Fragile X syndrome analysis. Martin-Bell syndrome: signs, symptoms and treatment regimen

In the 40s of the twentieth century, scientists James Martin from Ireland and the Englishwoman Julia Bell were first described clinical picture diseases. Over the course of some time, geneticists have observed a family where absolutely normal woman mentally retarded boys were born. Having traced the family history, we identified precedents among men in previous generations. Scientists have identified the cause of the genetic abnormality, which was the fragility of the distal arm of the X chromosome. A narrowing of the ends was visually noted due to secondary constriction in the thinned area at the Xq27-28 locus (photo).

In the 90s, through a cytogenetic examination, a mutated gene was identified that caused fragile chromosome syndrome. The name of the pathology included the names of the first scientists who paid attention to this type of change in the genome. The disease is inherited and is gender-linked. In boys, the symptoms are clearly expressed, in girls they occur much less frequently and occur in a mild form of mental retardation. It is a common anomaly (1:4000), and in terms of frequency of occurrence it occupies a leading place among hereditary pathologies.

Causes

The human genotype consists of 46 chromosomes, two of which determine sex - X, Y. Women have a set of 46 XX, men have 46 XY. This explains the rare manifestation of the disease in girls, when compensation occurs from the second chromosome of the karyotype. The genetic memory chain consists of repeated combinations of cytosine-guanine-guanine (CGG), and increasing copies (expansion) thin out sections of DNA, causing Martin-Bell Syndrome (MBS). The anomaly occurs against the background of a mutation in FMR1, the gene responsible for encoding protein, the main participant in the formation nervous system.

Sections of the X chromosome are characterized by four categories

State	Trinucleotide alternation index	Development of the disease
normal	29–30	lack of SMB
intermediate (gray area)	44–55	risk of development
premutation	60–200	the syndrome does not develop, the person is a carrier of a broken gene, the disease will manifest itself in subsequent generations
complete disruption of the chain	250–4000	appearance of anomaly

A gene mutation inhibits the functionality of a protein involved in the development of a child, affecting his ability to learn and remember new material. Enzyme deficiency affects the formation of axons and synapses that are directly involved in nerve connections; against this background, neurological abnormalities and mental retardation develop.

Genetic pathology is inherited by female line. In a man who has one X chromosome, after the transmission of a broken gene from his mother, the onset of the syndrome occurs in the twelfth month of life with subsequent progression. He can only pass on the anomaly to his daughter. In a girl, the deficiency is replenished by the second chromosome. The pathology does not manifest itself, in the worst case it is accompanied by mild symptoms. A woman passes on fragile X syndrome to offspring of both sexes, and the circle closes. Therefore, within the same clan, men have mental development disorders, while the female half is completely healthy or with minor deviations.

Characteristic signs of pathology

The genetic disease is accompanied by a variety of symptoms; each case is individual with its own set of symptoms. MSD is distinguished from other neurological pathologies by a number of features: disorder of psycho-emotional perception, progressive mental retardation, deviation in physical development. Martin-Bell syndrome in children is characterized by symptoms that make it easy to determine the form genetic mutation. A newborn boy is distinguished by greater weight and increased testicular size (macroorchidism), without hormonal abnormalities.

There is a decrease in the sucking and grasping reflex, muscle tone, and it reacts poorly to external stimuli. The child lags behind his peers in physical and intellectual development. In most cases, they are born with congenital diseases: heart defects, joint deformities. Therefore, children with SMS begin to walk late, practically do not crawl, their speech function is inhibited, their vocabulary is poor, their diction is slurred, and in severe cases it manifests itself complete absence communication abilities, the child is silent.

As Martin-Bell syndrome progresses, the signs become more pronounced and become more pronounced. When psychomotor development is delayed, movements acquire hyperkinetic features:

• random waving of arms, clapping of hands, shaking of phalanges;
• jumping in place;
• circular movements of the body, turns around its axis;
• incoordination, meaninglessness and pomposity of poses.

Psychological abnormalities:

• emotional lability (reaction to stimuli does not correspond to age);
• uncontrolled manifestation of anger, aggression;
• unreasonable stubbornness, tearfulness, attention deficit;
• fear of physical contact, crowds of unfamiliar people, loud sounds;
• symptoms of autism.

