Martin-Bell syndrome

Martin-Bell syndrome was described in 1943 by doctors, after whom it was named. The disease is a genetic disorder consisting of mental retardation. In 1969, changes in chromosome X (fragility in the distal arm) characteristic of this disease were identified. In 1991, scientists discovered the gene responsible for the development of this disease. This disease is also called "fragile X syndrome". Both boys and girls are susceptible to the disease, but boys are more often (3 times) affected.

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Epidemiology

Martin-Bell syndrome is a fairly common disease: 0.3-1.0 out of 1,000 men suffer from this disease, and 0.2-0.6 out of 1,000 women. Moreover, children with Martin-Bell syndrome are born on all continents with the same frequency. Obviously, nationality, skin color, eye shape, living conditions, and people's well-being do not affect the occurrence of the disease. Its frequency of occurrence is comparable only to the frequency of Down syndrome (1 disease out of 600-800 newborns). A fifth of male carriers of the altered gene are healthy, have no clinical or gene abnormalities, the rest have signs of mental retardation from mild to severe forms. Among female carriers, slightly more than a third are sick.

Fragile X syndrome affects approximately 1 in 2,500–4,000 males and 1 in 7,000–8,000 females. The carrier prevalence among females is estimated to be 1 in 130–250; the carrier prevalence among males is estimated to be 1 in 250–800.

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Causes Martin-Bell syndrome

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

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Risk factors

An obvious risk factor is heredity. The more generations involved in these mutations, the more severe the disease. It has not yet been studied why the structure of the genetic apparatus changes.

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Pathogenesis

The pathogenesis of Martin-Bell syndrome is based on mutations of the gene apparatus, which lead to blocking the production of FMR protein, a protein vital to the body, especially in neurons, and is present in various tissues. Research shows that FMR proteins are directly involved in the processes of regulating translations that occur in brain tissue. 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 it has not yet been possible to definitively identify the mechanism of development of this disorder.

At the same time, locus heterogeneity of the pathology was also discovered, which is associated with polyallelism, as well as polylocus. The presence of allelic variants of the disease development was determined, which are caused by the existence of point mutations, as well as the destruction of the FMRL type gene.

Patients also have 2 fragile triplets sensitive to folic acid, located 300 kb, as well as 1.5-2 million bp from the fragile triplet containing the FMR1 gene. The mechanism of mutations occurring in the FRAXE and FRAXF genes (they are identified in the above-mentioned fragile triplets) is related to the mechanism of disorders in Martin Bell syndrome. This mechanism is caused by the spread of GCC and CGG repeats, which cause methylation of the so-called CpG islands. In addition to the classical form of the pathology, there are also 2 rare types that differ due to the expansion of trinucleotide repeats (in male and female meiosis).

It was found that in the classical 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 promotes the formation of a complex that helps carry out translation processes inside ribosomes.

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Symptoms Martin-Bell syndrome

How to recognize the 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 a decrease in muscle tone is observed. After a year, the clinical picture of the disease is more obvious: the child begins to walk and talk late, sometimes speech is completely absent. He is hyperactive, waves his arms randomly, is afraid of crowds and noise, is stubborn, there are sharp outbursts of anger, emotional instability, epileptic seizures occur, does not make eye contact. In patients with Martin-Bell syndrome, the disease is also given away by their appearance: ears are protruding and large, the forehead is heavy, the face is elongated, the chin is protruding, strabismus, wide hands and feet. They are also characterized by endocrine disorders: often large weight, obesity, large testicles in men, early puberty.

Among patients with Martin-Bell syndrome, the level of intelligence varies greatly: from mild mental retardation to severe cases. If a normal person has an intelligence quotient (IQ) of 100 on average, and a genius has 130, then people susceptible to the disease have 35-70.

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

• oligophrenia (IQ is 35-50);
• dysmorphophobia (protruding ears and prognathism are observed);
• macroorchidism, which appears after the onset of puberty.

Approximately 80% of patients also have bicuspid valve prolapse.

However, the full form of the syndrome manifests itself only in 60% of all patients. In 10%, only mental retardation is detected, and in the rest, the disease develops with a different combination of symptoms.

Among the first signs of the disease, which appear at an early age:

• the sick child exhibits significant mental retardation in comparison with the development of other peers;
• attention and concentration disorders;
• strong stubbornness;
• children start walking and talking quite late;
• hyperactivity and speech development disorders are observed;
• very strong and uncontrollable bouts of anger;
• mutism may develop - this is a complete lack of speech in a child;
• the baby experiences social anxiety and is capable of panicking due to loud noise or any other loud sounds;
• the child waves his arms uncontrollably and chaotically;
• shyness is observed, the child is afraid of being in crowded places;
• the emergence of various obsessive ideas, unstable emotional state;
• The baby may be reluctant to make eye contact with people.

In adults, the following symptoms of the 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 may develop;
• Quite often, heart defects are observed in Martin-Bell syndrome;
• in men, enlargement of the testicles is observed;
• the articulations of the joints become very mobile;
• weight and height increase sharply.

Diagnostics Martin-Bell syndrome

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

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Tests

At an early stage 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, an area of the chromosome is identified where there is a noticeable thinning - this is a sign of the presence of fragile X syndrome.

