broken chromosome. Fragile X Syndrome

The modern rapid development of medicine has made it possible to discover many previously unknown diseases for mankind. Especially great importance in the twentieth century, decoding played, which made it possible to identify the causes of many gene and chromosomal pathologies. More than 3,000 diseases associated with quantitative and qualitative changes in the genetic material are known. A relatively new pathology is Martin-Bell syndrome, which has a fairly high percentage of childhood disability.

Martin-Bell disease - a syndrome or a neurological disorder?

Martin-Bell syndrome is a congenital pathology associated with fragility of the X chromosome. The concept of "fragility" means a visual sharp narrowing of the ends of the X chromosome. Such changes confirm the Martin-Bell syndrome. The photo of children on the left indicates a lag in psychomotor development, which tends to progress from early childhood.

The reasons

As you know, the normal human genotype is 46 chromosomes, two of which are sex X and Y. In women, respectively, the chromosome set will look like - 46 XX, and in men - 46 XY. These carriers of genetic information consist of chains of repetitions of amino acids, which contain information about the structure and functions of the future living organism.

Martin-Bell disease (fragile X syndrome) develops due to changes in the X chromosome, so both women and men can get sick with it. The thinning of the X-chromosome site is due to a pathological increase in specific repeats of amino acid residues - cytosine-guanine-guanine (C-G-G). Such a combination of repetitions is present several times in other genes, but it is important, in fact, the number of these repetitions. Normally, it ranges from 29 to 31. In the case of Martin-Bell syndrome, this number is sharply increased and can occur from 230 to 4000 times, which leads to an increase in the chromosome and impaired functioning of a special gene - FMR1, which is responsible for the proper functioning and development nervous system. The result becomes apparent after a short period of time after the birth of the child and is manifested by a delay in psychomotor development.

Manifestation options

The number of repeats of cytosine-guanine-guanine causes various variants of the clinical manifestations of Martin-Bell's disease. The syndrome may have hidden forms. If the study reveals from 55 to 200 repetitions, a premutation occurs - borderline changes that make a person a carrier, but without visible changes in the nervous system. In mature and senile age, ataxic syndrome and primary ovarian failure in women may develop. In this case, the probability of transmission of the syndrome is high. An intermediate state is also distinguished - this is from 40 to 60 nucleotide repeats, which is not clinically manifested in any way and can be inherited after several generations.

Inheritance

Geneticists refer this disease to a group of pathologies linked to sex, that is, to the X chromosome. In men, the disease manifests itself more often and more distinctly, since their genotype contains one X chromosome. In women, pathology develops in the presence of both "pathological" X-autosomes. Very rarely, a premutational variant and carriage are possible in a man. Women are much more likely to be carriers of the disease, and pass on the "pathological" chromosome with the same probability for both daughters and sons. A sick father can only pass on the X chromosome to his daughters. The inheritance of the syndrome gradually increases from generation to generation, which is called the Sherman paradox. The clinical course of the syndrome is much more severe in men.

Symptoms

Martin-Bell syndrome, the symptoms of which resemble autism, cannot always be recognized in time even by an experienced pediatrician or neuropathologist.

The clinical picture may differ depending on the number of C-G-G repetitions.

In the classic version, the delay indicates a potential Martin-Bell syndrome. The photo of the child allows you to see the first characteristics illness. There is lethargy and discoordination of movements, muscle weakness develops. Quite often, children suffer from autism. On examination, a neuropathologist reveals malfunctions and some abnormalities in the functioning of the brain. With age, the situation worsens, the picture gradually grows

Mental disorders are always present: the child often mutters to himself, shows grimaces unmotivatedly, often claps his hands, sometimes behaves very aggressively. These symptoms are somewhat reminiscent of schizophrenia. Another option is autism, which begins to develop in early childhood.

Martin-Bell syndrome: signs

A specific sign in boys is enlarged testicles (macroorchism), but this can only be detected in puberty. However, there are no endocrine disorders.

Changes itself appearance are relatively nonspecific, but may lead the physician to seek the correct diagnosis. The child often has a large head, a long face, and a slightly beak-shaped nose. There are large sizes of the hands and feet, the fingers have a significantly increased range of motion. Often the skin has increased elasticity.

Manifestations of the premutational variant of the disease have certain character traits. The ataxic syndrome is characterized by the presence of tremor and memory impairment, especially short-term memory, mood changes and the gradual development of dementia with a decrease (inability to read and understand speech). Symptoms develop more frequently in male carriers and are more severe than in females.

For primary insufficiency of ovarian function, the appearance of premature menopause and impaired functioning of the pituitary-ovarian system is characteristic. The content of follicle-stimulating hormone increases, which leads to the disappearance of menstruation and the appearance of vegetovascular symptoms. The disease gradually progresses and requires hormone replacement therapy.

How to diagnose the syndrome

For an approximate definition of the disease on early stages the child is suitable cytogenetic method. The patient's cell material is taken and vitamin B₁₀ (folic acid) is added as a provocateur of changes in chromosomes. After some time, the study reveals a section of the chromosome with significant thinning, which indicates Martin-Bell disease, fragile X syndrome. This laboratory method examination is not accurate enough in the later stages, which is associated with the widespread use of multivitamins, which include folic acid.