Neurological abnormalities characteristic of the syndrome:

• epileptic seizures against the background of muscle cramps, temporary loss of consciousness;
• a nervous tic localized in the lower part of the face and eyelids, causing distortion of facial expressions and frequent blinking;
• tremor of the upper extremities;
• hypermobility, the patient is unable to stay in one place for a long time:
• oculomotor, pyramidal disorders.

Fragile chromosome syndrome causes physical developmental abnormalities; affected boys are visually different from healthy peers:

• head big size with a convex high forehead, this gives the face an oval shape;
• the palatine vault is deep, the lower jaw is heavy;
• the ears are round, protruding, set low on the skull;
• the nose is pointed, hook-shaped;
• eyes set wide, squinting.

The phenotype is complemented by skin elasticity, flat feet, curvature of the legs, wide feet and hands.

In all carriers of broken FMR1, the constant symptomatology is dysfunction of the thyroid gland and adrenal glands. Endocrine disorders cause metabolic failure (obesity), early puberty. The level of mental retardation ranges from light form to heavy clinical course. The main percentage of patients are at the stage of oligophrenia.

Women have high libido, but they go through early menopause. The ovaries degenerate into cystic neoplasms. In men, obvious macroorchidism is observed.

Diagnostic tests

Determination of Martin-Bell syndrome involves the use of specific tests to analyze the state of the X chromosome at the Xq27-28 site. It is carried out by a geneticist according to the following algorithm:

1. Examination of the patient, taking into account specific changes in appearance and hypotonicity of muscle mass.
2. The main method in diagnosing pathology, giving 100% results at an early stage clinical development, is a cytogenetic method. The patient's cells are taken and processed folic acid, which starts the process of chromosome change. If an anomaly is noted on Xq27-28 litmus, the presence of the syndrome is beyond doubt.
3. At a later stage, a study of the pair of chromosomes responsible for sex (karyotyping) is used. The mutation confirms SMB.
4. Using a polychain reaction, the composition and structure of trinucleotides are analyzed.
5. Molecular genetic study determines the frequency of CGG repeats.
6. In fragile X syndrome, all patients have the same bioelectrical activity brain, which allows the diagnosis to be confirmed using electroencephalography.

The disease can be detected by early stages pregnancy. Perinatal examination is based on ultrasound, analysis of the woman’s blood serum, and chorionic villus biopsy. If a genetic abnormality in the fetus is confirmed, termination of pregnancy is proposed, but in any case, the choice remains with the expectant mother.

Effective treatment

Like any genetic disease that is inherited, Martin-Bell syndrome cannot be eliminated. Medication therapy is carried out in combination with physiotherapy; in extreme cases, they resort to surgical intervention. The measures are aimed at reducing symptoms and are designed to improve the quality of life, prevent the progression of mental retardation and neurological abnormalities.

Conservative methods

Treatment of a genetic abnormality involves the use of the following drugs:

• blood thinners - Clexane, Plavix;
• preventing epileptic seizures - “Mazepin”;
• nootropic action – “Piracetam”;
• to improve the condition of blood vessels and cerebral circulation - Cerebrolysin, Vinpocetine;
• sedative (calming) effect - “Seduxen”, “Diazepam”;
• antidepressants - Sertraline, Fluoxetine, Clomipramine;
• somatic action (psychostimulants) - “Solcoseryl”, “Cavinton”, “Lidaza”;
• neuroleptics - “Chlorpromazine”, “Haloperidol”, “Periciazine”.

IN complex therapy lithium-based drugs are used together with a set of vitamins that normalize cognitive function. The attempt to treat the syndrome with folic acid has proven ineffective. The therapy temporarily improved behavioral and communication abilities, but did not slow down the process of mental degradation.

Physiotherapy

To help provide a conservative effect on the manifestations of the syndrome, a number of physiotherapeutic measures are prescribed:

• physiotherapy;
• exercises in the pool;
• Charcot's shower;
• mud baths with radon;
• acupuncture (acupuncture);
• hirudotherapy (leeches to thin the blood);
• muscle relaxation.

Classes with a speech therapist and training with a psychotherapist are shown.

Surgical treatment

Surgery is advisable if a complication of Martin-Bell syndrome affects vital organs. Surgery is performed for congenital heart defects, cystic degeneration of the ovaries with the risk of transition to malignancy.

