The fragile X syndrome: a peculiar pattern of inheritance

Article Abstract:

Males with fragile X syndrome are mentally retarded, and have long, thin faces with prominent jaws and protuberant ears. These patients tend to have large testes and autistic characteristics. It is now appreciated that the fragile X syndrome is the most common inherited cause of mental retardation. The diagnosis of fragile X syndrome is generally made by chromosome analysis, which is not only laborious, but is also inaccurate about 5 percent of the time. Most often the error is a false negative. In the December 12, 1991 issue of The New England Journal of Medicine, two research groups report the efficacy of using DNA probes to diagnose the presence of the fragile X gene. This may prove to be one of the first genetic disorders in which DNA analysis becomes the primary means of diagnosis. The disease has a particularly unusual mode of inheritance. Unlike most X-linked diseases, in which males with the gene are invariably afflicted, about one-fifth of males carrying the fragile X gene are unaffected. Conversely, about half the women carrying the gene are affected to some degree, and 35 percent are mentally retarded. Another peculiar feature of the inheritance of this disorder is that there seem to be no cases in which the disorder occurs as a spontaneous mutation; all affected individuals are born to mothers carrying the gene. This fact is surprising; since affected males are not likely to reproduce, it was anticipated that new mutations must occur frequently. The apparent lack of new mutations may be due to an unusual sequence of events. The fragile X mutation apparently must be preceded by a 'premutation'. This is a smaller region of fragile DNA than is observed in the full fragile X syndrome. Males with the premutation may or may not be retarded, but males with the full mutation are invariably retarded. Traditional chromosome studies cannot reliably distinguish the extent of the affected DNA, and therefore can not account for the difference between males who are carriers of the gene and males who are actually affected by fragile X syndrome. Further studies will be necessary to determine the actual prevalence of the fragile X mutation in the population. These studies should also determine the frequency with which the smaller premutation increases in size to become the full fragile X mutation. (Consumer Summary produced by Reliance Medical Information, Inc.)

Editorial

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Prenatal diagnosis of fragile X syndrome by direct detection of the unstable DNA sequence

Article Abstract:

The fragile X chromosome is familial disorder characterized by mental retardation. The abnormality associated with this condition may be visualized directly under the microscope. However, the preparation of chromosomes for viewing is laborious and the microscopic examination of chromosomes requires some expertise. Even with expertise, the misdiagnosis rate for such cytogenetic analysis is about 5 percent. This error rate is significant, since fragile X syndrome is the single most common cause of inherited mental retardation. Researchers have now shown that it is possible to use the techniques of molecular biology to obtain a more reliable diagnosis. The fragile region on the X chromosome, which is located near the end of the long arm, is characterized by a repeated triplet, CCG (the DNA bases cytosine, cytosine, guanine). Apparently, the more this sequence is repeated, the more serious is the resulting fragile X syndrome. A combination of specific DNA probes and gel electrophoresis were used to evaluate this repeated genetic structure in a pregnant woman. The woman had one normal X chromosome, which revealed a repeated sequence about 1,000 bases in length. The other X chromosome had a repeated sequence of 1,200 bases, suggesting that the woman was a carrier of the fragile X syndrome. A sample from the chorionic villi revealed that the fetus was male. DNA analysis of the male fetus revealed a repeated sequence of 2,300 bases, strongly suggesting the presence of the full fragile X gene, which would mean the child would be mentally retarded. Previous research has shown that the fragile X gene in affected males is methylated to varying degrees; that is, the DNA is chemically modified by the presence of methyl groups. DNA analysis performed after the termination of this affected pregnancy confirmed that this was the case for many tissues of the fetus. However, the fragile X gene in the chorionic villi was not methylated, indicating that the methylation of DNA in a biopsy of chorionic villi is not satisfactory for the prenatal diagnosis of fragile X syndrome. The DNA analysis method appears to be appropriate not only for prenatal diagnosis of fragile X syndrome, but also for the identification of unaffected gene carriers as well. (Consumer Summary produced by Reliance Medical Information, Inc.)

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Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation

Article Abstract:

Fragile X syndrome is the most common form of inherited mental retardation. Unlike many gene mutations located on the X chromosome, fragile X syndrome is not inherited as a simple sex-linked trait. In contrast with other sex-linked traits, about 35 percent of the female carriers have some mental impairment, and at least 20 percent of the males carrying the gene appear normal. Currently, most diagnoses are made on the basis of cytogenetic analysis; microscopic examination reveals an abnormality in the Xq27.3 region of the long arm of the X chromosome. However, this diagnostic method is not completely satisfactory. Furthermore, cytogenetic analysis is most likely to fail to identify carriers, people who carry the gene but are unaffected by the syndrome. Therefore, cytogenetic analysis is of little benefit for genetic counselling of possible carriers. Using molecular genetics, a test has now been developed that is both more reliable and simpler to perform than cytogenetic analysis. Restriction nucleases, special enzymes that cleave the DNA into highly specific pieces of manageable size, were used by researchers to investigate the genetic status of 511 individuals from 63 affected families. In all cases, the molecular analysis was able to determine if the person was genetically normal, carried the full fragile-X mutation, or carried a so-called premutation. This premutation is apparently responsible for the unusual inheritance pattern of the fragile X syndrome. All 103 males and 31 of the 59 females with the full mutation were mentally retarded. However, among the patients with the premutation, the rate of mental retardation was similar to that of the population in general. The existence of a premutation in one generation apparently sets the stage for the development of the full mutation in the next. The DNA diagnosis appears to be more reliable than cytogenetic analysis. The relative simplicity of the test makes it possible to test all patients with unexplained mental retardation or learning impairment, not just retarded patients with a family history suggesting fragile X. (Consumer Summary produced by Reliance Medical Information, Inc.)

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