No abstract

A new series of 96 pedigrees with the fra(X) syndrome was analysed using complex segregation analysis with pointers, defining affection as any degree of mental impairment. These families were found to exhibit the same segregation pattern as the first series of 110 pedigrees (Sherman et al. 1984). The best estimate for penetrance of mental impairment in males was 79% and in females was 35% for the combined data. Again, there was little evidence for sporadic cases among affected males. Many more intellectually normal transmitting males have been observed since the existence of such males and the concomitant need to investigate the paternal side of pedigrees was recognized. On further investigation of all 206 pedigrees from the old and new data sets, the sibships of nonexpressing males appeared to be different from those of expressing males. Our analysis, using mental impairment as the phenotype, suggested that obligate carrier mothers and daughters of intellectually normal transmitting males are rarely, if ever, mentally impaired and that the sibs of transmitting males are much less likely to be retarded than the sibs of mentally impaired males. Though mothers and daughters of transmitting males are similar in phenotype, the expression of the gene in their offspring appears to be different: the penetrance of mental impairment is higher in offspring of intellectually normal daughters of transmitting males than in offspring of intellectually normal mothers of transmitting males. The implications of these observations for genetic counseling and for genetic models of the fra(X) syndrome are discussed.

The preliminary results of an international collaborative study examining premature menopause in fragile X carriers are presented. A total of 760 women from fragile X families was surveyed about their fragile X carrier status and their menstrual and reproductive histories. Among the subjects, 395 carried a premutation, 128 carried a full mutation, and 237 were noncarriers. Sixty-three (16%) of the premutation carriers had experienced menopause prior to the age of 40 compared with none of the full mutation carriers and one (0.4%) of the controls. Based on these preliminary data, there is a significant association between fragile X premutation carrier status and premature menopause.

The preliminary results of an international collaborative study examining premature menopause in fragile X carriers are presented. A total of 760 women from fragile X families was surveyed about their fragile X carrier status and their menstrual and reproductive histories. Among the subjects, 395 carried a premutation, 128 carried a full mutation, and 237 were noncarriers. Sixty-three (16%) of the premutation carriers had experienced menopause prior to the age of 40 compared with none of the full mutation carriers and one (0.4%) of the controls. Based on these preliminary data, there is a significant association between fragile X premutation carrier status and premature menopause.

Retrospective longitudinal studies have noted declines in IQ scores in many but not all fra(X) (fragile X) males and females. We report on a prospective investigation of longitudinal changes in cognitive ability (IQ) and adaptive behavior (DQ) in 24 fra(X) males from four test sites. Individuals who were tested ranged in age from 3–15 years. To determine cognitive ability, all males were administered the Stanford‐Binet test (4th Edition). To assess adaptive behavior, all males were evaluated using the Vineland Adaptive Behavior Scales. Mean intertest interval was 2.3 years. Using identical DNA protocols, all subjects were identified as bearing the fra(X) mutation. Results showed declines in IQ scores in 18/24 (75%) males. Four males showed no change in scores. Declines in DQ scores were noted in 22/24 (92%) of those tested. DQ scores were higher than IQ scores in 20/24 (83%) subjects. From a descriptive cohort analysis, decreases in IQ scores appear to follow a well‐defined, negatively decelerating function. Declines in DQ were steeper and more nearly linear. Declining scores are not indicative of regression of intellectual and/or social skills, but of a relative inability to keep pace with their age‐normed cohort. We conclude that the fra(X) mutation affects cognitive abilities in a uniform, nonlinear manner comparable to outcomes observed in earlier retrospective studies. Adaptive behavior also declines, but in a more linear fashion. © 1996 Wiley‐Liss, Inc.