Fragile X Syndrome Analysis Essay

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The human genome is split into 23 pair’s chromosomes (DNA), which are coiled in a spiral ladder-type through nucleotide hydrogen bases (cytosine-c, guanine-g, thymine-t, adenine-a). Human cells have 46 chromosomes – 22 pairs of autosomes chromosomes 1 to 22 and two sex chromosomes X and y or X and X depending on gender (sex-linked). Within these chromosomes are roughly 30,000 genes that control and construct the organs in the body.

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There are over more or less 250 documented sex-linked diseases, affecting every organ system. Of these, 95% affect males as it reflects the existence of the irregular gene on the X chromosome, which exists in two copies in females and one in males. Males become heir to the X chromosome from their mother and the Y chromosome from their father. Since this is the case, abnormalities on the X chromosome from the mother will frequently manifest as a disease within 50% of her male offspring. Since females have a chromosomal make-up of XX, inheriting an X chromosome with disease mutations in it normally will not generate the disease condition.

The strong X chromosome that the female has inherited from her other parent male, masks the sickly X chromosome. The female with one mutated X chromosome would be known as a carrier because she can pass the mutation onto her children, though she may not be directly affected by it. An X-linked disease could affect a female, in a lesser percentage, if her mother is a carrier and the ailment affects her father. If her mother and her father are both affected by the disease, she will most positively be afflicted with the disease as well.

Despite these many sex-linked diseases, at present prenatal diagnosis can specifically be made in fewer than 40 diseases. The fragile X syndrome is an inherited disorder, has an incidence of 1 per 4000 males and 1 per 7000 females (Ramos, F. J. et all 2003). It is generally characterized by the phenotype of mental retardation, macroorchidism (enlarged testicles), large ears, prominent jaw, hyperactivity, preservative speech, hyperextensible joints. Only in the early 1990s, this study made place with the availability of molecular biology tests such as polymerase chain reaction and Southern blot analysis which was very useful to understand it.

The grounds of Fragile X syndrome are mutations of repeated triplet – CGG- nucleotide bases stretch in a coding sequence of FMR1 gene located at Xq 27.3, which codes for a fragile mental retardation protein (FMRP) through RNA messenger (Oostra, B.A. & Chiurazzi, P. 2001), in the referred X chromosome. It has been found that the triplet repeating is caused by a lack of folic acid production. In individuals with Fragile X have repeated triplet ranged between 50 to 200 and those are called carrier (premutation) (Ramos, F. J. et all 2003) which are the key to affecting their offspring. If in case the repeated triplet is found in a range 200 + the individual is affected with it (full mutation). The expansion of the triplets was known as a Sherman Paradox as it was first figured out in 1985 in a family lineage of fragile X syndrome story.

When a female carrier marries a male non-carries their offspring have half with the disease and half carriers either males or females. The females who are passing the disease to their daughters and sons as they have an X chromosome affected. As a male’s carrier, this is an exception to the principle of males’ severity. This can be explained by an “unstable length mutation” of the FMR gene.

A study of 147 women with idiopathic premature ovarian failure encountered a significant association with pre mutations in the FMR1 gene, in 6 women having it, including 4 familial and 2 irregular cases, but no women with full mutations in the FMR1 gene. They concluded that pre mutations of FMR1 could affect ovarian development or function, or both.

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Underlined this issue in 2003 Steyaert et al. investigated reaction time on different tasks of attention in three groups of females subjects: premutation, full mutation, and control subjects using the Sonneville Visual Attention Task (SVAT) method. Reported that premature ovarian failure and underlying hormonal changes are recognized as a distinct phenotype in female fragile X premutation carriers and also they found that females carriers may affect neurocognitive function, in particular aspects of attention.

In addition, Hundscheid et al. (2003) investigated whether premutation carriers have an increased risk for other diseases. They assessed firstly, 264 women of 84 fragile X families, the occurrence of diseases that are associated with menopause with premature ovarian failure and compared this to those with normal FMR1 and full mutation. They establish no statistically significant differences in the occurrence of diseases known to be associated with menopause, such as cardiovascular diseases and osteoporosis. However, was observed lower bone mineral density only in premutation carriers which they designated PC.

