HIGH FUNCTIONING FRAGILE-X MALES - DEMONSTRATION OF AN UNMETHYLATED FULLY EXPANDED FMR-1 MUTATION ASSOCIATED WITH PROTEIN EXPRESSION

Fragile X (fra(X)) males with a standardized IQ score of 70 or higher represent a high functioning (HF) or nonretarded fra(X) male group. Th is group, which does not include nonpenetrant males, has received litt le research attention to date. Of 221 fra(X) males who had been evalua ted through The Children's Hospital in Denver since 1981 and had compl eted cognitive or developmental testing, 29 (13%) were high functionin g by the above definition. We found that HF males on the whole had a l ower cytogenetic score and were younger than retarded fra(X) males, bu t there was no difference between these two groups in the number of ty pical fra(X) physical manifestations present. FMR-1 DNA testing was pe rformed on 134 fra(X) males and methylation status was determined for 51 of these. A greater percentage of HF males had a mosaic pattern or an incompletely methylated full mutation than did retarded males. A un ique DNA pattern, an unmethylated fully expanded mutation, was discove red in 3 of the highest functioning fra(X) males. Protein studies perf ormed on 2 of these males demonstrated the presence of FMR-1 protein, albeit at lower levels than normal. FMR-1 protein was not present in r etarded fra(X) males. Significant FMR-1 protein expression may be resp onsible for higher cognitive functioning in the 2 males with unmethyla ted fully expanded mutations compared to retarded fra(X) males. (C) 19 94 Wiley-Liss, Inc.,Inc.