Louis bar first signs after 4 years. Louis-Bar syndrome: symptoms, diagnostic methods and therapy

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The disease was first described as “progressive familial choreoathetosis” (Syllaba, Henner, 1926; Louis Bar, 1941; Wells, Shy, 1957).

Inherited in an autosomal recessive manner.

The incidence of the disease varies in different populations from 1 in 40 thousand to 1 in 100-300 thousand people.

The frequency of heterozygous carriers can range from 0.7 to 7.7%, with the most likely value being 2.8%. The average mutant allele frequency is 0.007 (Swift et al., 1987).

Louis-Bar syndrome manifests itself from early childhood with progressive cerebellar ataxia during the first attempts to walk. Subsequently, lesions of the striopallidal system appear in the form of hypokinesia, choreathetoid hyperkinesis in the muscles of the face and arms, intention tremor and incoordination increase, and speech disorders appear in the form of dysarthria with slow pronunciation of words.

Patients have symptoms of diencephalic disorders, and also exhibit symptoms of slowly progressive mental retardation to a significant extent. Less commonly, a parkinson-like syndrome with rigidity and hypomimia develops. At the age of 3-6 years, telangiectasias appear, first on the conjunctiva of the eyeballs (Fig. 94), and subsequently on the eyelids, face, ears, on the mucous membrane of the oral cavity, soft and hard palate, and limbs.

Rice. 94. Telangiectasia on the conjunctiva of the eyeballs with Louis-Bar syndrome

On the skin there are coffee-colored spots, single angiomas, areas of hyper- and hypopigmentation, keratosis, and scleroderma. The ability to move independently disappears by 10-15 years. One of the most significant symptoms of the disease is an immunodeficiency state, manifested by an increased tendency to respiratory diseases, sinusitis, pneumonia with the development of bronchiectasis and pneumosclerosis against the background of hypogammaglobulinemia and thymic dysplasia, as well as delayed physical development.

Extraneural manifestations of Louis-Bar syndrome include endocrine disorders such as hypogenitalism, hypoplasia of the uterus and ovaries, and in men - disorders of spermatogenesis, the formation of a high-pitched voice. Changes in the skeletal system are not excluded. A feature of this disease is early progeric changes: graying of hair, skin atrophy, disappearance of subcutaneous fat in the facial area, chronic seborrheic blepharitis and dermatitis, senile keratosis.

In the blood serum of patients there is a high concentration of fetal liver protein - alpha-fetoprotein. A pathological examination reveals atrophy and gliosis of the cerebellum, globus pallidus, substantia nigra, multiple telangiectasias in the brain substance, as well as aplasia of the thymus, underdevelopment of the adenohypophysis, and bronchiectasis.

Patients are characterized by an increased tendency to malignant neoplasms, most often of lymphoid tissue. Women with ataxia-telangiectasia have a significantly increased incidence of breast cancer. Heterozygous carriers of the disease may have skin changes, an immunodeficiency state, and a significant increase in the incidence of malignant neoplasms.

In a retrospective analysis of two groups of subjects - adult blood relatives of patients (1599 people) and their spouses (821 people), conducted in 131 families with ataxia-telangiectasia - it was shown that the incidence of cancer was significantly higher in the first group (Swift et al. , 1991). A particularly high incidence of malignant neoplasms was observed in the subgroup of relatives who were reliably known to be heterozygous carriers of the ATM gene (294 people).

Among male carriers of the ATM gene, the risk of developing cancer of any location was increased by 3.8 times compared to non-carriers, and among female carriers - by 3.5 times, and the likelihood of developing breast cancer in these women was increased by 5.1 times. The incidence of mortality from any cause in the group of blood relatives of patients, both men and women, was also increased by 3 and 2.6 times, respectively, and this was especially noticeable in the age period from 20 to 59 years.

Ataxia-telangiectasia is characterized by a progressive course. The most common causes of death are oncological diseases: various forms of malignant lymphomas, medulloblastoma, astrocytoma, breast, skin, kidney, ovarian cancer, as well as intercurrent diseases. The vital prognosis is unfavorable. Patients usually die in the second or early third decade of life.

A number of features characterize cultured cells from patients with ataxia-telangiectasia. They have a shorter lifespan, require the presence of more serum growth factors, and are prone to the formation of cytoskeletal defects. In addition, there is an increased incidence of chromosomal breaks, structural rearrangements and point mutations in somatic tissues in vivo and in cultured cells of patients.

Patients with ataxia-telangiectasia and their cultured cell lines are extremely sensitive to ionizing radiation and radio-mimicking drugs, just as cells from patients with xeroderma pigmentosum are sensitive to ultraviolet light. Cells from patients with Louis-Bar syndrome are abnormally resistant to the inhibitory effect of ionizing radiation on synthesis deoxyribonucleic acid (DNA) and progression through the cell cycle, which suggests the presence of defects at the checkpoint of the transition from G1 to 02 phases of the cell cycle.

This latter feature is used to identify complementation groups in the classical form of the disease (Jaspers et al., 1988). The method for identifying complementation groups is based on the analysis of the radiation sensitivity of heterodicaryons obtained by fusion of cultured fibroblasts from unrelated patients. Patients are assigned to different complementation groups if the radiosensitivity of the hybrid cells formed during this fusion is normalized.

Such a diagnosis makes it possible to divide patients with ataxia-telangiectasia into at least four complementation groups - A, C, D and E, the frequencies of which among patients are 55%, 28%, 14% and 3%, respectively (Jaspers et al., 1989) . The very existence of such complementation groups was considered a factor of clinical and possibly genetic heterogeneity. However, it was unclear whether these groups represented mutant variants of four different genes or were alleles of a single gene capable of interallelic complementation.

Heterozygous carriers of mutations in the ataxia-telangiectasia gene cannot be clinically diagnosed, although they have an increased risk of developing neoplasia and have increased radiosensitivity. Obviously, identifying heterozygous carriers of recessive mutations associated with severe monogenic human diseases is an important practical task that contributes to the prevention of such diseases.

A relatively recently developed method for analyzing gene expression profiles, based on the use of modern microarray technology, allows one to reliably identify heterozygous carriers of mutations in the ataxia-telangiectasia gene (Watts et al., 2002). It turned out that in the culture of heterozygous lymphoblasts there are characteristic changes in the expression levels of many genes, which are especially obvious when the cells are irradiated. Thus, heterozygous carriers of mutations in the ataxia-telangiectasia gene are characterized by a certain “expression phenotype,” the analysis of which allows not only to diagnose such patients, but also to study the molecular nature of the increased radiosensitivity of heterozygous cells.

One of the most rapid diagnostic tests for ataxia-telangiectasia is based on the hypersensitivity of cultured patient lymphocytes to gamma irradiation. It has been shown that this test, performed on a culture of fetal chorionic cells, can be effectively used for prenatal diagnosis of the disease already in the first trimester of pregnancy (Uerena et al., 1989).

During pathomorphological examination, degenerative changes are observed in the cerebellar cortex, with the vermis being affected to a greater extent than the hemispheres, as well as in the dentate nucleus, inferior olives, subcortical ganglia, posterior columns of the spinal cord, spinocerebellar and hemispheric tracts, and peripheral nerves. Malignant tumors of various locations can also be diagnosed outside the nervous system.

We observed 14 patients with Louis-Bar syndrome; no familial cases were registered. When studying the karyotype in one case, several cell lines with a chromosomal imbalance were identified, indicating genome instability - 48, XX, +6, +8, t(7;14) (q36;q11)/46, XX, t(7; 14)/48, XX+6+8/46, XX/47, XX+8.

Genetic instability in ataxia-telangiectasia

Most often, chromosome 14 and especially the 14q12 region are involved in rearrangements. A specific rearrangement t(14;14)(q12;q32) is found in T cells of 10% of patients with ataxia-telangiectasia. Characteristic disorders are also pericentric inversions of chromosome 7. In ataxia-telangiectasia, a new type of rearrangement between chromosomes 7 and a 14-telomere-centromere translocation (tct) following a double duplication has been described (Aurias et al., 1988).

