Basics of Medical Genetics - Buzhiyevska T.I. 2001

Hereditary Diseases
Hereditary diseases of the blood, hematopoietic organs, and plasma protein defects

The most well-known Examples of this group of hereditary disorders are hemoglobinopathies (which are significantly prevalent in malaria-endemic regions) and hemophilias. Hemoglobinopathies encompass the following genetic defects.

Hemolytic anemia caused by impaired Structure or synthesis rate of Hemoglobin due to Mutations in genes encoding the alpha, beta, gamma, or sigma chains of the globin molecule, or in the regulatory regions of these genes. Currently, over 200 variants of such point mutations are known. Based on the severity of clinical manifestations, hemoglobinopathies are classified into 3 groups: severe

— characterized by pronounced hemolysis; mild — with subtle clinical symptoms; and intermediate forms. The most widespread abnormal Hemoglobins are HbS, HbC, HbE, and HbD.

Sickle Cell hemolytic anemia is caused by the substitution of glutamine by valine at the sixth position in the polypeptide chain (HbS: alpha-2, beta-2, 6 GLU—>VAL) resulting from a single nucleotide mutation in the DNA. The clinical course is characterized by hemolytic crises, jaundice, hepatomegaly, clubbing of the fingers, and sickle-shaped erythrocytes. Compensatory cardiomegaly and Bone Marrow hyperplasia develop. This pathology is inherited in an autosomal recessive (AR) manner. Blood transfusions are administered during a hemolytic crisis, while post-crisis management includes a nutritious diet, aspirin, and Folic acid.

Hemolytic anemia (HbC: alpha-2, beta-2, 6 GLU—>LYS) is an allelic variant of Sickle cell anemia. It is characterized by episodes of hemolysis, abdominal pain, and hemorrhagic syndrome, with target Cells visible on blood smears. Splenectomy is rarely performed, and blood transfusions are usually unnecessary. The condition is inherited in an AR manner.

Hemolytic anemia (HbE) is a moderate form of anemia featuring microcytosis and target cells. It exhibits an AR inheritance pattern, and Treatment is primarily symptomatic.

Hemolytic anemia (HbD: alpha-2, beta-2, 121 GLU—>GLY). In this case, a point mutation in the globin Gene leads to the substitution of glutamine at position 121 with Glycine. Hemolytic crises may occur. Inheritance follows an AR pattern, and treatment is symptomatic.

These disorders manifest clinically not only in the homozygous state but also as compound heterozygotes, where an individual carries two different mutant alleles of the same gene.

There are 3 known forms of hemolytic anemia associated with fetal hemoglobin (HbF). The most common is congenital hypoplastic anemia (Diamond—Blackfan syndrome). This is a heterogeneous disorder that can be inherited in either an autosomal dominant (AD) or AR manner. At three months of age, pallor appears, followed by tachycardia and Heart Failure. The Liver and Spleen enlarge. Hemosiderosis may develop due to frequent blood transfusions.

In addition to hemoglobinopathies, there are anemias caused by mutant forms of Proteins that constitute The erythrocyte membrane, including Enzymes. Some of these conditions are described in the section on Pharmacogenetic enzymopathies.

Hemophilia results from Genetic Defects in proteins involved in the coagulation cascade. Currently, 10 hereditary defects leading to impaired blood clotting have been identified. The most common are hemophilia A (deficiency of factor VIII) and hemophilia B (deficiency of factor IX). Both genes are located on the X chromosome, and thus the pathology is inherited in an X-linked recessive (XR) manner. Hemophilia is transmitted from a grandfather through a mother to his grandson; this was recognized in antiquity and documented in the Talmud, which warned against the danger of circumcision in boys whose older brothers or maternal uncles suffered from bleeding disorders. The mutation responsible for hemophilia A occurs with a frequency of 1:10,000, while hemophilia B occurs at 1:100,000 (10 times less frequently). However, hemophilia B is observed in the population only 5 times less frequently than hemophilia A due to the higher early mortality rate among boys with hemophilia A. In 28% of cases, the condition arises from de novo mutations.

Hemophilia A, or classical hemophilia, is characterized by bleeding and hemarthrosis, and it is usually diagnosed during the 2nd or 3rd year of life when the child begins to walk actively on their own. In severe cases, cephalhematomas and umbilical stump bleeding are observed in boys immediately after birth. Typical manifestations include hemorrhages into the knee, elbow, and ankle joints, leading to stiffness and deformity. A reduction in the procoagulant activity of blood clotting factor VIII is noted. The population frequency is 1:25,000 live-born males.

The clinical picture of hemophilia B, or Christmas disease, is similar to the one described above. Blood tests show a reduced activity of factor IX and a prolonged clotting time.

In 5% of cases, The Development of hemophilia is linked not to these genetic mutations, but to the appearance of autoantibodies against protein factors VIII and IX. Linkage with HLA genes is possible. Treatment for such patients requires The Use of aminocaproic acid. In all other cases, replacement therapy with the appropriate protein factors is performed under the monitoring of their ratio in the patient's blood.

von Willebrand disease (vascular pseudohemophilia, capillaropathy) is characterized by prolonged bleeding following injections, cuts, and microtraumas, as well as recurrent epistaxis and hypermenorrhea in women. Gastrointestinal bleeding may also occur. Osteoarthritis typically does not develop. Laboratory findings reveal a prolonged bleeding time, decreased procoagulant and antigenic activity of factor VIII, and impaired platelet aggregation in the presence of ristocetin. The condition is inherited in an AD manner. Treatment includes hemostatic agents, fresh plasma transfusions, and whole blood. Cryoprecipitates are also used. Temporary improvement is achieved through the administration of corticosteroid Hormones, serotonin, adrenoxon, etc. The patients' condition tends to improve with age.

Plasma protein abnormalities include the following pathological conditions.

Analbuminemia may be asymptomatic, though it is sometimes accompanied by edema (since albumin transports various substances and maintains oncotic pressure).

Abetalipoproteinemia is characterized by altered erythrocyte Morphology with spiky projections on their surface (acanthocytes), as well as steatorrhea in early childhood. Older children may exhibit sensory neuropathy, and adults often develop retinitis pigmentosa. Plasma levels of Cholesterol, Phospholipids, and triglycerides are drastically reduced. The condition is inherited in an AR manner.

Analphalipoproteinemia (Tangier disease) is characterized by enlarged Tonsils with a characteristic orange discoloration, hepatosplenomegaly, and lymphadenopathy. Blood levels of cholesterol and high-density Lipoproteins are decreased. This pathology follows an AR inheritance pattern.

Transferrin deficiency leads to hemosiderosis and liver cirrhosis.

Ceruloplasmin deficiency causes hemosiderosis and is observed in Wilson's disease.