Martin-Bell Syndrome

The Martin-Bella syndrome was described in 1943. Doctors, whose names have been named. The disease is a genetic disorder, consisting of mental retardation. In 1969 the changes characteristic of this disease in chromosome X (fragility in the distal shoulder) were revealed. In 1991 Scientists have discovered a gene that is responsible for the development of this disease. This ailment is also called the "fragile chromosome-X syndrome." The disease affects both boys and girls, but more often (3 times) boys are ill.

[1], [2], [3], [4], [5]

Epidemiology

The Martin-Bella syndrome is a fairly common disease: there are 0.3-1.0 people suffering from this ailment per 1000 men, and 0.2-0.6 per 1000 women. And children with Martin-Bell syndrome are born on all continents with the same frequency. Obviously, the nationality, skin color, the incision of the eyes, the living conditions, the well-being of people do not affect the onset of the disease. The frequency of its occurrence is comparable only with the frequency of Down syndrome (for 600-800 newborns, 1 disease). A fifth of the male carriers of the altered gene are healthy, have no clinical and genetic abnormalities, the rest with signs of mental retardation from mild to severe forms. Among female carriers of patients a little more than a third.

The fragile X chromosome syndrome affects approximately 1 in 2500-4000 men and 1 in 7000-8000 women. The prevalence of carriers of the disease among women's population is estimated to be 1 per 130-250 people; the prevalence of carriers among males is estimated to be 1 per 250-800.

[6], [7], [8], [9], [10], [11], [12]

Causes of the the Martin-Bell syndrome

The Martin-Bella syndrome develops due to the complete or partial cessation of the production of a specific protein by the body. This is due to the lack of response from a gene like FMR1, localized in the X chromosome. Mutation occurs as a result of rearrangement of the structure of the gene from unstable structural variants of gene states (alleles), and not from the very beginning. The disease is transmitted only through the male line, with which a man may not necessarily be sick. Male carriers, transmit the gene to their daughters in unchanged form, so their mental retardation is not obvious. With the further transfer of the gene from the mother to her children, the gene mutates, and then all the signs characteristic of this disease appear.

[13], [14]

Risk factors

An obvious risk factor is heredity. The more generations involved in these mutations, the harder the disease progresses. Until now, it has not been investigated why there is a change in the structure of the genetic apparatus.

[15], [16]

Pathogenesis

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

In the pathogenesis of the disease, the key violation is the hypermethylation of the gene, but it has not been possible to finally determine the mechanism of the development of this disorder.

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

Also in patients, 2 sensitive to folic acid fragile triplets located in Z00 kb are detected, and also 1.5-2 mp. From the fragile triplet, which contains the gene FMR1. The mechanism of the FRAXE genes, as well as FRAXF (they are identified in the above mentioned triple triplets) mutations correlate with the mechanism of disorders in Martin Bell syndrome. This mechanism is due to the propagation of GCC-, as well as CGG-repeats, under which methylation of so-called CpG-islands occurs. In addition to the classical form of pathology, there are also 2 rare types that differ due to the expansion of trinucleotide repeats (in masculine and in female meiosis).

It was revealed that in the classical form of the syndrome the patient does not have a special nucleocytoplasmic protein of the FMR1 type, which performs the function of binding a variety of mRNAs. In addition, this protein promotes the formation of a complex that helps to carry out translational processes inside the ribosome.

[17], [18], [19], [20], [21]

Symptoms of the the Martin-Bell syndrome

How to recognize the disease in children? What are the first signs? In the first months of the child's life, the symptom of Martin-Bell can not be recognized, 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 late and talk, sometimes speech is completely absent. He is hyperactive, randomly waving his arms, afraid of crowds and noise, stubborn, there are sharp outbursts of anger, emotional instability, epileptic fits occur, does not go to eye contact. In patients with Martin-Bella syndrome, the disease also produces appearance: the ears protruding and large, the forehead heavy, the face elongated, the chin protruding, strabismus, broad brushes and feet. Endocrine disorders are also characteristic of them: often heavy weight, obesity, men have large testicles, early puberty.

Among the patients with Martin-Bell syndrome, the level of intelligence is very different: from a small mental retardation to its severe cases. If a normal person has an IQ of 100 on average and a genius of 130, then 35-70 people are at risk of an ailment.

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

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

Approximately in 80% of patients also reveal the prolapse of the bicuspid valve.

But the full form of the syndrome manifests itself in only 60% of all patients. In 10% only mental retardation is found, while in others the disease develops with a different combination of symptoms.

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

• the sick child has significant mental retardation in comparison with the development of other peers;
• attention and focus disorders;
• strong stubbornness;
• children quite late start to walk and talk;
• there are hyperactivity and disturbances in speech development;
• very strong and uncontrolled bouts of anger;
• can develop a mutism - this is the complete absence of a child's speech;
• the kid feels social anxiety, is able to panic because of loud noise or any other strong sounds;
• the child uncontrollably and chaotic waving his hands;
• there is shyness, the child is afraid of staying in places of a large crowd of people;
• the emergence of various obsessions, an unstable emotional state;
• the baby may be reluctant to establish eye contact with people.

