Causes of Alport syndrome
The genetic basis of the disease is a mutation in gene a-5 of the collagen chain of type IV. This type is universal for the basal membranes of the kidney, cochlear, lens capsule, retina and the cornea of the eye, which is proven in studies using monoclonal antibodies against this collagen fraction. Recently, they indicate the possibility of using DNA probes for prenatal diagnosis of hereditary nephritis.
The importance of testing all members of the family using DNA probes to identify carriers of the mutant gene is emphasized, which is of great importance in conducting medical genetic counseling of families with this disease. However, up to 20% of families do not have relatives with kidney disease, which suggests a high incidence of spontaneous mutations in the abnormal gene. The majority of patients with hereditary nephritis in families have individuals with kidney disease, hearing loss and vision pathology; related marriages between people who have one or more ancestors, since the marriage of related individuals increases the likelihood of obtaining the same genes from both parents. Autosomal dominant and autosomal recessive and dominant, linked to the X chromosome of the transmission pathway are established.
Children are more likely to distinguish three variants of hereditary nephritis: Alport syndrome, hereditary nephritis without hearing loss and family benign hematuria.
Alport Syndrome - hereditary nephritis with hearing damage. The basis is a combined defect in the structure of the collagen of the basal membrane of the glomeruli of the kidneys, the structures of the ear and eye. The gene of the classic Alport syndrome is located at the locus 21-22 q of the long arm of the X chromosome. In most cases, it is inherited by the dominant type linked to the X chromosome. In this regard, in men, Alport syndrome is more difficult, because in women the mutant gene function is compensated by a healthy allele of the second, intact chromosome.
Genetic basis of development of hereditary nephritis are mutations in the genes of alpha chains of type IV collagen. Six a-chains of IV type G collagen are known: the genes of a5- and a6-chains (Co4A5 and Co4A5) are located on the long arm of the X chromosome in the 21-22q zone; genes of a3- and a4-chains (Co4A3 and Co4A4) - on the 2-nd chromosome; genes of a1- and a2-chains (Co4A1 and Co4A2) - on the 13th chromosome.
In most cases (80-85%), an X-linked type of disease inheritance is associated with damage to the Co4A5 gene due to deletion, point mutations or splicing disorders. Currently, more than 200 mutations of the gene Kol4A5, responsible for the violation of synthesis of a5-chains of collagen type IV, are found. In this type of inheritance, the disease manifests itself in children of both sexes, but in boys it is more difficult.
Mutations in the loci of the genes Co4A3 and Co4A4, responsible for the synthesis of a3 and a4 - chains of type IV collagen, are inherited autosomally. According to research, autosomal dominant type of inheritance is observed in 16% of cases of hereditary nephritis, autosomal recessive - in 6% of patients. There are about 10 mutations of the genes of Co4A3 and Co4A4.
The result of mutations is a violation of the processes of assembly of type IV collagen, leading to a disruption in its structure. Collagen type IV is one of the main components of the glomerular basement membrane, the cochlear apparatus and the lens of the eye, the pathology of which will be revealed in the clinic of hereditary nephritis.
Collagen type IV, which is part of the glomerular basement membrane, consists mainly of two al-chains (IV) and one a2-chain (IV), and also contains a3, a4, a5-chains. Most often, with X-linked inheritance, the mutation of the Co4A5 gene is accompanied by the absence of a3, a4, a5 and a6 chains in the structure of type IV collagen, and the number of o1 and a2 chains in the glomerular basement membrane increases. The mechanism of this phenomenon is unclear, it is assumed that the cause is the posttranscriptional changes in mRNA.
The absence of a3-, a4- and a5-chains in the structure of type IV collagen of the basal glomeruli membranes leads to their thinning and brittleness in the early stages of Alport syndrome, which is clinically manifested more often by hematuria (less often hematuria with proteinuria or only proteinuria), hearing loss and lenticone. Further progression of the disease leads to a thickening and disruption of the permeability of the basal membranes in the late stages of the disease, with the proliferation of collagen V and VI types, manifested in the growth of proteinuria and the reduction of renal functions.
The nature of the mutation underlying hereditary nephritis largely determines its phenotypic manifestation. When deletion of the X chromosome with a simultaneous mutation of the genes Co4A5 and Co4A6, responsible for the synthesis of the a5 and a6 chains of type IV collagen, Alport syndrome is combined with the esophageal and genital organs leiomyomatosis. According to the research data, the mutation of the Co4A5 gene associated with deletion shows a great severity of the pathological process, a combination of renal damage with extrarenal manifestations and early development of chronic renal failure, compared to the stem mutation of this gene.
Morphologically, electron microscopy reveals the thinning and delamination of glomerular basal membranes (especially lamina densa) and the presence of electronically dense granules. The lesion of the glomerulus may be non-uniform in the same patient, from minimal focal lesion of mesangium to glomerulosclerosis. Glomerulitis in Alport syndrome is always immune-negative, which distinguishes it from glomerulonephritis. Characteristic are the development of canal atrophy, lymphohistiocyte infiltration, the presence of "foam cells" with inclusions of lipids - lipofagi. With the progression of the disease, a thickening and marked destruction of the basal glomeruli membranes are revealed.
Certain changes in the state of the immune system are revealed. In patients with hereditary nephritis, a decrease in the level of Ig A and a tendency to increase the concentration of IgM in the blood are noted, the level of IgG can be increased in the early stages of the development of the disease and decrease in late terms. Perhaps an increase in the concentration of IgM and G is a kind of compensatory response in response to a deficit of IgA.
The functional activity of the T-lymphocyte system is reduced; there is a selective decrease in B-lymphocytes responsible for the synthesis of Ig A, the phagocytic link of immunity is violated, mainly due to the violation of chemotaxis and intracellular digestion in neutrophils
In the study of the kidney biopsy in patients with Alport syndrome according to electron microscopy, ultrastructural changes in the basal glomerular membrane are observed: thinning, structural breakdown and splitting of glomerular basal membranes with a change in its thickness and uneven contours. In the early stages of hereditary nephritis, the defect determines the thinning and fragility of the glomerular basal membranes.
Thinning of glomerular membranes is a more favorable sign and is more common in girls. A more constant electron microscopic feature in hereditary nephritis is the cleavage of the basal membrane, and the severity of its destruction correlates with the severity of the process.