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

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

Causes of occurrence

The human genotype consists of 46 chromosomes, two of them determine the sex - X, Y. Women have 46 XX, men - 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 repeating combinations of cytosine-guanine-guanine (CHG), increasing copies (expansion) thinning sections of DNA, causing Martin-Bell Syndrome (MBS). The anomaly occurs against the background of a mutation in FMR1, a gene responsible for encoding a protein, a major participant in the formation of the nervous system.

The X chromosome segments are characterized by four categories

A gene mutation inhibits the functionality of a protein involved in the development of a child, which affects his ability to learn and memorize new material. Insufficiency of the enzyme affects the formation of axons, synapses, which are directly involved in nerve connections, against this background, neurological abnormalities and mental retardation develop.

Genetic pathology in the female line is inherited. In a man with one X chromosome, after the transfer of the broken gene from the 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. The girl's deficiency is replenished by the second chromosome. Pathology does not manifest itself, in the worst case, it is accompanied by mild symptoms. The woman transmits the fragile X syndrome to the offspring of both sexes, the circle is closed. Therefore, within the limits of one clan clan, men have a mental disorder, while the female half is completely healthy or with minor deviations.

Characteristic signs of pathology

A genetic disease is accompanied by a variety of symptoms, each case is individual with a set of its own symptoms. SMB differs 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 of the genetic mutation. A newborn boy is distinguished by a large weight and an enlarged testicle (macro-orchism), without hormonal abnormalities.

There is a decrease in the sucking and grasping reflex, muscle tone, it reacts poorly to external stimuli. The child lags behind peers in physical and intellectual development. In most cases, he is born with congenital diseases: heart defects, deformation of the joints. Therefore, children with SMD start to walk late, practically do not crawl, speech function is inhibited, vocabulary is scarce, diction is indistinct, in severe cases, a complete lack of communication skills is manifested, the child is silent.

As the Martin-Bell syndrome progresses, the signs are supplemented and more pronounced. With a delay in psychomotor development, movements acquire hyperkinetic features:

• haphazard waving of hands, claps of hands, shaking of phalanges;
• jumping in place;
• circular movements of the body, turns around its axis;
• discoordination, meaninglessness and pomp of poses.

Psychological deviations:

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

Neurological abnormalities inherent in 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 curvature of facial expressions and frequent blinking;
• tremor of the upper limbs;
• hypermobility, the patient is unable to stay in one place for a long time:
• oculomotor, pyramidal disorders.

Fragile chromosome syndrome forms physical abnormalities in development, sick boys visually differ from healthy peers:

• the head is large in size with a convex high forehead, from which the face takes the shape of an oval;
• the palatine arch is deep, the lower jaw is heavy;
• ears are round, protruding, with a low set on the skull;
• pointed nose, in the form of a hook;
• eyes set wide, squint.

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

All carriers of broken FMR1 have unchanged symptoms of thyroid and adrenal dysfunction. Endocrine disorders cause metabolic failure (obesity), early puberty. The level of mental retardation ranges from mild to severe clinical course. The main percentage of patients are at the stage of oligophrenia.

Women have a high libido, but they enter early menopause. The ovaries degenerate into cystic neoplasms. Men have obvious macro-orchism.

Diagnostic tests

Definition of Martin-Bell syndrome involves the use of specific tests to analyze the state of the X chromosome in the Xq27-28 region. 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 hypotonia of muscle mass.
2. The main technique in the diagnosis of pathology, which gives a 100% result at an early stage of clinical development, is the cytogenetic method. The patient's cells are taken, processed with folic acid, which starts the process of changing the chromosome. If an anomaly is noted on the Xq27-28 litmus, the presence of the syndrome is beyond doubt.
3. At a later date, the study of a pair of chromosomes responsible for sex (karyotyping) is used. The mutation confirms the BMP.
4. The composition and structure of trinucleotides are analyzed using the polycepic reaction.
5. Molecular genetic studies determine the frequency of CHG repeats.
6. With fragile X syndrome, all patients have the same bioelectrical activity of the brain, which makes it possible to confirm the diagnosis using electroencephalography.

The disease can be detected in the early stages of pregnancy. Perinatal examination is based on ultrasound, analysis of the woman's blood serum, chorionic 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

As with any inherited genetic disease, it is impossible to get rid of Martin-Bell syndrome. Therapy with medicines is carried out in a complex 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 disorders.

Conservative methods

Treatment of a genetic anomaly involves the use of such drugs:

• blood thinners - "Kleksan", "Plavix";
• preventing epileptic seizures - "Mazepin";
• nootropic action - "Piracetam";
• to improve the state 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", "Peritsiazin".