Plastic correction is used, the purpose of which is to eliminate physical defects characteristic of the disease. Using a surgical method, the limbs are brought back to normal, the shape of the ears is changed, and the external anomaly of the genital organs is eliminated.

Prognosis and prevention

Genetic fragility of the X chromosome does not create big problems with health, if not complicated by pathologies intrauterine development. Life expectancy is no different healthy people. The prognosis for recovery is unfavorable. With adequate symptomatic treatment, psychological correction, helping a person adapt to society, the quality of life will significantly improve, but in the end the syndrome will lead to disability.

Prevention of the disease is perinatal examination of the fetus for early stages. Screening of biological material will help identify a mutation in the Xq27-28 region. In this case, termination of pregnancy is recommended. A man or woman with a family history of the FMR1 mutation must undergo a test before planning a child. If an abnormality is confirmed in one of the parents, there are ways to correct the X chromosome defect at the molecular level and perform in vitro fertilization. IVF will make it possible to give birth to a baby with a healthy genetic code.

Fragile chromosomes X syndrome (Martin-Bell syndrome).

This condition affects on average one in 1,200 men and perhaps 1 in 800 women. It is the most common cause of mental retardation and is the most common among various forms mental retardation is second only to Down syndrome.

This disease is classified as monogenic, but the patterns of inheritance of this disease are unusual for an X-linked trait.

In a significant number of cases, from 20 to 40%, mental retardation in boys was transmitted from a mother who carried a damaged X chromosome. In these 20-40%, the carrier mother received her damaged chromosome not from the mother, as usual, but from a seemingly healthy father. The second oddity of this disease - the so-called Sherman paradox - lies in varying degrees penetrance of the Fragile X syndrome mutation depending on the carrier’s place in the pedigree. Finally, there is a third oddity. Among female carriers of the mutant chromosome, approximately one third are affected to varying degrees by the disease, and, in addition, the children of such affected women are more likely to be affected than the children of intellectually normal carrier women. These affected women receive their damaged X chromosome from their mother rather than their father. In general, it appears that daughters of normal male transmitters are more likely to have affected children than mothers of normal male transmitters. Healthy male transmitters pass on their damaged X chromosome to their daughters, who become carriers but are healthy, but the sons of these daughters are highly likely to be sick (Sherman's paradox).

Under certain conditions of culturing cells obtained from patients with such symptoms, a fragment was separated from its main part at the distal (remote from the centromere) end of the long arm of the X chromosome (Xq28). That's why the disease was named Fragile X Syndrome. This site on the chromosome is called FraXA from English, fragile. This kind of behavior of various chromosomes is quite well known, although the reasons for it are unclear. All such sites are called fragile, and the one in question is also XA, because it is located on the X chromosome, but there are also other fragile sites there. This cytogenetic effect is difficult to observe.

In this regard, the interest in gene cloning was very understandable. Physical isolation of the gene responsible for this pathology, was accomplished through the coordinated efforts of many groups. It turned out to be the FMR1 gene. It was also found that the effect of the so-called dynamic mutation plays a decisive role in the development of the disease. Relatively recently, a new class of so-called dynamic mutations, or expansion mutations, associated with instability in the number of trinucleotide repeats in functionally significant parts of genes, was identified. The disease develops only when the number of repeats in these sites exceeds a certain critical level. The inheritance of such mutations differs from the classical Mendelian type. They are characterized by: varying penetrance combined with incomplete dominance; genomic imprinting (differences in phenotypic manifestations depending on whether the mutation was received from the mother or from the father) and the phenomenon of anticipation - an increase in the severity of the disease in subsequent generations. This type of mutation has so far been found only in humans and has not been recorded in any species of mammals or other studied organisms.

A classic example of expansion mutations is fragile X syndrome (FraXA), caused by the presence of elongated CGG repeats in the 5" untranslated regulatory region of the FMR 1 gene (Xq27.3). Subsequently, similar dynamic mutations were described in 7 other hereditary diseases controlled by genes located on different chromosomes.

The cause of the damaging effect of some “dynamic” mutations is a block of gene expression, that is, loss of function (coss-of-function mutation), while other mutations of the same type associated with neurodegenerative diseases lead to the appearance of protein products with abnormal functions (mutations like gain-of-function). For each expansion disease, its own diagnostic option has been developed, based on the polymerase chain reaction.

