Martin-Bell syndrome: what is it, signs and symptoms, treatment, prognosis

general information

Martin Bell Syndrome (fragile X syndrome) Is a hereditary disease characterized by moderate mental retardation in boys and girls. Affected boys sometimes have other distinctive physical features, including a large head, long face, protruding forehead and chin, protruding ears, and large testicles, but these signs develop over time and may not appear until sexual activity ripening. Motor and language delays are usually present, but over time they become more evident. Behavioral abnormalities, including autistic behavior, are common to both sexes.

Fragile X syndrome has been found in all major ethnic groups and races and is caused by an abnormality (mutation) in a gene FMR1. FMR1 Is a gene located on the X chromosome that produces a protein called FMRP, which is essential for the proper functioning of cells. The syndrome has come to be known as fragile X syndrome because some people with it the disorder discovered a segment of their X chromosome that appeared to be broken (although not completely disconnected). Later it became known that the gene 

FMR1 located exactly where the X chromosome appears to be “fragile” in affected individuals.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information of every person. The cells of the human body usually have 46 chromosomes. Pairs of human chromosomes are numbered 1 through 22, and the sex chromosomes are labeled X and Y. Men have one X and one Y chromosome, while women have two X chromosomes. Each chromosome has a short arm, labeled "p", and a long arm, labeled "q". Chromosomes are further subdivided into many numbered bands. For example, "chromosome Xq27.3" refers to band 27.3 on the long arm of the X chromosome, where the gene is located FMR1. The numbered stripes indicate the location of the thousands of genes present on each chromosome.

X-linked dominant disorders, such as fragile X syndrome, are caused by an abnormal gene located on the X chromosome. Women with the abnormal gene can be affected by this disorder. Men tend to be more seriously ill than women.

It is the absence or serious decrease in the protein produced by the genome FMR1, FMRP, causes Martin-Bell syndrome. Gene mutation FMR1 causes a loss or decrease in FMRP. Almost all affected individuals have an instability in the gene, resulting in an increase in the copy number of a portion of the gene called the cytosine-guanine-guani (CHG) trinucleotide repeat. If there are more than 200 repetitions, abnormal chemical changes occur in FMR1, called methylation. The expansion of the CHG repeat region to more than 200 repeats, accompanied by methylation of a gene called "complete mutation", causes the loss of FMRP, leading to Martin-Bell syndrome. The disease is more common in men and is more severe in them.

Mutations in FMR1 unusual compared to mutations found in other genes. Some people carry 55 to 200 CHH repeats called "premutations", usually without symptoms associated with Martin-Bell syndrome. However, these people are at risk of having children or grandchildren with Martin-Bell syndrome, as well as the risk of having two disorders arising in adulthood, fragile X-linked tremor / ataxia syndrome and primary ovarian failure. These diseases have been termed FMR1-related disorders. (Please read the "Causes and Symptoms Related Disorders" sections in this article to get more detailed explanations of the preliminary estimates and a brief description of these violations, associated with FMR1).

Signs and symptoms

Martin-Bell syndrome is characterized by mild mental retardation in affected men and women. Physical characteristics in affected males are variable and may not be apparent until puberty. These symptoms may include:

• big head;
• long face;
• protruding forehead and chin;
• protruding ears;
• loose joints;
• large testicles.

Other symptoms may include:

• flat feet;
• frequent ear infections;
• low muscle tone;
• long narrow face;
• high vaulted palate;
• dental problems;
• strabismus;
• heart problems, including mitral valve prolapse.

Some patients may also experience delays in motor development, hyperactivity, behavior problems, tip-toe walking, and / or occasional seizures. Autistic behaviors are also common, such as poor eye contact, hand clapping, and / or self-stimulating behavior. Motor and language delays are usually present, but over time they become even more evident.

Causes

As mentioned above, Martin Bell Syndrome (Fragile X Syndrome) is caused by a mutation in the gene FMR1located on the X chromosome at Xq27.3. People with fragile X syndrome almost always have (more than 99% of cases) a complete gene mutation FMR1, which means they have over 200 CHH repeats and abnormal gene methylation. Methylation is a chemical change in the DNA that carries the genetic code of a gene, and the abnormal methylation associated with the syndrome Martin-Bell, leads to the fact that the gene is not able to produce FMRP, a protein produced by the FMR1 gene, which is necessary for normal development.

In rare cases, some patients with the syndrome have some or all of the gene missing FMR1 due to a DNA deletion on the X chromosome, where FMR1 is located, and have this syndrome due to the fact that their cells do not produce FMRP. Ultra-rare patients with the disease have been found to have a mutation in one DNA base (called point mutations), resulting in a missing or defective FMRP. FMRP is involved in making connections between neurons (nerve cells) in the brain. The absence or severe reduction of this protein leads to symptoms of Martin-Bell syndrome.

Premutations (preliminary mutations) have 55-200 CHG repeats and are potentially unstable. Individuals with a gene premutation FMR1do not have Martin-Bell syndrome, but adults are at risk for fragile X-linked tremor / ataxia syndrome and primary ovarian failure.

When passed from generation to generation, pre-mutations can be unstable and become complete mutations, but the risk of instability differs depending on whether the pre-mutation is female or male floor. Women with a pre-mutated FMR1 gene are at risk of having a baby with Martin-Bell syndrome, since the number of CHH repeats can increase when the gene is passed on to the next generation. The more copies of CHH there are in the premutation, the more likely it is that they will grow and become a complete mutation causing the syndrome in the offspring.