The sites of chromosome breaks during rearrangements -7q14, 7q35,14q12,14qter, 2p11, 2p12 and 2q11-q12, often correspond to the sites of localization of members of the immunoglobulin superfamily of genes: IGK, IGH, IGL, TCRA, TCRB, TCRG (Gatti et al., 1985; Aurias et al., 1986). The factor that causes chromosomal rearrangements in ataxia-telangiectasia is a soluble peptide with a molecular weight of 500 to 1000 kDa (Shaham and Becker, 1981). It is present in the plasma of patients and in the culture medium of fibroblasts from patients, but is absent in the extract of the fibroblasts themselves.

Telomeric chromosome fusions are frequently observed in cultured T lymphocytes from patients with ataxia-telangiectasia (Kojis et al., 1989). Such fusions are facilitated by telomere shortening, which naturally occurs during ontogenesis and, in accordance with modern concepts, is considered as one of the factors of human aging. In patients with ataxia-telangiectasia, the rate of telomere shortening has been shown to increase with age (Metkalfe et al., 1996).

The frequency of intrachromosomal recombination in cultured fibroblasts from patients with ataxia-telangiectasia is 30-200 times higher than in control lines (Meup, 1993). In this case, the frequencies of interchromosomal recombination are close to normal. Increased frequency of recombination is another factor of genetic instability, which, apparently, may contribute to the increased incidence of malignancies in ataxia-telangiectasia.

All of the above features of ataxia-telangiectasia suggest that the main defect in this disease is associated with a system of negative regulation of the cell cycle, aimed at maintaining genetic stability.

ATM gene mapping

Further analysis using a panel of 10 markers localized the ATM gene to the 11q23 region, with the genes of four complementation groups - A, C, D and E, representing about 97% of all families with ataxia-telangiectasia, mapped to the same cytogenetic region.

Linkage analysis of the ATM gene with DNA markers of this region, carried out in more than 180 families with ataxia-telangiectasia living in different parts of the world, did not reveal any genetic heterogeneity of the disease (Gatti et al., 1993). In all but two families, the mutant gene mapped to region 11 q22.3 over a 6-cM region.

Linkage analysis of the ATM gene with variable microsatellite repeats, carried out on the basis of an interlaboratory consortium in 176 families from the USA, Great Britain, Turkey, Italy and Israel, limited the localization region of the candidate gene to markers located at a distance of about 500 kb from each other. In this case, the maximum linkage was shown for the D11S535 locus.

Identification of the ATM gene

The search for transcribed sequences was carried out using two methods: (1) hybridization of genomic DNA immobilized on a solid matrix, isolated from cosmid and YAC clones, with a set complementary deoxyribonucleic acid (cDNA) from various tissue-specific gene libraries and (2) exon amplification. Using the radiation hybrid technique, selected cDNA fragments and amplified exons were remapped to the 11q22-q23 region.

Thus, a detailed expression map of this region was constructed. Pools of contiguous cDNA fragments and exons presumably representing the same transcription units were used to rescreen tissue-specific cDNA libraries. It turned out that a cluster of five cDNA fragments and three exons, closely linked to the D11S535 marker, is localized in one cDNA clone of 5.9 kb in size, isolated from a fibroblast gene library.

In addition, 10 other cDNA clones were isolated from various libraries, hybridizing with isolated expression sequences and containing overlapping smaller cDNA fragments. The 5.9-kb cDNA contained an open reading frame consisting of 5124 nucleotides and including a stop codon, 538 nucleotides of the 3" untranslated region with a poly(A) signal, and 259 nucleotides of the 5" untranslated region, which is a fragment of the intron.

Comparison of this cDNA with a physical map of the genomic region showed that the corresponding gene is transcribed in a centromere-to-telomere direction. This evolutionarily conserved gene is expressed in all cell and tissue types studied. The size of the main RNA transcript is 12 kb. In addition, minor template ribonucleic acids (mRNA) of varying length, possibly representing products of alternative splicing.

In a systematic screening of mutations in the identified gene in cell lines of patients with ataxia-telangiectasia and in families of various ethnic origins, small deletions or insertions were found, often accompanied by a frameshift or leading to the loss of 1-3 amino acids in conserved regions of the protein (Savitsky et al. , 1995a; Vorechovsky et al., 1998). Thus, it was proven that this particular gene, called ATM (ataxia-telangiectasia mutated), is responsible for Louis-Bar syndrome. Mutations in the new gene were found in patients with various complementation forms of ataxia-telangiectasia, which was evidence of their allelic nature.

The coding portion of the ATM gene consists of 68 small exons distributed over an area of ​​150 kb of genomic DNA (Uziel et al., 1996; Rasio et al., 1995). The first two exons of the gene, 1a and 1b, are alternatively spliced. The ATM gene is one of the members of the ATM-related gene family involved in cell cycle regulation, telomere length control and/or response to flHK damage (Zakian V.A. 1995).

A candidate gene for ataxia-telangiectasia (termed ATDC by the authors) was independently identified by another research group (Brzoska et al., 1995). Its involvement in the development of the disease was proven by studying the ability to inhibit sensitivity to radioionizing radiation in primary cultures of fibroblasts obtained from patients with complementation group D ataxia-telangiectasia.

Primary biochemical defect. Two groups of observations contributed to a better understanding of the molecular basis of the pathogenesis of ataxia-telangiectasia: (1) the main cause of death of irradiated cultured cells of patients is the unusual nature of p33-mediated apoptosis, (2) the ATM gene belongs to a family of highly conserved genes, the products of which are necessary for the passage of cell checkpoints cycle.

To explain the pleiotropic phenotype observed in ataxia-telangiectasia, a model has been developed in which the ATM gene product (Atm) plays a critical role in a signal transduction network that activates multiple cellular functions in response to DNA damage (Meup, 1995). According to this model, the primary defect in ataxia-telangiectasia is not directly related to the DNA repair system. The Atm protein activates at least five cellular functions upon DNA damage: prevents p53-mediated apoptosis, activates the function of p53 in relation to the induction of the DNA repair system and the passage of the G1-S checkpoint, and directs the passage of S phase and the G2-M checkpoint.

A functional defect in the ATM gene results in the inability to (1) inhibit the passage of DNA damage checkpoints, (2) activate the DNA repair system when it is damaged, and (3) prevent switching to apoptosis upon spontaneous or induced DNA damage. As a result, disturbances in the normal process of ontogenetic rearrangement of immunoglobulin genes may occur, leading to genetic instability and carcinogenesis. Disruption of the apoptotic system is responsible for the increased radiosensitivity of homozygotes and patient-specific cell death leading to cerebellar ataxia, thymic atrophy, lymphocytopenia and germ cell deficiency.

The full-length cDNA of the ATM gene encodes the ubiquitously expressed Atm protein, consisting of 3058 amino acids with a molecular weight of approximately 350 kDa (Savitsky et al., 1995b; Byrd et al., 1996). In cultured fibroblasts, as well as in other cells in vivo, this protein is predominantly localized in the nuclei, although in lymphoid tissues it is present in both nuclear and microsomal fractions (Brown et al., 1997). At all stages of the cell cycle, its level and localization remain constant. Gamma irradiation of normal cells or treatment of them with radio-mimic drugs (in particular, neocarzinostatin) does not affect the level of Atm, in contrast to p53, the content of which increases sharply under these effects.

The Atm protein has significant similarities to a family of eukaryotic signal transduction mediators involved in the regulation of cell cycle checkpoint transition (Rotman and Shiloh, 1998). In primary cell cultures obtained from patients with ataxia-telangiectasia, this transition system is disrupted (Painter et al., 1982). Enzymatic control of progression through the cell cycle, recombination, and cell response to DNA damage is carried out by high-molecular-weight proteins belonging to the family Phosphotidylinositol 3"-kinase (PI3"K).