Head of
"Oncogenetics"

Zhusina
Yulia Gennadievna

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

2015 - internship in therapy at the Department of Faculty Therapy of VSMU named after. N.N. Burdenko.

2015 - certification course in the specialty “Hematology” at the Hematology Research Center in Moscow.

2015-2016 – therapist at VGKBSMP No. 1.

2016 - the topic of the dissertation for the competition was approved scientific degree candidate of medical sciences “studying the clinical course of the disease and prognosis in patients with chronic obstructive pulmonary disease with anemic syndrome" Co-author of more than 10 published works. 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 RMANPO.

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, Department of Medical Genetics, Russian medical academy continuous professional education.

He graduated from the Faculty of Medicine of the Moscow State Medical and Dental University in 2009, and in 2011 – a residency in the specialty “Genetics” at the Department of Medical Genetics of the same university. In 2017, he defended his dissertation for the degree of Candidate of Medical Sciences on the topic: Molecular diagnostics of copy number variations of DNA sections (CNVs) in children with congenital malformations, phenotypic anomalies and/or mental retardation when using high-density SNP oligonucleotide microarrays"

From 2011-2017 he worked as a geneticist at the Children's Clinical Hospital named after. N.F. Filatov, scientific advisory department of the Federal State Budgetary Institution "Medical Genetics" science Center" From 2014 to the present, he has been the head of the genetics department of the Genomed Medical Center.

Main areas of activity: diagnosis and management of patients with hereditary diseases and congenital malformations, epilepsy, medical and genetic counseling of families in which a child was born with hereditary pathology or developmental defects, prenatal diagnosis. During the consultation, clinical data and genealogy are analyzed to determine the clinical hypothesis and the necessary 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 gives presentations at conferences. Gives 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.

Area of ​​professional interests is the implementation of modern genome-wide research into clinical practice and 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 interpreting genetic tests xGenCloud (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 at a clinical residency in neurology at the Federal State Budgetary Institution "Scientific Center of Neurology".

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

In 2015, he completed training in Italy at the school “2nd International Residential Course on Drug Resistant Epilepsies, ILAE, 2015”.

In 2015, advanced training - “Clinical and molecular genetics for medical practitioners”, RDKB, RUSNANO.

In 2016, advanced training - “Fundamentals of molecular genetics” under the guidance of a bioinformatician, Ph.D. Konovalova F.A.

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

In 2016, he completed training 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 – school “NGS in Medical Genetics 2017”, Moscow State Research Center

Currently conducting scientific research in the field of genetics of epilepsy under the guidance of Professor, Doctor of Medical Sciences. Belousova E.D. and professor, doctor of medical sciences. 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” has been 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 diagnosis and interpretation of genetic testing results using the XGenCloud expert system for 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. "Epilepsy surgery for multifocal brain lesions in children with tuberous sclerosis." Abstracts XIV Russian Congress "INNOVATIVE TECHNOLOGIES IN PEDIATRICS AND CHILDREN'S SURGERY". Russian Bulletin of Perinatology and Pediatrics, 4, 2015. - p.226-227.
*
Dadali E.L., Belousova E.D., Sharkov A.A. "Molecular genetic approaches to the diagnosis of monogenic idiopathic and symptomatic epilepsies." Thesis of the XIV Russian Congress "INNOVATIVE TECHNOLOGIES IN PEDIATRICS AND CHILDREN'S SURGERY." Russian Bulletin of Perinatology and Pediatrics, 4, 2015. - p.221.
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Sharkov A.A., Dadali E.L., Sharkova I.V. " Rare option early epileptic encephalopathy type 2 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.
*
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 myoclonus epilepsy type 3, caused by mutations in the KCTD7 gene // Medical Genetics.-2015.- Vol.14.-No.9.- p.44-47
*
Dadali E.L., Sharkova I.V., Sharkov A.A., Akimova I.A. "Clinical and genetic features and modern methods diagnosis of hereditary epilepsies". Collection of materials “Molecular biological technologies in medical practice” / Ed. Corresponding member RAIN A.B. Maslennikova.- Issue. 24.- Novosibirsk: Akademizdat, 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 seizures: clinical and genetic characteristics and diagnostic methods. //Russian Journal of Child 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 CHILD NEUROLOGY” / Edited by Professor Guzeva V.I. St. Petersburg, 2016, p. 391
*
Hemispherotomy for 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 CHILD 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. Yes they did. Journal of Neurology and Psychiatry, 9, 2016; Vol. 2doi: 10.17116/jnevro 20161169267-73
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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 of epilepsies and epileptic seizures of the International League Against Epilepsy. Journal of Neurology and Psychiatry. C.C. Korsakov. 2017. T. 117. No. 7. P. 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. She studied 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 Advanced Training of Physicians of the Federal State Budgetary Educational Institution of Higher Professional Education "MSUPP"

Since 2013, he has been conducting consultations at the State Budgetary Institution "Center for Family Planning and Reproduction" of the Department of Health.

