Fragile X syndrome is the prototype of diseases in which the causative mutation occurs in a long repeating sequence of three nucleotides. Other examples of diseases associated with trinucleotide repeat mutations are Huntington disease and myotonic dystrophy. This type of mutation is now known to cause about 40 diseases, and all disorders discovered so far are associated with neurodegenerative changes. In each of these conditions, amplification of specific sets of three nucleotides within the gene disrupts its function. Certain unique features of trinucleotide repeat mutations, described later, are responsible for the atypical pattern of inheritance of the associated diseases.
Fragile X syndrome results from a mutation in the FMR1 gene, which maps to Xq27.3 and is the second most common genetic cause of mental retardation, after Down syndrome. It has a frequency of 1 in 1550 for males and 1 in 8000 for females. The syndrome derives its name from the karyotypic appearance of the X chromosome in the original method of diagnosis. Culturing patient cells in a folate-deficient medium typically showed a discontinuity of staining or constriction in the long arm of the X chromosome. This method has now been supplanted by DNA-based analysis of triplet repeat size, as discussed later. Clinically affected males have moderate to severe mental retardation, although the extent of impairment is highly variable. It is not unusual for some children to initially be diagnosed with autism-like symptoms. The typical physical phenotype includes a long face with a large mandible, large everted ears, and large testicles (macroorchidism). Although characteristic of fragile X syndrome, these abnormalities are not always present or may be quite subtle. The only distinctive physical abnormality that can be detected in at least 90% of postpubertal males with fragile X syndrome is macroorchidism.
As with all X-linked diseases, fragile X syndrome predominantly affects males. Analysis of several pedigrees, however, shows some patterns of transmission not typically associated with other X-linked recessive disorders (
Fig. 7.17 ). These include the following:
Carrier males. Approximately 20% of males who, by pedigree analysis, are known to carry a fragile X mutation do not manifest the typical neurological symptoms or physical characteristics of fragile X during childhood. As discussed below, these carrier males (also known as “transmitting males”) harbor a detectable molecular abnormality at the FMR1 locus but not the full-fledged mutation observed in symptomatic children.
Affected females. From 30% to 50% of carrier women with the fragile X mutation on one chromosome might show features of mild cognitive impairment or other behavioral disturbances. Approximately 20% develop features of premature reproductive failure (see below). The presence of symptoms in carrier females, albeit mild, is unusual for an X-linked recessive disease.
Anticipation. This term refers to the phenomenon whereby clinical features of fragile X syndrome worsen with each successive generation, as if the mutation becomes increasingly deleterious as it is transmitted from a man to his grandsons and great-grandsons.
These unusual features have been related to the dynamic nature of the mutation. In the normal population, the number of repeats of the sequence CGG in the FMR1 gene is small, averaging around 29, whereas affected persons have 200 to 4000 repeats. These so-called “full mutations” are believed to arise through an intermediate stage of premutations characterized by 52 to 200 CGG repeats. Carrier males and females have premutations. During oogenesis (but not spermatogenesis), the premutations can be converted to full mutations by further amplification of the CGG repeats, which can then be transmitted to both the sons and the daughters of the carrier female. These observations provide an explanation for why some carrier males are unaffected (they have premutations), and certain carrier females are affected (they inherit full mutations).