Fragile X Syndrome
| Classification according to ICD-10 | |
|---|---|
| Q99.2 | Fragile X chromosome
Fragile X Chromosome Syndrome |
| ICD-10 online (WHO version 2019) | |
The Fragile X Syndrome ( FXS ) is the most common cause of inherited cognitive impairment in humans. The reason for this is a genetic change on the X chromosome , the mutation of an expanding trinucleotide repeat in the FMR1 gene ( fragile X mental retardation 1 ). The disability, which is counted as an X-linked mental retardation , can vary widely in its severity and range from mild learning difficulties to extreme cognitive impairment.
The syndrome is also referred to as Martin Bell Syndrome (MBS) or Marker X syndrome, as well as fra (X) syndrome in the abbreviated form , after its first description . This name is derived from the observation of cell cultures of affected people: Under appropriate culture conditions, an apparent break point, the so-called fragile area , is observed in some of the cells due to a decrease in the degree of condensation of the X-chromosomal chromatin in the affected region .
Symptoms
Fragile X syndrome can affect both men and women. The main symptom is a varying degree of intellectual impairment, the severity of which can range from learning problems to severe cognitive impairment and is associated with language disorders and attention deficits.
In children, around 12% of those affected have autistic behaviors, such as B. Little eye contact, social phobia, over-excitability and hypersensitivity to certain stimuli and repetitive behavior, pronounced, almost 20% of children get seizures ( epilepsy ).
In women, the symptoms are often milder, which is due to the accidental inactivation of one of the two X chromosomes in female cells ( Lyon hypothesis ).
In 80% of affected men there is an enlargement of the testicles , which can occur even before puberty . Other physical symptoms can be a protruding forehead, protruding and large ears and a protruding chin with a narrow face .
Around 50% have abnormal ligament looseness, 20% have flexible flat feet and occasionally scoliosis .
distribution
The frequency of fragile X syndrome is given very broadly in the literature, as many studies also used different assessment bases for a full mutation.
The average frequency is 1: 1,200 for men and 1: 2,500 for women. After Down's syndrome (trisomy 21) , this peculiarity is the most common form of genetically determined cognitive disability.
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, albeit quite unreliable, method, since fragile sites also occur in neighboring gene areas. Today, diagnostics are carried out using molecular genetic analysis methods from a blood sample using the polymerase chain reaction (PCR) and Southern blot . If a suspicion remains despite negative results, the FMR protein concentration can be determined directly by means of immunohistochemical diagnostics with monoclonal antibodies . For fetuses at increased risk, either an amniocentesis can be performed prenatally in the 16th to 18th Week of pregnancy (SSW) or a chorionic villus sampling in the 10th – 12th SSW to be carried out.
Differential diagnosis
Since the symptoms in early childhood are often unspecific and developmental delays are possible for many people, the differential diagnosis is comparatively difficult.
Particularly contemplated that come Sotos syndrome , the Prader-Willi Syndrome , autism and attention-deficit / hyperactivity disorder (ADHD), with the Fragile X Syndrome apparently shares several causing genes, the further Cherubism .
A test for fragile X syndrome should therefore be considered in children with speech and language delays and motor deficits, especially if they have a corresponding family history .
history
Fragile X syndrome was first described from a scientific point of view in 1943 by James Purdon Martin (1893–1984) and Julia Bell on the basis of a family with eleven cognitively retarded men. An X-linked inheritance was already assumed here.
It was only in 1969 that Herbert Lubs was able to prove this in a family of four with two affected men and two unaffected women. In his cell cultures he observed a contraction of the longer arm (q arm) in X chromosomes. Such a mutation could later also be detected in the first family.
The discovery was initially forgotten until Grant Sutherland found out by chance that the corresponding evidence can only be reproduced in a folic acid- free culture medium: when he moved from Melbourne to Adelaide , where another culture medium was used that enabled better chromosome staining, his Results initially not be repeated until he reinstated the previous culture medium.
In terms of inheritance of Fragile X Syndrome, it was not clear for a long time why it did not always match other X-linked inheritance patterns. In particular, heterozygous female carriers were also found who were supposed to remain symptom-free. In 1985, this phenomenon prompted Stephanie Sherman and her colleagues to examine the family trees more closely. They found that daughters of an unaffected vector were more likely to have affected offspring. From this they concluded that the mutation had to take place in two steps, which in the first step still remains symptom-free and in the second only occurs when the woman is transmitted to her offspring. These observations have since been known in medicine as the Sherman Paradox .
