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The Seventh International Workshop on the Fragile X and X-linked Mental Retardation was held at the University of Tromso in Norway on August 2-5, 1995. Approximately 120 participants from 20 countries attended the Workshop. By special invitation Dr. Felix de la Cruz, who initiated the first international Workshop on fragile X, attended this Workshop. For the first time, the workshop took place in Scandinavia and was hosted by Lisbeth Tranebjaerg and Herbert Lubs. For most participants this Workshop, held at the northernmost university in the world, presented a unique opportunity to visit this exotic place. Between sessions, the participants hadmore » a chance to experience 24 hours of daylight, codfishing, and extreme weather situations with excessive amounts of rain as well as spectacular changes in the light and rainbows. The format of the Workshop was a combination of platform presentations and poster presentations. In contrast to previous meetings, the Workshop opened with syndromal and non-syndromal X-linked mental retardation in order to allow time for discussion. 34 refs., 1 fig.« less

A current list of all known forms of X-linked mental retardation (XLMR) and a slightly revised classification are presented. The number of known disorders has not increased because 6 disorders have been combined based on new molecular data or on clinical grounds and only 6 newly described XLMR disorders have been reported. Of the current 105 XLMR disorders, 34 have been mapped, and 18 disorders and 1 non-specific XLMR (FRAXE) have been cloned. The number of families with nonspecific XLMR with a LOD score of {ge}2.0 has more than doubled, with 42 (including FRAXE) now being known. A summary ofmore » the localization of presumed nonspecific mental retardation (MR) genes from well-studied X-chromosomal translocations and deletions is also included. Only 10-12 nonoverlapping loci are required to explain all localizations of non-specific MR from both approaches. These new trends mark the beginning of a significantly improved understanding of the role of genes on the X chromosome in producing MR. Continued close collaboration between clinical and molecular investigators will be required to complete the process. 105 refs., 2 figs., 6 tabs.« less

We reevaluated a family previously described as having nonspecific X-linked mental retardation (XLMR) by Snyder and Robinson (MINI 309583). Clinical and DNA studies were conducted on 17 relatives, including 6 males with mild-to-moderate mental retardation, 3 carrier females, and 8 normal males. In contrast to the normal appearance and minimal clinical findings reported 22 years ago, affected males were found to have a characteristic set of clinical findings. These developed gradually over the first 2 decades, and included thin body build with diminished muscle mass, osteoporosis and kyphoscoliosis, slight facial asymmetry with a prominent lower lip, nasal speech, high narrowmore » or cleft palate, and long great toes. Carrier females were clinically normal. Multipoint linkage analysis indicated linkage to markers distal to the 3{prime} end of DMD (DXS41 and DXS989), with a maximal lod score of 4.7. On the basis of these findings, this entity is redefined as XLMR syndrome. 22 refs., 6 figs., 2 tabs.« less

The initial goal of this study was to localize as many genes as possible that lead to syndromic and non-specific XLMR. More recently, this goal has been redefined to include narrowing these localizations and cloning specific genes. In the last 5 years, 61 families have participated in this study; 34 have a projected or actual lod score greater than 2.0. Restudy of 12 families reported previously has been a particularly productive aspect of this study and has led to clinical redefinition and new or improved localization of most of these syndromes. Five possible new XLMR syndromes have been identified. Fivemore » large families with non-specific XLMR have been regionally localized. Since many XLMR conditions are based on only 1 or 2 family reports, one of the major purposes of this summary is to provide clinical data on the study families so that collaborative projects can be undertaken with other centers that have similar families. 34 refs., 1 fig., 5 tabs.« less

We provide a comprehensive list of all known forms of X-linked mental retardation. It comprises 127 entries, subdivided into 5 categories (syndromes, dominant disorders, and nonspecific mental retardation). Map location of 69 putative loci demonstrates several overlaps, which will only be resolved by more refined mapping or cloning of the respective genes. The ultimate goal of identifying all the genes on the X chromosome whose mutations cause mental retardation will require a concerted effort between clinical and molecular investigators. 74 refs., 2 figs., 5 tabs.

A family described as non-specific XLMR by Snyder and Robinson was re-evaluated 23 years later. Clinical and DNA studies were conducted on 17 family members; 6 affected males, 3 carrier females, and 8 normal males. All carrier females were clinically normal and the pattern of inheritance was clearly X-linked. Initial localization studies indicated linkage to the region near the DMD locus in Xp21.22. Further analysis focused on this region using (CA)n repeat polymorphisms for the dystrophin gene and for two markers distal to the gene. The dystrophin markers detected recombination across the entire gene, making it unlikely that the DMDmore » locus was involved in the Snyder-Robinson syndrome. Normal dystrophin staining in a muscle biopsy in one affected male confirmed this observation. Multipoint analysis also indicate that the SRS (Snyder-Robinson Syndrome) locus was distal to DMD, and located near locus DXS41 (lod score = 4.00 at theta = 0.00). The presence of mild to moderate mental retardation, asthenic body build, diminished muscle bulk, nasal speech, high narrow/cleft palate, long thin fingers and great toes and mild to severe scoliosis permitted the delineation of a specific syndrome associated with this previously non-specific disorder. It is important, therefore, to recognize that today`s {open_quotes}non-specific{close_quotes} family may be tomorrow`s syndrome.« less

In 1962 Renpenning et al. reported a Canadian family with X-linked mental retardation. The affected males were described as having no definitive abnormalities apart from prominent ears and small head circumferences. However, upon restudy, Fox et al. thought the affected males differed in enough respects from other males in the family that the authors suggested they represented a distinct clinical entity. The clinical presentation was severe mental retardation, head circumference two standard deviations below normal, testicle size ranging from very small to normal, and a tendency toward short stature. We have been able to locate many members of this familymore » and have initiated linkage studies. Results at present indicate linkage to loci located in the proximal region of the short arm of the X chromosome. No recombination is observed with the following loci: DXS84 (Z{sub max} = 1.35), DXS255 (Z{sub max} = 1.66), DXS14 (Z{sub max} = 1.24), DXS159 (Z{sub max} = 1.48). Recombination was observed at the DMD and AR loci. Recently, we analyzed a second family (K8240) which clinically appears to be similar to the Renpenning family. The males are severely retarded, have small testes, smaller than average head circumference and are shorter than average. Preliminary linkage analysis in the family shows tight linkage (theta = 0.00) at AR (Z{sub max} = 2.59), DXS566 (Zmax = 3.39), DXYS1 (Zmax = 2.73) and DXS3 (Zmax = 2.84). Based on these two families, we have strong evidence for a pericentric location for the Renpenning syndrome gene. However, as these two families each exhibit recombination at markers that the other does not, it is quite possible 2 different genes in the pericentric region may lead to a Renpenning phenotype.« less

Aarskog-Scott syndrome was tentatively mapped to Xq13 on the basis of an X:8 translocation by Bawle et al. A review of the cytogenetics and the use of molecular markers in that family have resulted in revision of the breakpoints of the translocation to Xp 11.2 and 8q 11.21. Two families, including one of the two initial families with Aarskog-Scott syndrome, have participated in our study to evaluate the localization of the gene for Aarskog-Scott syndrome to the pericentromeric region of the X chromosome. Using a series of DNA probes, we have been able to confirm linkage to the X chromosome,more » with multipoint analysis indicating the most likely localization of the gene to be on the proximal short arm. 24 refs., 4 figs., 4 tabs.« less