Fragile X-associated tremor/ataxia syndrome: phenotypic comparisons with other movement disorders

The purpose of this paper is to review the typical cognitive and motor impairments seen in fragile X-associated tremor/ataxia syndrome (FXTAS), essential tremor (ET), Parkinson disease (PD), spinocerebellar ataxias (SCAs), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) in order to enhance diagnosis of FXTAS patients.

We compared the cognitive and motor phenotypes of FXTAS with each of these other movement disorders. Relevant neuropathological and neuroimaging findings are also reviewed. Finally, we describe the differences in age of onset, disease severity, progression rates, and average lifespan in FXTAS compared to ET, PD, SCAs, MSA, and PSP. We conclude with a flow chart algorithm to guide the clinician in the differential diagnosis of FXTAS.

By comparing the cognitive and motor phenotypes of FXTAS with the phenotypes of ET, PD, SCAs, MSA, and PSP we have clarified potential symptom overlap while elucidating factors that make these disorders unique from one another. In summary, the clinician should consider a FXTAS diagnosis and testing for the Fragile X mental retardation 1 (FMR1) gene premutation if a patient over the age of 50 (1) presents with cerebellar ataxia and/or intention tremor with mild parkinsonism, (2) has the middle cerebellar peduncle (MCP) sign, global cerebellar and cerebral atrophy, and/or subcortical white matter lesions on MRI, or (3) has a family history of fragile X related disorders, intellectual disability, autism, premature ovarian failure and has neurological signs consistent with FXTAS. Peripheral neuropathy, executive function deficits, anxiety, or depression are supportive of the diagnosis.

Distinct profiles in the cognitive and motor domains between these movement disorders may guide practitioners in the differential diagnosis process and ultimately lead to better medical management of FXTAS patients.