Highly specific is which allows you to decipher the structure of amino acid residues in the X chromosome and indicate the Martin-Bell syndrome. A photo taken with an electron microscope shows an area of ​​autosome thinning.

A separate, even more specific option is the combination of PCR with capillary electrophoresis detection. This examination with high accuracy reveals the pathology of chromosomes in patients with ataxic syndrome and primary ovarian failure.

Treatment

After PCR and diagnosis of "Martin-Bell syndrome", treatment should begin as early as possible.

Since the disease is congenital and has a chromosomal origin, therapy is reduced to alleviating the main symptoms of the disease.

The treatment scheme is aimed at minimizing the manifestations of psychomotor retardation, correcting changes in ataxic syndrome and hormonal support in primary ovarian failure.

Children with mental retardation and a confirmed PCR result are diagnosed with Martin-Bell syndrome. Russia does not have medical institutions, where rehabilitation is carried out for such children, so the pediatrician and related specialists are involved in the treatment. It is immediately worth noting that the treatment of children is more effective than adults. Apply methods of cognitive-behavioral therapy, sessions with a psychiatrist on an individual basis, exercise therapy, light forms of psychostimulants. A relatively new direction is the use of drugs based on folic acid, but long-term results are still being studied.

For adults medical therapy includes psychostimulants and antidepressants, constant dynamic monitoring is carried out by a psychiatrist and psychologist. In private clinics, sessions of microinjections of the drug "Cerebrolysin" and its derivatives, cytomedines (drugs "Lidase", "Solcoseryl") are carried out.

In ataxic syndrome, nootropics and blood thinners, angioprotectors and mixtures of amino acids are used. Primary ovarian failure in women is subject to correction by estrogens and herbal remedies.

The effectiveness of treatment is relatively low, but it allows for some time to slow down the development of the disease.

Prevention

Pregnancy screening is the only way to prevent. In developed
In the countries of the world, examinations have been introduced that make it possible to detect Martin-Bell syndrome in the early stages and terminate the pregnancy. An alternative option is in vitro fertilization, which can help ensure that the unborn child inherits a “healthy” X chromosome.

Etiology and occurrence of fragile X syndrome. Fragile X Syndrome (MIM #309550) is an X-linked mental retardation disorder caused by mutations in the FMR1 gene at Xq27.3. Fragile X syndrome occurs at a frequency of 16-25 per 100,000 in the general population among men and half as often among women.

Makes up 3-6% of all cases mental retardation among boys with a positive family history of mental retardation in the absence of congenital malformations.

Fragile X syndrome pathogenesis

Product gene FMR1, FMRP, is expressed in many cell types, but is most strongly expressed in neurons. FMRP can accompany a specific subclass of mRNA from the nucleus to the ribosome.

More 99% mutations in the FMR1 gene- expansion of the (CGG)n nucleotide repeat in the 5"-untranslated region of the gene. In normal FMR1 alleles, the number of CGG repeats ranges from 6 to approximately 50. In pathogenic alleles (or with complete mutations), the number of repeats is more than 200. Alleles with more than 200 repeats CGGs typically have a hypermethylated sequence of CGG repeats and the adjacent FMR1 promoter Hypermethylation inactivates the FMR1 promoter, causing a decrease in FMRP expression.

Full mutations arise from premutation alleles (from 59 to 200 CGG repeats) with the transmission of the mutant FMR1 allele from the mother (but not from the father); in fact, in paternal transmission, premutations are often, on the contrary, reduced. Full mutations cannot arise from normal alleles. Since the length of unstable CGG repeats increases with each successive generation if passed on by a female, there is usually an increase in the number of affected offspring in successive generations in a family; this phenomenon is called genetic anticipation.

Expansion risk premutations to full mutation increases with the number of repeats in the premutation. However, not all premutations are equally prone to expansion. Although premutations are relatively common, the transition to a full mutation is observed only in a limited number of haplotypes, i.e. when there is a tendency for the haplotype to expand.

This inclination haplotype may in part be due to the presence of multiple AGG triplets inserted into the CGG repeat sequence; It turns out that such AGG triplets inhibit the expansion of CGG repeats; therefore, their absence in some haplotypes may predispose to expansion.

Phenotype and Development of Fragile X Syndrome

Fragile X Syndrome causes mild mental retardation in men and mild mental retardation in women. The most affected individuals also have behavioral abnormalities, including hyperactivity, arm waving, tantrums, poor eye contact, and signs of autism. physical characteristics men change with puberty.

Before sexual maturation affected boys have a slightly enlarged head and some other indistinct symptoms; after the onset of puberty, they often have more distinct features (a long face with a protruding jaw and forehead, large auricles, macroorchidism).

Since these Clinical signs are not unique to fragile X syndrome, diagnosis depends on molecular detection of mutations. Patients with fragile X syndrome have a normal life expectancy.

