Repeat Size and X Inactivation in the Clinical Phenotype of Fragile X Premutation Carrier Sisters: A Familial Case Series (P5.384)
OBJECTIVE: To present a case series of four sisters with similar premutation size Fragile X mental retardation 1 (FMR1) alleles and varying activation ratios for the normal allele (AR) to determine whether AR, in addition to CGG repeat size, could account for their discordant neurological phenotypes. BACKGROUND: Skewed X inactivation may be responsible for mediating some of the phenotypic variability seen in FMR1 premutation carrier women. These discordant clinical phenotypes may be explained by variation in the combination of CGG repeat size and AR. DESIGN/METHODS: Four sisters with premutation size FMR1 repeats underwent detailed clinical characterization. CGG repeat length was determined by PCR and AR was determined using a newly developed commercial mPCR assay (Asuragen) and confirmed with results from Southern blot with densitometric image analysis. The mPCR assay was found to be simpler and faster, and results correlated well with AR determined based on Southern blot. RESULTS: Sister 1 had the largest CGG expansion (90) and the lowest AR (10[percnt] with the most severe clinical presentation. Sister 2 had a lower CGG expansion (70) and an AR of 10[percnt] and had milder neurological symptoms. Sister 3 had a CGG expansion of 79, but a slightly higher AR of 15[percnt] and less neurological involvement. Sister 4 had a similar CGG expansion (80) but had the largest AR (40[percnt] and was the only sister not to be affected by FXTAS or show any neurological signs. CONCLUSION: Women in the same family who have higher AR or lower CGG repeat sizes than their sisters may be less likely to show manifestations of FXTAS. Using AR data could be beneficial to supplement CGG repeat size when counseling premutation carrier women in the clinic if larger studies show similar patterns. Disclosure: Dr. Robertson Dick has nothing to disclose. Dr. O9Keefe has nothing to disclose. Dr. Hadd has received personal compensation for activities with Asuragen, Inc. as a full time employee and options holder. Dr. Zhou has nothing to disclose. Dr. Berry Kravis has received personal compensation for activities with Seaside Therapeutics, Novartis, Roche, Alcobra, and Neuren Parmaceuticals as a consultant. Dr. Hall has received research support from Neurocrine and Pfizer.