Such kinases for the G1 phase of the cell cycle are TOR1 and TOR2 in yeast and their homologues in mammals, designated mTOR or RAFT in rats and FRAP in humans. The greatest similarity between Atm and yeast proteins, reaching 32-42%, is observed in the C-terminal region, consisting of 400 amino acid residues. This region is very similar to the lipid kinase domain of the p110 catalytic subunit, a mediator of PI3"K-type signal transduction in mammalian cells. However, Atm does not have lipid kinase activity, but is a specific serine/threonine kinase.

The most functionally significant target of Atm catalytic activity is the suppressor protein p53. Normally, with gamma irradiation, the level of p53 increases 3-5 times, but such induction does not occur in the cells of patients. In this regard, it has been proposed that the ataxia-telangiectasia gene product acts at an earlier stage than p53 in the metabolic pathway leading to the activation of the G1-S and G2-M transitions (Kastan et al., 1992).

The Atm protein, which has endogenous kinase activity, phosphorylates p53 at serine 15 (Banin et al., 1998; Canman et al., 1998). Bo interaction with p53 involves two regions of Atm, one of which, located at the C-terminus, corresponds to the PI3"-kinase domain (Khanna et al., 1998). Under ionizing irradiation (as opposed to UV irradiation), the kinase activity of Atm in relation to to p53 increases rapidly.

In response to genotoxic stress, the affinity of p53 for specific DNA sequences increases. In vitro, this process is regulated by the C-terminal sequences of p53, which contain two serine phosphorylation sites. In non-irradiated cells, serines at positions 376 and 378 are phosphorylated. Ionizing irradiation dephosphorylates ser378, which is necessary to create a consensus binding site for 14-3-3 proteins, after which the affinity of p53 for specific DNA sequences increases (Waterman et al., 1998).

When cells mutant for the ATM gene are irradiated, ser376 in the p53 protein remains phosphorylated, and p53 does not bind to 14-3-3 proteins. Phosphorylation of p53 by Atm kinase leads to the appearance of p21 transcriptional activity followed by cell cycle arrest. In cells defective in the ATM gene, this process slows down sharply.

Ectopic expression of the ATM gene in mutant cells restores ionizing radiation-induced p53 phosphorylation, while this activity is suppressed when antisense ATM mRNA is introduced into normal cells. Thus, one of the most important functions of Atm is the activation and stabilization of p53. Mutations in the ATM gene seriously impair the functioning of the p53-mediated cell cycle arrest system in response to DNA damage.

Cells defective in ATM are impaired in the correct response to oxidative stress (Shackelford et al., 2001). Mutant fibroblasts exhibit increased sensitivity to t-butylhydropyroxide, due to the inability to induce p53 functions necessary for the correct regulation of the G1-G2 phases of the cell cycle.

Another consequence of defective passage of the G1-S checkpoint during ionizing radiation is “radioresistant DNA synthesis,” a phenomenon that is observed in patients with ataxia-telangiectasia, who are prone to developing tumors. Initiation of DNA replication requires the appearance of cyclin-dependent kinase 2 (Cdk2), which is activated by the phosphatase Cdc25a by dephosphorylation of Cdk2. When DNA is damaged or replication stops, Cdc25a becomes inactive.

This is achieved by phosphorylation of the Chk2 signal molecule by Atm kinase and subsequent phosphorylation by C11k2 kinase of the phosphatase Cdc25a at serine at position 123 - Fig. 95 (Falck et al., 2001). As a result, DNA replication temporarily stops. Thus, the Atm-Chk2-Cdc25a-Cdk2 signaling pathway prevents “radioresistant DNA synthesis.” It has been shown that experimental inactivation of the Chk2 signaling kinase function in human cell culture leads to partial “radioresistant DNA synthesis” (Falck et al., 2002).

With overexpression of the full-length cDNA of the ATM gene in cells mutant for the ATM gene, correction of many defects that determine increased radiosensitivity occurs (Zhang et al., 1997). Thus, the survival of transduced cells after radioirradiation increases, the number of radiation-induced chromosomal aberrations decreases, “radioresistant DNA synthesis” decreases, the passage of cell cycle checkpoints is partially corrected, and stress-induced kinase activity is restored. These results prove the multiple nature of the effector functions of Atm kinase and are the basis for the development of promising approaches to gene therapy for ataxia-telangiectasia.

Rice. 95. Model of the passage of the S-phase of the cell cycle induced by ionizing radiation: A) normal; B) in cells defective in ATM

The central part of the Atm protein (between amino acid residues 95-1080) has homology with the yeast Rad3 protein, which is required for the transition of the G2-M cell cycle checkpoint. Mutations in the Rad3 gene in yeast are accompanied by increased sensitivity to gamma and ultraviolet radiation. Atm has a high percentage of homology with at least two other yeast proteins: with Esr1/Mec1, a protein simultaneously involved in DNA repair and meiotic recombination, and with the peptide sequence YBL088, encoded by the tell gene (Greenwell et al., 1995).

The med gene was identified as a yeast homolog of the ATM gene (Paulovich and Hartwell, 1995). The main function of the tell gene is to maintain normal telomere length, which determines the stability of linear eukaryotic chromosomes. Mutations in this gene in yeast lead to a sharp reduction in the number of telomeric repeats. The unusually large tell gene product (322 kD) has motifs present in PI3" kinases.

Double mutants of Schizosaccharomyces pombe for the teh and rad3 genes (teh-; rad3-) lose telomeric sequences of all three chromosomes with a high frequency (Naito et al., 1998). Due to chromosome instability, they grow poorly, forming unusually shaped colonies. However, with long-term cultivation, colonies with normal morphology appear at high frequency. All three yeast chromosomes in these colonies appear to be circular and have no telomeric sequences.

This is the first example of eukaryotic cells in which all chromosomes are circular. Derivatives of these cells form very few viable spores, indicating serious disruption of the meiotic process in cells with ring chromosomes that do not have telomeres. It turned out that the teh and med genes are functionally related, and the ATM gene product is capable of simultaneously performing the functions of each of these two yeast homologues (Morrow et al., 1995). Thus, the participation of Atm in the maintenance of telomeric regions of chromosomes is beyond doubt.

In non-irradiated cells, Atm is in a state of dimers or multimers, and its kinase domain is associated with the region surrounding the series at position 1981 (Bakkenist and Kastan, 2003). Irradiation of cells induces intermolecular autophosphorylation at serl 981, resulting in dissociation of dimers and activation of Atm kinase - Fig. 96.

Rice. 96. Model of activation of Atm-kinase during irradiation

Most Atm molecules in the cell are rapidly phosphorylated even at low doses of radiation, and their binding to phosphospecific antibodies is detected after the introduction of only a few DNA molecules containing double-strand breaks into the cell.

Changes in chromatin structure caused by double-strand breaks induce autorosphorylation at ser1981 and dissociation of Atm dimers. Activated Atm monomers migrate freely and phosphorylate substrates such as p53 and the Nbs1 protein, which is necessary for the formation of the Brc1 repair complex. Thus, activation of Atm kinase appears to be the initial event in the cell's response to irradiation, and this process does not depend on direct protein binding to broken DNA strands, but rather results from changes in chromatin structure.

Among the large number of substrates activated by Atm in response to cell irradiation with low doses of ionizing radiation, one can highlight histone H2AX and p53-binding protein 53BP1 (Fernandez-Capetillo et al., 2002). 53BP1 is one of the participants in the cell's response to DNA damage. This protein belongs to the family of Brc1-related proteins that have specific C-terminal repeats, such as the yeast protein Rad9 and the mammalian proteins Bardl, Nbs1, and Brcal itself. 53BP1 plays a central role in the regulation of the passage of S- and 02-control points under the influence of ionizing radiation or other genotoxic agents.

After cell irradiation, this protein is detected in nuclei close to double-strand breaks, where it is colocalized with the activated H2AX token. A similar arrangement of these two proteins promotes the organization of DNA damage sites and facilitates the access of the serine protein kinase Atm to specific substrates - Fig. 97 (Abraham, 2002; DiTullio et al., 2002).