Almost all men and 40-50% of women who inherit the full mutation will have fragile X syndrome. The severity of the phenotype depends on the mosaicism of repeat methylation and their number. Because full mutations are unstable, some patients have a mixture of cells with repeat numbers ranging from premutation to full mutation (repeat number mosaicism).

All men with mosaicism in the number of repeats are sick, but often have higher mental development than patients with a complete mutation in each cell; in women with mosaicism in the number of repetitions, clinical manifestations vary from normal to complete manifestation. Similarly, some patients have a mixture of cells with and without CGG repeat methylation (repeat methylation mosaicism). All males with methylation mosaicism are diseased, but often have higher intelligence scores than those with per-cell hypermethylation; women with methylation mosaicism can also be healthy or diseased.

Very rarely Patients have a full mutation, unmethylated in all cells; regardless of gender, their severity varies from normal to complete clinic. In addition, in women, the phenotype depends on the degree of X-chromosome inactivation bias.

Bearers premutations(but not complete mutations) have a 20% risk of early ovarian dysfunction. Male carriers of the premutation are at risk of developing FXTAS. FXTAS presents as late progressive cerebellar ataxia with intention tremor. Patients may also present with decreased short-term memory and motor function, cognitive impairment, as well as parkinsonism, peripheral neuropathy, and proximal muscle weakness. lower limbs and dysautonomy.

Penetrance FXTAS age dependent, found in 17% during the sixth decade of life, 38% during the seventh decade, 47% during the eighth decade, and three-quarters over 80 years of age. FXTAS may also occur in some women who carry the premutation.

Peculiarities phenotypic manifestations of fragile X syndrome:
Age of onset: childhood
mental deficiency
Dysmorphic face
Postpubertal testicular enlargement in men (macroorchidism)

Fragile X Syndrome Treatment

To the present time no pathogenetic treatment Fragile X syndrome does not. Assistance is aimed at training and pharmacological treatment behavioral problems.

Risks of Inheriting Fragile X Syndrome

The risk that woman with the premutation will have an affected child, determined by the size of the premutation, the sex of the fetus, and family history. Empirically, the risk for a rearrangement carrier to have an affected child can be as high as 50% for each boy and 25% for each girl, but depends on the size of the premutation. Based on the analysis of a relatively small number of carrier mothers, it is known that the risk of recurrence may decrease if the premutation is reduced from 100 to 59 repeats. Prenatal diagnosis is available through the use of fetal DNA from chorionic villi or amniocytes.

Otherwise child healthy. His mother and maternal aunt had minor learning problems as children, and his maternal uncle was mentally retarded. Data medical examination normal, except for hyperactivity.

It occurs in 1 in about 4,000 men (boys) and 1 in 6,000 to 8,000 girls, regardless of racial or ethnic origin. Genetic mutations accumulate from generation to generation, and this, obviously, becomes a problem for humanity.

Signs and symptoms of fragile X syndrome.

Children and adults with fragile X syndrome have a range of mental and physical signs and symptoms that range from mild to severe. In males, the changes are more pronounced. General mental symptoms include:

Some degree of intellectual impairment or problems in educational learning (school), in particular with mathematics; attention disorder; speech delay; anxiety, depression, shyness; limited social skills. Behavioral problems such as difficulty concentrating and frequent tantrums Autistic behavior, such as repetitive movements, actions, or words Behavioral learning delays - will not learn to sit, walk and talk for a long time; speech problems; Anxiety and instability of mood; Sensitivity to light, sounds, touch, and surroundings; In severe cases, the clinic of schizophrenia.

Fragile X patients may have physical signs of developmental disabilities that become more evident with age: Large head; Long, narrow face; Big ears; Bulging forehead and chin; Overly flexible joints (especially fingers) Boys have enlarged testicles, which enlarge even more after puberty. In girls, the physical signs of fragile X syndrome are less pronounced. Their intellectual abilities suffer in 1/3-1/2 cases of the presence of this pathology.

Other health problems associated with Martin-Bell syndrome.

Most children with Fragile X Syndrome do not have major medical problems and generally lead normal lives. Approximately 15 percent of boys and about 5 percent of girls with Fragile X Syndrome have seizures that are easily managed with anticonvulsant medications. Children with fragile X syndrome often have chronic infectious diseases inner ear. It is also possible to identify heart murmurs, which are often caused by prolapse mitral valve. This heart defect is not life-threatening and, in most cases, does not require treatment.

Causes of genetic pathology - fragile X syndrome.