Since 2017, he has been the head of the “Prenatal Diagnostics” direction of the Genomed laboratory

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

Provides medical and genetic counseling to pregnant women on prenatal diagnostics in order to prevent the birth of children with congenital malformations, as well as families with presumably hereditary or congenital pathology. Interprets the obtained DNA diagnostic results.

SPECIALISTS

Latypov
Arthur Shamilevich

Latypov Artur Shamilevich is a geneticist doctor of the highest qualification category.

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

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

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

Area of ​​scientific interests: metabolic diseases in children, prenatal diagnostics.

Reception hours: Wed 12-15, Sat 10-14

Doctors are seen by appointment.

Geneticist

Gabelko
Denis Igorevich

In 2009 he graduated from the Faculty of Medicine of KSMU named after. S. V. Kurashova (specialty “General Medicine”).

Internship at the St. Petersburg Medical Academy of Postgraduate Education of the Federal Agency for Healthcare 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 Fundamental Fundamentals clinical medicine Institute of Fundamental Medicine and Biology.

Area of ​​professional interests: prenatal diagnosis, use of modern screening and diagnostic methods to identify 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.

Consultation by appointment

Doctors are seen by appointment.

Geneticist

Grishina
Kristina Alexandrovna

She graduated from the Moscow State Medical and Dental University in 2015 with a degree in General Medicine. In the same year, she entered residency in the specialty 08/30/30 “Genetics” at the Federal State Budgetary Institution “Medical Genetic Research Center”.
She was hired at the Laboratory of Molecular Genetics of Complexly Inherited Diseases (headed by Dr. A.V. Karpukhin) in March 2015 as a research assistant. Since September 2015, she has been transferred to the position research fellow. 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 in conferences on medical genetics.

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

A 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 definition accurate forecast recommendations for conducting and evaluating the results of prenatal diagnostics everything you need to know when planning a family consultation when planning IVF on-site and online consultations

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

Conducts medical and genetic counseling for families with suspected hereditary or congenital pathologies, including monogenic diseases and chromosomal abnormalities, determines indications for laboratory genetic studies, and interprets the results of DNA diagnostics. Consults pregnant women on prenatal diagnostics 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 “General Medicine”). She graduated from clinical residency at FBGNU "MGNC" with a degree in Genetics. In 2014, she completed an internship at the Maternity and Childhood Clinic (IRCCS materno infantile Burlo Garofolo, Trieste, Italy).

Since 2016, he has been working as a consultant physician at Genomed LLC.

Regularly participates in scientific and practical conferences by genetics.

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

Study of CGG repeat polymorphism in the FMR1 gene (associated with the carriage of premutations of the fragile X syndrome (fragile X chromosome))

• Martin-Bell syndrome (fragile X syndrome, fragile X mental retardation syndrome, FraX) is a hereditary disease that is characterized by physical, behavioral and emotional characteristics, and learning difficulties. This condition affects 1 in 4,000 boys and 1 in 5,000 to 8,000 girls.
• This condition develops due to changes in the FMR1 gene (“Fragile X Mental Retardation 1”) and, as a consequence, in the brain protein of the same name, FMRP. This gene is located on the X chromosome. Girls have two copies of the X chromosome, and boys have one X and one Y. A change in the gene is expressed in multiple repetitions of one of the parts of the gene (triplet CGG). Most people have few repeats, anywhere from 6 to 50 times, with an average of 30 - which does not usually cause a fragile X chromosome.
• With an average number of repetitions (from 50 to 200 times) development is said to be a carrier state. premutations. In this case, the gene continues to work, fragile X syndrome does not develop and mental activity does not suffer, but there is a risk of developing neurological disorders at the age of 50 and the risk of developing premature ovarian failure (early menopause (menopause) and infertility). These conditions are called fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI).
• From 40 to 55 repeats is the “gray zone” in which the normal variant and the premutation overlap.
• When the number of repeats is too high, more than 200, the gene becomes damaged, this is called full mutation. In men, since there is only one X chromosome, fragile X syndrome develops. The woman will be a carrier of the fragile X chromosome. There may be manifestations of the syndrome, it depends on the activity of the FMR1 gene.
• Inheritance this state- X-linked. That is, from mother to any child, and from father - only to daughters. The size of the repeat sequence can increase during inheritance: for example, a mother or father with a premutation can have a child with a full mutation. So, if the mother has a premutation, but the father does not have the X chromosome mutation, during each pregnancy their sons have a 1 in 2 chance that they will inherit the defective gene and develop fragile X syndrome. For a daughter, there is a similar percentage of the possibility of inheriting a defective gene.
• Genetic testing allows you to determine the carriage of a gene with a premutation or a complete mutation. The main diagnostic method is PCR (polymerase chain reaction).

