Fragile X syndrome

Fragile X chromosome syndrome

The fragile X syndrome ( FXS) is the most common cause of inherited cognitive impairment in humans. This is caused by a genetic mutation on the X chromosome, a mutation of the FMR1 gene (fragile X mental retardation 1). The syndrome is referred to by its Erstbeschreibern as Martin- Bell Syndrome ( MBS) or marker - X syndrome as well as in the abbreviated form as a FRA (X) syndrome. The disability can vary greatly in their severity, ranging from mild learning difficulties to extreme cognitive impairment. The name is derived from the observation of cell cultures of people affected: Under appropriate culture conditions, on the X chromosome in some of the cells have a breaking point, the so-called fragile area can be detected.

• 8.1 The mGluR theory of FXS

Symptoms

From the fragile X syndrome, both men and women can be affected. The main symptom is a varying degrees of mental retardation, whose severity can range from learning disabilities to schwergradiger cognitive impairment and is associated with language disorders and attention deficits.

In children, autistic behaviors are pronounced at about 12 % of patients, almost 20% of children get cramp symptoms ( epilepsy).

In women, the symptoms are often milder, which is due to the random inactivation of one of the two X chromosomes in female cells (Lyon hypothesis).

In 80% of affected men there is a testicular enlargement, which may occur before puberty. Other physical symptoms may include a protruding forehead, and large protruding ears and a protruding chin at the same time existing narrow face.

Dissemination

The frequency of the fragile X syndrome is very widely reported in the literature, as in many studies, different bases for a full mutation have been created.

On average, the frequency is 1:1.200 in males and 1:2500 in females. Therefore this feature by Down's syndrome ( trisomy 21) is the most common form of genetically -related cognitive disability dar.

Diagnosis

Until the discovery of the underlying gene in 1991, the detection of a gap in the X - chromosome in cell cultures was the only one, but quite unreliable method as in neighboring gene regions also fragile sites occur. The test has been done today on molecular genetic analysis of a blood sample using polymerase chain reaction (PCR) and Southern blot. If, despite negative findings a suspect directly FMR protein concentration can be determined by immunohistochemical diagnosis with monoclonal antibodies. For fetuses with increased risk can prenatally either an amniocentesis in the 16th - 18th Week of pregnancy (SSW ) or chorionic villus sampling in the 10th - 12th SSW be performed.

Differential Diagnosis

Since the symptoms are often nonspecific in early childhood and developmental delays for many people come into consideration in the differential diagnosis is relatively difficult.

Particularly suitable are the Sotos syndrome, Prader- Willi syndrome, autism and attention deficit hyperactivity disorder, the (ADS ), with the fragile X syndrome shares several apparently causing genes.

In children with speech, language delay, and motor deficits, therefore, a test should be drawn to the fragile X syndrome into consideration, especially in a family history.

History

The fragile X syndrome was first described in 1943 by James Purdon Martin ( 1893-1984 ) and Julia Bell on the basis of a family with eleven cognitive remaining men from the scientific perspective. Even here, an X -linked pattern of inheritance was assumed.

Only in 1969 could this be detected by Herbert Lubs to a family of four with two affected men and two women are not affected. In its cell cultures, he observed a contraction of the longer arm (Q- arm) in the X- chromosome. Such a mutation could be subsequently detected in the first family.

The discovery was first forgotten until Grant Sutherland found out by accident that the relevant evidence is understandable only in a folic acid - free culture medium: In his move from Melbourne to Adelaide, where another culture medium was used, which allowed better chromosome staining, were his results are not initially repeated until he again began the previous culture medium.

The inheritance of fragile X syndrome was long unclear why it is not always consistent with other X-linked Erbgängen bound. In particular, heterozygous female carriers were identified that should remain free of symptoms. This phenomenon led 1985 Stephanie Sherman and her staff to a more detailed examination of the pedigrees. They found that daughters of a non-affected transfer agent had a higher probability of getting affected offspring. From this they concluded that the mutation would have to occur in two steps, which still remains symptom-free in the first step and takes place in the second only to the transfer of women to their offspring. These observations are known as the Sherman paradox in medicine ever since.

The causative disease mutated gene was discovered in 1991 jointly by several researchers and classified the syndrome in the group of Trinukleotiderkrankungen ( Verkerk et al., 1991).

