Fragile X-associated Tremor/Ataxia Syndrome (FXTAS)
Approximately four years ago, my research was fundamentally transformed by my growing involvement with fragile X syndrome, a trinucleotide (CGG) repeat expansion disorder of the FMR1 gene. FXS is the leading heritable cause of mental retardation and leading single-gene disorder associated with autism. Fragile X syndrome is generally caused by methylation-coupled silencing of the FMR1 gene for alleles with more than 200 repeats (i.e., deficiency or absence of structurally normal protein). Premutation carriers (~55 to 200 CGG repeats) were generally regarded as clinically unaffected, since their FMR1 gene is rarely methylated. However, accumulating clinical data have established that many premutation carriers are indeed clinically involved (e.g., ADHD, mood lability).
My laboratory recently observed that FMR1 protein (FMRP) levels in these patients were, indeed, decreasing in the upper end of the premutation range, consistent with the clinical findings although paradoxical in the absence of gene methylation. However, contrary to expectation, we found that FMR1 mRNA levels are invariably elevated in premutation individuals, by as much as ten-fold in the upper premutation range. This set of observations [Tassone et al. (2000) AJHG 66:1] provided direct molecular evidence of dysregulation of the FMR1 gene in the premutation range.
We have since identified a new neurological syndrome in adult premutation carriers over 50 years of age. The syndrome includes progressive action tremor, ataxia, and cognitive decline, and has associated findings of neuropathy and emotional disturbances [Hagerman et al. (2001) Neurology 57:127]. Based on our preliminary (unpublished) estimates of prevalence, in excess of 25% of all carriers could be affected with this progressive, neurodegenerative syndrome. Because of the extensive involvement of premutation carriers, who have near-normal levels of FMRP, the (tentative) lack of tremor/ataxia in full mutation individuals, late onset, and the progressive nature of the syndrome, we believe that this tremor/ataxia disorder is distinct from fragile X syndrome, although it is associated with premutation alleles of the FMR1 gene.
Our current research interests involve studies of the mechanistic basis for dysregulation of the FMR1 gene during both transcription and translation, the relationships between molecular dysregulation and clinical involvement, and the origins and prevalence of the tremor/ataxia syndrome.