FMR1 gene changes

Our chromosomes are long strands of DNA that contain genes. The information in the gene is written in the form of a genetic code in 4 letters - A, T, G, C. These letters indicate the simple components of DNA. Each gene consists of a string of “code words”, each of which consists of 3 letters. Each word is called a triplet. In some genes, these triplets are repeated several times. The triplet repeated in the FMR1 gene consists of three letters - CGG. When the number of triplet repeats becomes too large, the gene becomes so long that it becomes faulty.

The number of repeats of the CGG triplet creates different lengths of the repeat region in the FMR1 gene.

Length of repeats.	Influence
Short gene (6-50 repeats)	Does not affect
Average length (50-200 repeats) Premutation	Men and women are carriers. Ataxia syndrome may develop (more often in men over 79 years of age), in women - primary premature ovarian failure(in 20% of women).
Long gene (more than 200 repeats) Full mutation	Men have fragile X syndrome, which is expressed in developmental, physical, speech, and coordination delays; behavioral and emotional problems, including impaired coordination of attention, speech disorders, sensory problems, mood swings with attacks of aggression and depression. Epilepsy, heart problems, recurrent ear infections and eye problems may develop. Appearance Features: Large protruding ears, elongated face, large testicles, high, wide forehead, slightly beak-shaped nose, high arched palate and problems with connective tissue(flat feet, scoliosis, joint hypermobility).
	Women will be carriers of a fragile X chromosome with a chance to pass this mutation on to their offspring. Women usually do not have such vivid manifestations. About 60% have moderate mental impairment; hyperactivity or, conversely, shyness may be observed. Behavioral and emotional changes similar to men may be observed. The variability in the manifestations of the presence of a fragile X chromosome is explained by the system of switching off or inactivating one of the two X chromosomes in the cell. This means that in women, as in men, only one of the X chromosomes in the cell is working, the second is inactive. Which one works and which one doesn't - random process. So, half of the cells will have a working X chromosome without mutation, and the other half will have a mutation. However, this is usually sufficient for normal gene function and adequate production of an important brain protein, FMRP. The severity of the manifestations depends on the proportion of cells carrying the defective gene.

Background

At the beginning of the century, scientists noticed the predominance of mental retardation in males. For the first time in 1934, J. Martin and Julia Bell described a family in which mental retardation was inherited in a sex-linked pattern. In this English family there were 11 men with mental retardation and 2 women with mild degree mental retardation. Further, more and more such families were described.

Martin Bell syndrome is an inherited genetic disorder linked to the X chromosome that results in developmental delays and mental and behavioral problems. It is also called fragile X syndrome or marker X syndrome.

Fragile X syndrome symptoms occur due to a mutation in the FMR1 gene.

Martin-Bell is the most common inherited cause of mental retardation, affecting approximately 1 in 4,000 to 6,000 men and 1 in 8,000 to 10,000 women. The syndrome is associated with abnormalities of the FMR1 gene.

This change occurs from an increase in the number of repeats of the cytosine-guanine-guanine trinucleotide. Because the mutation is X-linked, males are more severely affected than females, predominantly exhibiting mental retardation, with characteristic physical features and behavioral changes.

Predominant clinical manifestations are an elongated and narrow face with a large forehead, a prominent chin, large, anteverted ears, hypothyroidism, strabismus, hypoplasia of the middle third of the face, and a mandibular protrusion.

