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Neurogenetics

Mental retardation is a very common clinical problem with a prevalence of approximately 1-2%. Research into genetic forms of mental retardation which may account for one half of the severely retarded patients has been hampered by the enormous complexity of this condition. Because mental retardation is more frequent in males than in females, it has been estimated that 25 to 50% of all mental handicaps are caused by X-linked gene defects that give rise to recognizable mental retardation syndromes, or to so-called "non-specific" forms where mental retardation is the only detectable clinical feature.
Of all known causes of X-linked mental retardation, the fragile X (FRAXA) syndrome is by far the most frequent one; the FRAXA syndrome is due to the expansion of a trinucleotide repeat, CGG(n), in the 5' untranslated portion of the FMR1 gene which appears to code for an RNA binding protein. In patients with n > 200, FMR1 expression is decreased or absent. It has become apparent, though, that the fragile X syndrome accounts for only 40% of all cases with non syndromic X-linked mental retardation (XMR). This implies that for the remaining 60% there is presently neither prevention nor therapy.
To shed more light on the nosology of unspecific XMR and as a prerequisite for the biochemical elucidation of this group of disorders we have initiated systematic clinical, linkage and molecular studies in > 50 Dutch families where FRAXA had been excluded. So far, linkage studies have been completed in 13 families and in some of them, detailed clinical studies including IQ testing and psychological examination have revealed numerous specific features that had been overlooked previously. In one of these families, a characteristic behavioural abnormality was found consisting of inability to cope with frustration which could be ascribed to defect in the monoaminoxidase A gene (Brunner et al., Science 262: 1236, 1993). In another family, mental retardation was associated with small stature due to isolated growth hormone deficiency; here, the defect could be mapped by linkage studies to the Xq26 region (B. Hamel et al., Am J Med Genet 1995, in press). In other families, complex, recognizable phenotypes were defined (e.g., Hamel et al., Am J Med Genet 51: 591, 1994). Linkage studies in syndromic and non-syndromic cases revealed a conspicuous clustering of the underlying gene defects around the centromere and in particular, the proximal short arm of the X chromosome. A similar clustering of breakpoints in the mid-portion of the X-chromosome was observed in mentally retarded patients with balanced X-autosome translocations and inversions (collaboration with Simone Gilgenkrantz, Nancy and J.P. Fryns, Leuven). For three of these X-chromosomal breakpoints, overlapping YAC clones could be identified by fluorescence in situ hybridization (Van der Maarel et al., submitted), and a gene overlapping one of these breakpoints could be isolated by positional cloning (Van der Maarel et al., submitted). This gene is highly expressed in brain and contains 26 exons. Mutation screening in unrelated patients with X-linked mental retardation is in progress.


Headings
"Non-specific" X-linked mental retardation

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