General characteristics and main groups
Hereditary pathology represents an extensive branch of medicine that studies diseases through the prism of the fundamental laws of general genetics. Globally, the classification is based on the etiological principle: it takes into account the specific type of mutations and the nature of the interaction between the altered genotype and environmental factors.
All hereditary pathologies are divided into five fundamental groups:
- Monogenic diseases — caused by mutations at the level of individual genes.
- Chromosomal diseases — associated with changes in the structure or number of chromosomes.
- Diseases with hereditary predisposition — an external triggering factor is required for their development.
- Genetic diseases of somatic cells — mutations occur in body cells rather than germ cells.
- Diseases with genetic incompatibility — an immune or genetic conflict between the mother's organism and the fetus.
The clinical presentation of these pathologies has a number of characteristic features. First of all, this is a familial pattern of transmission and, in the vast majority of cases, a congenital nature. The diseases run a chronic course, often accompanied by multiple combined alterations—congenital malformations of several organ systems at once. An important and severe feature is their resistance (high tolerance) to basic, traditional therapeutic methods.
The timing of manifestation, i.e., the appearance of pathology in ontogeny, is distributed unevenly. A quarter of all cases (25%) develop prenatally. The bulk of diseases (45%) manifest in the pre-pubertal period. About 20% of pathologies appear during puberty, and only 10% of diagnoses first make themselves known in patients older than 20 years.
Mechanisms of development of monogenic diseases
Monogenic diseases represent a very heterogeneous group of conditions whose primary cause is mutations at the gene level. The pathogenesis of these states is related to the fact that mutations can affect both the coding and regulatory parts of a gene. Because of this, the normal activity of vital proteins and enzymes is disrupted. The final clinical presentation always depends on which specific protein product was controlled by the altered gene and what the nature of its functional impairment is.
The etiology of monogenic diseases boils down to five main types of mutations:
- Missense mutations: a point substitution of a nucleotide occurs, which alters the biological meaning of the codon. As a result, a defective protein is synthesized.
- Nonsense mutations: due to a coding error, a stop codon appears suddenly. This leads to premature termination (stopping) of protein synthesis, resulting in a shortened protein.
- Frameshift: occurs when a deletion (loss) or insertion of nucleotides takes place in a number not a multiple of three.
- Splicing errors: defects in molecular editing. Errors occur during the excision of non-informative regions (introns) and the joining of coding sequences (exons).
- Expansion of trinucleotide repeats: so-called repeat expansion, when certain sequences of three nucleotides multiply uncontrollably within the gene structure.
Principles of classification of monogenic diseases
Due to the vast diversity of pathologies caused by mutations, specialists use three main classification principles.
The first is the genetic principle. It is strictly based on the type of trait inheritance in the pedigree. Autosomal dominant and autosomal recessive diseases are distinguished here. Pathologies linked to sex chromosomes are considered separately: X-linked dominant, X-linked recessive, as well as Y-linked (holandric) disorders. In addition, this group includes mitochondrial diseases transmitted via the maternal line.
The second is the clinical principle. It is based on which system or organ undergoes primary involvement. This classification is considered rather arbitrary, as genetic diseases often affect the entire body at once. Nevertheless, according to it, nervous, neuromuscular, skin, endocrine, psychiatric disorders, as well as blood and musculoskeletal diseases are distinguished.
The third is the pathogenetic principle. It is based on the direct mechanism of development (pathogenesis) of the disease. According to this principle, two large-scale groups are distinguished: inborn errors of metabolism and congenital malformations.
Briefly: answers to topical questions
Which specific syndromes belong to chromosomal diseases?
Chromosomal diseases include pathologies associated with changes in the number or structure of chromosomes, among which autosome and sex chromosome aneuploidies are distinguished.
- Down syndrome — trisomy 21 (47, 21+).
- Patau syndrome — trisomy 13.
- Edwards syndrome — trisomy 18.
- Turner syndrome — sex chromosome monosomy (45, X0).
- Klinefelter syndrome — sex chromosome polysomy (47, XXY).
- Trisomy X syndrome — polysomy (47, XXX).
Which diseases belong to the group of diseases with hereditary predisposition?
Diseases with hereditary predisposition (multifactorial) include pathologies whose development is determined by a combination of multiple genes and the mandatory impact of the environment.
- Psychiatric and nervous diseases — schizophrenia, epilepsy, manic-depressive psychosis, multiple sclerosis.
- Middle-age somatic diseases — psoriasis, bronchial asthma, peptic ulcer of the stomach and duodenum, coronary heart disease (CHD), hypertension, diabetes mellitus.
What is the mechanism of development of mitochondrial diseases?
The mechanism of development of mitochondrial diseases is associated with impaired structure and biochemical processes in mitochondria.
- Mutations in the mitochondrial genome exhibit a maternal pattern of transmission, since mitochondria are of maternal origin and are derived from the egg cytoplasm.
- Mutations in nuclear genes are inherited in a Mendelian manner; the nuclear genome controls the synthesis of most proteins involved in oxidative phosphorylation.
The clinical presentation of mitochondrial diseases is characterized by a diversity of manifestations: delayed physical development, lesions of various parts of the nervous system, myopathies, cardiomyopathies, and liver failure.
What pathologies occur in case of genetic incompatibility between mother and fetus?
Genetic incompatibility between mother and fetus leads to pathologies caused by the mother's immunological reaction to fetal antigens.
- Hemolytic disease of the newborn (HDN) — the most typical and studied disease of this group; in Rh incompatibility, hemolytic jaundice and severe anemia are possible.
- Fetal hydrops — may be caused by isoimmunization.
- Miscarriage or stillbirth — listed among the consequences of immunological conflict for the fetus/child.
GP — three principles of classification of monogenic diseases: Genetic (how it is transmitted), Clinical (where it manifests), Pathogenetic (how it develops).
Class and exam questions
At what age do hereditary diseases most commonly manifest for the first time?
The highest number of cases (45%) manifest in the pre-pubertal period. Another 25% are detected prenatally, 20% in puberty, and only 10% in individuals older than 20 years.
How does a missense mutation differ from a nonsense mutation?
In a missense mutation, the meaning of the codon is altered, leading to the incorporation of the wrong amino acid into the protein. A nonsense mutation creates a stop codon that causes premature termination of protein synthesis.
What is a splicing defect?
This is an error at the RNA maturation stage, during which non-coding regions (introns) are excised incorrectly, and coding regions (exons) are joined with defects.
What else to study on this topic
- Autosomal dominant and autosomal recessive types of inheritance
- X-linked, Y-linked, and mitochondrial diseases
- Chromosomal diseases and types of chromosomal aberrations
- Diseases with hereditary predisposition (multifactorial)
- Genetic incompatibility between mother and fetus (Rh conflict and others)
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