Fragile X syndrome is associated with an anomaly in one gene, the Xq27.3 site. In 1991, a gene called FMR-1 was found to be located on the X chromosome. Each person has 23 pairs of chromosomes, or 46 individual chromosomes. A pair of sex chromosomes (X and Y) determine the sex of a person, women have two X chromosomes, and men have one X chromosome and one Y chromosome. It is precisely because women have 2 similar chromosomes that the severity of the disease is less in them, the missing function of one is replaced by the second. An exception may be the option of having 2 defective X chromosomes, but this probability tends to zero. In men, the only X chromosome with a mutated gene is what causes fragile X syndrome. Such mutations are called genetic "stuttering." This means that a small piece of genetic material (namely the 3 CHG nucleic acid sequence) is repeated too many times. At healthy people this section is repeated from 5 to 40 times, in patients with Martin-Bell syndrome up to 200 or more repetitions. More than 200 repeats is called a complete mutation. Complete mutations completely turn off the gene and the protein, for the synthesis of which this locus is responsible, ceases to be synthesized. The protein controlled by this gene is found in many cell types, but mainly in nerve cells. Scientists believe that protein helps brain development and is responsible for communication nerve cells between themselves. The syndrome got its name from the appearance of the chromosome. The locus containing the mutated gene looks thinner and the terminal fragment seems to be hanging by a thread.

Diagnosis of fragmented X syndrome and the likelihood of inheritance.

Fragile X syndrome is diagnosed by a blood test. The blood sample is sent to a genetic laboratory, the test is quite affordable. The analysis can be performed immediately after the birth of the child. Most often, in the presence of an appropriate clinic, in boys, genetic confirmation of the diagnosis is observed by the age of 3, in girls by 4-5 years. The child should be diagnosed if there is an intellectual disability, developmental delay or autism, physical or behavioral signs and symptoms of Fragile X Syndrome, a family history of Fragile X Syndrome, or other mental impairment of unknown cause. Women planning pregnancy should have a carrier test if they have the following: a family history of fragile X syndrome or disorders associated with fragile X syndrome; family history of mental impairment of unknown cause; a personal or family history of developmental delay or autism; personal history of reproductive disorders and early menopause. Identified genetic disorders should be discussed with a geneticist.

Diagnosis of genetic disorders in a child is possible during pregnancy, before birth. Prenatal (amniotic and chorionic) genetic tests will help determine the likelihood of inheriting a mutation or premutation.

Inheritance is difficult, there is an accumulation of the number of repeats of the mutated gene. With a normal number of repetitions of the locus in parents (5-40), the number of repetitions in the child does not change and the likelihood of pathology in the newborn is practically absent. With an intermediate number of repetitions (41-58), a similar or slightly larger number of repetitions is transmitted from parents to children, the likelihood of a disease in a child is also not high, but accumulation can progress from generation to generation (Sherman's paradox), the number of repetitions can reach 4000.

A premutation is considered to be the number of gene repeats from 59 to 200, approximately 1 in 250 women and 1 in 800 men have a premutation in the genome. Of these, only women can give birth to a child with fragile X syndrome. There is a 50% chance of passing the abnormal gene to the baby with each pregnancy. In some children who have inherited the abnormal gene, if the number of repeats does not increase more than 200, then symptoms of fragile X syndrome do not occur. If there is an increase in the number of repeats and the premutation turns into a full mutation (more than 200 repeats), then the children suffer from fragmented X chromosome syndrome. A father with a premutation passes it on only to all his daughters. Y is transmitted to boys from their father. The daughters of such fathers usually do not have symptoms of fragile X syndrome, but are carriers of the premutation.

Full Mutation: A woman with a full mutation has about a 50 percent chance of passing it on to her child in every pregnancy. Males with the complete mutation are usually infertile.

Risks and health problems in individuals with a premutation

In such children, bright manifestations of fragile X syndrome, as a rule, are not observed, but certain problems are still present.

Educational and behavioral problems: intelligence is normal, but there are mild behavioral and educational disorders;

Neurological disorders: hand tremor and ataxia (incoordination of movements) in approximately 30% of men occur over the age of 50 years. In women, violations are also possible in 4-8%, but at an older age and are less pronounced;

Impaired fertility - a gradual fading of ovarian function and, as a result, a decrease in the possibility of becoming pregnant is observed in 20% of women with a premutation. They have an early menopause by the age of 40.

Treatment of fragile (fragmented, fragile) X chromosome syndrome

There is no specific treatment. Treatment is carried out according to an individual plan, starting from preschool age. Treatment is provided by healthcare professionals and educators. Consistent and timely correction of disorders and stimulation of lagging functions allows children to realize their potential. The focus should be on the development of speech, social adaptation and vocational guidance, the development of physical health. Medications are used symptomatically and improve prognosis. Prescribe antidepressants, anticonvulsants, stimulants and antipsychotics. Researchers are developing drugs that replace the missing protein and drugs that improve intercellular communication.

Head of
"Oncogenetics"

Zhusina
Julia Gennadievna

Graduated from the Pediatric Faculty of the Voronezh State medical university them. N.N. Burdenko in 2014.

2015 - internship in therapy on the basis of the Department of Faculty Therapy of the Voronezh State Medical University. N.N. Burdenko.

2015 - certification course in the specialty "Hematology" on the basis of the Hematological Research Center in Moscow.

2015-2016 – therapist of the VGKBSMP No. 1.

