The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group

Abstract

The recent identification of fragile X-associated tremor ataxia syndrome (FXTAS) associated with premutations in the FMR1 gene and the possibility of clinical overlap with multiple system atrophy (MSA) has raised important questions, such as whether genetic testing for FXTAS should be performed routinely in MSA and whether positive cases might affect the specificity of current MSA diagnostic criteria. We genotyped 507 patients with clinically diagnosed or pathologically proven MSA for FMR1 repeat length. Among the 426 clinically diagnosed cases, we identified four patients carrying FMR1 premutations (0.94%). Within the subgroup of patients with probable MSA-C, three of 76 patients (3.95%) carried premutations. We identified no premutation carriers among 81 patients with pathologically proven MSA and only one carrier among 622 controls (0.16%). Our results suggest that, with proper application of current diagnostic criteria, FXTAS is very unlikely to be confused with MSA. However, slowly progressive disease or predominant tremor are useful red flags and should prompt the consideration of FXTAS. On the basis of our data, the EMSA Study Group does not recommend routine FMR1 genotyping in typical MSA patients.

Sleep disorders in cerebellar ataxias

“…The recent identification of fragile X-associated tremor ataxia syndrome (FXTAS) associated with premutations in the FMR1 gene and the possibility of clinical overlap with multiple system atrophy has raised important questions. These neurodegenerative diseases may have similar clinical presentations, including sleep disorders 28 . Alexander disease (AD) in its typical form is an infantile lethal leucodystrophy, characterized pathologically by Rosenthal fibers accumulation.…”

Fragile X-associated tremor/ataxia syndrome - FXTAS

“…Screening for the FMR1 premutation in populations of patients with movement disorders found that the frequency of premutation alleles was 13 times greater (OR = 12.4; 95% CI: 1.6, 93.5) in patients with cerebellar ataxia (16/1049) than expected based on its prevalence in the general population (2%; 16/818 for age-of-onset >50 years of age) [25]. Five carriers of premutation alleles were also identified among 663 patients with a prior diagnosis of multiple system atrophy; 2-3% of patients diagnosed with the cerebellar subtype of probable multiple system atrophy likely had FXTAS as the cause of their symptoms [28][29][30]. Premutation alleles were absent in the other diagnostic groups studied, e.g.…”

Neuroimaging - Clinical Applications

“…In this regard, the MCP sign, which was originally proposed to be a characteristic and specific feature for FXTAS, that could be used for screening purposes, has been also reported in patients with other forms of adult-onset cerebellar ataxia, thus lacking specificity for FXTAS (Okamoto et al, 2003). Patients with atypical parkinsonism, and particularly those having a clinical picture including dysautonomia, and ataxia -a condition currently known as the cerebellar form of Multiple System Atrophy (MSA)-, may show the MCP sign on MRI, so that middle cerebellar peduncles hyperintensities in a patient with parkinsonism should be regarded as a non-specific finding, which can be seen in FXTAS, but also in MSA (Kamm et al, 2005). Additionally, the sensitivity of the MCP sign may be less than previously thought, as the frequency of the MCP sign among women with FXTAS seems to be less (Hagerman et al, 2004), and its presence among premutated men with subtle neurological, psychiatric, or cognitive dysfunction remains unknown.…”