Rice. 97. 53BP1-dependent pathway for regulation of cell cycle checkpoints under the influence of ionizing radiation

It turned out that activation of histone H2AX is necessary for the accumulation of the 53BP1 protein and some other factors in the chromatin structure at a distance not exceeding several megabases from the double break. The local concentration of signal transduction complexes in this area leads to amplification of the initial signal, which prevents the cell from entering the 62nd phase of mitosis - Fig. 98.

Rice. 98. Model of ATM/H2AX/53BP1-mediated regulation of passage through the G2-M checkpoint

In tumor cells expressing mutant p53, 53BP1 is constantly localized in the center of the nuclei and the ATM-dependent cell cycle checkpoint pathway is constitutively activated (Femandez-Capetillo et al., 2002).

Atm kinase activity is also required for the phosphorylation of Bgs 1, which occurs in response to cell irradiation (Cortez et al., 1999). It has been shown that in vivo and in vitro these two proteins are capable of forming a complex, after which Bgca1 is phosphorylated in the region containing clusters of serine-glutamine residues. At least 4 serines in this region are phosphorylated - serl 189, serl457, serl 524, ser1542. A cell line in which, as a result of a mutation in the BRCA1 gene, two phosphorylation sites in the corresponding protein (ser1423 and ser1524) are missing, is characterized by hypersensitivity to radiation.

Thus, phosphorylation of Brc1 by Atm kinase plays a critical role in the correct response of cells to DNA double-strand breaks. When cells are irradiated, the CtIP protein associated with Bgca1 is also hyperphosphorylated at two sites (ser664 and ser745), and this process also requires the presence of Atm kinase (Li et al., 2000). After phosphorylation, dissociation of the CtlP-Brca1 complex occurs - Fig. 99.

Rice. 99. Model of regulation of Brc1 transcriptional activity by Atm kinase

Mutations in the CTIP gene affecting phosphorylation sites disrupt the process of Brc1 release from the complex. In this case, there is a stable repression of Brcal-dependent induction of Gadd45, which occurs normally during ionizing irradiation of cells. Activation of the GADD45 gene by ionizing radiation depends on the presence of p53, and this system is also impaired in cells mutant for the ATM gene.

The authors suggest that Atm may modulate Brcal-mediated regulation of the GADD45 gene, which occurs during DNA damage. Apparently, these molecular mechanisms underlie the predisposition to breast cancer in patients with ataxia-telangiectasia and heterozygous carriers of mutations in the ATM gene. In Fig. 100 summarizes modern ideas about the signaling pathways activated by ATM kinase in response to ionizing radiation.

Rice. 100. Modern ideas about signaling pathways induced by ionizing radiation and mediated by Atm kinase

Atm has been shown to interact with two more proteins: the intermediate filament protein vimentin, which is a substrate for protein kinase C, and also with the protein kinase C inhibitor encoded by the RCSI gene (Brzoska et al., 1995). The authors proposed that Atm and protein kinase C inhibitor proteins are partners in the ionizing radiation-induced and protein kinase C-mediated signaling pathway.

Using a yeast 2-hybrid system, Atm was shown in vitro to interact with beta-adaptin, one of the components of the cytoplasmic vesicle adapter complex involved in clathrin-mediated receptor endocytosis (Lim et al., 1998). Atm also interacts with the neuronal homolog of beta-adaptin, p-NAP, which has been identified as an autoantigen in patients with cerebellar degeneration. Apparently, the ATM gene product can take part in the intracellular transport of vesicles and/or proteins, and this is another of its functions.

Mutations in the ATM gene

Similar deletions were previously found in 5 unrelated patients; they account for about 8% of all mutations identified in the ATM gene. A similar analysis conducted in 55 families with ataxia-telangiectasia identified 44 mutations, 39 of which (89%) completely inactivated Atm function (Gilad et al., 1996a). Most patients were compound heterozygotes.

In one of the review works, an analysis was carried out of more than 100 mutations identified by that time in the ATM gene (Concannon and Gatti, 1997). About 70% of mutations lead to premature termination of translation and the formation of a truncated protein. Many of them disrupt the splicing process, resulting in erroneous excision of more than half of the coding part of the gene.

In patients with ataxia-telangiectasia, homozygous for mutations leading to premature termination of translation, as a rule, truncated forms of Atm are not detected. The large size of the ATM gene, the random nature of the intragenic distribution of mutations and their diversity make it difficult to use molecular methods of analysis for diagnostic purposes or as a way to identify heterozygous carriers. This does not apply to those populations in which the founder effect can be traced. For example, among Jews of North African origin, the same type of nonsense mutation 103C-T was found, screening for which can be very effective in this ethnic group (Gilard et al., 1996b).

Another study showed that about half (48%) of mutations in the ATM gene are accompanied by abnormal splicing with subsequent formation of a truncated protein (Tegaoka et al., 1999). Less than half of the splicing mutations affected canonical splicing sites: acceptor - AG and donor - GT.

The remaining mutations occurred at less conserved splice sites, including the last nucleotide of exons, or created new splice sites in introns or exons. No immunological forms of Atm could be detected in any of the cell lines with identified splicing mutations. In a number of cases, the authors were unable to find genomic mutations that led to erroneous exon excision.

A wide range of mutations, 25% of which were missense mutations and small deletions without frameshifts, were found in UK patients with ataxia-telangiectasia associated with leukemia, lymphomas or T-cell preleukemic proliferation (Stankovic et al., 1998). In two families, whose patients had less severe cerebellar degeneration, the same type of missense mutation 7271T-G was discovered. Homo- and heterozygous carriage of this mutation is significantly associated with an increased risk of breast cancer.

Suppressor role of the ATM gene

All this suggests that ATM is one of the tumor suppressor genes. Malignant neoplasms develop in 30% of patients with ataxia-telangiectasia, that is, their risk of developing tumors is increased by more than 100 times. It appears to be no coincidence that lymphoid tumors are the most common in ataxia-telangiectasia, as well as in the p53-deficient mutant mouse strain. In lymphoid cells, DNA strand breaks normally occur during the rearrangement of immunoglobulin genes. To eliminate errors in this process, the normal functioning of the G1 checkpoint transition system during DNA damage is necessary.

In addition, heterozygotes for mutations in the ATM gene, who make up about one percent of the total population, have a 3-5 times increased risk of developing cancer. Let us recall that an increased frequency of neoplasia, in particular breast cancer, is observed in heterozygous carriers of mutations in the p53 gene - dominant Li-Fraumeni syndrome (Swift et al., 1987; 1991).

Oncological diseases in carriers of mutations in the ATM gene debut at a relatively early age. In accordance with theoretical models based on assessing the incidence of breast cancer in close relatives (mothers, sisters) of patients with ataxia-telangiectasia, about 8% of women who developed the disease before the age of 40 years carry mutations in the ATM gene. In a group of breast cancer patients aged 40 to 59 years, the proportion of heterozygous carriers of mutations in the ATM gene decreases to 2% (Easton, 1994).

To test this hypothesis, the frequency of heterozygous carriage of mutations in the ATM gene was directly assessed in a sample of 400 women with early onset breast cancer (FitzGerald et al., 1997). The survey was carried out using the above-mentioned shortened protein test (PTT), the formation of which leads to up to 70% of all mutations in the ATM gene. Two mutations were found in both the study and control groups, consisting of 200 women of the same age without breast cancer. Thus, the frequencies of mutations in the ATM gene leading to the formation of a truncated protein in the group of women with early onset breast cancer were comparable to the general population values ​​and did not exceed 1%.

These data are in conflict with the results of a study conducted in families of patients with ataxia-telangiectasia (Athma et al., 1996). A group of women who developed breast cancer was selected from among the patients' relatives. Using DNA markers flanking the ATM gene, an analysis of the carriage of mutations in the ATM gene was carried out in each of the representatives of this group. It turned out that the relative risk of developing breast cancer in carriers of mutations in the ATM gene is 3.8 compared to those relatives who did not have such mutations. This estimate of the risk of breast cancer in heterozygous carriers of mutations in the ATM gene is close to that obtained previously (Easton, 1994).

