MEDICAL BIOLOGY, HUMAN ANATOMY, PHYSIOLOGY, AND PATHOLOGY - Ya.I. Fedonyuk 2010

BIOLOGY

SECTION 1. BIOLOGICAL BASES OF HUMAN VITAL ACTIVITY

1.4. ONTOGENETIC LEVEL OF LIFE ORGANIZATION

1.4.2. Fundamentals of Human Genetics

Gene (Molecular) Diseases

Gene diseases are hereditary disorders caused by Gene Mutations. Their underlying cause is an alteration in the Chemical Structure of a gene (DNA molecule), which is why they are also referred to as molecular diseases. Classical gene mutations are inherited as Mendelian traits and result from a mutation in a single gene (Monogenic Diseases). Generative mutations are considered full forms. Mosaic forms are also known to occur when mutations arise during early Cleavage Stages of the zygote within a single Cell. Such an Organism will be mosaic for the given gene, with some Cells containing the normal allele and others the mutant one. Mosaic forms of gene diseases can be diagnosed using modern molecular-Genetic Methods.

Monogenic and polygenic diseases are distinguished. Monogenic diseases are caused by the action of a single mutant gene. Polygenic diseases are determined by multiple genes, the expression of which depends on environmental factors. Monogenic diseases are inherited in accordance with G. Mendel's Laws. Depending on the mode of inheritance, Monogenic Disorders are classified as autosomal dominant, autosomal recessive,

Autosomal dominant diseases are caused by a mutation of a dominant gene in an autosome, with an Autosomal dominant inheritance pattern. The pathological trait appears in every generation. The gene manifests phenotypically in both homozygous AA and heterozygous Aa states, provided there is complete penetrance and expressivity. The clinical course is more severe in homozygotes than in heterozygotes. Recessive homozygotes aa are unaffected. Examples of Autosomal Dominant Disorders include Marfan Syndrome, Achondroplasia, Huntington's chorea, Polycystic Kidney Disease, aniridia (absence of the iris), hypercholesterolemia, Steinert's disease, polydactyly (6 or more digits), and brachydactyly (short fingers/toes).

Autosomal recessive diseases are caused by a mutation of a recessive gene in an autosome, with an Autosomal Recessive Inheritance pattern. Only recessive homozygotes (aa) are affected; heterozygotes (Aa) do not manifest the disease, but are carriers of the pathological gene. This group of hereditary disorders includes phenylketonuria, galactosemia, cystic fibrosis, spinal muscular atrophy, primary hemochromatosis, amaurotic idiocy, and others.

Cystic fibrosis is a hereditary autosomal recessive disorder associated with impaired transport of Cl^- and Na⁺ ions across cell membranes. The disease is caused by a mutation in a gene (chromosome 7) that determines the Synthesis of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in epithelial cells. This leads to excessive chloride excretion, which causes hypersecretion of thick mucus in the Cells of the endocrine Pancreas, bronchial epithelium, and gastrointestinal mucosa. Elevated concentrations of Cl^- and Na⁺ ions are detected in sweat, serving as the primary diagnostic test. Four Clinical forms of cystic fibrosis are distinguished: intestinal, bronchopulmonary, and mixed, which manifest in early childhood, as well as congenital—meconium ileus in newborns (complete intestinal obstruction).

X-linked dominant diseases are caused by a mutation of a dominant gene on the X chromosome. A key feature is that an affected father (X^{^}Y) will have all daughters affected and all sons unaffected (p. 94). This group of disorders includes hypophosphatemia (vitamin D-resistant Rickets), Goltz syndrome (focal dermal hypoplasia), and Coffin-Lowry syndrome (intellectual disability and osteocartilaginous anomalies).

Vitamin D-resistant rickets (hypophosphatemia) is a form of rickets that does not respond to vitamin D Treatment. Hypophosphatemia can be detected immediately after birth, while signs of rickets appear at the end of the first or beginning of the second year of life when children begin to walk. The most pronounced changes affect the lower limbs, specifically the curvature of long tubular bones. Characteristic features include short stature, limited mobility in large joints, dolichocephaly, and nail Dysplasia (impaired nail formation). The condition is caused by decreased tubular reabsorption of phosphates in the Kidneys.

X-linked recessive diseases are caused by a mutation of a recessive gene on the X chromosome, following an X-linked recessive inheritance pattern. This group of disorders includes hemophilia, color blindness (daltonism), Duchenne muscular dystrophy, Lesch-Nyhan syndrome, and others.

Hemophilia is a classic example of an X-linked recessive abnormal gene that manifests phenotypically in males. In heterozygous females, its effect is suppressed by the dominant allele for normal Blood clotting. Fathers with hemophilia never transmit the hemophilia gene to their sons; consequently, their sons are healthy, but all their daughters are born as carriers of the disease. Various clinical manifestations of hemophilia exist, ranging from mild bleeding to massive hemorrhages, likely depending on different mutations within the same gene. The two most common forms are hemophilia A and B, which are characterized by a deficiency of different antihemophilic globulins in Blood Plasma. The incidence ratio of hemophilia A to B is 5:1, and both forms occur with a frequency of 1 in 5,000 newborn boys.

Color blindness (daltonism) is one of the most common hereditary disorders inherited via the X chromosome. It is characterized by impaired color perception (primarily red and green). Its inheritance principles are identical to those of hemophilia.

Y-linked diseases. The mutant gene is localized in the non-homologous region of the Y chromosome, with inheritance strictly along the male line. Examples include hypertrichosis and ichthyosis.