In complex therapy, lithium-based drugs are used along with a set of vitamins that normalize cognitive function. The pursuit of treating folic acid syndrome has proven ineffective. The therapy temporarily improved behavioral and communication capabilities, but did not inhibit the process of mental degradation.

Physiotherapy

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

• physiotherapy;
• exercise in the pool;
• charcot shower;
• mud baths with radon;
• acupuncture (acupuncture);
• hirudotherapy (blood thinning leeches);
• muscle relaxation.

Shown are classes with a speech therapist, trainings with a psychotherapist.

Operative treatment

Surgical intervention is advisable if the complication of Martin-Bell syndrome has affected vital organs. An operation is performed for congenital heart defects, cystic degeneration of the ovaries with the risk of transition to a malignant formation.

Plastic correction is applied, the purpose of which is to eliminate physical defects inherent in the disease. Surgically, the limbs are brought back to normal, the shape of the ears is changed, and the external anomaly of the genitals is eliminated.

Forecast and prevention

Genetic fragility of the X chromosome does not pose major health problems, if not complicated by intrauterine pathologies. Life expectancy does not differ from healthy people. The prognosis for recovery is poor. With adequate symptomatic treatment, psychological correction, assistance to a person with adaptation in society, the quality of life will significantly improve, but as a result, the syndrome will lead to disability.

The prevention of the disease is a perinatal examination of the fetus in the early stages. Screening of biological material will help identify a mutation in the Xq27-28 region. In this case, termination of the pregnancy is recommended. A man or woman with a family history of FMR1 mutation should be tested before planning a child. If the abnormality in one of the parents is confirmed, there are molecular ways to correct the defect in the X chromosome and to carry out in vitro fertilization. IVF will enable the birth of a baby with a healthy genetic code.

Fragile X syndrome

Little known until the 1980s, the fragile X chromosome is a chromosomal abnormality now considered the most common hereditary cause of mental retardation. Down's syndrome - d. a genetically determined cause of mental underdevelopment - arises due to the failed separation of the 21st chromosome pair during meiosis; it is genetic in nature, but not inherited. Situated in a weak or fragile region on the X chromosome, fra (X) is associated with iol and is therefore more common in males. It is just one of more than 50 X-linked disorders that cause mental retardation. development, a cut is widespread. Although different studies give different estimates, morbidity is about 1: 1500 for men and 1: 2000 for women. Fra (X) is the cause of 2-7% of cases of mental retardation in men. She has two unusual genetic characteristics: a) heterozygous (carriers) women with one normal X chromosome and one with a fragile region may show decreased intelligence and lack of specific learning; b) about 20% of men who have inherited a fragile area are non-penetrant, not showing noticeable physical. or psychol. effects and signs of fragility in cytogenetic analysis. They, however, pass on the X chromosome to their daughters, who can pass it on to their sons. Another difficulty is that during repeated cytogenetic examinations, the fragile area is not found in more than 50% of female carriers.

Historical excursion

Since the beginning of the XX century. Researchers have noticed in some families an increased percentage (often about 25%) of persons with mental retardation. Martin and Bell in 1943, and others later, described families in which mental retardation. development was transmitted in a form linked to the X chromosome. Although Labs first described the fragile site X in 1969, his description attracted little interest until Sutherland reported that fragility only manifests itself when lymphocytes are grown in a folate-deficient culture. The discovery of the sensitivity of fra (X) and some other fragile localizations to folic acid made it possible to increase the accuracy of diagnosis, which, in turn, led to the discovery of a high prevalence of fra (X) and an increasing interest in X-linked mental retardation. development. Subsequent issled. confirmed the findings of Martin and Bell on the role of fra (X) in the genesis of mental retardation.

Specifications

About 66% of adult male patients show a "clinical triad": a) moderate to severe mental retardation; b) skull and facial features, including a high forehead, prominent chin, and elongated ears; c) enlarged testicles (macroorchidism). However, the individual variability of signs is so high that a confident diagnosis is possible only with cytogenetic analysis. The spread of signs is even higher in women and males in the prepubertal period. Although the majority of male patients exhibit “advancing growth syndrome” at birth (head, fontanelle, and body sizes exceed the 97th percentile), macroorchidism and craniofacial features in prepubertal boys are much less pronounced. The following signs of pathology DOS. on the following publications: Bregtap, Dykens, Watson, Ort, and Leckman; Brown et al .; Curfs et al .; Dykens & Leckman; Fryns; Hagerman.

