Fragile X-associated tremor/ataxia syndrome: An under-recognised cause of tremor and ataxia

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive degenerative movement disorder resulting from a fragile X “premutation”, defined as 55–200 CGG repeats in the 5′-untranslated region of the FMR1 gene. The FMR1 premutation occurs in 1/800 males and 1/250 females, with FXTAS affecting 40–45% of male and 8–16% of female premutation carriers over the age of 50. FXTAS typically presents with kinetic tremor and cerebellar ataxia. FXTAS has a classical imaging profile which, in concert with clinical manifestations and genetic testing, participates vitally in its diagnosis. The revised FXTAS diagnostic criteria include two major radiological features. The “MCP sign”, referring to T2 hyperintensity in the middle cerebellar peduncle, has long been considered the radiological hallmark of FXTAS. Recently included as a major radiological criterion in the diagnosis of FXTAS is T2 hyperintensity in the splenium of the corpus callosum. Other imaging features of FXTAS include T2 hyperintensities in the pons, insula and periventricular white matter as well as generalised brain and cerebellar atrophy. FXTAS is an under-recognised and misdiagnosed entity. In patients with unexplained tremor, ataxia and cognitive decline, the presence of middle cerebellar peduncle and/or corpus callosum splenium hyperintensity should raise suspicion of FXTAS. Diagnosis of FXTAS has important implications not only for the patient but also, through genetic counselling and testing, for future generations.