2016 - approved the topic of the dissertation for the degree of candidate of medical sciences "study clinical course disease and prognosis in patients with chronic obstructive pulmonary disease with anemic syndrome. Co-author of more than 10 publications. Participant of scientific and practical conferences on genetics and oncology.

2017 - advanced training course on the topic: "interpretation of the results of genetic studies in patients with hereditary diseases."

Since 2017 residency in the specialty "Genetics" on the basis of RMANPE.

Head of
"Genetics"

Kanivets
Ilya Vyacheslavovich

Kanivets Ilya Vyacheslavovich, geneticist, candidate of medical sciences, head of the genetics department of the medical genetic center Genomed. Assistant of the Department of Medical Genetics of the Russian Medical Academy of Continuous Professional Education.

He graduated from the Faculty of Medicine of the Moscow State University of Medicine and Dentistry in 2009, and in 2011 he completed residency in the specialty "Genetics" at the Department of Medical Genetics of the same university. In 2017 he defended his thesis for the degree of candidate of medical sciences on the topic: Molecular diagnosis of copy number variations of DNA segments (CNVs) in children with congenital malformations, phenotype anomalies and/or mental retardation using SNP high-density oligonucleotide microarrays»

From 2011-2017 he worked as a geneticist in the Children's clinical hospital them. N.F. Filatov, scientific advisory department of the Federal State Budgetary Scientific Institution "Medical Genetic Research Center". From 2014 to the present, he has been in charge of the genetics department of the MHC Genomed.

Main areas of activity: diagnosis and management of patients with hereditary diseases and congenital malformations, epilepsy, medical genetic counseling of families in which a child with hereditary pathology or malformations, prenatal diagnosis. During the consultation, an analysis of clinical data and genealogy is carried out to determine the clinical hypothesis and the required amount of genetic testing. Based on the results of the survey, the data are interpreted and the information received is explained to the consultants.

He is one of the founders of the School of Genetics project. Regularly makes presentations at conferences. He lectures for geneticists, neurologists and obstetricians-gynecologists, as well as for parents of patients with hereditary diseases. He is the author and co-author of more than 20 articles and reviews in Russian and foreign journals.

The area of ​​professional interests is the introduction of modern genome-wide studies into clinical practice, the interpretation of their results.

Reception time: Wed, Fri 16-19

Head of
"Neurology"

Sharkov
Artem Alekseevich

Sharkov Artyom Alekseevich– neurologist, epileptologist

In 2012, he studied under the international program “Oriental medicine” at Daegu Haanu University in South Korea.

Since 2012 - participation in the organization of the database and algorithm for the interpretation of xGenCloud genetic tests (https://www.xgencloud.com/, Project Manager - Igor Ugarov)

In 2013 he graduated from the Pediatric Faculty of the Russian National Research Medical University named after N.I. Pirogov.

From 2013 to 2015 he studied in clinical residency in neurology at the Federal State Budget Scientific Institution "Scientific Center of Neurology".

Since 2015, he has been working as a neurologist, researcher at the Scientific Research Clinical Institute of Pediatrics named after Academician Yu.E. Veltishchev GBOU VPO RNIMU them. N.I. Pirogov. He also works as a neurologist and a doctor in the laboratory of video-EEG monitoring in the clinics of the Center for Epileptology and Neurology named after A.I. A.A. Ghazaryan” and “Epilepsy Center”.

In 2015, he studied in Italy at the school "2nd International Residential Course on Drug Resistant Epilepsies, ILAE, 2015".

In 2015, advanced training - "Clinical and molecular genetics for practicing physicians", RCCH, RUSNANO.

In 2016, advanced training - "Fundamentals of Molecular Genetics" under the guidance of bioinformatics, Ph.D. Konovalova F.A.

Since 2016 - the head of the neurological direction of the laboratory "Genomed".

In 2016, he studied in Italy at the school "San Servolo international advanced course: Brain Exploration and Epilepsy Surger, ILAE, 2016".

In 2016, advanced training - "Innovative genetic technologies for doctors", "Institute of Laboratory Medicine".

In 2017 - the school "NGS in Medical Genetics 2017", Moscow State Scientific Center

Currently, he is conducting scientific research in the field of epilepsy genetics under the guidance of Professor, MD. Belousova E.D. and professor, d.m.s. Dadali E.L.

The topic of the dissertation for the degree of Candidate of Medical Sciences "Clinical and genetic characteristics of monogenic variants of early epileptic encephalopathies" was approved.

The main areas of activity are the diagnosis and treatment of epilepsy in children and adults. Narrow specialization - surgical treatment of epilepsy, genetics of epilepsy. Neurogenetics.