Physical signs. In addition to the characteristic features of the skull and face, macroorchidism, and advancing growth, males with fra (X) may also exhibit signs such as increased joint mobility, a high roof of the palate, mitral valve prolapse (with noise on auscultation), flat feet and low muscle tone. Female carriers, especially those at the lower limit of the normal development of intelligence, also exhibit such features as a high and wide forehead, a long face, and increased joint mobility.

Cognitive traits. Approximately 70% of male patients have moderate to severe mental retardation, but overall the range is mild to severe; a small percentage of cases have intelligence at the lower limit of the norm. The decline in the level of intelligence in men with age is not total. Violations here concern, first of all, the sequential processing of information., The reduction of short-term memory for the serially presented information., Imitation of sequential behavioral acts. This deficit in the sequential processing of information. distinguishes individuals with fra (X) from patients with other forms of mental retardation. Male patients cope relatively well with tasks that require simultaneous (simultaneous) processing of information. and integration (eg dice folding).

Although most fra (X) carriers have normal intelligence, about 30% of female patients show mental retardation. Even those who have an average level of intelligence very often show insufficient specific learning. Patients also have violations of sequential processing of information. and lack of visual-spatial skills, they poorly perform digital and arithmetic tests, tasks with cubes. There is some evidence that the IQ level in female patients, in contrast to men, increases with age.

Speech. In male patients, speech skills develop with a lag. In addition, specific problems are often observed - perseveration, echolalia, impaired fluency of speech, - some of which may be the result of a general deficiency in sequential processing of information.

Behavioral signs. Hyperactivity and attention deficit are particularly frequent consequences of fra (X), especially in males. Pl. often there is a tendency towards social. isolation, avoidance of eye contact, and self-harm, especially self-biting.

Relationship to other disorders. In male patients, convulsive syndrome may also occur. Fra (X) is also comorbid with autism. Pl. male patients with fra (X) show signs of autism, while many others. in male patients diagnosed with autism fra (X) is detected on a cytogenetic test. The variability of agreement between studies is very high, probably due to the discrepancy in the use of diagnostic criteria for autism. However, the recommendation that all male patients diagnosed with autism should be screened for fra (X) appears to be warranted.

Folic acid therapy

Folic acid has been used frequently in attempts to reduce fra (X) symptoms. Issled. double-blind studies show that this treatment does not affect scores on intelligence tests, but may reduce hyperactivity and improve focus. Whether folic acid treatment is as effective as stimulant therapy traditionally used in attention deficit hyperactivity disorder (ADHD) remains an open question.

Psychol. approach is important in issled. fra (X), for at least two reasons: a) diffuseness and variability of physical. changes at fra (X) gives additional importance to the role of psychol. examinations to identify children with indications for cytogenetic analysis; b) the cognitive characteristics of patients with fra (X) are important for the design of treatment and ped. programs. The variety of problems associated with fra (X) justifies the recommendation of a team approach in the treatment of such patients. Further, a clear distinction between the signs of fra (X) syndrome and Down syndrome means the heterogeneity of these groups of organic decrease in intelligence, which theor has. significance. Fra (X) syndrome can be identified before birth with a specific test, but incomplete penetrance in males, phenotypic effects in a significant number of female carriers, and difficulty in diagnosis in asymptomatic females complicate genetic counseling. Finally, although much is known about fra (X), Wells and Brown's observation that “subsequent investig. can change the present. the idea of \u200b\u200ba fragile X chromosome ”seems to be a reasonable warning.

It is one of the most common forms of mental retardation after Down's disease. The population frequency is 1: 2000 - 1: 2500 newborns. There are 2-3 times more sick boys than girls and they get sick more severely.

The appearance of patients is not always specific. Characterized by an elongated face, a high protruding forehead, macro- and dolichocephaly, hypoplasia of the middle part of the face. The lips are thick, the lower lip is often inverted. Macrootia, large hands and feet are characteristic. A typical symptom - macroorchidism - appears in adolescents. The testicles are enlarged due to the development of connective tissue. Sexual activity is minimal. There are symptoms of congenital connective tissue dysplasia - joint ligament weakness, flat feet, sometimes spinal deformity, etc.

Mental retardation is often moderate, rarely deep (10-15%). Most of the patients are socially adapted, can perform simple physical work. In female carriers, the IQ is low.

The disease is caused by a mutation in the FMR-1 gene (fragile mental retardation), which is localized in the long arm of the X chromosome (Xq). The pathological gene has a large number of trinucleotide repeats (CHR) in 5 1 - the untranslated region of this gene. Normally, the number of repeats is from 6 to 42. A chromosome with 50-200 repeats is considered a premutation. In the next generation, the number of repetitions can increase to 1000, which leads to a pronounced clinical picture. The clinical picture depends on the number of repetitions.