The mutated gene causing the disease was discovered jointly by several researchers in 1991 and the syndrome was classified in the group of trinucleotide diseases (Verkerk et al., 1991).
Genetic cause
Genetic cause is a change in the 38 kbp comprehensive gene FMR1 ( F ragile X linked M ental R etardation type 1 ) in the band of the X chromosome Xq27.3 (or in the significantly rarer variant-E FraX a change in the localized at position Xq28 Gene FMR2 ). The FMR1 gene consists of 17 exons and contains a repeating sequence of - trinucleotides . The normal range of these base triplets per allele is 6 to 44 repetitions, which are usually interrupted by 2 triplets at position 9/10 or 19/20. 29 to 30 triplets are most common in the general population.
CGGAGG
In people with Fragile X syndrome, two types of mutations occur in this gene region, which are caused by the lengthening of the CGGtriplet ( trinucleotide repeat disease ). 59 to 200 repetitions are referred to as premutation and, in older age, can be associated with a separate clinical picture, the Fragile X-Associated Tremor / Ataxia Syndrome (FXTAS). The premutation represents a preliminary stage of the disease-causing full mutation , which is given from 200 or more repetitions. This leads to methylation (an addition of methyl groups) of the corresponding DNA segment and thus to a shutdown of the gene expression of the FMRP1 protein . The function of this protein is currently the subject of intense research , and it is likely a key protein in the production of other proteins, the lack of which leads to atrophy of brain cells. The methylation also leads to the loosening of the affected area of the structure of the chromosome and thus to the typical appearance of the fragile area.
A number of 45 to 58 repetitions of the CGGtriplets is referred to as the “gray zone”, in which the alleles are usually stably transmitted to the offspring. Since almost 2% of the normal population have such an FMR1 allele, this area is difficult for genetic counseling to prognostically .
The smallest known premutation so far, in which a full mutation developed in a family within one generation, had 59 triplets. The absence of the inserted AGGtriplets in long premutations is held responsible for the instability towards the full mutation. In individual cases, de novo point mutations of the gene are known that impair the functioning of the FMR1 protein.
The number of triplet repetitions increases in the course of successive meioses . This also explains the increase in the severity of the disease over the generations (also called anticipation ). The molecular cause of the triplet expansion is possibly the slippage of the newly synthesized DNA strands on the replication forks during meiosis.
Inheritance
Fragile X syndrome is a hereditary syndrome that can occur more frequently in some families. Since the gene mutation on which this peculiarity is based only occurs on the X chromosome, inheritance should actually also follow that of other X-linked inheritance patterns, but in the case of FXS there are some as yet unexplained deviations from this.
The X-linked inheritance
The typical X-linked inheritance, also known as X-linked recessive inheritance, is based on the fact that women each have two X chromosomes, while men only have one. Correspondingly, women always pass on an X chromosome to their offspring, men can either inherit an X chromosome or a Y chromosome and determine whether the offspring are male or female. In the case of X-linked mutations, this results in a typical inheritance that is characterized by the following properties:
- The mother usually shows no symptoms from the mutation if the change in the gene only exists on one of her two X chromosomes and the effect is compensated for by the other , i.e. H. the inheritance is recessive.
- The mother has a 50% chance of passing the faulty gene on to her offspring. This means that 50% of their female offspring can become carriers again, 50% not. If the faulty gene is passed on to a male offspring, it is expressed in the latter due to the lack of compensation.
- The father can never pass the faulty gene on to his male offspring, as they receive the Y chromosome from him. However, daughters will inherit the mutant X chromosome from their affected fathers in 100% of the cases and will therefore always be carriers.
For these reasons, the symptoms of an X-linked recessive mutation, such as hemophilia , mainly occur in men ( hemizygosity ), while women are more often only carriers of the faulty gene. Only in the worst case that the daughters receive a mutated gene from both the mother and the father does the mutation also affect women.
Deviations from the X-linked inheritance
In Fragile X syndrome, however, there are some special features that do not correspond to the inheritance described above:
- Not all men to whom the faulty gene was transferred develop fragile X syndrome, around 20 percent remain symptom-free. This is known as nonpenetrance .