Scientific publications

Sharkov A., Sharkova I., Golovteev A., Ugarov I. "Optimization of differential diagnostics and interpretation of results of genetic testing by the XGenCloud expert system in some forms of epilepsy". Medical Genetics, No. 4, 2015, p. 41.
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Sharkov A.A., Vorobyov A.N., Troitsky A.A., Savkina I.S., Dorofeeva M.Yu., Melikyan A.G., Golovteev A.L. "Surgery for epilepsy in multifocal brain lesions in children with tuberous sclerosis." Abstracts of the XIV Russian Congress "INNOVATIVE TECHNOLOGIES IN PEDIATRICS AND PEDIATRIC SURGERY". Russian Bulletin of Perinatology and Pediatrics, 4, 2015. - p.226-227.
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Dadali E.L., Belousova E.D., Sharkov A.A. "Molecular genetic approaches to the diagnosis of monogenic idiopathic and symptomatic epilepsy". Abstract of the XIV Russian Congress "INNOVATIVE TECHNOLOGIES IN PEDIATRICS AND PEDIATRIC SURGERY". Russian Bulletin of Perinatology and Pediatrics, 4, 2015. - p.221.
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Sharkov A.A., Dadali E.L., Sharkova I.V. "A rare variant of type 2 early epileptic encephalopathy caused by mutations in the CDKL5 gene in a male patient." Conference "Epileptology in the system of neurosciences". Collection of conference materials: / Edited by: prof. Neznanova N.G., prof. Mikhailova V.A. St. Petersburg: 2015. - p. 210-212.
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Dadali E.L., Sharkov A.A., Kanivets I.V., Gundorova P., Fominykh V.V., Sharkova I.V. Troitsky A.A., Golovteev A.L., Polyakov A.V. A new allelic variant of type 3 myoclonus epilepsy caused by mutations in the KCTD7 gene // Medical genetics.-2015.- v.14.-№9.- p.44-47
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Dadali E.L., Sharkova I.V., Sharkov A.A., Akimova I.A. "Clinical and genetic features and modern ways diagnosis of hereditary epilepsy. Collection of materials "Molecular biological technologies in medical practice" / Ed. corresponding member RANEN A.B. Maslennikova.- Issue. 24.- Novosibirsk: Academizdat, 2016.- 262: p. 52-63
*
Belousova E.D., Dorofeeva M.Yu., Sharkov A.A. Epilepsy in tuberous sclerosis. In "Brain Diseases, Medical and Social Aspects" edited by Gusev E.I., Gekht A.B., Moscow; 2016; pp.391-399
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Dadali E.L., Sharkov A.A., Sharkova I.V., Kanivets I.V., Konovalov F.A., Akimova I.A. Hereditary diseases and syndromes accompanied by febrile convulsions: clinical and genetic characteristics and diagnostic methods. //Russian Journal of Children's Neurology.- T. 11.- No. 2, p. 33-41. doi: 10.17650/ 2073-8803-2016-11-2-33-41
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Sharkov A.A., Konovalov F.A., Sharkova I.V., Belousova E.D., Dadali E.L. Molecular genetic approaches to the diagnosis of epileptic encephalopathies. Collection of abstracts "VI BALTIC CONGRESS ON CHILDREN'S NEUROLOGY" / Edited by Professor Guzeva V.I. St. Petersburg, 2016, p. 391
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Hemispherotomy in drug-resistant epilepsy in children with bilateral brain damage Zubkova N.S., Altunina G.E., Zemlyansky M.Yu., Troitsky A.A., Sharkov A.A., Golovteev A.L. Collection of abstracts "VI BALTIC CONGRESS ON CHILDREN'S NEUROLOGY" / Edited by Professor Guzeva V.I. St. Petersburg, 2016, p. 157.
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Article: Genetics and differentiated treatment of early epileptic encephalopathies. A.A. Sharkov*, I.V. Sharkova, E.D. Belousova, E.L. Dadali. Journal of Neurology and Psychiatry, 9, 2016; Issue. 2doi:10.17116/jnevro20161169267-73
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Golovteev A.L., Sharkov A.A., Troitsky A.A., Altunina G.E., Zemlyansky M.Yu., Kopachev D.N., Dorofeeva M.Yu. " Surgery epilepsy in tuberous sclerosis" edited by Dorofeeva M.Yu., Moscow; 2017; p.274
*
New international classifications epilepsy and epileptic seizures of the International Epilepsy League. Journal of Neurology and Psychiatry. C.C. Korsakov. 2017. V. 117. No. 7. S. 99-106

Head of
"Prenatal Diagnosis"

Kyiv
Yulia Kirillovna

In 2011 she graduated from the Moscow State Medical and Dental University. A.I. Evdokimova with a degree in General Medicine Studied in residency at the Department of Medical Genetics of the same university with a degree in Genetics

In 2015, she completed an internship in Obstetrics and Gynecology at the Medical Institute for Postgraduate Medical Education of the Federal State Budgetary Educational Institution of Higher Professional Education "MGUPP"

Since 2013, he has been conducting a consultative appointment at the Center for Family Planning and Reproduction, DZM

Since 2017, he has been the head of the Prenatal Diagnostics department of the Genomed laboratory

Regularly makes presentations at conferences and seminars. Reads lectures for doctors of various specialties in the field of reproduction and prenatal diagnostics

Conducts medical genetic counseling for pregnant women on prenatal diagnosis in order to prevent the birth of children with congenital malformations, as well as families with presumably hereditary or congenital pathology. Conducts interpretation of the obtained results of DNA diagnostics.

