Dr. Aurora Sànchez
Dr. Montserrat Milà
Genetics Service
Center for Biomedical Diagnostics
Hospital Clínic of Barcelona

Fragile X syndrome is the most frequent cause of familial mental retardation and the second chromosomal disorder in frequency after Down syndrome. It is transmitted in dominant inheritance linked to sex with an incomplete penetrance (80% for men and 30% for women) and a variable clinical expression. The estimated frequency of the syndrome for men is 1 / 4000 and 1 / 6000 for women. Clinically it is characterized by the presence of mild to moderate mental retardation, facial dysmorphism (long triangular face, and large winged ears) and macro-orquidism.

Fragile X syndrome is caused by the expansion of a tri-nucleotide (CGG) in the first exon of the FMR1 gene in band q27.3of chromosome X. The expansion is associated with hypermethylation of the repetitive area and the adjacent CpG island, which entails a lack of gene transcription and an absence of protein (FMRP), this absence being the ultimate cause of the syndrome. The CGG triplet is polymorphic in the general population ranging from 6 to 52 repeats. CGG repeats between 53 and 200 set the pre-mutation which is not accompanied by clinical signs but it is very unstable and can grow to full mutation (over 200 CGG repeats) when it is transmitted by a female to the next generation.

The clinical signs of fragile X syndrome are highly variable depending on age and sex.  Physical manifestations may be overlooked in childhood, when the behavioral disorders such as hyperactivity, poor attention and hand flapping are much more obvious, while after teen age the most evident physical manifestations (macro-orquidism and large ears) characterize the syndrome.

Regarding clinical diagnosis after evaluation (checklist according to Hagerman 1991) of 153 patients with mild to moderate mental retardation of unknown etiology and 76 patients with fragile X syndrome, the Hagerman’s checklist was shown to be an excellent clinical guide, showing some differences between child patients and the post-teenage ones. Puber patients show high scores in clinical behavioral traits: hyperactivity, poor eye contact, repetitive language and touch defense, whereas in post-puber patients the features with highest physical scores were: winged and large ears, large heads and the presence of a family history of mental retardation. Overall the checklist scores higher in postpuberty than in puberty because the checklist assesses 8 behavioral items and only 5 physical ones. This difference was not significant in negative FRAXA patients.

The results obtained by our Genetic Services show an average positive checklist in the FRAXA population of 14.09 while the population was 5.9 FRAXA negative, these results are statistically significant and show a high specificity and sensitivity for the checklist.

FXS laboratory diagnosis should include FMR1 gene studies and genetic counseling should be provided after the molecular test.

Every individual, man or woman, with normal FMR1 gene molecular studies places no risk on their descendants with regard to the syndrome. Therefore there is no longer an indication to further test their descendants, a fact that cannot be avoided in FXS cases.

Regarding carriers:

– Man carrier (NTM): All daughters will be clinically healthy carriers, always in a pre-mutation state. None of his sons will be carriers, and all will be clinically healthy. Therefore diagnosis of their descendants is not indicated, contrary to FXS cases.

– In women carrying a pre-mutation, 50% of their sons inherit the risk allele. If the mutation expands they will inherit the full mutation and will be affected.The other 50% will inherit the healthy allele and will be non-carriers. With regards to daughters, 50% will be carriers of a complete mutation or pre-mutation depending on the size of the expansion, and 50% will be clinically healthy non-carriers. In this case a prenatal, preconceptional or pre-implantation diagnosis is the best option.

– Women carrying the full mutation: the risk is the same as above, but here the gene penetrance is 100%, making it virtually impossible to have NTM pre-mutated sons and daughters. The person who inherits the risk allele, inherits the full mutation and all men will be affected, in  woman the clinical involvement will depend on the X chromosome inactivation. The best option is, again, a prenatal, preconceptional or preimplantation diagnosis.

– In the case of affected men, all his male offspring will be normal and all the female descendants will be clinically healthy carriers of the premutation. In conclusion, none of his male descendants will manifest the syndrome and therefore it is not recommended tests for them.

The risk of mental retardation is related to the individual’s place within the family tree, because the mutation grows with eacg generation. The pre-mutation can be unchanged for several generations, or switch to full mutation in one generation, but the change always happens through a woman.

In women premutation carriers (50-200 CGG) the risk of expansion to the full mutation allele (> 200 CGG) depends on the number of repeats. From a 90 CGG repeat mutation there will always be an expansion to a full mutation in the next generation, if the mutated allele is trasmitted.

The early clinical diagnosis of FXS is difficult given the scarcity of clinical signsd present in the first years of life, that’s why school staff and parents play a crucial role in early detection. In most cases behavioral problems represent the most apparent signs. Early diagnosis brings up the issue of genetic family counseling, which is nowadays the only way to prevent the syndrome.

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