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August 23/30, 2006

X Inactivation and Cellular Mosaicism—Reply

JAMA. 2006;296(8):930-931. doi:10.1001/jama.296.8.931-a

In Reply: In the context of a review, I was not able to discuss many of the diseases listed in Table 2 in depth. In response to the concerns of Drs Hagerman and Hagerman, Table 2 only considered the phenotype expected for the full mutation—the one associated with the classic fragile X syndrome—and not the premutation.

Hagerman and Hagerman suggest that for carriers of the full FMR1, random X inactivation (approximately 50% normal cells) is not enough to prevent all the subtle manifestations of the full mutation. It seems that a completely normal phenotype requires some skewing in favor of the normal cells. In any case, females with a full mutation have less severe disease than males, with a significant association between the proportion of normal FMR1 alleles on the active X chromosome and IQ.1,2 Females with the severest manifestations have the most cells expressing the mutation.3 Therefore, X inactivation has an important role in determining the IQ of full mutation carriers. As the tremor/ataxia syndrome associated with the premutation is also more severe in males than females,4 it seems that no matter what the nature of the FMR1 mutation is, the manifestations are more severe in males, which was my point.

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