of differing chromosome abnormalities were detected. Fluorescence in situ hybridization made it possible to identify the chromosomal abnormalities associated with the need for more frequent treatments and those with the longest treatment-free intervals. From this information they were able to design DNA probes to identify the atypical genes and select the best treatments.

    It appears that B-cell leukemia can arise from B-cells of different stages in their development; further evaluations of B-lymphocytes are investigating how present clinical, biochemical and genetic markers can be improved.

    MicroRNAs Play Important Roles in Gene Regulation
    Recent studies have desclosed that small versions of RNA, known as microRNAs, are regulatory molecules which control gene expression by degrading or repressing target messenger RNAs (mRNAs). MicroRNAs have their own genes and are quite plentiful -- up to 1,000 of them exist in a human genome, each capable of regulating as many as 200 target genes. Some of these microRNAs appear to be associated with chronic lymphocytic leukemia (CLL), lymphomas and prostatic cancer. Profiles of microRNA have been found to be very useful in classfying cancers and predicting their origins. Hopefully, research will help diagnose and treat leukemia, as microRNA appears to be associated with the development of aggressive B-cell leukemia from lymphomas.

    Genomic Cartography
    Extensive research is being conducted on haplotypes, sets of closely linked markers on a single chromosome which tend to be inherited in stable DNA chunks. Because of limited mitotic changes, genealogists use these to study distant origins and population migrations. The stable sections are flanked with foci of active recombination. Study of this phenomenon has led to the creation of the "HapMap", which has speeded up genetic research. Focusing on single-nucleotide polymorphisms called SNPs helps to ientify variants likely to be associated with disease. Such variants are labelled "mis-sense mutations". The HapMap will be a valuable means of identifying genetic susceptibility to disease.



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