However, this test is not suitable for diagnosis in the later stages of the disease, because its accuracy is reduced by the widespread use of multivitamins containing folic acid.

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

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Instrumental diagnostics

A highly specific method of instrumental diagnostics is PCR (polymerase chain reaction), which allows one 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 of pathology diagnostics – a combination of PCR and detection using capillary electrophoresis. This method is highly accurate and detects chromosomal pathology in patients with primary ovarian failure, as well as ataxic syndrome.

The presence of the defect can be determined after performing diagnostics on EEG. Patients with this disease have similar bioelectric brain activity.

Differential diagnosis

Differentiated methods that help to 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 protruding chin and forehead; 68.4% of boys have enlarged testicles, 41.4% have speech peculiarities (uneven speech rate, uncontrollable volume, etc.);
• cytogenic - blood is examined for lymphocyte culture, the number of cells with fragile X chromosome per 100 cells studied is determined;
• Electroencephalography - changes in electrical impulses of the brain that are specific to Martin-Bell syndrome are recorded.

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Treatment Martin-Bell syndrome

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, microinjection procedures with drugs such as Cerebrolysin (or its derivatives), as well as cytomedines (such as Solcoseryl or Lidase) are performed in private clinics.

In the development of ataxic syndrome, blood thinning drugs and nootropics are used. In addition, amino acid mixtures and angioprotectors are prescribed. Women with primary ovarian failure are prescribed corrective treatment using herbal medicines and estrogens.

Glutamine receptor antagonists are also used in treatment.

Traditionally, the treatment of Martin-Bell syndrome involves the use of medications that affect the symptoms of the disease, but not its cause. This therapy involves prescribing antidepressants, neuroleptics, and psychostimulants. Not all drugs are indicated for use in children, so the list of drugs is quite limited. Neuroleptics that can be used after 3 years (the earliest age for their prescription) include haloperidol in drops and tablets, chlorpromazine in solution, and periciazine in drops. Thus, the dose of haloperidol for children is calculated depending on body weight. For adults, the dose is prescribed 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 improvement occurs, they switch to a lower dose to maintain the achieved condition. In case of psychomotor agitation, 5-10 mg is prescribed intramuscularly or intravenously, several repetitions are possible after 30-40 minutes. The daily dose should not exceed 100 mg. Side effects in the form of nausea, vomiting, muscle spasms, increased pressure, arrhythmia, etc. are possible. Elderly people should take special precautions, since cases of sudden cardiac arrest have been registered, and tardive dyskinesia (involuntary movements) may occur.

Antidepressants increase the activity of brain structures, relieve depression, tension, and improve mood. These drugs, recommended for use from 5-8 years of age for Martin-Bell syndrome, include clomipromine, sertraline, fluoxetine, and fluvoxamine. Thus, fluoxetine is taken orally during meals 1-2 times (preferably in the first half of the day), starting with 20 mg per day, increasing to 80 mg if necessary. Elderly people are not recommended a dose higher than 60 mg. The course of treatment is determined by a doctor, but not more than 5 weeks.

Possible side effects: dizziness, anxiety, tinnitus, loss of appetite, tachycardia, edema, etc. Caution is required when prescribing to the elderly, those with cardiovascular diseases, and diabetes.

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

Diazepam is prescribed as a sedative for neuroses, anxiety, epileptic seizures, and convulsions. It is taken orally, intravenously, intramuscularly, rectally (into the rectum). It is prescribed individually, depending on the severity of the disease, with the smallest doses of 5-10 mg, daily - 5-20 mg. The 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, constipation. It is dangerous to combine with alcohol, addiction to the drug is possible.

In the treatment of Martin-Bell syndrome, there have been cases of improvement in the condition and with the introduction of drugs made from animal material (brain): cerebrolysate, cerebrolysin, cerebrolysate-M. The main components of these drugs are peptides that promote the production of protein in neurons, thus replenishing the missing protein. Cerebrolysin is administered as a jet of 5-10 ml, the course of treatment consists of 20-30 injections. The drug is prescribed to children from one year of age, administered intramuscularly every day 1-2 ml for a month. Repeated sessions of administration are possible. Side effects in the form of fever, contraindicated for pregnant women.

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

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

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

Physiotherapy treatment

To eliminate neurological manifestations, special physiotherapeutic procedures are carried out - such as exercises in the pool, muscle relaxation and acupuncture.

Surgical treatment

An important stage of treatment is also considered to be plastic surgery methods - operations that help improve the patient's appearance. Plastic surgery of the limbs and auricles is performed, as well as 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 early detection of the pathology, after which it is recommended to terminate the pregnancy. As an alternative, IVF is used, which can help the child to inherit a healthy X chromosome.

Prevention of the patient depends on whether the gene mutation has arisen again or has been inherited. For this, molecular genetic diagnostics are carried out. The fact that the test did not reveal the "fragile X chromosome" in relatives speaks in favor of the "freshness" of the mutation, which means the risk of having a child with Martin-Bell syndrome is very small. In families where there are sick people, the test will help to avoid repeated cases.

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Forecast

The prognosis for Martin-Bell syndrome is favorable for life, but not for recovery. Life expectancy depends on the severity of the disease and associated defects. The patient can live a normal life. In severe forms of Martin-Bell syndrome, patients are at risk of lifelong disability.

Life expectancy

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

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