In adults, the following symptoms of pathology are observed:

• specific appearance: an elongated face with a heavy forehead, large protruding ears, a strongly protruding chin;
• flat feet, otitis and strabismus;
• puberty occurs quite early;
• obesity can develop;
• quite often in the syndrome of Martin Bell there are defects in the development of the heart;
• in men there is an increase in testes;
• joints of the joints become very mobile;
• The weight, and also growth sharply increases.

Diagnostics of the the Martin-Bell syndrome

To diagnose the syndrome of Martin Bell, you need to contact a qualified geneticist. The diagnosis is made after carrying out specific genetic tests, which allow to determine the defective chromosome.

[22], [23], [24]

Analyzes

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

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

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

[25], [26], [27], [28], [29]

Instrumental diagnostics

A highly specific method of instrumental diagnostics is PCR (polymerase chain reaction), which allows studying the structure of amino acid residues contained in the X chromosome and thereby determining the presence of Martin Bell syndrome.

There is also a separate, even more specific, method for diagnosing pathology - a combination of PCR and detection with the help of capillary electrophoresis. This method is highly accurate and reveals a chromosomal pathology in patients with a primary form of ovarian insufficiency, as well as ataxic syndrome.

Determine the presence of a defect can be after the diagnosis on the EEG. In patients with this disease, similar bioelectric brain activity is observed.

Differential diagnosis

Differentiated methods that help to suspect a syndrome include:

• clinical - 97.5% of patients have obvious signs of mental retardation (moderate or deep); 62% had protruding large ears; 68.4% had a prominent prominent forehead and forehead; in 68,4% of boys - testicles are enlarged, in 41,4% - features of speech (the rate of speech is uneven, loudness is uncontrollable, etc.);
• cytogenetic - the blood is examined for the culture of lymphocytes, the number of cells with the breaking of the X chromosome per 100 cells studied is determined;
• electroencephalography - the changes in the electrical impulses of the brain are specific for the Martin-Bell syndrome.

[30], [31], [32]

Treatment of the the Martin-Bell syndrome

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

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

Also, antagonists of glutamine receptors are used in treatment.

Traditional for the treatment of Martin-Bell syndrome is the use of medications that affect 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 medicines is rather limited. Neuroleptics that can be used after 3 years (the earliest age of their appointment) include haloperidol in drops and tablets, chlorpromazine in solution, pericyazine in drops. So, the dose of taking haloperidol for children is calculated depending on the body weight. For adults, the dose is administered individually. Accepted inside, begin 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, go to a lower dose, to maintain the achieved state. With psychomotor stimulation appoint 5-10 mg intramuscularly or intravenously, several repetitions in 30-40 minutes are possible. The daily dose should not exceed 100 mg. Possible side effects in the form of nausea, vomiting, spasms, increased pressure, arrhythmia, etc. Special precautions should be followed by elderly people. Cases of sudden cardiac arrest have been reported, and late discenezia may appear (the occurrence of involuntary movements).

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

Possible adverse reactions: dizziness, anxiety, tinnitus, a decrease in appetite, tachycardia, swelling, etc. Care should be taken when appointing elderly people, with cardiovascular diseases, diabetes mellitus.

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

As a sedative with neuroses, anxiety, epileptic seizures, seizures, diazepam is prescribed. 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 - 5-20 mg. Duration of treatment is 2-3 months. For children, the dose is calculated taking into account the body weight and individual characteristics. Side effects include lethargy, apathy, drowsiness, nausea, constipation. It is dangerous to combine with alcohol, possibly addictive to the drug.

In the treatment of Martin-Bell syndrome, cases of improvement of the condition were also recorded when drugs based on animal material (brain) were made: cerebrolizate, cerebrolysin, cerebrolyzate-M. The main components of these drugs are peptides, which contribute to protein production in neurons, thus replenishing the missing protein. Cerebrolysin injected at 5-10 ml, the course of treatment consists of 20-30 injections. Children prescribe the drug from the age of life, injected intramuscularly every day for 1-2 ml during the month. Possible repeated sessions of admission. Side effects in the form of heat, contraindicated in pregnant women.

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

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

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

Physiotherapeutic treatment

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

Operative treatment

An important stage of treatment is also considered methods of plastic surgery - operations that help improve the appearance of the patient. Plastic of extremities and auricles, and besides this genitals are carried out. There is also a correction of gynecomastia with epispadia, and with it other defects of appearance.

Prevention

The only method of preventing the disease is prenatal screening of pregnant women. There are special tests that allow early detection of the presence of pathology, after which it is recommended to terminate the pregnancy. As an alternative, IVF is used that can help a child to inherit a healthy chromosome X.

Prophylaxis of the patient depends on whether the mutation of the gene has arisen again, or was inherited. For this, molecular genetic diagnosis is carried out. In favor of the "freshness" of the mutation, the fact that relatives did not reveal a "fragile X-chromosome" testifies that the risk to have a child with Martin-Bell syndrome is very small. In families where there are patients, the test will help to avoid repeated cases.

[33], [34], [35], [36]

Forecast

The prognosis of Martin-Bell syndrome for life is favorable, for recovery - no. Life expectancy depends on the severity of the disease and accompanying vices. The patient can live a life of usual duration. In severe forms of Martin-Bell syndrome, life-threatening disability threatens patients.

Lifespan

Martin Bell syndrome does not have a serious negative impact on health, so the life expectancy of most people who have found this pathology, does not differ from the standard indicators.

[37], [38], [39]