Fragile X syndrome. II. Cognitive and behavioral correlates of mutations of the FMR-1 gene

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The fragile X (or Martin Bell) Syndrome is inherited as a dominant X-linked genetic condition of mental retardation with incomplete penetrance: 79% for males, 35% for females (Sherman et al, 1985). Unlike other X-linked conditions (eg, X-linked colour blindness), the fragile X syndrome does not affect only male individuals but also female carriers of the genetic abnormality. In fact, concerning cognitive functioning, recent data indicate the existence of a broad continuum ranging from severe forms of mental retardation as well as several degrees of reduced intellectual abilities to circumscribed selective neuropsychological dysfunctions in males and females, although males being typically more affected than females. On the psychopathological level, some psychiatric conditions have also been observed within fragile X family members. For all these reasons it is therefore difficult to talk about affected versus non affected fragile X family members, since the ‘status of affection’ may exist on different levels: different genotypes (eg, full mutation, premutation, mosaic) reflecting variable phenotypes. This part of the report will address these different phenotypic levels and provide a review of the current state of knowledge concerning the clinical aspects of the fragile X syndrome in relationship to the different genotypes. For reasons of simplicity and clairity, this paper will focus mainly on the clinical picture of three groups: affected males with the fragile X syndrome (methylation of the cytosine phosphate guanine (CpG) island, CGG repeats > 200; = full mutation of the FMR-1 gene), normal transmitting males (NTM) (unmethylated CpG island, CGG repeats > 50 50 < 200; premutation of the FMR-1 [fragile X mental retardation 11 gene).