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The marker(X)(q28) chromosome associated with one type of X-linked mental retardation has been demonstrated in lymphoblastoid cell lines established from affected individuals. The mar(x) can reliably and repeatedly be seen by the addition of FUdR to the cultures for 24 hrs prior to harvest. This simple technique provides an excellent in vitro experimental test system for investigation of the mar(X).
The association of the fragile X chromosome with X-linked mental retardation is now well established. The main clinical features are mental retardation, typical facial dysmorphism and macroorchidism. Cytogenetically there is a fragile site in band Xq27-28 which can be demonstrated using specific techniques. The genetic studies are compatible with a X-linked dominant inheritance with an incomplete penetrance. A preliminary estimation of an overall frequency of 1: 2000 males for the fra(X)(q) condition is suggested.
The fragile-X syndrome, an X-linked form of mental retardation, is estimated to affect one in every 1,000 to 2,000 live-born male infants. Most commonly, fragile-X syndrome has been detected only after patients clearly demonstrate developmental delay, and frequently detection occurs only if the family history is consistent with X-linked mental retardation. Macro-orchidism is a finding commonly associated with the fragile-X syndrome. It has been suggested that the sparsity of reports of macro-orchidism among prepubertal boys with the fragile-X syndrome might be due to lack of careful measurement of the tests rather than to initiation of the enlargement at puberty. A 5-month-old infant with fragile-X syndrome, ascertained through testicular enlargement noted by actual measurement of testicular size as part of his physical examination, is reported.
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Three young males of Azorian origin who exhibited significant mental retardation, minor congenital anomalies, behavior disorders, and macro-orchidism were described. The chromosomal analysis revealed a fragile X chromosome in all three patients.
Description of the first Swiss family with the new syndrome of X-linked mental retardation. The three brothers described are the first of all males traced back for four generations to be affected. In two of the brothers macroorchidism and the fragile X-chromosome were demonstrated, while the third brother died before diagnosis. As expected, the fragile X was not demonstrable in the 75-year-old mother of the three brothers.
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Six males, four adults and two children, with very important mental deficiency and speech disturbances, belonging to two families are presented. The six patients show the clinical peculiarities of the "X-linked mental retardation, macroorchidism, and the Xq27 fragile site", but the chromosomal alteration only was presented in five cases. Patient who did not have the chromosomal defect presented the same IQ than his brothers, but he had a less severe macroorchidism, a better speech and more normal clinical features. One of the patients shows a shorter arm which linkage with the syndrome is discussed.
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A family is described in which three normal females transmitted to seven males X-linked mental retardation associated with macro-orchidism and a fragile site on the long arm of the X chromosome -- fra(X)(q27). The affected males also had minor clinical features in common: a large forehead, long face, large ears, a long upper lip and large extremities.
In males affected by a special form of X-linked mental retardation a characteristic chromosomal abnormality can be demonstrated, - i.e. a fragile site on the long arm of the X chromosome, fra(X) (q27 or 28) (marker-X chromosome). Male carriers are physically normal, but in most cases show macroorchidism. The demonstration of the marker-X chromosome requires special cell culture conditions, above all a folic acid-deficient medium. The frequency of cells with fragile X chromosome varies interindividually, ranging from 2 to 50%. In female heterozygous carriers the number of cells with fra(X) decreases with age and cannot be demonstrated in some cases. Distribution and frequency of X-linked mental retardation with marker-X chromosome and macro-orchidism are discussed, as well as possibilities of prenatal diagnosis of this disorder.
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A fragile site near the end of the long arm (q) of the X chromosome appears to be directly related to the gene responsible for the mental retardation found among males and some females who possess this variant X chromosome. Macro-orchidism is present in most males studied. Other mild phenotypic similarities may exist. The expression of the fragile X (fra[X]) chromosome is dependent on the concentration of folic acid and thymidine in the culture medium, which partly explains why fra(X) was not noted earlier and connected promptly with X-linked mental retardation. Whereas prenatal diagnosis is now possible, genetic counseling is complicated by recent reports of "intellectually normal" fra(X) males. Further studies are needed to form solid conclusions about intellectual deficits, learning behavior or personality characteristics of fra(X) persons.
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The subjects of this study were individuals with the form of X-linked mental retardation that is associated with the presence of a cytologically variant X chromosome having a secondary constriction or "fragile site" at Xq 27-28 (Fra X). Studies were carried out to test the hypothesis that deletions or modifications at neighboring loci occur as a consequence of events at the fragile site. Skin fibroblasts and peripheral blood lymphocytes from affected males were analyzed with respect to the expression of two X-lined enzymes: glucose-6-phosphate dehydrogenase (G6PD) and hypoxanthine phosphoribosyltransferase (HPRT); loci for these enzymes are known to be located in the region of the fragile site. Although the number of cells resistant to thioguanine (HPRT-deficient) obtained from some cultures from one Fra X male and blood cells of another was greater than expected, the frequency of these cells was not increased in cultures from other Fra X males. Furthermore, our results indicate that the G6PD activity and electrophoretic mobility in Fra X males is similar to that in normal cells, thus providing no evidence for the loss of the long-arm telomere in the fragile X syndrome.
This report describes the first cases of X-linked mental retardation with a marker X chromosome seen in South Africa, and forms part of an ongoing study. The marker was found in 11 affected males and 1 carrier female in 4 families investigated. The demonstration of the marker X chromosome characterized by a fragile site at the long arm (fra(X) (q27) in association with nonspecific X-linked mental retardation heralds a new era in cytogenetics. The attention of human geneticists everywhere is focused on various aspects of this fascinating phenomenon. It has now become possible to diagnose an apparently common familial cytogenetic condition with a high risk of recurrence and to identify female carriers; perhaps in time we will be able to provide prenatal diagnosis. Because of the familial involvement through X-linked inheritance the syndrome is believed to be more common than trisomy 21. The nature of the association of mental retardation with the marker X chromosome is unknown, but it could be related to close linkage with abnormal gene(s) or due to faulty transcription of the genes beyond the fragile site.
AIMS: To establish a DNA-based test for the diagnosis and carrier detection of fragile X syndrome, and to investigate the nature of the mutation and patterns of inheritance in New Zealand families. METHODS: A probe for the FRAXA region was generated by polymerase chain reaction, cloned in a plasmid vector, and its structure was confirmed by DNA sequencing. This probe was used in a Southern blot assay to detect full mutations or premutations associated with fragile X syndrome in DNA from peripheral blood samples submitted to our laboratory for routine testing. RESULTS: We tested 379 individuals from throughout New Zealand. Full mutations were found in 29 males, leading to a fragile X diagnosis, or confirmation of an earlier cytogenetic diagnosis. Premutations were detected in 45 females and 11 males, all of whom are asymptomatic carriers of the disease. CONCLUSIONS: The DNA test is rapid and accurate, in contrast to the cytogenetic test. It allows unequivocal detection of carriers, enabling effective counselling, prenatal testing, and more generalised screening of at-risk populations. Our discovery of one large pedigree with many carriers and no prior history of X-linked mental retardation demonstrates that the DNA test is appropriate even in apparently sporadic cases of mental retardation.