If a woman has inherited a large number of repetitions, then she will also be sick. But this is rare.

The main diagnostic method is karyotyping. The patient's lymphocytes are cultured in an environment without folic acid. In the long arm, the X chromosomes show a “fragile” (“fragile region”). Outwardly, it resembles a secondary constriction and a satellite. The chromosome is damaged in the region of a large number of trinucleotide repeats.

Molecular genetic diagnostics is possible, methods of prenatal diagnostics have been developed.

Phosphate diabetes (hypophosphatemia)

The type of inheritance is X-linked dominant. The gene is localized Xp 22.2 - p 22.I.

Hypophosphatemia can be detected immediately after birth, and signs of rickets appear at the end of the first - beginning of the second year of life, when children begin to walk. Changes in the lower extremities are more pronounced: varus curvature of the long bones. Characterized by low growth, limited mobility in large joints (hip, knee, elbow), dolichocephaly, nail dysplasia. The gait is uncertain, in severe cases the patients cannot walk at all. Unlike vitamin - D - deficient rickets, the general condition is not disturbed. In women, skeletal disorders are less pronounced. X-ray reveals changes typical for rickets - a coarse-fibrous structure of the spongy substance of the bones. The level of alkaline phosphatase is increased in the blood, the level of calcium is normal. The disease is caused by a decrease in phosphate reabsorption in the renal tubules.

Hereditary diseases linked to the X chromosome.

Head of
"Oncogenetics"

Zhusina
Yulia Gennadevna

Graduated from the pediatric faculty of the Voronezh State Medical University named after V.I. N.N. Burdenko in 2014.

2015 - internship in therapy at the Department of Faculty Therapy of V.G. N.N. Burdenko.

2015 - Certification course in the specialty "Hematology" at the Hematological Research Center in Moscow.

2015-2016 - physician therapist, VGKBSMP №1.

2016 - the topic of the dissertation for the degree of candidate of medical sciences "study of the clinical course of the disease and prognosis in patients with chronic obstructive pulmonary disease with anemic syndrome" was approved. Co-author of over 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 RMANPO.

Head of
"Genetics"

Kanivets
Ilya Vyacheslavovich

Kanivets Ilya Vyacheslavovich, Geneticist, Candidate of Medical Sciences, Head of the Genetics Department of the Genomed Medical Genetic Center. Assistant of the Department of Medical Genetics of the Russian Medical Academy of Continuing Professional Education.

He graduated from the medical faculty of the Moscow State University of Medicine and Dentistry in 2009, and in 2011 - 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 variations in the number of copies of DNA regions (CNVs) in children with congenital malformations, phenotype abnormalities and / or mental retardation when using SNPs of high-density oligonucleotide microarrays "

From 2011-2017, he worked as a geneticist at the Children's Clinical Hospital. N.F. Filatov, scientific advisory department of the Federal State Budgetary Scientific Institution "Medical Genetic Research Center". From 2014 to the present, he is the head of the genetics department at MGC Genomed.

The main areas of activity: diagnosis and management of patients with hereditary diseases and congenital malformations, epilepsy, medical and genetic counseling for families in which a child was born with hereditary pathology or developmental defects, prenatal diagnostics. During the consultation, clinical data and genealogy are analyzed 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 speaks at conferences. Gives lectures for doctors, geneticists, neurologists and obstetricians-gynecologists, as well as for parents of patients with hereditary diseases. She is the author and co-author of over 20 articles and reviews in Russian and foreign journals.

The area of \u200b\u200bprofessional 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 the Daegu Haanu University in South Korea.

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

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 Scientific Center of Neurology.

Since 2015, he has been working as a neurologist, research fellow at the Academician Yu.E. Veltischev GBOU VPO RNIMU them. N.I. Pirogov. He also works as a neurologist and doctor in the laboratory of video-EEG monitoring in the clinics “Center for Epileptology and Neurology named after AA Kazaryan "and" Epilepsy Center ".

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

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 department of the Genomed laboratory.

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

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 conducts 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, epilepsy genetics. Neurogenetics.

