Mental impairment and instability of the CCG repeat at FRAXE is described in six kindreds. Cosegregation of FRAXA and FRAXE was found within one of these kindreds. Cytogenetic expression of FRAXE was shown to skip a generation when associated with a reduction in size of the CCG expansion when transmitted through a male; however, in general, transmission occurred through females and copy number increased from one generation to the next. In these respects the behaviour of FRAXE paralleled that of FRAXA. A relationship between FRAXE and non-specific mental impairment is strongly suggested by the occurrence in these families of more mentally impaired male and female carriers, after removal of index cases, than could reasonably be expected by chance. (Jt Med Genet 1995;32:162-169) Cytogenetic detection of the fragile X (FRAXA) has been confused by the discovery of two nearby rare folate sensitive fragile sites.

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SUMMARY Thirty‐five schoolchildren who share a common history of early undernutrition and who were reared after recovery by adoptive families (16), in institutional care (eight) or by their biological families (11) were assessed for physical and intellectual outcome. The adopted children had mean normal weight and height for age, but the children from institutions were significantly shorter. Adopted children had mean Full‐scale, Verbal and Performance IQs in the normal ranges, with significant differences from the other two groups, mainly for the Verbal subscale. These results emphasize that the growth and development of early‐undernourished children are not irreversibly fixed by the acute illness, but are highly sensitive and modifiable by early and stable environmental improvement. RÉSUMÉ Devenir intellectual et physique des enfants dénutris au début de leur vie, en fonction de l'environnement größen, aber die Heimkinder waren signifikant kleiner. Die adoptierten Kinder hatten normale full‐scale, verbal und performance IQs und unterschieden sich besonders im verbalen Bereich signifikant von den anderen Gruppen. Die Ergebnisse zeigen, daß Wachstum und Entwicklung von frühkindlich unterernährten Patienten nach der akuten Erkrankung nicht irreversibel gestört sind, sondern durch frühzeitige bleibende Veränderung des sozialen Umfeldes gut zu beeinflussen und zu modifizieren sind. Le devenir intellectuel et physique a été apprécié chez 35 écoliers partageant une histoire identique de malnutrition précoce, et élevés ensuite après correction dans des families adoptives (16 cas), en institution (huit cas) ou par leurs families biologiques. Les enfants adoptés présentaient une taille et un poids normaux pour l'âge mais les enfants en institution étaient significativement plus petits. Les enfants adoptés présentaient des QI verbaux, performance et globaux dans la normale, avec des différences significatives pour les autres groupes, notamment pour l'échelle verbale. Ces résultats soulignent que la croissance et le développement des enfants initialement dénutris ne sont pas irrémédiablement fixés par l'affection aiguë et sont hautement sensibles et modifiables vers un progrès dans un environnement favorable précoce et stable. ZUSAMMENFASSUNG Intellektueller und körperlicher Befund bei Kindern, die im frühen Lebensalter unternährt waren, und ihr soziales Umfeld 35 Schulkinder, die im frühen Lebensalter unterernährt waren und die nach ihrer Genesung in Adoptivfamilien (16), in Heimen (acht) oder bei ihren Eltern in aufwuchsen, wurden im Hinblick auf ihre körperliche und intellektuelle Entwicklung untersucht. Die adoptierten Kinder hatten normale, altersentaprechende Durchschnittsgewichte und ‐ größen, aber die Heimkinder waren signifikant kleiner. Die adoptierten Kinder hatten normale full‐scale, verbal und performance IQs und unterschieden sich besonders im verbalen Bereich signifikant von den anderen Gruppen. Die Ergebnisse zeigen, daß Wachstum und Entwicklung von frühkindlich unterernährten Patienten nach der akuten Erkra...

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Very little is known about the phenotype of FRAXE‐positive individuals and the relation between the genotype/phenotype and genotype/cytogenetic expression. We describe three families with normal and mildly affected individuals and a severely retarded male expressing fragility at the FRAXE locus or presenting different expansions at the CGG FRAXE triplet. In addition, we analyze the FRAXE mutation in sperm DNA from a retarded male carrier with a handicapped daughter expressing fragility at the FRAXE locus. Mental status in FRAXE individuals is highly variable and, although mild mental retardation is observed in most cases, several carrier males are apparently normal. It seems that methylation is not as strictly associated with size of CGG triplets in the FRAXE locus as in FRAXA, and it is possible that normal carrier individuals with fully methylated increments in lymphocytes have a certain proportion of unmethylated alleles in the critical (i.e., neural) tissues. FRAXE mutation is apparently similar to FRAXA in that males with somatic large methylated increments are carriers of small unmethylated ones in germinal cells. © 1996 Wiley‐Liss, Inc.

The fragile X mental retardation syndrome is caused by an expansion of a trinucleotide repeat (CGG)n in the FMR-1 gene. Molecular genetic study of fragile X provides accurate diagnosis and facilitates genetic counseling in families with affected members. We present here the molecular study of 59 Spanish fragile X syndrome families using probe StB 12.3 and the polymerase chain reaction (PCR) of the (CGG)n repeat sequence of the FMR-1 gene. The results obtained have allowed us to characterize 455 individuals, including eight prenatal diagnoses. The clinical diagnosis of fragile X in 89 affected males was confirmed, 137 female carriers were identified (48 of whom were mentally retarded), 176 individuals "at risk" were found not to have the expansion, and 12 cases of normal transmitting males (NTM) were detected. In the sample studied, no de novo mutations were detected, nor any mutation different from that described for the (CGG)n expansion. One nonmentally retarded male was detected as having an unmethylated CpG island for the FMR-1 gene, but with more than 200 CGG repeats (high functioning male). The analysis of the (CGG)n repeat in 208 normal chromosomes gave an allele distribution similar to that in other Caucasoid population groups, with alleles of 29 and 30 CGG repeats accounting for 46% of the chromosomes. The combination of Southern analysis and PCR of the (CGG)n repeat is highly efficient for diagnosis, compared with cytogenetic techniques, especially in the detection of female carriers, NTMs, and prenatal diagnosis, enabling accurate genetic counseling to be provided in all cases.

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In a Spanish region with a population of one million, we screened 371 mentally retarded males, who had no previous diagnosis for fragile X [fra(X))] syndrome. Fifty-three of the 371 males were fra(X) positive. Of these 44 of 362 or 12.1% were unrelated. Family studies identified a large number of obligate carriers and women at risk for being carriers who were given genetic counseling including prenatal diagnostic information. Considering the age of the carriers and the fertility rate, 23 affected males could be born to these women. The prevention potential of this program suggests that it is highly cost-effective.