When pre-mutated males breed, their male children are not at risk of inheriting the pre-mutation because fathers do not pass the X chromosome to their sons. In contrast, women whose fathers have a pre-mutation always inherit it, and thus the grandchildren of men with pre-mutation are at risk of developing fragile X syndrome. Because premutation is relatively stable when passed from father to daughter, daughters are almost never affected by fragile X syndrome. However, their children are at increased risk because premutation can be unstable when passed on to the next generation.

Normal genes FMR1 have approximately 5-44 CHG repeats, and this number remains stable from generation to generation. Sometimes, some people with 45-54 reps will have some minor instability, so these people will have a few (or fewer) reps than their parents. The number of FMR1 repetitions between 45 and 54 is called the "intermediate" or "gray zone", but this is insignificant. instability does not lead to the appearance of any symptoms of Martin-Bell syndrome or disorders, associated with FMR1. The presence of an intermediate repetition rate of CHG is still considered to be in the normal repetition range.

Affected populations

Martin-Bell syndrome affects about 1 in 4,000 men and 1 in 6,000 to 8,000 women; that is, the disease affects about twice as many men as women. However, about four times more women carry the altered gene than men (1: 250 women and 1: 1000 men). Fragile X syndrome has been found across all major ethnic groups and races.

Symptomatic disorders

Gene premutation FMR1 are associated with two other disorders, and these conditions are called disorders associated with FMR1. Not all people with premutation will develop disorders related to FMR1, but the presence of premutation increases the risk of their development.

1. Fragile X-linked tremor / ataxia syndrome characterized by progressive motion abnormalities in adults (ataxia) and rhythmic involuntary movements (tremors), which mainly affect men. People with this condition have a gene premutation. FMR1 (55-200 repetitions of CHG). Diagnosis of this syndrome can be complicated by its similarities to other late adult disorders such as Parkinson's disease.
2. Associated with FMR1primary ovarian failure (PNI) defined as menopause under the age of 40 in women with gene pre-mutation FMR1 (55-200 repetitions of CHG). The risk of PJI in carriers of premutation is approximately 21%. Women with PNI of unknown cause have a 1/50 risk of being carriers of gene premutation FMR1.

Some of the symptoms of the following disorders may also be similar to those of Martin-Bell syndrome. Comparisons can be useful for differential diagnosis:

• Freiks Syndrome rare and caused by an abnormal gene FMR2located on the X chromosome very close to the gene site FMR1. Normal gene FMR2 contains 6-35 copies of CCG, and people with the disorder have more than 200 copies of CCG in the gene FMR2. Gene effect FMR2 with 35-200 copies, CCG has not yet been identified, probably because the disorder is mild. Common symptoms of Freiks syndrome include mild mental retardation and possible developmental delays.
• Renpenning syndrome is one of the chromosomal X-linked mental retardation disorders that affects boys, almost to the exclusion of girls. It is very rare for girls to have this syndrome. It is characterized by severe mental retardation, short stature, small head (microcephaly), and small testicles. Developmental delay occurs early in Renpenning syndrome, when children learn to walk at the age of 2-3 years and can pronounce simple words at the age of 3-4 years. Although the sick boy may appear physically normal, his head circumference and height will be in the lower normal range. After puberty, the testes will be smaller than usual. Diagnosis is very difficult, especially if there is only one person with mental disabilities in the family. The diagnosis should be based on evidence of inheritance as a trait of the X chromosome and the determination that the affected gene is located on the short arm (at Xp11.1-p11.4) of the X chromosome.

Diagnostics

More than 99% of people with Martin-Bell syndrome have a complete mutation (more than 200 CHH repeats and abnormal methylation) in the gene FMR1. Molecular genetic testing is used to determine the number of CHG repeats in the FMR1 gene, and for to determine the methylation status of the FMR1 gene, testing is often used to identify an enlarged area CHG.

Chromosome analysis using special techniques to induce fragile regions in chromosomes was once used to diagnose Martin-Bell syndrome, but is no longer used for this purpose. Fragile X syndrome is the second name given to this condition because some affected people, the X chromosome looked as if it had "broken" and was held together by the slightest of connections. This method is no longer used in the diagnosis of this syndrome because it is less accurate and expensive than molecular methods.

Standard treatments

There are many treatments for Martin Bell Syndrome that can improve the lives of affected people and their families. These include special education, speech training, professional and sensory integration, and behavior change programs. Through educational efforts, therapy, and support, all people with Martin-Bell syndrome can make progress. Additional treatment may depend on the patient's specific symptoms. Genetic counseling is also recommended for affected individuals and their families.

There are many clinics in the United States and around the world that treat Fragile X Syndrome. These clinics specialize in the treatment, therapy and support of people with the syndrome and can help parents choose medications to treat specific symptoms. New drugs are likely to emerge to treat patients, and specialized clinics can help parents with up-to-date information.

Forecast

The life expectancy of people with fragile X syndrome is generally normal. Many affected people are active and in good health. Some people are more prone to a variety of medical conditions, such as ear infections and / or epileptic seizures. Regular check-ups and awareness of increased health risks can improve patients' prognosis.