The description of families with multiple cancers, in which patients are heterozygous carriers of mutations in the ATM gene, also confirms the suppressor role of the ATM gene. In one such family, a mutation in the ATM gene resulting in an erroneous excision of exon 61 was identified in two sisters who developed breast cancer at ages 39 and 44, respectively, and in their mother, who developed breast cancer at age 67. diagnosed with kidney cancer (Bay et al., 1999). In the tumor tissues of one of the sisters, a loss of heterozygosity was detected in the localization region of three genes - ATM, BRCA1 and BRCA2.

A high frequency of heterozygous carriers of mutations in the ATM gene was found among Danish patients with sporadic breast cancer (Broeks et al., 2000). In 82 patients in this observation, breast cancer developed before the age of 45 years. Heterozygous mutations in the ATM gene were found in 7 (8.5%) women, and three of them turned out to be carriers of the same type of splicing mutation - IVS10-6T-G. According to the authors, heterozygous carriers of mutations in the ATM gene have a 9-fold increased risk of developing breast cancer at a relatively early age.

To explain the contradictory nature of the epidemiological data described above and the results of direct screening studies of mutations based on the truncated protein test, it was hypothesized that rare missense mutations in the ATM gene, as well as widespread polymorphic ones, were most associated with breast cancer. variants of this gene.

To assess the functional significance of such mutations, cell lines expressing various pathogenic missense mutations and neutral polymorphisms of the ATM gene were constructed (Scott et al., 2002). The two groups of nucleotide substitutions studied initially differed in their ability to correct the radiosensitive phenotype of ATM-deficient cells.

It turned out that only when expressing missense mutations, but not neutral polymorphisms, control cells lost the ability to induce Atm kinase activity under the influence of ionizing radiation, which resulted in chromosomal instability and a decrease in overall cell viability. At the same time, the expression levels of mutant and endogenous Atm in transduced cells were comparable.

Apparently, the mutant and normal variants of the protein compete with each other during Atm multimerization. The results of these experiments show that missense mutations, even in a heterozygous state, can have an inhibitory effect on Atm function, so their association with a predisposition to breast cancer and other oncological diseases cannot be excluded.

Mutations in the ATM gene have been found in patients with sporadic T-cell prolymphotic leukemia, a rare clonal malignant neoplasia that has features similar to mature T-cell leukemia, often developing in patients with ataxia-telangiectasia (Vorechovsky et al., 1997). 2 of the 17 identified mutations were previously described in patients with ataxia-telangiectasia.

One of them is the recurrent deletion of 9 nucleotides mentioned above, the other is a rare missense mutation identified in a patient with an atypical form of ataxia-telangiectasia. Notably, in contrast to ataxia-telangiectasia, the remaining genetic defects found in prolymphotic leukemia included a high percentage of missense mutations clustered in the region corresponding to the Atm kinase domain. Missense mutations in the ATM gene were also found in patients with B-cell non-Hodgkin lymphomas (Vorechovsky et al., 1997).

Inactivation of Atm function plays a critical role in the pathogenesis of most cases mantle cell lymphoma (MCL), the cytogenetic marker of which is the t(11;14) translocation. With this translocation, a 1-Mb DNA sequence, including the ATM locus, located at the breakpoint of chromosome 11 in the region 11q22-q23, is often deleted (Stilgenbauer et al., 1999).

Therefore, mutational analysis of the ATM gene was performed in 12 patients with MCL, seven of whom had a deletion of one copy of the ATM gene (Schaffner et al., 2000). In all seven cases, inactivating point mutations were found in the remaining allele of the ATM gene. In addition, homozygous mutations in the ATM gene were also identified in two patients who did not contain deletions in the 11q region. In 3 cases, mutations in the ATM gene were detected only in tumor cells.

Experimental models

Null mutants for the Atm gene, as well as for the p53 gene, develop mainly T-cell lymphomas. Obviously, both of these genes have a similar effect on the formation of thymocytes. The rate of formation of T-cell lymphomas sharply increases in double null mutants for the Atm and p53 genes, indicating the complementary nature of their anti-oncogenic role (Westphal et al., 1997). Loss of Atm function results in only partial resistance of thymocytes to radiation-induced apoptosis, and this resistance becomes complete with additional loss of p53 function.

When exposed to ionizing radiation, phosphorylation of the p53 protein by Atm kinase and activation of the cell cycle control signaling system in response to DNA damage occurs in the thymus. In the absence of Atm kinase, this signaling pathway does not work, which can result in immunodeficiency, abnormal cellular response to radiation, and infertility as a result of defective progression through the cell cycle in meiosis with subsequent degeneration of germ cells.

All of these symptoms are observed in patients with ataxia-telangiectasia, and similar phenotypic features are characteristic of Atm mutant mice. Disturbances in the interaction of the Atm protein with beta-adaptin in the cytoplasm can affect axonal transport and movement of vesicles in the central nervous system and this may explain the neuronal dysfunctions and neurodegenerative processes that often accompany ataxia-telangiectasia. The pleiotropy of the disease may be due to the fact that different tissues express different Atm targets and possibly express different members of the Atm protein family, the functions of which may overlap, complement, and partially replace the functions of Atm (Brown et al., 1999).

The functional homolog of Atm kinase in Drosophila melanogaster is the mei-41 gene product, which belongs to the family of P13K-containing proteins. In the mei-41 - Drosophila melanogaster lineage, defects in the transition of the G1-S and G2-M checkpoints are observed (Hari et al., 1995). In mutant homozygotes mei-41 (-/-), the process of meiotic recombination is disrupted, and therefore they are highly sensitive to the effects of ionizing radiation and various chemical mutagens. In the somatic cells of such flies, the frequency of chromosomal breaks and rearrangements is increased. The percentage of such disorders increases sharply with X-irradiation, so that after irradiation at a dose of 220 R, each cell that has passed through the metaphase of division contains at least one chromosomal defect.

Hereditary diseases associated with molecular defects in signaling pathways regulated by Atm kinase.

NBS syndrome

The NBS1 gene responsible for this disease has been identified in the 8q21 region. This gene, containing 16 exons distributed over a region of more than 50 kb of genomic DNA, is actively expressed in all tissues studied, producing two mRNA transcripts of 2.4 and 4.4 kb in size (Carney et al., 1998). In most patients with NBS syndrome, the NBS1 gene exhibits a similar deletion of five nucleotides, leading to a reading frame shift. Other mutations have also been described that are also accompanied by premature cessation of translation.

The protein encoded by the NBS1 gene is called nibrin or Nbs1. It consists of 754 amino acids and contains four domains. Two of them are homologous to domains present in proteins that regulate the passage of cell cycle checkpoints. One domain is involved in interaction with DNA and the last one has homology with the C-terminal domain of Brcal.

The main function of nibrin is to regulate the repair of double-strand DNA breaks. It turned out that nibrin is identical to the p95 protein of the repair complex, which includes five proteins: p95, p200, p400, Mre11 and Rad50 (Varon et al., 1998). It has been shown that experimental inactivation of the function of nibrin-Mre11 (as well as the Chk2 signaling kinase) in human cell culture leads to partial “radioresistant DNA synthesis” (Falck et al., 2002).

The clinical similarity of NBS syndrome and ataxia-telangiectasia provided the basis for analyzing the functional relationships between the protein products of the NBS1 and ATM genes (Lim et al., 2000; Zhao et al., 2000; Wu et al., 2000). It turned out that Atm and nibrin are participants in a common signaling pathway that mediates the normal cell response to ionizing radiation - Fig. 100.

Within an hour of irradiation of normal cells, nibrin is phosphorylated at several serine sites, including ser278, ser343, ser397, and ser615. This reaction is necessary to maintain cell radioresistance. Cells mutated at the serine phosphorylation sites of nibrin are hypersensitive to radiation. In both irradiated and intact cells in vitro and in vivo, Atm forms a complex with nibrin, and radiation-activated Atm kinase phosphorylates this protein at the sites mentioned above (Gatei et al., 2000).

