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Two brothers are reported who share mental retardation, conjunctival teleangectasias (mainly equatorial) and characteristic flat face with small mouth and thin prolabia. At the neuropsychological examination, the older brother at 14 years showed a full scale IQ of 40 (WISC), with verbal IQ 45 and performance IQ 44. The younger brother at 7 years showed a full scale IQ of 58 (WPPSI), with verbal IQ 67 and performance IQ 55. Chromosome studies showed a duplication Xp22-Xpter in both brothers and in the inactivated X of their mother. The anomaly was not present in a 3rd healthy brother and in other healthy relatives. The mother has normal intelligence and did not present any of the physical features of her affected sons.

We describe the neuropsychological and behavioral profiles of 48 critical members of a previously reported Sardinian pedigree [Filippi et al., 1991], in which the fully manifested Martin-Bell syndrome (MBS), observed among males of the latest generations, is clearly the result of step-wise mutational events occurred repeatedly along the X-chromosome pathway linking all of them to a common ancestress, who must have been heterozygous for a fragile X (FRAX) premutation. We found that the unquestionable presence in the family of normal transmitting males and females could not be determined on the basis of neuropsychological and behavioral data alone. However, we think that the large variation observed in the expression of most diagnostic parameters among the MBS patients and their close female relatives in this family, could by itself be a connotation of the genome instability which characterizes the FRAX region in pedigrees segregating for the FRAX premutation(s) and mutation(s).

Neuropsychological studies were performed in 82 subjects of 12 families with x-linked, fragile X negative, mental retardation (MR). Subjects were examined with Wechsler tests (WPPSI, WISC-R or WAIS, according to their capabilities), Progressive Matrices, Bender or Santucci and memory tests. Physical findings in 5 families were characterised by micro-orchidism (MiO), microcephaly (MiC), short stature (SS) and non-specific facial features (XMR +/- MiO +/- MiC +/- SS). The 11 males with MR had a very low IQ, ranging from 13 to 37 (mean 21.2 +/- 8.8); this did not constitute a profile definition. Among the females of their families, 4 had subnormal or borderline IQ, respectively 74, 66, 38 and 37. A second group (2 families) had MiO but with normal stature and occipito-frontal circumference (XMR +/- MiO). The 7 males with MR had an IQ ranging from 24 to 43 (mean 35.1 +/- 5.8) and showed frequently better results in performance than in verbal subtests. In these 2 families, 5 females had subnormal or borderline IQ, respectively 77, 72, 71, 70 and 20. In the 5 families of the third group, XMR +/- MaO (fraX-), several affected males had macro-orchidism (MaO) and facial changes similar to those of fragile X syndrome. IQ variability, also in the same family (e.g.: the 3 brothers of family 3 had, respectively, an IQ of 26, 28 and 68; and 2 brothers of family 1 had an IQ of 13 and 63) and different profiles. Two females were severely affected (IQ 16 and 24), while another 4 had an IQ, respectively, of 63, 69, 71 and 72.

One hundred forty-nine subjects from 18 families with fragile X [fra(X)] syndrome were evaluated for their neuropsychological, psychiatric, and physical characteristics. The 36 fra(X) males had intelligence quotients ranging from less than 20 to 61, which prevented the delineation of a reliable neuropsychological profile. Behaviour fitted DSM-III-R and ADI diagnostic criteria of autism in only 2 subjects, both with very low intelligence level (IQ less than 20). Of 36 heterozygotes (HZ), 22 had an IQ between 20 and 80 and 14 between 81 and 99. The neuropsychological profile of the latter was compared with IQ-age-environment-matched 14 normal females and 14 normal males. Significantly poorer results in HZ were found on immediate digit memory and on Raven's progressive matrices (a visuo-spatial test of logical capabilities). The latter result, in conjunction with those results on the Bender visual-motor gestalt test and on some WAIS subtests, suggests a frequent deficit in spatial capabilities in such subjects. Such results tended to be confirmed by the profiles of the 22 HZ with IQ 20-80. No psychiatric abnormalities were found in HZ, except in one subject with IQ less than 20 which fitted DSM-III-R and ADI criteria for autism. Typical physical manifestations, especially cranio-facial, were more frequently present in the HZ group with lower IQ. Subnormal IQ was probably the most reliable abnormality for the detection of HZ in 49 females at 50% and 25% risk of heterozygosity.