In a study of five males with the fragile X pre-mutation, ranging from 78 to 98 nucleotide repeats, which was obtainable in the sixth decade with progressive intention tremor, Parkinsonism, cognitive decline, generalized atrophy on MRI, and impotence (Hagerman et al. 2001). They found that the levels of FMR1 mRNA were two to four times higher than normal, and resulted in a pathogenic gain-of-function effect. Emphasizing this, Leehey et al. (2003) investigated two unrelated males’ subjects with tremor and generalized brain atrophy at ages 58 and 49 years. They found that the subjects carry the fragile X premutation 90 and 150 nucleotides repeats, respectively, and elevated FMR1 mRNA.

At the same Berry-Kravis et al. (2003) in a comparison study of 21 fragile X premutation carriers, 7 male and 14 female, to 16 non-carriers, found that the male premutation carriers had significantly increased postural and kinetic tremor and limb ataxia, measured in a standard scale scoring. The female carrier and control groups did not differ on any measure. The authors noted that the premutation is associated with increased levels of CGG repeat-containing FMR1 mRNA, which may interfere with nuclear function and lead to neurodegenerative symptoms.

Late-onset tremor, gait instability, and dementia can be linked with brain atrophy in males of standard intelligence who are premutation carriers of the fragile X syndrome. Rogers et al. (2003) using a telephone survey showed that this association is probably causal rather than coincidental. The premutation males were grandfathers judged through one of their daughter’s sons having had the fragile X syndrome. The proscribed subjects were the related grandfathers on the paternal side of the family.

Jacquemont et al. (2003) demonstrated that carriers of the fragile X premutation could be affected by a multi-system, progressive neurological disorder, which they named the ‘fragile X tremor/ataxia syndrome.’ They presented a sequence of 26 patients around 50 years of age, who were carriers of the fragile X premutation and affected by a neurological disorder with 2 main clinical features, cerebella ataxia and/or intention tremor. Other recognized symptoms were short-term memory loss, administrative function deficits, cognitive decline, Parkinsonism, peripheral neuropathy, lower limb proximal muscle weakness, and autonomic dysfunction.

Macpherson et al. (2003) presented further evidence that pre-mutations of the FMR1 gene may have clinical effects. They analyzed a cohort of patients with neurodegenerative disorders referred for genetic analysis of spinocerebellar ataxia genes and found that 3 of 59 males carried the premutation.

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Much of the focus on fragile X syndrome is on the extension of the repeated CGG’s. It is technically not the expansion that directly causes the trouble. Instead, having more than 200 CGG repeats sets in motion methylation of part of the FMR1 gene (Beresford, et al, 2001). The methylation (methyl group) stops the synthesis of FMRP and the absence of FMRP causes fragile X syndrome. In the vast reports cited previously, it’s relevant that the major part of males’ offspring have mutant fragile X resulted from the mothers as a carrier that it could be viewed in the pedigree mentioned.

At this time, there is no cure for fragile X syndrome however there is a need for an early implantation strategy to evaluate/diagnosing the fragile X syndrome through radiological, electrophysiological studies, and other programs of intervention in parents affected and or their offspring are emphasizing into familiar pedigree (Kabra M, & Gulati S. 2003) which may have better prognosis though, special education, speech, and language therapy, occupational therapy, and behavioral therapies help address many of the physical, behavioral, and cognitive impacts of it.

In addition, medical intervention can be helpful for aggression, anxiety, hyperactivity, and poor attention span. Because the impact of fragile X is so varied, it is important to do a careful evaluation of a person’s power and limitation. That way, it is possible to mold an action plan to address specific needs by a wide variety of therapeutic and chemical means which are used to provide patients with the best quality of life and the most independence possible.