Possible coexistence with, joint hyperlaxity (with increased mobility), unilateral or bilateral large testes (macrocorchism).

The most common intraoral anomalies are:

• sharp, cleft palate,
• the presence of mesiodens,
• hypomineralization of teeth,
• abrasion of occlusal surfaces and cutting edges,
• an increase in the size of dental crowns of mesiodistal, cervico-occlusal orientation, causing severe osteo-dental discrepancies.

Each cell of the body has two sex chromosomes. Although women have two X chromosomes in each cell, men have one X and one Y chromosome.

Fragile X syndrome occurs due to a mutation in the FMR1 gene, which is located on the X chromosome. Because of this defect, the body cannot produce a protein that is essential for nerve function. In some cases, produces smaller amounts of the same protein.

Although the condition is very rare, men are more likely to suffer the effects of this mutation. Women suffer from less severe forms diseases.

Clinical features depend on the degree of mutation. Individuals with Martin Bell syndrome experience mental retardation, autistic-like behavior, and hyperactivity.

They have distinctive physical features such as:

• large head circumference,
• long face with a pronounced forehead and jaw,
• protruding ears,
• weak joints,
• flat legs,
• enlarged testicles, especially during puberty.

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There may be a defect heart valve called mitral valve prolapse.

Characteristic symptoms help diagnose the condition, which is confirmed by genetic tests. Treatment is symptomatic and includes supportive care, behavioral and occupational therapies.

Causes

Loss or deficiency of the FMR1 protein disrupts the functioning of the nervous system and causes symptoms of Martin Bell syndrome.

This is a hereditary disorder resulting from a mutation in the FMR1 (Fragile X Mental Retardation 1) gene, located on the X chromosome. The FMR1 gene is required to create a protein called FMRP, which is important for nerve function.

Some people have the full mutation and show the characteristic features of this condition. Others have some changes in the gene that do not produce visible signs. Such people can pass the condition on to their offspring without suffering from it.

Men have only one X chromosome, which they pass on to their daughters. Thus, if a man has a son, he does not inherit this defect from his father. However, since the father passes on the X chromosome to the daughter (the other X chromosome will come from the mother), she will be able to carry the gene but will not suffer from the condition. However, there is a good chance that her child will inherit and suffer from Martin Bell syndrome.

Symptoms

Fragile X syndrome is characterized by mental retardation, autistic behavior, intellectual deficits, learning difficulties, emotional problems, social anxiety along with severe physical appearance.

Signs and symptoms depend on the extent of the gene abnormality and vary from patient to patient. Men usually suffer from a more severe form of the disease. More often character traits appear in adolescence.

This is especially true for mental impairment, characteristic physical features in men that become apparent during puberty.

Signs of Martin Bell syndrome:

1. In infancy and childhood, children exhibit impairments in motor skills and delayed speech development. The baby may also experience poor muscle tone, gastric reflux, vomiting, and an inability to gain weight. Toilet training has been delayed.
2. Patients usually have a lower than normal IQ.
3. Exhibit autistic-like features such as poor eye contact. They suffer from attention deficit hyperactivity disorder (ADHD), depression, shyness, social anxiety, emotional problems, random seizures, and self-injurious behavior. Features such as obsessive-compulsive disorder, sensory integration disorder, or both may also be present.
4. Many people are especially sensitive to certain sensory stimuli, such as loud noise, bright lights, or the feel of certain clothing, which can lead to behavioral problems.
5. Patients with Martin Bell syndrome have certain abnormalities in the bones, muscles, joints, such as flat legs, concave, sunken chest, weak joints, curved spine, joint dislocation. Facial Features: Long, thin face with prominent forehead and jaw, prominent ears, enlarged testicles in males. These features are more noticeable in adolescents and adults.
6. Mitral valve prolapse, a heart valve defect, is often observed.

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Tremor, ataxia

Both men and women who are carriers are at risk of developing tremors and ataxia. Characteristic features include trembling of the hands, legs, loss of coordination, balance problems, dementia, decreased sensation, numbness, tingling, anxiety, depression, irritability.

Symptoms of primary ovarian insufficiency (POI)

Female carriers may develop primary ovarian insufficiency (POI). In this disorder, the ovaries stop functioning normally at age 40 or earlier.

Diagnostics

The defective gene in Martin Bell syndrome is detected through genetic testing.