Scientific publications

Sharkov A., Sharkova I., Golovteev A., Ugarov I. "Optimization of differential diagnosis and interpretation of the results of genetic testing by the XGenCloud expert system in some forms of epilepsy." Medical genetics, no. 4, 2015, p. 41.
*
Sharkov A.A., Vorobiev A.N., Troitsky A.A., Savkina I.S., Dorofeeva M.Yu., Melikyan A.G., Golovteev A.L. "Surgery of epilepsy for 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.
*
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 PEDIATRIC SURGERY". Russian Bulletin of Perinatology and Pediatrics, 4, 2015. - p. 221.
*
Sharkov A.A., Dadali E.L., Sharkova I.V. "A rare variant of early type 2 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. SPb .: 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 type 3 myoclonus epilepsy caused by mutations in the KCTD7 gene // Medical genetics. -2015.- v.14.-№9.- p.44-47
*
Dadali E.L., Sharkova I.V., Sharkov A.A., Akimova I.A. "Clinical and genetic features and modern methods of diagnosing hereditary epilepsies." Collection of materials "Molecular biological technologies in medical practice" / Ed. Corresponding Member RAYEN A.B. Maslennikov. - Issue. 24.- Novosibirsk: Akademizdat, 2016.- 262: p. 52-63
*
Belousova E.D., Dorofeeva M.Yu., Sharkov A.A. Epilepsy in tuberous sclerosis. In "Diseases of the brain, medical and social aspects" edited by Gusev EI, Gekht AB, Moscow; 2016; pp. 391-399
*
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 Pediatric Neurology.- T. 11.- №2, p. 33- 41.doi: 10.17650 / 2073-8803- 2016-11- 2-33- 41
*
Sharkov A.A., Konovalov F.A., Sharkova I.V., Belousova E.D., Dadali E.L. Molecular genetic approaches to the diagnosis of epileptic encephalopathy. Collection of abstracts "VI BALTIC CONGRESS ON CHILD NEUROLOGY" / Edited by Professor Guzeva V.I. St. Petersburg, 2016, p. 391
*
Hemispherotomy for pharmacoresistant epilepsy in children with bilateral brain damage Zubkova NS, Altunina G.Ye., 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.
*
*
Article: Genetics and differential treatment of early epileptic encephalopathy. A.A. Sharkov *, I.V. Sharkova, E. D. Belousova, E.L. Dadali. Journal of Neurology and Psychiatry, 9, 2016; Issue 2doi: 10.17116 / jnevro 20161169267-73
*
Golovteev A.L., Sharkov A.A., Troitsky A.A., Altunina G.E., Zemlyansky M.Yu., Kopachev D.N., Dorofeeva M.Yu. "Surgical treatment of epilepsy in tuberous sclerosis" edited by M. Dorofeeva, Moscow; 2017; page 274
*
New international classifications of epilepsy and epileptic seizures of the International League Against Epilepsy. Journal of Neurology and Psychiatry. C.C. Korsakov. 2017.Vol. 117.No. 7.P. 99-106

Head of
"Prenatal diagnostics"

Kievskaya
Yulia Kirillovna

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

In 2015 she graduated from an internship in the specialty Obstetrics and Gynecology at the Medical Institute for Advanced Training of Doctors of the FSBEI HPE "MGUPP"

Since 2013, he has been conducting a consultative reception at the State Budgetary Healthcare Institution "Center for Family Planning and Reproduction" DZM

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

He regularly gives reports at conferences and seminars. Gives lectures for doctors of various specialties in the field of reproduction and prenatal diagnostics

Conducts medical and genetic counseling of 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 results of DNA diagnostics.

SPECIALISTS

Latypov
Arthur 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 the head of the medical genetic center of the Republican Hospital of Tatarstan, chief specialist of the Ministry of Health of the Republic of Tatarstan, teacher of the departments of Kazan Medical University.

Author of over 20 scientific papers on problems of reproductive and biochemical genetics, participant in many national and international congresses and conferences on problems of medical genetics. Introduced methods of mass screening of pregnant women and newborns for hereditary diseases into the practical work of the center, conducted thousands of invasive procedures for suspected hereditary diseases of the fetus at different stages of pregnancy.

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

Research interests - metabolic diseases in children, prenatal diagnostics.

Reception of doctors is carried out by appointment.

Geneticist

Gabelko
Denis Igorevich

In 2009 he graduated from the medical faculty 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 Foundations of Clinical Medicine of the Institute of Fundamental Medicine and Biology.

Sphere of professional interests: prenatal diagnostics, the use of modern screening and diagnostic methods to identify the genetic pathology of the fetus. Determination of 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.

Reception of doctors is carried out by appointment.

Geneticist

Grishina
Kristina Alexandrovna

Graduated in 2015 from the Moscow State Medical and Dental University with a degree in General Medicine. In the same year she entered the residency in the specialty 30.08.30 "Genetics" at the Federal State Budgetary Scientific Institution "Medical Genetic Research Center".
She was employed at the Laboratory of Molecular Genetics of Difficult Inherited Diseases (headed by A.V. Karpukhin, Doctor of Biological Sciences) 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 over 10 articles and abstracts on clinical genetics, oncogenetics and molecular oncology in Russian and foreign journals. Regular participant of conferences on medical genetics.