- About 30 percent of women who are carriers get the syndrome even though they also have an unmutated version of the gene. With them, however, the symptoms are usually less pronounced. The manifestation of symptoms in a female carrier is known as X-linked dominant inheritance.
- The syndrome can become worse in phases in families, but it may not occur at all for generations, although it is inherited.
The reasons for these peculiarities in inheritance are not yet clear. It is common to try to explain it through external influences on the gene.
Basis of advice
The following constellations thus arise for genetic counseling :
- Male carriers with an FMR1 premutation are not affected. The same applies to their daughters, who will inherit the premium allele (usually unchanged) in any case. Since sons receive the Y chromosome, they are not affected.
- Male carriers of a full mutation are affected; the clinical picture can range from mild to severe illness. They are fertile , even if they rarely father children. Contrary to the expected full mutation, their sperm only contains one allele with a premutation, which they transmit to their daughters.
- Female carriers of an FMR1 prevalence are not affected. Your sons or daughters can develop fragile X syndrome. The likelihood of this depends on the number of CGG repetitions. In a human genetic counseling, the risk can be estimated using statistical tables. These figures have to be assessed with caution as they only with small patient collective was recovered.
- Female carriers of a full mutation are sometimes not affected. The majority, however, have mental impairments, the severity of which is often less pronounced than that of men. This is explained by the accidental inactivation of one of the two X chromosomes. They can pass either the healthy or the abnormal X chromosome on to their offspring. The probability that this full mutation will be passed on to the children is therefore 50%. The clinical picture of the children can differ considerably from the mother.
Neurobiology of Fragile X Syndrome
An animal model was developed to research the neurobiological basis that causes the symptoms of Fragile X syndrome. This is a so-called FMR1 - knockout mouse , a mouse strain in which by appropriate molecular biological techniques focused FMR1 gene was removed. The deletion of FMR1 in mice is accompanied by some symptoms, which are also characteristic of FXS patients. These include hyperactivity, epileptic seizures and the enlargement of the testicles. In contrast, observations of a lower learning ability of the FMR1 knockout mice were not directly transferable to humans, also because of the poor comparability of cognitive abilities between mice and humans.
However, more recent findings show that a simple form of associative learning , namely classical conditioning , which is found in humans and mice alike and obeys the same mechanisms, is severely impaired in both FMR1 knockout mice and FXS patients. This is the conditioning of the eyelid closing reflex .
The eyelid closing reflex is a protective reflex of the eyelid. It is activated when an unpleasant or painful stimulus hits the surface of the eyeball. The eyelid closes. The conditioning of the eyelid closing reflex in the experiment takes place as follows: A short puff of air on the eyeball serves as a so-called unconditioned stimulus . The conditioned stimulus is a tone that begins before the puff of air and ends with it (so-called delay conditioning ). After a few attempts with the same interval between the start of the sound and the blast of air, the eye closes exactly at a point in time that ensures that it is already closed when the blast of air hits. The timing of the reflex is conditioned.
The conditioning of the blink reflex can be carried out in animal experiments as well as on humans. The neural circuits that are responsible for the correct adaptation of the reflex are very well known and have been extensively studied. The neurons involved are located in the cerebellum . A form of synaptic plasticity at the parallel fiber synapse of the Purkinje cells is of central importance for the conditioning of the eyelid closing reflex . The finding that the conditioning of the eyelid closing reflex is worsened in FXS patients can certainly be of therapeutic importance. One could use the blink reflex as a parameter to measure the effectiveness of possible therapies quite objectively.
Cortical nerve cells of the FMR1 knockout mice and the FXS patients show an increased number and greater 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. It is now 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 dendrite . There the FMR1 protein then functions as a kind of switch that releases the RNA and enables its translation in response to synaptic signals. Accordingly, the FMR1 protein is one of the factors that are required for activity-dependent protein synthesis at synapses.
