Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that affects some adult carriers of pre-mutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. FXTAS is thought to be caused by a toxic 'gain-of-function' of the expanded CGG-repeat FMR1 mRNA, which is found in the neuronal and astrocytic intranuclear inclusions associated with the disorder. Using a reporter construct with a FMR1 5' untranslated region harboring an expanded (premutation) CGG repeat, we have demonstrated that intranuclear inclusions can be formed in both primary neural progenitor cells and established neural cell lines. As with the inclusions found in post-mortem tissue, the inclusions induced by the expanded CGG repeat are alphaB-crystallin-positive; however, inclusions in culture are not associated with ubiquitin, indicating that incorporation of ubiquitinated proteins is a later event in the disease process. The absence of ubiquitinated proteins also argues against a model in which inclusion formation is due to a failure of the proteasomal degradative machinery. The presence of the expanded CGG repeat, as RNA, results in reduced cell viability as well as the disruption of the normal architecture of lamin A/C within the nucleus. This last observation, and the findings that lamin A/C is present in both the inclusions of FXTAS patients and the inclusions in cell culture, suggests that lamin A/C dysregulation may be a component of the pathogenesis of FXTAS; in particular, the Charcot-Marie-Tooth-type neuropathy associated with FXTAS may represent a functional laminopathy.

Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder, was described recently among male carriers of expanded alleles (55-200 CGG repeats; premutation range) of the fragile X mental retardation 1 (FMR1) gene. Major features of the syndrome include intention tremor, gait ataxia, and parkinsonism in men over 50 years of age. This disorder is believed to be relatively common, possibly affecting 1 in 3,000 men over the age of 50 years in the general population. This raises the possibility that some patients presenting with essential tremor (ET) may harbor expanded FMR1 alleles. We screened 81 ET patients (40 males, 41 females) for expanded FMR1 alleles to determine whether ET is associated with such alleles. None of the ET cases had the premutation genotype. CGG repeat sizes ranged from 5 to 47 repeats within this study population, suggesting that expanded FMR1 alleles are uncommon among patients with ET. Screening of movement disorder patients with other clinical features of FXTAS (e.g., ataxia and parkinsonism) may be more likely to yield expanded FMR1 alleles.

Fragile X syndrome is the most common cause of hereditary mental retardation. The FMR1 gene, which is involved in fragile X syndrome, contains a polymorphic CGG repeat, which expands in affected patients. Expanding triplet repeats have been shown to be a new type of mutation, termed "dynamic mutation", responsible for more than 12 genetic diseases. These mutations occur as multiple steps rather than as a single event. The first step leads to an unstable allele that then becomes increasingly unstable generally achieving further increases in copy or occasionally contraction. In this report, we describe a fragile X boy with both a hypermethylated full mutation and a deletion of 905 bp encompassing the CGG repeat. The upstream breakpoint is 438 bp 5' to the CGG repeat and the downstream breakpoint is 420 bp 3' of the triplet repeats. The deletion includes the ATG starting codon for translation of the FMR1 gene. This was confirmed by using FMRP immunocytochemistry both on blood smears and hair roots. The deleted region is flanked by a ccgg direct repeat next to the breakpoints; this may have had a critical role in the formation of a secondary DNA structure leading to the deletion.

Fragile X syndrome, the most common inherited form of mental retardation, arises in individuals with more than 200 CGG repeats in the 5' untranslated region of the fragile X mental retardation 1 ( FMR1) gene. Although CGG repeat numbers comparable to those found in the normal human population are found in various non-human primates, neither the within-species size variation nor the propensity for expansion of the CGG repeat has been described for any non-human primate species. The allele distribution has now been determined for FMR1 (homologue) CGG repeats of 265 unrelated founder females of Macaca mulatta monkeys. Among 530 X chromosomes, at least 26 distinct repeat lengths were identified, ranging from 16 to 54 CGG repeats. Of these alleles 79% have between 25 and 33 CGG repeats. Detailed examination of the CGG region revealed a conserved G (CGG)(2 )G interruption, although in no case was an AGG trinucleotide detected. Two animals carried borderline premutation alleles with 54 CGG repeats, within the region of marginal instability for humans. Thus, M. mulatta may be useful as an animal model for the study of fragile X syndrome.

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