FXTAS: new insights and the need for revised diagnostic criteria.

OBJECTIVE: Fragile X-associated tremor ataxia syndrome (FXTAS) is defined by FMR1 premutation, cerebellar ataxia, intentional tremor, and middle cerebellar peduncle (MCP) hyperintensities. We delineate the clinical, neurophysiologic, and morphologic characteristics of FXTAS.

METHODS: Clinical, morphologic (brain MRI, (123)I-ioflupane SPECT), and neurophysiologic (tremor recording, nerve conduction studies) study in 22 patients with FXTAS, including 4 women.

RESULTS: A total of 43% of patients had no family history of fragile X syndrome (FXS), which contrasts with previous FXTAS series. A total of 86% of patients had tremor and 81% peripheral neuropathy. We identified 3 electroclinical tremor patterns: essential-like (35%), cerebellar (29%), and parkinsonian (12%). Two electrophysiologic patterns evocative of non-length-dependent (56%) and length-dependent sensory neuropathy (25%) were identified. Corpus callosum splenium (CCS) hyperintensity was as frequent (68%) as MCP hyperintensities (64%). Sixty percent of patients had parkinsonism and 47% abnormal (123)I-ioflupane SPECT. Unified Parkinson's Disease Rating Scale motor score was correlated to abnormal (123)I-ioflupane SPECT (p = 0.02) and to CGG repeat number (p = 0.0004). Scale for the assessment and rating of ataxia correlated with dentate nuclei hyperintensities (p = 0.03) and CCS hyperintensity was a marker of severe disease progression (p = 0.04).

CONCLUSIONS: We recommend to include in the FXTAS testing guidelines both CCS hyperintensity and peripheral neuropathy and to consider them as new major radiologic and minor clinical criterion, respectively, for the diagnosis of FXTAS. FXTAS should also be considered in women or when tremor, MCP hyperintensities, or family history of FXS are lacking. Our study broadens the spectrum of tremor, peripheral neuropathy, and MRI abnormalities in FXTAS, hence revealing the need for revised criteria.