Genetic cause

Genetic cause is a change of 38 kbp comprehensive gene FMR1 ( Fragile X Mental Retardation linked type 1) in the band Xq27.3 of the X chromosome ( or the much rarer variant FraX - E is a variation of the localized at position Xq28 gene FMR2 ). The FMR1 gene consists of 17 exons and contains a repeating sequence of CGG trinucleotides. The normal range of these base triplets per allele is 6 to 44 repetitions, which are interrupted usually by 2 AGG triplets at position 9 /10 or 19/20. Most commonly 29-30 triplets occur in the normal population.

In people with the fragile X syndrome occur two types of mutations in this gene region, which are executed ( Trinukleotidrepeat disease) by extending the CGG triplets. 59-200 repeats are referred to as premutation and can later in life with a distinct syndrome, the Fragile X -associated Tremor-/Ataxie-Syndrom ( FXTAS ) associated. The premutation is a precursor of the disease-causing full mutation, which is given as 200 or more repetitions. This leads to a methylation ( an addition of methyl groups ) of the corresponding DNA segment and consequently to a closure of the gene expression of the FMRP1 protein. The function of this protein is currently the subject of intensive research, most likely it is a key protein in the production of other proteins whose absence leads to atrophy of brain cells. Methylation also leads to the loosening of the affected area of ​​the structure of the chromosome, and thus the typical image of the fragile area.

A number of 45-58 repetitions of the CGG triplets is called " gray zone " in which the alleles are stably transmitted normally to offspring. Since almost 2% of the general population have such a FMR1 allele, this area for genetic counseling is prognostically difficult.

The number of triplet repeats increases during the course of successive meioses. This also explains the increase in the severity of the disease in the course of generations (also called anticipation ). The molecular basis for the triplet expansion may slippage ( slippage ) of the newly synthesized DNA strands at the replication forks during meiosis.

Heredity

The fragile X syndrome is a hereditary conditional syndrome, which in some families may accordingly occur frequently. Since the gene mutation that is this special feature based only on the X chromosome occurs, the inheritance should really follow the other X-linked modes of inheritance, in the case of FXS, there are however some hereof not yet clarified deviations.

The X-linked inheritance

The X-linked pattern of inheritance based on the fact that women are two X chromosomes, but men only ever have one. Accordingly, women always give an X chromosome to their offspring, men can either an X chromosome or a Y chromosome inherited and set according to whether the offspring are male or female. In the case of X-linked mutations thereby gives a typical pattern of inheritance, which is characterized by the following properties:

• The nut is generally no symptoms of the mutation, if the change of the gene exists only on one of its two X - chromosomes and the effect is compensated by the other.
• The mother can pass the defective gene with a probability of 50 % to their offspring. This allows 50% of their female offspring are winners again, 50 % do not. If the faulty gene passed on to a male offspring, as it shapes itself out of this due to the lack of compensation.
• The father can bequeath to his male descendants of the faulty gene never, as they received from him the Y chromosome.

For these reasons, the symptoms of X-linked mutation such as hemophilia occur mainly in men ( hemizygosity ), while women are more likely to only female carriers of the faulty gene. Only in the worst case that the daughters get both from the mother or the father a mutated gene, the mutation also impressed with the women.

Deviations from the X-linked inheritance

In fragile X syndrome but there are some features that do not match the pattern of inheritance described above:

• Not all men, to which the faulty gene has been transferred, get the fragile X syndrome, about 20 percent remain free of symptoms.
• Approximately 30 percent of women who are winners, get the syndrome, although they have a unmutated gene version. However, for them, the symptoms of shape usually less.
• The syndrome can in families phased reinforced for generations but also did not occur even though it is inherited.

The reasons for these peculiarities in the mode of inheritance is unknown as yet. Commonly it is attempted to explain it by external influences on the gene.

Consulting Basics

For genetic counseling thus following situations arise:

• Male carriers with FMR1 premutation are not affected. The same is true for their daughters who will inherit in any case, the premutated allele (usually the same). Since sons receive the Y chromosome, they are not affected.
• Male carriers of a full mutation are affected; the clinical picture may range from mild to severe disease. They are fertile, although they rarely produce children. In their sperm is contrary to the expected full mutation only one allele with premutation, which they transmit to their daughters.
• Female female carriers of the FMR1 premutation are not affected. Your sons or daughters can fall ill at the fragile X syndrome. The probability of this happening depends on the number of CGG repeats. In a genetic counseling, risk can be estimated using statistical tables. These figures need to be assessed with caution because they were obtained only in small groups of patients.
• Female carriers of a full mutation are not affected part. For the majority, however, are mental impairment whose severity is often pronounced lower in comparison to men. This is explained by random inactivation of either the X- chromosome. You can either healthy or give the morbid X chromosome to her offspring. The probability that this full mutation is transferred to the child, is thus 50%. The children may differ in their clinical picture considerably from the mother.