The FXS mGluR theory
The FMR1 protein is synthesized at synapses after activation of metabotropic glutamate receptors (mGluR). The group 1 mGluR stimulate protein synthesis on the one hand, but also the transport of FMR1 protein-associated RNA in the dendrites on the other. This suggests that the FMR1 protein has an inhibitory effect on the synthesis of other synaptic proteins. Consistent with this, it was found that certain forms of synaptic plasticity in the hippocampus , which are dependent on protein synthesis, are increased in the FMR1 knockout mice, while other forms, which are independent of the synthesis of proteins, remain unchanged. From this it was concluded that other forms of mGluR- and protein synthesis-dependent synaptic plasticity must also be upregulated by deletion of the FMR1 gene. In fact, this was also the case in Purkinje cells. There, the long-term depression at the parallel fiber synapse is also mGluR-dependent and was found to be increased in the FMR1 knockout mice. The spines of the Purkinje cells are elongated in FMR1 knockout mice. All of these changes suggest that the FMR1 protein acts as a regulator of synaptic structure and mGluR-dependent plasticity.
treatment
Due to the genetic cause, a cure is not possible according to the current state of research. Symptomatic , after a detailed child psychiatric, pediatric and neurological examination, an individual support program can be drawn up, which includes behavior therapy , occupational therapy , music therapy , art therapy and speech therapy . These programs can be very successful if a favorable environment is created. Furthermore, in Germany, “integration aid measures” according to SGB IX can be applied for through the responsible health authorities and the district social welfare offices as cost bearers .
literature
Scientific literature
- JP Martin, J. Bell: A pedigree of mental defect showing sex-linkage. In: Journal of Neurology, Neurosurgery, and Psychiatry , Volume 6, Numbers 3-4, July 1943, pp. 154-157, PMID 21611430 , PMC 1090429 (free full text).
- HA Lubs Jr .: A marker X chromosome. In: American Journal of Human Genetics Volume 21, Number 3, May 1969, pp. 231-244, PMID 5794013 , PMC 1706424 (free full text).
- B. Beek, PB Jacky, GR Sutherland: Heritable fragile sites and micronucleus formation. In: Annales de Genetique , Volume 26, 1983, pp. 5-9.
- B. Beek, PB Jacky, GR Sutherland: DNA precursor deprivation-induced chromosomal damage . In: Mutation Research , Volume 113, 1983, p. 331.
- PB Jacky, B. Beek, GR Sutherland: Fragile sites in chromosomes: possible model for the study of spontaneous chromosome breakage. In: Science . Volume 220, Number 4592, April 1983, pp. 69-70, PMID 6828880 .
- EJ Kremer, M. Pritchard, et al .: Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p (CCG) n. In: Science , 252.1991, pp. 1711-1714, PMID 1675488 , ISSN 0036-8075
- BA Oostra, P. Chiurazzi: The fragile X gene and its function. In: Clinical genetics. An international journal of genetics in medicine (Clin. Genet.) , 60.2001, Blackwell Munksgaard, Oxford, pp. 399-408, PMID 11846731 , ISSN 0009-9163
- AL Reiss, E. Aylward, LS Freund, PK Joshi, RN Bryan: Neuroanatomy of fragile X syndrome, the posterior fossa. In: Annals of neurology , 29.1991, 1 (Jan), Wiley-Liss, New York NY, pp. 26-32, PMID 1996876 , ISSN 0364-5134
- AJ Verkerk, M. Pieretti, JS Sutcliffe, YH Fu, DP Kuhl, A. Pizzuti, O. Reiner, S. Richards, MF Victoria, FP Zhang: Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. In: Cell. 31; 65. 1991, pp. 905-914, PMID 1710175 , ISSN 0092-8674
Further literature
- Ursula G. Froster (Ed.): The Fragile X Syndrome. Quintessenz-Verlag, Berlin 1998, ISBN 3-8208-1764-6
- Suzanne Saunders: The Fragile X Syndrome - A Guide for Professionals and Parents. Verlag der Bundesvereinigung Lebenshilfe for people with intellectual disabilities e. V., Marburg 2003, ISBN 3-88617-306-2
See also
Web links
- Fragile X Syndrome. In: Online Mendelian Inheritance in Man . (English)
- The National Fragile X Foundation (English)
- Interest group Fragiles-X eV (German)
Individual evidence
- ^ J. Davids, R. Hagerman, R. Eilert: Orthopedic aspects pf fragile-X-syndrome. , 1990, in: Journal of bone and Joint Surgery (Am) 77, p. 889
- ↑ FraX-E variant ( page no longer available , search in web archives ) Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice. (PDF)
- ↑ Reiss et al., 1991