Field 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 questions:

whether the child's symptoms are signs of a hereditary disorder what research is needed to identify the cause determining an accurate forecast recommendations for the conduct and assessment of the results of prenatal diagnosis everything you need to know when planning a family iVF planning consultation on-site and online consultations

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

Conducts medical and genetic counseling for families with presumably 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 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 the specialty "Obstetrics and Gynecology"

Internship in 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, the Faculty of Medicine (specialty "General Medicine"). She graduated from the clinical residency of the Federal State Budgetary Scientific Institution "MGNC", specializing in "Genetics". In 2014, she completed an internship at the clinic for mothers and children (IRCCS materno infantile Burlo Garofolo, Trieste, Italy).

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

She regularly participates in scientific and practical conferences on genetics.

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

Q99.2 Fragile X chromosome

Epidemiology

Martin-Bell syndrome is a fairly common disease: for 1000 men there are 0.3-1.0 suffering from this disease, and for 1000 women - 0.2-0.6. Moreover, children with Martin-Bell syndrome are born on all continents at the same frequency. Obviously, nationality, skin color, eye shape, living conditions, well-being of people do not affect the occurrence of the disease. The frequency of its occurrence is comparable only with the frequency of Down syndrome (1 disease per 600-800 newborns). A fifth of the male carriers of the altered gene are healthy, do not have clinical and genetic abnormalities, the rest with signs of mental retardation from mild to severe forms. Slightly more than a third of female carriers are sick.

Fragile X syndrome affects approximately 1 in 2500-4000 men and 1 in 7000-8000 women. The prevalence of carriers of the disease among women is estimated to be as high as 1 in 130-250 people; the prevalence of male carriers is estimated to be 1 in 250-800.

Causes of Martin-Bell Syndrome

Martin-Bell syndrome develops due to the complete or partial cessation of the body's production of a specific protein. This is due to the lack of a response from the FMR1 gene located on the X chromosome. Mutation occurs as a result of restructuring of a gene from unstable structural variants of gene states (alleles), and not from the very beginning. The disease is transmitted only through the male line, and a man may not necessarily be sick. Male carriers pass the gene on to their daughters unchanged, so their mental retardation is not obvious. With further transmission of the gene from the mother to her children, the gene mutates, and here all the symptoms characteristic of this disease appear.

Risk factors

Pathogenesis

At the heart of the pathogenesis of Martin-Bell syndrome are mutations in the gene apparatus that lead to blocking the production of FMR protein, a protein vital for the body, especially in neurons, and is present in various tissues. Research shows that FMR proteins are directly involved in the regulation of translations that take place in brain tissues. The absence of this protein or its limited production by the body leads to mental retardation.

In the pathogenesis of the disease, gene hypermethylation is considered a key disorder, but the mechanism of the development of this disorder has not yet been finally identified.

Along with this, the locus heterogeneity of the pathology was also found, which is associated with polyallelism, as well as polylocality. The presence of allelic variants of the development of the disease was determined, which are caused by the existence of point mutations, as well as the destruction of the FMRL type gene.

Also, in patients, 2 fragil triplets, sensitive to folic acid, located at 300 kb, as well as 1.5-2 million bp, are detected in patients. from a fragile triplet containing the FMR1 gene. The mechanism of mutations occurring in the FRAXE and FRAXF genes (they are identified in the aforementioned fragile triplets) of mutations correlates with the mechanism of disorders in Martin Bell syndrome. This mechanism is determined by the proliferation of GCC and CGG repeats, in which methylation of the so-called CpG islands occurs. In addition to the classical form of pathology, there are also 2 rare types, which differ due to the expansion of trinucleotide repeats (in male and female meiosis).

It was revealed that in the classic form of the syndrome, the patient lacks a special nucleocytoplasmic protein of the FMR1 type, which performs the function of binding various mRNAs. In addition, this protein contributes to the formation of a complex that helps to carry out translational processes within the ribosomes.

Symptoms of Martin-Bell Syndrome

How to recognize a disease in children? What are the first signs? In the first months of a child's life, it is impossible to recognize the Martin-Bell symptom, except that sometimes there is a decrease in muscle tone. After a year, the clinic of the disease is more obvious: the child begins to walk and talk late, sometimes speech is completely absent. He is hyperactive, waving his arms randomly, afraid of the crowd and noise, stubborn, there are sharp outbursts of anger, emotional instability, epileptic seizures occur, and does not make eye contact. In patients with Martin-Bell syndrome, the disease also gives out appearance: ears, protruding and large, a heavy forehead, an elongated face, a protruding chin, squint, wide brushes and feet. They are also characterized by endocrine disorders: often heavy weight, obesity, men have large testicles, early puberty.

