“From seven years old, Michael’s speech was still rather incoherent, he spoke very quickly and under his breath and didn’t make much eye contact. Only up until the last couple of years his speech has improved and is much clearer, although he still tends to perseverate and get stuck on a subject and repeat the same thing over and over. Michael has a sister 2 years older and in 1992 they were both referred to the genetics clinic in the Royal Children’s Hospital by our pediatrician as they both presented with significant developmental delays and the doctor suspected some genetic condition may be at the root of the problem. Tests were performed, even an X-ray on Michael’s head as they noted he had rather dysmorphic features, but nothing proved positive and there was no known reason for their problems.”
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______________________________________________________________________________The patient presented in the above case study is a classic case of Fragile X-Syndrome, the most frequent cause of inherited mental retardation. Patients presenting with this syndrome are affected in various facets of functioning, including intellect, emotion, behavior, and physical characteristics. The cause of the syndrome involves the expansion of a single trinucleotide gene sequence on the X chromosome. Other disorders that are placed in this category include Huntington’s Disease, Kennedy Disease, Dentatorubralpallidoluysian atrophy, and Friedrich’s ataxia. This consequently results in the failure to express a protein that is required for normal neural development, and coded by the FMR1 gene. Because it is an X-linked disorder, cases are seen in all carrier males and in 35% of carrier females. Because of the subtle nature of signs of the syndrome and difficulty in diagnosis, all children with mental retardation should be tested for Fragile X syndrome and family members are advised to undergo genetic counseling in order to decrease the recurrence of Fragile X in the family.
The abnormality of the chromosome presented in Fragile X syndrome is found on the Xq27.3 site and commonly used as a diagnostic marker for the syndrome . In most cases, the expansion of the single trinucleotide gene sequence includes 50 to 200 CGG repeats at the site and these repeats are passed down from generation to generation . In comparison, the number
of repeats in a normal individual is between 6 and 50. Due to the increasing expansion of the trinucleotide gene sequence, there is methylation of the DNA which in turn silences the FMR1 protein . FMRP plays important roles in learning and memory, and also appears to be involved in development of axons, formation of synapses, and the wiring and development of neural circuits.
Because there is no clinical diagnostic criteria, scoring systems have been developed to select individuals for Fragile X Syndrome . It can also be diagnosed using molecular genetics testing of the FMR1 gene. One method of diagnosis is based on chromosomal study to present the chromosome under special folic acid deficient culture conditions . There are two different types of molecular DNA tests. The screening tests are polymerase chain reaction based. Additionally, they need to be confirmed using Southern blot hybridization .
It is important to diagnose affected patients as early as possible to provide early intervention and supportive care (i.e., specific developmental therapy and an individualized education plan) and to inform parents for further family planning . One half of families in a 2002 survey reported having an additional child with fragile X syndrome before the older affected child was diagnosed . Family history collection should include questions about other family members, with particular attention to developmental delay, mental retardation, and psychiatric disorders . In addition, a family history of women with premature ovarian failure and men with FXTAS should be ascertained. A positive family history in a proband with developmental delay should prompt consideration of genetic testing of the FMR1 gene . The American College of Medical Genetics recommends testing, regardless of family history, for all males and females with mental retardation of unknown etiology .
Treatment is supportive, requiring a multidisciplinary team and including anxiety-reducing measures, behavior modification, and medications to manage associated psychiatric disorders. Individual education plans are necessary for school-age children . Although several
medications have been proposed to treat fragile X syndrome, none of them are supported by ]good evidence . While there is no current cure for the syndrome, there is hope that further understanding of its underlying causes would lead to new therapies. Currently, the syndrome can be treated through behavioral therapy, special education, and when necessary, treatment of physical abnormalities . Persons with the fragile X syndrome in their family histories are advised to seek genetic counseling, to assess the likelihood of having children who are affected, and how severe any impairments may be in affected descendants .
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The Fragile X syndrome been the subject of numerous studies, and recent investigations have addressed the question of whether this disorder is amenable to either prenatal diagnosis or to treatment with folic acid . In a previous study, the effect of oral folic acid therapy (10 mg/day) in a blind study of 14-year-old monozygous twins with the fragile X syndrome was examined . They reported on eight patients with psychotic-like symptoms. Seven were improved by therapy with I M 5-formyltetrahydrofolate (folinic acid) at doses of 0.5 mg/kg body weight for a period of a few weeks . Three patients had an almost total recovery from psychotic-like symptoms . One 14-year-old boy who was severely hypotonic and disinterested in his environment became responsive and able to sit and crawl after 2 months of therapy with folic acid in doses of 1 mg/kg day . Harpey also reported some success with therapy with intramuscular folinic acid and hydroxocobalamin by mouth . In a recent report, a male fetus was diagnosed as having fragile X and the mother was started on a regime of folic acid 2 mg/day . After delivery, the baby was treated with 1 mg/day of folic acid. On evaluation at 6 weeks of age, the baby was described as having a dolicocephalic head, long ears, a flattened malar area, enlarged testes, and a high frequency of fragile X chromosomes (20/60 cells). Two studies attempted controlled trials of folate in the fragile X syndrome, and one of these has been reported in some detail . Brown conducted a double-blind crossover study in which two brothers with the fragile X syndrome were treated with either intravenous folic acid (1.6 mg/kg daily as a single dose) or saline placebo for 8 days . Following the controlled trial, the brothers were maintained on 10 mg/day of oral folic acid for 3 weeks. Over 6 weeks, the dose was increased to 500 mg/day for the younger brother and 1,000 mg/day for the older brother, and then both
brothers were maintained on 1,000 mg/day from 1 month to 5 months after the onset of the study .
Because this disorder is a very common cause of familial mental retardation, and because of the in vitro effect of folate in decreasing expression of the fragile site, one may be tempted to attempt folate therapy in these patients. However, two studies to date have failed to demonstrate any abnormality of folate metabolism in cultured cells from patients with the fragile X syndrome . Therefore, we urge continued caution in the expectation of beneficial results and advise against routine use of folate therapy in patients with established mental retardation and the fragile X syndrome .
Because there is no cure for Fragile X syndrome, the hope is that future investigations into the underlying causes that will further lead to new therapies.
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