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Distinctive signs: The severity of fragile X symptoms, including physical characteristics such as tapered fingers and an elongated face, varies less predictably in girls with the disorder than in boys.
The symptom severity of three girls with fragile X syndrome tracks with how much the levels of the fragile X protein in their blood differs from that of their unaffected mothers1.
If the results, published 29 January in Molecular Syndromology, are confirmed in a larger study, they may help doctors predict how the disorder will manifest in girls.
Fragile X syndrome is the most common cause of inherited intellectual disability, and is frequently accompanied by autism. People with the disorder typically have more than 200 repeats of a three-nucleotide sequence within the FMR1 gene, which tamps down the production of the FMRP protein. However, other deletions or mutations that affect the gene can also lead to fragile X syndrome.
Because FMR1 is located on the X chromosome, women with the disorder have more variation in the severity of their symptoms than men do. Women have two X chromosomes, but cells randomly express only the genes from one of the chromosomes — a process known as X inactivation. Among women who have one copy of mutant FMR1, the proportion of cells expressing the mutant versus the normal copy may differ considerably, leading to symptoms of varying severity.
In the new study, the researchers examined three girls, who were 3, 9 and 16 years old, with fragile X syndrome. All carry de novo microdeletions — mutations that spontaneously occur in the child but not the parent — in FMR1. All three have intellectual disability or developmental delay and other features common in fragile X; none have autism.
The girls all make significantly less FMRP than their mothers do, the researchers found. And the more different a girl’s level is from her mother’s, the more severe her symptoms are.
If larger studies confirm this link, looking at FMRP levels and X inactivation status may help predict the severity of symptoms.
References:
1. Zink A.M. et al. Mol. Syndromol. 5, 65-75 (2014) PubMed
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