Among patients with Martin-Bell syndrome, the level of intelligence is very different: from mild mental retardation to its severe cases. If a normal person has an intelligence quotient (IQ) of 100 on average, and a genius of 130, then for people susceptible to an illness it is 35-70.

All clinical symptoms of pathology can be characterized by a triad of main manifestations:

• mental retardation (IQ is 35-50);
• dysmorphophobia (protruding ears are observed, as well as prognathism);
• macroorchidism, which manifests itself after the onset of puberty.

In about 80% of patients, bicuspid valve prolapse is also detected.

But at the same time, the full form of the syndrome manifests itself in only 60% of all patients. In 10%, only mental retardation is found, and in the rest, the disease develops with a different combination of signs.

Among the first signs of the disease, manifested already at an early age:

• a sick child has significant mental retardation in comparison with the development of other peers;
• disorders of attention and concentration;
• strong stubbornness;
• children start walking and talking quite late;
• hyperactivity and speech disorders are observed;
• very strong and uncontrollable fits of anger;
• mutism can develop - this is a complete lack of speech in the child;
• the baby feels social anxiety, is able to panic due to loud noise or any other strong sounds;
• the child uncontrollably and chaotically waving his arms;
• shyness is observed, the child is afraid of being in places of a large crowd of people;
• the emergence of various obsessions, an unstable emotional state;
• your toddler may be reluctant to make eye contact with people.

In adults, the following pathology symptoms are observed:

• specific appearance: an elongated face with a heavy forehead, large protruding ears, a strongly protruding chin;
• flat feet, otitis media and squint;
• puberty occurs quite early;
• obesity may develop;
• quite often with Martin Bell syndrome, defects in the development of the heart are observed;
• in men, there is an increase in the testes;
• the joints of the joints become very mobile;
• weight increases dramatically, as well as height.

Diagnostics of the Martin-Bell syndrome

To diagnose Martin Bell syndrome, you need to contact a qualified geneticist. The diagnosis is made after specific genetic tests are performed to identify the defective chromosome.

Analyzes

At an early stage of the development of the disease, a cytogenetic method is used, in which a fragment of cellular material is taken from the patient, to which folic acid is then added to provoke changes in the chromosomes. After a certain period of time, a region of the chromosome is identified on which a noticeable thinning is observed - this is a sign of the presence of the fragile X-chromosome syndrome.

But this analysis is not suitable for diagnosis in the later stages of the disease, because its accuracy is reduced due to the widespread use of multivitamins containing folic acid.

An integrated diagnosis of Martin-Bell syndrome is a molecular genetic examination, which consists in determining the number of so-called trinucleotide repeats in a gene.

Instrumental diagnostics

A highly specific method of instrumental diagnostics is PCR (polymerase chain reaction), which makes it possible to study the structure of amino acid residues contained in the X chromosome and thereby determine the presence of Martin Bell syndrome.

There is also a separate, even more specific, method for diagnosing pathology - a combination of PCR and detection using capillary electrophoresis. This method is highly accurate and detects chromosomal abnormalities in patients with primary ovarian failure, as well as ataxic syndrome.

It is possible to determine the presence of a defect after diagnostics on the EEG. Patients with this disorder have similar bioelectrical brain activity.

Differential diagnosis

Differentiated methods to help suspect the syndrome include:

• clinical - 97.5% of patients have obvious signs of mental retardation (moderate or profound); 62% have protruding large ears; 68.4% have a large chin and forehead protruding forward; in 68.4% of boys - enlarged testes, in 41.4% - peculiarities of speech (speech rate is uneven, volume is uncontrollable, etc.);
• cytogenic - blood is examined for a culture of lymphocytes, the number of cells with a fragile X chromosome is determined per 100 cells studied;
• electroencephalography - changes in the electrical impulses of the brain are recorded specific to the Martin-Bell syndrome.

Martin Bell Syndrome Treatment

In the treatment of adult patients, antidepressants with psychostimulants are used. The process of drug therapy is constantly monitored by a psychologist and psychiatrist. In addition, in private clinics, microinjection procedures are performed with drugs such as Cerebrolysin (or its derivatives), as well as cytomedins (such as Solcoseryl or Lidaza).

With the development of ataxic syndrome, drugs that thin the blood are used, as well as nootropics. In addition, amino acid mixtures and angioprotectors are prescribed. Women with primary ovarian failure are prescribed corrective treatment with phyto-medications and estrogens.

Also, glutamine receptor antagonists are used in the treatment.

