Increasing severity of mental retardation in male members over generations is a result of
Ref Robbins 8/e p169-171; 9/e p169 Triplet Repeat Mutations: Fragile X Syndrome 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. About 40 diseases are now known to be caused by this type of mutation, and all dis- orders discovered so far are associated with neurodegen- erative changes. In each of these conditions, amplification of specific sets of three nucleotides within the gene disrupts its func- tion. Ceain unique features of trinucleotide repeat muta- tions, 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. The syndrome gets its name from the karyotypic appearance of the X chromosome inthe original method of diagnosis: Culturing patient cells in a folate-deficient medium typically revealed 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. With a frequency of 1 in 1550 for affected males and 1 in 8000 for affected females, fragile X syndrome is the second most common genetic cause of mental retardation, after Down syndrome. Clini- cally affected males have moderate to severe mental retar- dation. The characteristic physical phenotype includes a long face with a large mandible, large eveed 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 physi- cal abnormality that can be detected in at least 90% of postpubeal males with fragile X syndrome is macroorchidism. As with all X-linked diseases, fragile X syndrome pre- dominantly affects males. Analysis of several pedigrees, however, reveals some patterns of transmission not typi- cally associated with other X-linked recessive disorders (Fig. 6-17). These include the following: * Carrier males: Approximately 20% of males who, by ped- igree analysis and by molecular tests, are known to carry a fragile X mutation are clinically and cytogeneti- cally normal. Because carrier males transmit the trait through all their daughters (phenotypically normal) to affected grandchildren, they are called normal transmit- ting males.
Mitochondrial DNA mutation
Frameshift mutation
Y linked disorders
Trinucleotide repeat mutation
General anatomy