An epidemiological study was carried out on the group of moderately retarded brothers (IQ, 30-55) identified by Turner and Turner [1974]. Of the original 58 sets of brothers, 54 sets (now 17 to 32 years old) were traced; another four sets (missed in the earlier survey) were added. Forty-five of the 58 pairs were diagnosed as having nonspecific X-linked mental retardation (MR) giving an overall frequency of 5.57 moderately retarded males/10,000 male births. In 12 of the 45 families, affected males had the fragile(X) and macroorchidism; six had macroorchidism alone, giving a frequency of 2.8 moderately retarded males with X-linked MR and macroorchidism +/- the fragile(X) per 10,000 males. Corresponding heterozygote frequencies are 7.34 and 3.65/10,000 females respectively. A new subgrouping of nonspecific X-linked mental retardation is described in six families: X-linked MR, macroorchidism without the fragile(X). Three other X-linked conditions were identified: in one family, the Coffin-Lowry syndrome, in another, Duchenne muscular dystrophy, and in two families X-linked MR and muscle atrophy. Half (56%) of the obligatory carriers of fra(X)-MR in this study were dull to mildly retarded. The mildly retarded heterozygotes had a significantly higher percentage of fra(X) expressing lymphocytes as compared to the intellectually normal heterozygotes. When the three types of nonspecific X-linked MR for which population frequencies were calculated were considered together, half of the obligatory carriers (46%) were dull or mildly retarded, thus confirming that this condition is a significant cause of mild intellectual handicap in females.

The effect of FUdR on the expression of fra(X)(q27) was examined in lymphocytes and/or fibroblasts from 16 affected males and 5 carriers from 10 families; six different culture media were used: F10, 5% serum, pH 7.3(37 degrees C); medium 199, 5% serum, pH 7.6(37 degrees C); folate-free 199, 5% serum, pH 7.6(37 degrees C), and these three media with FUdR (0.05 micron). In lymphocytes there was no significant difference in the percentage of fra(X) expressing cells between any of the FUdR-containing media. The highest percentage of expressing cells seen in lymphocytes with FUdR was 56%. The average enhancement in males with FUdR in the 199 and folate-free 199 media was 30%. This relative enhancement with FUdR was very much higher in a few blood specimens delayed in transit and FUdR may prevent some of the false-negative results obtained from mailed specimens. FUdR did not induce the marker in four obligate carriers with previously negative results. The fibroblasts from affected males were grown in the six specific media for the last 48 hr. Two of the six media yielded reproducibly positive results. These were 199-FUdR and folate-free 199-FUdR with mean percentages of expressing cells of 12.8 +/- 7.1% and 11.3 +/- 6.1%, respectively. F10-FUdR, which contains thymidine, did not permit expression of the marker in fibroblasts and there was no difference in the percentage of fra(X) expression in 199-FUdR media with or without folate. It was concluded that FUdR shows promise as an agent to permit prenatal diagnosis of the condition and to enhance the detection of the marker in lymphocyte cultures.