SPECIALISTS

Latypov
Artur Shamilevich

Latypov Artur Shamilevich – doctor geneticist of the highest qualification category.

After graduating in 1976 from the medical faculty of the Kazan State medical institute for many years he worked first as a doctor in the office of medical genetics, then as head of the medical genetic center Republican Hospital Tatarstan, chief specialist of the Ministry of Health of the Republic of Tatarstan, lecturer at the departments of Kazan Medical University.

Author of over 20 scientific works on the problems of reproductive and biochemical genetics, a participant in many domestic and international congresses and conferences on the problems of medical genetics. Implemented in practical work center methods of mass screening of pregnant women and newborns for hereditary diseases, performed thousands of invasive procedures for suspected hereditary diseases of the fetus on different terms pregnancy.

Since 2012 she has been working at the Department of Medical Genetics with a course of prenatal diagnostics Russian Academy postgraduate education.

Research interests – metabolic diseases in children, prenatal diagnostics.

Doctors are admitted by appointment.

Geneticist

Gabelko
Denis Igorevich

In 2009 he graduated from the medical faculty of KSMU named after. S. V. Kurashova (specialty "Medicine").

Internship at the St. Petersburg Medical Academy of Postgraduate Education of the Federal Agency for Health and social development(specialty "Genetics").

Internship in Therapy. Primary retraining in the specialty "Ultrasound diagnostics". Since 2016, he has been an employee of the Department of the Department of Fundamental Foundations clinical medicine Institute of Fundamental Medicine and Biology.

Sphere of professional interests: prenatal diagnostics, application of modern screening and diagnostic methods to detect genetic pathology of the fetus. Determining the risk of recurrence of hereditary diseases in the family.

Participant of scientific and practical conferences on genetics and obstetrics and gynecology.

Work experience 5 years.

Doctors are admitted by appointment.

Geneticist

Grishina
Christina Alexandrovna

In 2015 she graduated from the Moscow State Medical and Dental University with a degree in General Medicine. In the same year, she entered residency in the specialty 30.08.30 "Genetics" at the Federal State Budgetary Scientific Institution "Medical Genetic Research Center".
She was hired in the Laboratory of Molecular Genetics of Complexly Inherited Diseases (Head - Doctor of Biological Sciences Karpukhin A.V.) in March 2015 as a research laboratory assistant. Since September 2015, she has been transferred to the position of a researcher. He is the author and co-author of more than 10 articles and abstracts on clinical genetics, oncogenetics and molecular oncology in Russian and foreign journals. Regular participant of conferences on medical genetics.

Area of ​​scientific and practical interests: medical genetic counseling of patients with hereditary syndromic and multifactorial pathology.

Consultation with a geneticist allows you to answer the following questions:

Are the child's symptoms signs of a hereditary disease? what research is needed to identify the cause determining an accurate forecast recommendations for conducting and evaluating the results of prenatal diagnosis everything you need to know about family planning IVF planning consultation field and online consultations

took part in the scientific-practical school "Innovative genetic technologies for doctors: application in clinical practice", conferences of the European Society of Human Genetics (ESHG) and other conferences dedicated to human genetics.

Conducts medical genetic counseling for families with presumably hereditary or congenital pathologies, including monogenic diseases and chromosomal abnormalities, determines the indications for laboratory genetic studies, interprets the results of DNA diagnostics. Advises pregnant women on prenatal diagnostics in order to prevent the birth of children with congenital malformations.

Geneticist, obstetrician-gynecologist, candidate of medical sciences

Kudryavtseva
Elena Vladimirovna

Geneticist, obstetrician-gynecologist, candidate of medical sciences.

Specialist in the field of reproductive counseling and hereditary pathology.

Graduated from the Ural State Medical Academy in 2005.

Residency in Obstetrics and Gynecology

Internship in the specialty "Genetics"

Professional retraining in the specialty "Ultrasound diagnostics"

Activities:

• Infertility and miscarriage
Vasilisa Yurievna



She is a graduate of the Nizhny Novgorod State Medical Academy, Faculty of Medicine (specialty "Medicine"). She graduated from the clinical internship of the FBGNU "MGNTS" with a degree in "Genetics". In 2014, she completed an internship at the clinic of motherhood and childhood (IRCCS materno infantile Burlo Garofolo, Trieste, Italy).

Since 2016, she has been working as a consultant doctor at Genomed LLC.

Regularly participates in scientific and practical conferences on genetics.

Main activities: Consulting on clinical and laboratory diagnostics genetic diseases and interpretation of the results. Management of patients and their families with suspected hereditary pathology. Consulting when planning a pregnancy, as well as during pregnancy on prenatal diagnostics in order to prevent the birth of children with congenital pathology.

Among the group of hereditary diseases, there are two diseases related to most common reasons intellectual disability. The most famous and most common pathology is Down syndrome, associated with the presence of an extra 21st chromosome in the human genome. In this article, we will talk about the second most common hereditary disease that leads to mental retardation, and can also be accompanied by other clinical manifestations.

