Chapter 64

## Abstract

1. Fragile X syndrome (MIM 309550) is an X-linked dominant disorder with reduced penetrance. Although not as frequent as once believed, the syndrome remains a relatively common form of inherited mental retardation. The syndrome typically presents in males with moderate mental retardation, characteristic, but subtle, facial features of a prominent jaw and large ears, and macroorchidism after puberty. Penetrant females are typically less severely affected.

2. Fragile X syndrome derives its name from a characteristic fragile site at Xq27.3 that is found in a proportion of chromosomes in metaphase spreads from appropriately cultured cells of affected males and many penetrant females. Coincident with this fragile site, is a CGG repeat within the 5′-untranslated region (UTR) of the fragile X mental retardation gene 1 (FMR1) (GenBank L29074). Among normal individuals, the FMR1 repeat is polymorphic in length and content, often punctuated by AGG interruptions. The most frequent normal allele in Caucasians contains 30 repeats and 2 AGG interruptions at positions 10 and 20. In affected individuals, this repeat is expanded over 230 repeats, with a mean of approximately 780 repeats. Thus, fragile X syndrome is among a unique class of human disorders resulting from unstable repeats, which are referred to as dynamic mutations. When the FMR1 repeat is expanded to this degree, the FMR1 gene becomes hypermethylated and transcriptionally silent. This is referred to as the full mutation to distinguish it from the premutation allele. Premutation alleles are found in nonpenetrant male carriers and many female carriers. The length of these alleles falls between that of the normal repeats and full mutations. Premutation alleles are exquisitely unstable upon transmission and the progression to the full mutation in offspring is dependent upon the length of the maternal premutation. This relationship explains the unusual inheritance patterns and the reduced penetrance of this disorder.

3. Fragile X syndrome is found among all ethnic groups studied. The prevalence in the general population is approximately 1/4500 males. Only 50 percent of females carrying the full mutation are penetrant, due to random X-inactivation. Because females only inherit maternal full mutations, the expected female prevalence is 1/9000. Premutation carriers are found in approximately 1/400 females and 1/1000 males.

4. Molecular laboratory diagnosis has now superseded cytogenetic testing for the fragile site, although routine karyotype analysis remains indicated in all cases of undiagnosed mental retardation. Molecular diagnostics routinely involve Southern blot studies, which provide information on the repeat length and methylation status. PCR studies can more accurately size normal and premutation alleles and, in some laboratories, can provide an initial screen for full mutations. Antibody detection of the FMR1 -encoded protein, Fragile X mental retardation protein (FMRP), is often a very useful test as the lack of FMRP is the cause of this syndrome. Indeed, a small but significant class of patients owe their disease to more typical mutations, such as deletions, which all predict null alleles. Significantly, missense mutations appear markedly infrequent, with the single exception of severely affected patients with a I304N mutation. Protein studies can be carried out quickly and inexpensively by a histochemical analysis of blood smears or, more accurately, by conventional Western analysis.

5. FMRP, the deficient protein in fragile X syndrome, is a selective RNA-binding protein that shuttles between the nucleus and cytoplasm. At steady state, most FMRP is cytoplasmic and associated as a ribonucleoprotein complex to translating polyribosomes or endoplasmic reticulum-associated ribosomes. In neurons, FMRP can also be found at the base of dendritic spines and may participate in the remodeling of the spine following synaptic activity. Thus, the loss of FMRP may directly influence neuronal plasticity resulting in cognitive deficit.

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