Phosphorylation of nibrin by Atm kinase is necessary for the activation of the S-phase checkpoint, the formation of the nuclear repair complex: nibrin-Mre11-Rad50, and the implementation of the cellular response to radiation-induced DNA damage. Thus, the interaction between Atm and nibrin mediates the connection between DNA damage checkpoint activation and DNA repair. A similar reaction is not observed in cells deficient in ATM or carrying the S343A mutation in the NBS1 gene, which affects one of the phosphorylation sites. These biochemical abnormalities underlie the clinical similarities between the two related diseases.

Ataxia-telangiectasia-like disease

Seckel syndrome

When cells are treated with genotoxic agents, Atm/Atr-dependent phosphorylation of the Rad17 protein normally occurs at two sites ser635 and ser645. Missense mutations resulting in the substitution of serine for alanine at any of these sites impair induction of the G2 checkpoint in response to DNA damage, resulting in a dramatic increase in cell sensitivity to genotoxic stress.

Currently, the existence of two parallel pathways activated by the proximal kinases Atm and Atr in various types of DNA damage has been proven - Fig. 101.

Rice. 101. Atm/Atr-signaling chain activated by various types of DNA damage

The Atm-dependent signaling pathway is responsible for the repair of DNA double-strand breaks and can be activated at all phases of the cell cycle. The Atm-dependent signaling pathway may involve many components of the Atr-dependent signaling pathway, which is also responsible for the repair of double-strand breaks, but its activation occurs much more slowly. The main function of the Atr-dependent signaling pathway is to correct replication defects that can occur under the influence of UV irradiation or some genotoxic agents.

Thus, DNA alkylating compounds can activate both signaling pathways. Activation of Atr kinase and its partner protein Atrip, as well as their approach to the defective site, is carried out using replication protein A (Rpa), which is capable of binding to single-stranded DNA. The consequence of this is the activation of the key kinase Chk1, which inhibits Cdc25 and arrests the cell cycle in response to DNA damage.

Recently, a splicing mutation in the ATR gene was discovered in patients from two Pakistani families with Seckel syndrome (O'Driscoll et al., 2003). This is a rare autosomal recessive disease, first described by Virchow and studied in more detail by Seckel in 1960. Seckel syndrome has clinical features common to NBS syndrome.Characterized by intrauterine malnutrition and, accordingly, low birth weight during full-term pregnancy.

Specific features include microcephaly, a narrow face with a beak-shaped nose, large eyes, sparse hair, and deformed, low-lying ears. Skeletal anomalies include clinodactyly of the fifth finger and hypoplasia of the first finger, the absence of some epiphyses of the phalanges, a decrease in the proximal part of the radius, congenital dislocation of the femur, the head of the radial bone, a sandal gap, and subsequently the formation of kyphosis, scoliosis, and flat feet. Partial adontia and enamel defects are possible. Boys often have hypoplasia of the external genitalia and cryptorchidism. Psychomotor development at an early age corresponds to the norm, but later there is a significant delay and mental retardation of varying degrees of severity.

LIG4 syndrome

Bloom's syndrome (nanism with skin lesions; congenital erythema telangiectatica with growth retardation). Bloom's syndrome is another autosomal recessive disorder characterized by chromosomal instability associated with growth retardation, sun sensitivity, telangiectasia, hyper- and hypopigmentation of the skin, and predisposition to malignancy.

Bloom's syndrome was first described by D.BIoom in 1954 and has an autosomal recessive mode of inheritance (German et al., 1994, Ellis et al., 1994). Clinically characterized by low birth weight due to full-term pregnancy, micro- and dolichocephaly. The face is narrow, with a massive nose, hypoplasia of the malar bones, and butterfly-shaped telangiectatic erythema.

Skin pigmentation disorders are represented by “café au lait” pigment spots, as well as depigmented areas of the skin and ichthyosoform changes. Patients are short in stature with a proportional body structure and retain a high timbre of voice. Disorders of sexual development are characteristic: hypogenitalism with hypospadias and cryptorchidism in boys; menstrual dysfunction in girls. “Early aging” syndrome is observed.

According to immunological studies, there is a deficiency of IgA and IgG, which contributes to a predisposition to infectious diseases of the middle ear, upper respiratory tract, and after 30 years, the occurrence of malignant tumors of the lymphoreticular organs and gastrointestinal tract. An increase in the frequency of exchanges between sister chromatids in the culture of lymphocytes and fibroblasts has great diagnostic value.

We are monitoring a family with two children with the above diagnosis. Pregnancy I ended in stillbirth, pregnancy II resulted in a proband, pregnancies III-VIII ended in early miscarriages, pregnancy IX resulted in the birth of a sick girl. The presented case of Bloom's syndrome remained undifferentiated for a long time, which is associated with the phenotypic similarity of a number of genetically heterogeneous diseases.

The BLM gene, responsible for the development of the disease, is mapped to the 15q26.1 region. He codes RecQ-like protein 3 (RecQI3), part of the protein complex for the repair of double-stranded DNA breaks by homologous recombination and directly involved in the stabilization of DNA replication and repair enzymes. A direct interaction between the Atm and RecQI3 proteins has been shown (Beamish et al., 2002). The region of binding to RecQI3, located between the 82nd and 89th amino acid residues of Atm, completely coincides with the regions of Atm binding to p53 and Brcal.

Mitosis-associated hyperphosphorylation of RecQI3 is partially dependent on Atm kinase activity, as Atm phosphorylates thr99 and thrl 22 in the N-terminal region of RecQI3. Ionizing irradiation of normal cells induces dose-dependent phosphorylation of RecQI3 at thr99, and this does not occur in ATM-deficient cells. Thus, proper interaction between Atm and RecQI3 is necessary to maintain the normal radiosensitivity status of the cell.

Fanconi anemia

The activated FancD2 protein was shown to colocalize with Brcal in protein complexes induced by ionizing radiation, as well as in synaptonemal complexes of meiotic chromosomes. It turned out that when cells are irradiated, FancD2 is phosphorylated by activated Atm kinase at ser222 (Taniguchi et al., 2002). This step is necessary to induce passage of the S-phase checkpoint.

The authors determined that FancD2 phosphorylation at ser222 and monoubiquitination at Iys561 are independent post-translational modifications that regulate different signaling pathways. Homozygous inactivating mutations in the FANCD2 gene simultaneously increase the sensitivity of cells to mitomycin C and to ionizing radiation.

V.N. Gorbunova, E.N. Imyanitov, T.A. Ledashcheva, D.E. Matsko, B.M. Nikiforov

Louis-Bar syndrome was first noticed and described in France in 1941. Since then, its frequency of occurrence has increased markedly and began to be found throughout the globe.

Statistics say that in modern society, 1 person out of 40 thousand of the population has a chance of having this syndrome.

Its essence lies in the innate abnormal immune state of the body, which in particular affects the T-link and begins to manifest itself in abnormal changes throughout the body.

People suffering from the syndrome are prone to frequent infectious diseases, and also have a high chance of developing malignant tumors throughout the body.

Most often, if Louis-Bar syndrome begins to manifest itself in children at birth, then this is fraught with death, even without a chance to correctly and timely diagnose such a patient.

The disease affects both men and women in equal proportions, quickly destroying their nervous system and skin.

Causes

The syndrome can occur at the genetic level, with the slightest failures or deviations from the norm.

Such a failure is fraught with neuroectodermal dysplasia, which is congenital in such people.

The pathology is classified as an autosomal recessive disease, which can manifest itself if gene disorders were present simultaneously in both parents.

The disease tends to completely change and destroy the tissue of the cerebellum, even reaching its nucleus.

Such situations lead to degenerative changes in the cerebral cortex, as well as the spinal tract.

Louis-Bar syndrome is often combined with other genetic diseases and carefully hides its symptoms behind them.

It can be manifested only after long and difficult treatments for infectious diseases that do not give the desired result.

Severe immune disorders lead to the formation of malignant tumors, which originate in the lymphoreticular system.

Symptoms of the syndrome

In modern medicine, the pathology is quite rare, but doctors are afraid of the possible development diseases.