Neurobiology of Fragile X syndrome

To investigate the neurobiological underpinnings that cause the symptoms of Fragile X syndrome, an animal model was developed. This is a so-called FMR1 knockout mouse, a mouse strain in which targeted the FMR1 gene was removed by suitable molecular biological methods. The deletion of the FMR1 in mice is accompanied by a number of symptoms, such as are characteristic for FXS patient. These include hyperactivity, which epileptic seizures and the enlargement of the testis. In contrast, observations of a lower learning capacity of the FMR1 knockout mice were not directly transferable to humans, also because of the low comparability of cognitive abilities between mice and humans.

Recent findings show that a simple form of associative learning, namely the classical conditioning, which is found in humans and mice alike and obeys the same mechanisms, both in FMR1 knockout mice and FXS patients is severely impaired. It is the conditioning of the blink reflex. In the blink reflex is a protective reflex of the eyelid. It is activated when an unpleasant or painful stimulus impinges on the surface of the eyeball. The eyelid closes. Conditioning of the blink reflex in the experiment is done as follows: As a so-called unconditioned stimulus is a short burst of air to the eyeball. The conditioned stimulus is a tone that starts before the air puff and ends with him ( the so-called delay conditioning ). After several attempts with the same interval between the onset of the tone and the air puff to the eye closes precisely at a time, which ensures that it is already closed when hitting the air puff. Conditioned here is the timing of the reflex.

Conditioning of the blink reflex can be performed both in animals and in humans. The neural circuits that are responsible for the correct adjustment of the reflex, are very well known and extensively studied. The neurons are involved in the cerebellum. Of central importance for the conditioning of the blink reflex is a form of synaptic plasticity at the parallel fiber synapses of the Purkinje cells. The finding that the conditioning of the blink reflex in FXS patients is deteriorating, may well win therapeutic significance. One could use the blink reflex as a parameter to measure the effectiveness of possible therapies objectively.

Cortical neurons of the FMR1 knockout mice and the FXS patients have an increased number and larger average length of the spinous processes (so-called spines ). This suggests a synaptic function of the FMR1 protein. The FMR1 - protein is an RNA binding protein. Today it is assumed that one of its functions is to inhibit the translation of the bound RNA as long as it is on the way from the cell nucleus in the perikaryon to the dendrites. There the FMR1 protein then acts as a kind of switch which releases the RNA, allowing the translation in response to synaptic signals. Accordingly, the protein FMR1 one of the factors that are required for an activity- dependent protein synthesis in synapses.

The mGluR theory of FXS

The FMR1 protein is synthesized at synapses by activation of metabotropic glutamate receptors ( mGluR ). The group 1 mGluR one hand stimulate protein synthesis, on the other hand also transportation FMR1 protein -associated RNA in the dendrites. This suggests that the FMR1 protein has an inhibitory effect on the synthesis of other synaptic proteins. Consistent with this, it has been found that are amplified in the FMR1 knockout mice in the hippocampus specific forms of synaptic plasticity, that are dependent on protein synthesis, while other forms, which are independent of the synthesis of proteins that remain unchanged. It was concluded that other forms of mGluR - and protein synthesis -dependent synaptic plasticity would have to be up-regulated by deletion of the FMR1 gene. In fact, this was also the case in Purkinje cells. Here, the long-term depression in the parallel fiber synapse is also mGluR - dependent and proved to be amplified in the FMR1 knockout mice. The spines of the Purkinje cells are elongated in FMR1 knockout mice. All these changes suggest that the FMR1 protein acts as a regulator of synaptic structure and the mGluR - dependent plasticity.

Treatment

Due to the genetic cause a cure is not possible. Symptomatic can be created, which includes behavioral therapy, occupational therapy, music therapy, art therapy and speech therapy after extensive child psychiatric, pediatric and neurological examinations, an individual support program. These programs can be very successful if a favorable environment is established. Furthermore, 53 ff can be applied for in Germany on the local public health departments and the county social services as cost objects " reintegration " according to SGB XII § §.