To conclude X linked disease affects often males through inheritance, as females carry on theirs X chromosomes. The males have an X and Y and the females have two XXs’. So the females’ pass to their sons the one X affected, thus males are infected with the disease. However, there is some exceptions regarding the severity of the disease in males, for example, Fragile x syndrome. The fragile x syndrome is caused by an unstable length mutation in theirs nucleotide CGG. So therefore the small mutations may produce few symptoms (male carrier) and or no symptoms, which could diminish the sternness of the syndrome in males.

References

Beresford, R. G.; Tatlidil, C.; Riddell, D. C.; Welch, J. P.; Ludman, M. D.; Neumann, P. E.; Greer, W. L. (2000) Absence of fragile X syndrome in Nova Scotia. J. Med. Genet. 37: 77-79, PubMed ID : 10691418

Berry-K., E.; Lewin, F.; Wuu, J.; Leehey, M.; Hagerman, R.; Hagerman, P.; Goetz, C. G. (2003). Tremor and ataxia in fragile X premutation carriers: blinded videotape study. Ann. Neurol. 53: 616-623

Hagerman, R. J.; Leehey, M.; Heinrichs, W.; Tassone, F.; Wilson, R.; Hills, J.; Grigsby, J.; Gage, B.; Hagerman, P. J. : (2001)Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57:pgs 127-130,.

Hundscheid, R. D. L.; Smits, A. P. T.; Thomas, C. M. G.; Kiemeney, L. A. L. M.; Braat, D. D. M. (2003) Female carriers of fragile X pre mutations have no increased risk for additional diseases other than premature ovarian failure.. J. Medical Genetics. 117A: Pgs 6-9,

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Jacquemont, S.; Hagerman, R. J.; Leehey, M.; Grigsby, J.; Zhang, L.; Brunberg, J. A.; Greco, C.; Des Portes, V.; Jardini, T.; Levine, R.; Berry-Kravis, E.; Brown, W. T.; Schaeffer, S.; Kissel, J.; Tassone, F.; Hagerman, P. J. (2003). Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am. J. Hum. Genet. 72: 869-878, PubMed ID : 12638084.

Kabra M, Gulati S. (2003) Mental retardation. Indian Journal of Paediatric. 70(2):153-8. Pubmed.

Leehey, M. A.; Munhoz, R. P.; Lang, A. E.; Brunberg, J. A.; Grigsby, J.; Greco, C.; Jacquemont, S.; Tassone, F.; Lozano, A. M.; Hagerman, P. J.; Hagerman, R. J. (2003). The fragile X premutation presenting as essential tremor. Arch. Neurol. 60: 117-121, PubMed ID : 12533098

Macpherson, J.; Waghorn, A.; Hammans, S.; Jacobs, P. : 2003. Observation of an excess of fragile-X premutations in a population of males referred with spinocerebellar ataxia. (Letter) Hum. Genet. 112: 619-620, PubMed ID : 12612802.

Oostra, B.A. & Chiurazzi, P. (2001) The fragile X gene and its function Clinical Genetics 60:6 p. 399 Blackwell publisher.

Ramos, F. J.& Willemsen, R. (2003) Diagnosis of the Fragile X Syndrome y the analysis of FMRP expression in blood and hair roots Archives de Pédiatrie 10:5: Pgs 401-402 ELSEVIER.

Rogers, C.; Partington, M. W.; Turner, G. M. :(2003). Tremor, ataxia and dementia in older men may indicate a carrier of the fragile X syndrome. Clin. Genet. 64: 54-56, PubMed ID : 12791039.

Steyaert, J.; Legius, E.; Borghgraef, M.; Fryns, J.-P. (2003).A distinct neuro cognitive phenotype in female fragile-X premutation carriers assessed with visual attention tasks. J. Medical Genetics. 116A: Pgs 44-51.

Sutcliffe, J. S., D. L. Nelson, (1992). DNA methylation represses FMR-1 transcription in fragile X syndrome. Human Molecular Genetics 1(6): 397-400.

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