Since this genetic disease partially or completely destroys cellular immunity, it is pathological in nature and cannot be treated. A full life is almost impossible.

Symptoms of the disease in adulthood may not appear immediately.

Most often, it is detected by the gradual deterioration of the functioning of internal organs, damage to the immune system, and the complete or partial absence of the thymus gland.

If Louis-Bar syndrome developed in utero, affecting the cerebellum and cerebral cortex of the child, then a newborn from birth has degenerative changes and a diagnosis doomed to torment.

If at birth the baby did not show the first signs of the disease, then already at the age of 3-24 months the syndrome will begin to manifest itself quite quickly.

Most often this is expressed in a complete lack of movement, poor coordination, stagnation of mental development and external signs of development of the face and limbs.

It could be:

• muscle hypotension;
• strabismus;
• lack of reflexes and functionality of muscles and eyes.

Louis-Bar syndrome often manifests itself in persistent infectious diseases that affect the respiratory tract and ears.

This can be otitis media, pharyngitis, bronchitis, sinusitis and other diseases.

Pneumonia and pneumonia almost never appear. Each subsequent disease has a more acute form and complications that cannot be treated.

Most often this is associated with the expansion of capillaries, however, if only this symptom is present, you need to look for other options for possible diseases.

As for the external appearance of the face and eyes, telangiectasia on the eyeball first begins to appear.

This is fraught with permanent conjunctivitis, the visual signs of which can appear not only in the eyes, but also on the neck, cheeks, ears, eyelids and even on the palms.

In addition to this, the whole body becomes dry and flaky, and hair falls out profusely.

In the most advanced situations, the syndrome can provoke malignant tumors, leukemia and lymphoma.

What is done for diagnosis?

At the first signs or suspicions of a disease of this kind, any doctor makes an appointment and referral to a doctor of a more narrow specialization.

Quite often, such patients are simultaneously observed by several doctors who prescribe treatment in a joint consultation.

This could be an immunologist, dermatologist, ophthalmologist, neurologist, oncologist and otolaryngologist. Only their joint consultations will be able to distinguish this symptom from other rare and dangerous types of diseases.

The final diagnosis for such a disease is always made only by a neurologist, if he has all the results of clinical tests and laboratory tests.

Most often, certain indicators that do not correspond to the norm help to establish a diagnosis. In particular, lymphocytes may be completely absent from the blood, and the level of immunoglobulin will be much lower than normal.

In this case, there will be absolutely no antibodies to fight viral infections and diseases.

In addition, the presence of the syndrome can be indicated by an ultrasound scan, MRI and radiography, where the size and the very presence of the thymus, cerebellum and foci of malignant tumors will be visible.

When the neurologist has the final diagnosis in hand, then it is possible to prescribe a specific course and treatment regimen for such a patient.

How to prolong a patient's life?

Currently, unfortunately, the level of medicine has not reached the level to find effective and quick methods to combat this genetic disease.

Treatment methods are still the subject of search and study by many scientists. However, to maintain the life support of such patients, it is customary to use palliative symptomatic treatment.

To prolong the life of such patients, special immune therapy is prescribed, which may include various dosages of T-activin and gamma globulin.

In this case, a constant high dosage of vitamin preparations is mandatory, which are administered comprehensively to maintain the proper functioning of the entire body.

If a patient with Louis-Bar syndrome has some kind of infectious disease, then he is treated primarily with intensive therapy in order to start the process of maintaining the body at the proper level without unnecessary bacteria and viruses.

Depending on the disorders observed in the body, medications and their dosages may vary significantly. Often the course of therapy is supplemented with antifungal and antiviral drugs, as well as strong antibiotics.

Real forecasts

Since Louis-Bar syndrome is quite new and completely unstudied, it is impossible to talk about high chances for treatment, and especially for the patient’s recovery.

The pathology has an unfavorable prognosis, which, depending on various factors, can either proceed at the same level for many years or rapidly slide down.

Most often, the symptom is detected in late childhood or at the birth of a child. The average life age of such children is about 3 years.

If symptoms appear later, then such patients survive until they are 20 years old.

Most often, the cause of their death is not the Louis-Bar disease itself, but the complete destruction of the immune system and the rapid development of cancer throughout the body.

The body's predisposition to frequent infectious diseases, malignant or benign neoplasms is called Louis Bar syndrome. A rather rare, but at the same time very dangerous disease, it is inherited and occurs once in 40 thousand people. However, this figure is rather arbitrary, since the disease is not always diagnosed. So, in early infancy, a baby may die from this disease, but the cause will remain unclear.

This disease was first diagnosed in 1941 by French doctor Louis Bart. The disease is autosomal recessive disease.

Autosomal recessive- means manifested in the presence of the disease in both parents.

Louis Barr syndrome involves damage to the T-link of the immune system, which ultimately leads to its incorrect formation. The result is the frequent occurrence of infectious diseases in the child, and with each new disease its severity increases, which affects the consequences and general condition of the baby. In the future (sometimes in parallel with infections), neoplasms (usually malignant) may grow in the baby.

As a rule, a sick child can be seen because during the course of the disease the patient develops skin disorders, uneven gait (as a result of damage to the cerebellum), and developmental delays.

Reasons for the development of the disease

As mentioned earlier, Bar syndrome is a hereditary disease and is transmitted only by inheritance. If only one of the parents has chromosomal abnormalities, the child will acquire this disease with a 50% probability, but if both parents have a 100% chance of the child becoming ill.

Currently, the level of diagnostics is quite high and makes it possible to identify possible problems even at the stage of embryo formation, however, this syndrome is insidious and often the doctor only makes an assumption about what the child can acquire and gives an approximate percentage, which reassures the expectant mother.

Ocular manifestations

In order not to torment yourself with such experiences, it is enough to know which factors have a negative impact on the development of the syndrome, including:

• bad habits during pregnancy (smoking, alcohol abuse);
• frequent stress of the expectant mother;
• external influence (toxic substances, radioactive radiation).

Symptoms of the disease

Like any other disease, Louis Bar syndrome has its own distinctive features, so patients may exhibit the following symptoms:

• cerebellar ataxia;
• telangiectasia;
• infectious predisposition;
• neoplasms.

Cerebellar ataxia

This symptom appears almost from the first months of life, but becomes noticeable to the naked eye during the period when the baby begins to learn to walk. As the cerebellum is damaged, the child develops unsteady gait. In more severe forms, the baby cannot move independently or even stand.

Manifestations on the face

In addition, the patient may develop strabismus, oculomotor problems, nystagmus, and the patient may lose or decrease tendon reflexes. In addition, as a result of the disease, cerebellar dysarthria may develop, which manifests itself in the form of slurred speech.

Dysarthria is a limitation of the mobility of the speech organs (palate, tongue, lips).

Telangiectasia

This symptom is less dangerous than the previous one, but can cause some inconvenience to the baby. Telangiectasia means the presence of dilated capillaries on the skin, which look like pink or red stars or spiders. As a rule, stars from blood capillaries begin to form by the age of 3-6 years of a baby’s life.

The most common places of formation:

• eyeball;
• conjunctiva of the eyes (mucous membrane of the eye behind the lower eyelid);
• dorsum of feet;
• places of bends (elbow cavities, knee cavities, armpits).

At the very beginning, telangiectasia appears on the conjunctiva of the eyes, after which the skin of the face suffers and gradually descends further down the body. There have been cases of the formation of similar “stars” on the soft palate.

Among other things, skin rashes associated with Louis Bar syndrome include freckles, dry skin, and early graying of hair (this is especially noticeable in the case of young children).

Infectious predisposition

Any child gets sick, but as for Louis Bar syndrome, this happens abnormally often and each time the severity of these diseases increases, but any infection can cause the death of the patient.

Skin manifestations

As a rule, the disease causes only respiratory and ear infections (rhinitis, pharyngitis, bronchitis, otitis media, sinusitis).
It is worth noting that such infections are less treatable than ordinary diseases, which leads to a rather long healing process.