Fragile X Syndrome or Martin-Bell syndrome is the result of a disorder in gene FMR1 (fragile X mental retardation-1), which is located on the X chromosome and plays an important role in the appearance and development of neural connections, learning and memorization. The frequency of this syndrome among boys is 1:4000.

The so-called “fragility” of the X chromosome is manifested in the fact that the chromosome looks atypical with special staining, as if one piece has separated, although physically it remains intact. The genetic basis of this phenomenon is an increase in the number of trinucleotide repetitionsCGG in the gene FMR1 located on the X chromosome.

In healthy people, the number of repeats in this gene fluctuates. from 5 to54 . If a repetitions more than 200, then the production of protein from the gene FMR1 disrupted, leading to the development of Martin-Bell syndrome and clinical manifestation diseases. premutational state is the number of CGG repeats from 55 to 200. In this condition, the disease in humans does not typically manifest, but the more repeats in this gene the carrier has, the more likely it is that her or his children will have a repeat count of more than 200 and the disease will develop. In the case of a carrier of a premutation during the formation of germ cells, the number of repeats may increase, therefore, if the parent has a number of repeats from 55 to 200, then the probability of having a child with a mutant gene is high. FMR1 and Martin-Bell syndrome. At the same time, the carriage of the premutational state by the future father and mother is not equivalent in terms of the probability of the occurrence of a mutant allele in their children: if the mother is the carrier, then the probability of a significant increase in the number of repeats is much higher. The number of repeats from 45 to 54 is an intermediate form that has no effect on human health, but can lead to problems in future generations, as in the case of a premutational state of the gene.

It is important to take into account that inheritance and development of the disease depends on sex, since the gene FMR1 is located on the X chromosome. Men have only one X chromosome, which they receive from their mother. Therefore, if this one chromosome turned out to be “fragile”, they have a disease. Women have two X chromosomes, but only one of them is active. Therefore, the presence of one X chromosome with a mutated gene FMR1 may not manifest itself clinically, in the case of inactivation of the “fragile” chromosome, or lead to the development of the disease in 30-50% of cases. A man with a fragile X chromosome can pass it on to all his daughters, but not to any of his sons. A woman with a mutant chromosome has a chance to pass it on to both sons and daughters with equal probability.

Premutational state of a gene affects both the fate of the descendants of the carrier of such a gene, and directly on his health:

Development primary ovarian failure (FXPOI) (decrease in ovarian reserve and the onset of menopause before the age of 40). Mutation FMR1 is the cause of premature ovarian failure in 5% of women with this diagnosis. Among carriers of the premutation, about a quarter develop this condition. It affects not only the general reproductive possibilities, but also the selection of the stimulation protocol for ART, as it often causes a poor ovarian response to stimulation. Interestingly, according to Genetico data, although poor ovarian response to stimulation affects the number of embryos produced per cycle, it does not lead to an increase in the proportion of aneuploid embryos.

Tremor/ataxia associated with the fragile X chromosome ( FXTAS). This condition develops more often in men: when the premutation is carried by a man, it manifests itself in 33% of cases, and when the premutation is carried by a woman - only in 5-10%. FXTAS syndrome begins to manifest in old age. There is a tremor, a wobbly gait, speech may suffer.

The diagnostic method used in the Genetico laboratory is based on the use of polymerase chain reaction with a special set of primers, allowing not only to detect normal, premutational and mutational states, but also accurately determine the number of repetitions in cases where there are less than 200 of them. Such a diagnosis makes it possible to identify fragile X syndrome at the molecular level, as well as to assess the likelihood of having a child with this syndrome and the possibility of developing disorders in the patient associated with an increased number of repeats in the gene FMR1 . This diagnosis also allows detect the presence of AGG repeats among CGG repeats. It is believed that AGG regions that interrupt a long sequence of CGG repeats confer DNA stability and reduce the risk of an increase in the number of repeats in the next generation.

Genetic test that determines the number of repeats in a gene FMR1 , recommended pass the first of all women with premature ovarian failure syndrome or with identified non-random inactivation of the X chromosome (indirect sign), families with sons with intellectual disabilities. Also gene state analysisFMR 1 needed:

1)women with reproductive problems or fertility problems associated with increased level follicle stimulating hormone (FSH)

2)patients with intellectual disability and their relatives

3) those who have Family history of Fragile X Syndrome or mental retardation without a definite diagnosis

4)women whose relatives had disorders associated with premutational state FMR1

5)patients with late onset tremor and cerebellar ataxia (violations of the coordination of muscle work due to damage to the brain systems that control muscle movement).

In case of detection asymptomatic mutation carrier in the gene FMR1 in a woman, the use of donor oocytes or preimplantation genetic diagnosis (PGD) may be recommended in order to exclude the possibility of a manifestation of the syndrome in a child. It is also important to correctly assess the risk of having a sick child in case of premutational state of a geneFMR 1 from future parents. In this case, according to the results of the test, it is recommended to consult a geneticist.

Genetico laboratory intern