The traditional treatment for Martin-Bell syndrome is the use of medications that act on the symptoms of the disease, but not on its cause. This therapy consists in the appointment of antidepressants, neuroleptics, psychostimulants. Not all drugs are indicated for use in children, so the list of drugs is rather limited. Antipsychotics that can be used after 3 years (the earliest age of their appointment) include haloperidol in drops and tablets, chlorpromazine in solution, peritsiazine in drops. Thus, the dose of haloperidol for children is calculated depending on the body weight. For adults, the dose is assigned individually. It is taken orally, starting with 0.5-5 mg 2-3 times a day, then the dose is gradually increased to 10-15 mg. When there is an improvement, they switch to a lower dose to maintain the achieved state. With psychomotor agitation, 5-10 mg intramuscularly or intravenously are prescribed, several repetitions are possible after 30-40 minutes. The daily dose should not exceed 100 mg. Side effects are possible in the form of nausea, vomiting, spasmodic muscles, increased pressure, arrhythmias, etc. Elderly people must take special precautions as they there have been cases of sudden cardiac arrest, possibly the appearance of tardive dyskinesia (the occurrence of involuntary movements).

Antidepressants increase the activity of the brain structures, relieve depressed mood, tension, and lift the mood. These drugs, recommended for admission from 5-8 years old with Martin-Bell syndrome, include clomipromine, sertraline, fluoxegin, fluvoxamine. So, fluoxetine is taken with meals inside 1-2 (preferably in the first half of the day), starting with 20 mg per day, increasing to 80 mg if necessary. For elderly people, a dose higher than 60mg is not recommended. The course of treatment is determined by the doctor, but not more than 5 weeks.

Side reactions are possible: dizziness, anxiety, tinnitus, loss of appetite, tachycardia, edema, etc. Care must be taken when prescribing to the elderly, with cardiovascular diseases, diabetes mellitus.

Psychostimulants - psychotropic drugs, are used to enhance the perception of external stimuli: they sharpen hearing, response, vision.

Diazepam is prescribed as a sedative for neuroses, anxiety, epileptic seizures, convulsions. It is taken orally, intravenously, intramuscularly, rectally (into the rectum). It is prescribed individually, depending on the severity of the disease, from the smallest doses of 5-10 mg, daily dose - 5-20 mg. Duration of treatment is 2-3 months. For children, the dose is calculated taking into account body weight and individual characteristics. Side effects include lethargy, apathy, drowsiness, nausea, and constipation. It is dangerous to combine with alcohol, addiction to the drug is possible.

In the treatment of Martin-Bell syndrome, cases of improvement in the condition were also recorded with the introduction of drugs made on the basis of material of animal origin (brain): cerebrolysate, cerebrolysin, cerebrolysate-M. The main components of these drugs are peptides, which promote the production of protein in neurons, thus replenishing the missing protein. Cerebrolysin is injected in a stream of 5-10 ml, the course of treatment consists of 20-30 injections. For children, the drug is prescribed from a year of life, injected intramuscularly every day, 1-2 ml for a month. Repeated reception sessions are possible. Side effects in the form of fever, contraindicated in pregnant women.

There were attempts to treat the ailment with folic acid, but only the behavioral aspect improved (the level of aggression, hyperactivity decreased, speech improved) and nothing changed at the intellectual level. To improve the conditions in the disease, folic acid, physiotherapy methods are prescribed, speech therapy, pedagogical and social correction is indicated.

Lithium preparations are also considered effective, which help to improve the patient's adaptation in the social environment, as well as cognitive activity. In addition, they also regulate his behavior in society.

The use of herbs in Martin-Bell syndrome is possible as antidepressants. Herbs that help relieve stress, anxiety, and improve sleep include valerian, peppermint, thyme, St. John's wort, chamomile. The infusions are prepared as follows: for 1 teaspoon of dry herbs, you need a glass of boiling water, infusions are insisted for at least 20 minutes, taken mainly at night before going to bed or in the afternoon. A spoonful of honey would be a good addition to them.

Physiotherapy treatment

To eliminate neurological manifestations, special physiotherapy procedures are performed, such as exercises in the pool, muscle relaxation and acupuncture.

Operative treatment

Methods of plastic surgery are also considered an important stage of treatment - operations that help to improve the patient's appearance. Plastic surgery of the extremities and auricles, and in addition to this, the genitals. Correction of gynecomastia with epispadias is also performed, as well as other defects in appearance.

Prevention

The only method of preventing the disease is prenatal screening of pregnant women. There are special examinations that allow you to determine the presence of pathology at an early stage, after which it is recommended to terminate the pregnancy. Alternatively, IVF is used to help the child inherit a healthy X chromosome.