Neoplasms

As a rule, in the presence of Bar's syndrome, a patient is 1000 times more likely to develop malignant tumors. The most common of these are leukemia and lymphoma.

The main difficulty associated with the treatment of such patients is the inability to use radiation therapy, due to hypersensitivity patients to ionizing radiation.

Diagnostics

Clinical manifestations are not enough to make a diagnosis, since many symptoms of this disease are also characteristic of other diseases.

ailments. As a rule, a consultation of doctors is required, in which includes:

• dermatologist;
  
• otolaryngologist;
  
• ophthalmologist;
  
• immunologist;
  
• pulmonologist;
  
• oncologist;
  
• neurologist.
  

Among other things, the patient is prescribed the following tests:

Instrumental diagnostics include:

• ultrasound (ultrasound) of the thymus;
  

Thymus - or thymus gland, the organ in which The body's immune T cells mature

• magnetic resonance tomography (MRI);
• pharyngoscopy;
• rhinoscopy;
• X-ray of the lungs.

When deciphering blood tests, a low number of lymphocytes is possible. When studying immunoglobulin, a decrease in IgA and IgE is usually observed.

IgA and IgE – level A antibody titers are responsible for local immunity, and E for allergic reactions.

In addition, autoantibodies to mitochondria, thyroglobulin and immunoglobulin can be detected in the blood.

Autoantibodies – aggressive, attacking their own

Mitochondria – participate in the process of energy formation

Thyroglobulin is a protein, a precursor to thyroid hormone, found in the blood of most healthy people.

Treatment

Treatment of Louis Bar syndrome is currently an open question and an effective way to eliminate this disease does not yet exist. The basis of therapy is the elimination of emerging symptoms and prolongation of life for the patient.

So, in treatment they use:

1. Antiviral drugs.
2. Broad antibiotics.
3. Antifungal agents.
4. Glucocorticosteroids.

Since infectious diseases are difficult to treat, the patient is advised to use a complex of vitamins in large dosages to stimulate their own immune reserves.

Forecast

Due to the lack of effective treatment, the maximum life expectancy of patients diagnosed with Louis Bar syndrome does not exceed 20 years. However, only a few survive even to this age. Malignant neoplasms and serious infectious diseases kill patients much earlier.

So, until doctors have learned to treat such rare and dangerous diseases, everyone is at risk of getting sick. Well, young mothers are responsible for their unborn children, and leading an unhealthy lifestyle during pregnancy is a crime. Take care of yourself and your kids.

With this rare form of phakomatosis, neurological symptoms, skin manifestations in the form of spider-like proliferation of blood vessels (telangiectasia), and a decrease in the immunological reactivity of the body are observed. The disease is caused genetically and is inherited in an autosomal recessive manner.

A pathological examination reveals a decrease in the number of nerve cells and proliferation of blood vessels in the cerebellum.

The first signs of the disease appear between the ages of 1 and 4 years. The gait becomes unstable, awkward movements appear, and the fluency of speech (chanted speech) is disrupted. The progression of cerebellar disorders gradually leads to the fact that patients stop walking independently. Involuntary movements of the limbs and poor facial expressions are often observed. Speech is monotonous and poorly modulated.

Another characteristic sign of the disease is vascular changes in the form of telangiectasia, located on the mucous membrane of the eyes, mouth, soft and hard palate, and skin of the extremities. Telangiectasia usually occurs after ataxia, but can also be the first symptom of the disease.

Children with Louis-Bar syndrome often suffer from colds, inflammation of the paranasal sinuses, and pneumonia. These diseases often recur and take a chronic course. They are caused by a decrease in the protective immunological properties of blood and the lack of specific antibodies.

As the disease progresses, intellectual impairment intensifies, attention and memory become impaired, and the ability to abstraction decreases. Children become exhausted quickly. Changes in mood are noted. Tearfulness and irritability are replaced by euphoria and foolishness. Sometimes patients are aggressive. They lack a critical attitude towards their own defect.

In the treatment of Louis-Bar syndrome, general restoratives and drugs that improve the functionality of the nervous system are used. Attempts are being made to replace the missing immunological blood fractions by transplanting a thymus gland taken from a deceased newborn and introducing thymosin extract from the thymus gland.

Therapeutic and pedagogical measures are very limited due to frequent colds and the steady progression of the process, leading to severe intellectual impairment.

Tuberous sclerosis

Tuberous sclerosis is a rare disease characterized by peculiar skin changes, seizures and dementia. Tuberous sclerosis occurs with a frequency of 1:30,000. In institutions for the mentally retarded, such patients account for 0.3%. The disease is caused genetically and is inherited in an autosomal dominant manner.

Pathomorphological examination reveals yellowish nodules of varying sizes and dense consistency in the brain tissue. These plaques are located mainly in the cerebral cortex, white matter, and ventricular walls. Plaques are a proliferation of connective tissue with an accumulation of specific cells that are found only in this disease. In addition to brain damage, kidney tumors are often found, less often - tumors of the heart (rhabdomyomas), lungs, liver, spleen, pancreas and other organs. This systemic nature of the lesion is due to impaired development of the main germ layers.

The disease begins in early childhood, often in the first year of life. The first symptoms are seizures. The same patient may experience seizures of various shapes, durations and frequencies (minor, major, psychomotor, focal, etc.). Minor seizures in the form of nodding, salaam convulsions are more typical for children in the first year of life. Then these seizures give way to large convulsive paroxysms, which can be combined with small seizures in the form of absences, freezing, “pecking”, etc. Sometimes there is a long non-convulsive interval (more than one year). As the disease progresses, these “bright” gaps become smaller.

Another symptom of tuberous sclerosis is dementia. In some cases, signs of mental retardation are detected at an early age. Children begin to speak late, are less emotional, and have difficulty learning self-care skills and new information. Thinking is concrete. There are deviations in behavior. In the first years of life, patients still advance in mental development, although they lag behind their peers. With the appearance of convulsive seizures, and sometimes without connection with seizures, regression of mental functions is observed: speech and behavior are impaired, acquired skills are lost. The psyche gradually completely disintegrates. Most patients experience a decrease in intelligence to the degree of idiocy, less often - deep imbecility. In other cases, children develop normally during the first years of life. With the onset of convulsive seizures, and sometimes even before them, changes in character and behavior are noted. Children begin to experience difficulties in the learning process, become aggressive and angry, speech is almost completely disrupted and skills are lost.

At the age of 2-6 years, changes appear on the skin. On the face in the cheek area, multiple or single adenomas of the sebaceous glands are localized, which look like pink or bright red protruding formations, reminiscent of juvenile acne. Pigmented or depigmented spots and warty tumors may appear on the trunk and limbs; a peculiar roughness of the skin (“shagreen skin”) is noted. Sometimes there are changes in the nails and the appearance of strands of gray hair.

The diagnosis of tuberous sclerosis is confirmed by examining the fundus, which reveals characteristic grayish-yellow growths resembling mulberries. X-rays of the skull reveal multiple small calcified formations located in the area of ​​the ventricles of the brain, in the cerebral cortex, and cerebellum. Electroencephalography reveals more severe disturbances in the bioelectrical activity of the brain than in epilepsy.

The disease progresses rapidly, patients rarely live more than 20 - 25 years. Death occurs during continuous convulsions due to cerebral edema.

In the treatment of tuberous sclerosis, anticonvulsants, sedatives, and drugs that reduce intracranial pressure are used. Sometimes surgical treatment and radiotherapy are performed.

Due to severe dementia, patients require constant care and supervision. As a rule, they are not trained and are found in social welfare institutions.

The content of the article

The disease was first described by a French woman Louis Bar in 1941. Ataxia-telangiectasia is a hereditary syndrome, transmitted in an autosomal recessive manner, consisting of progressive cerebellar ataxia, telangiectasia that occurs on the skin and conjunctiva of the eyes, and an increased susceptibility to infectious diseases.

Pathological anatomy of Louis-Bar syndrome

Louis-Bar syndrome clinic

Treatment of Louis-Bar syndrome