Fragile X tremor ataxia syndrome and white matter dementia.

OBJECTIVE: Fragile X tremor ataxia syndrome (FXTAS) is an inherited neurodegenerative disease in which dementia is common and disabling. The pathogenesis of dementia in FXTAS is poorly understood, but the salience of executive dysfunction and slowed processing speed, the frequent presence of the middle cerebellar peduncle sign on magnetic resonance imaging (MRI), and striking neuropathological alterations of white matter all suggest that myelinated tracts are significantly involved. This paper considers the role of white matter disease in FXTAS dementia, particularly with regard to the concept of white matter dementia (WMD).

METHOD: A focused review of FXTAS in relation to known white matter disorders is provided to propose that the concept of WMD may illuminate the basis of dementia in FXTAS. The putative pathogenetic contribution of white matter involvement in other neurodegenerative diseases is also considered.

RESULTS: Considerable evidence supports the importance of white matter disease in the pathogenesis of dementia in FXTAS. Whereas, gray matter regions are also involved, white matter degeneration is prominent, even early in the disease, and correlates with executive dysfunction and slowed processing speed. Evidence for white matter involvement in other neurodegenerative diseases lends additional support to the relevance of white matter in FXTAS.

CONCLUSION: The dementia of FXTAS is closely related to the profile of WMD, and white matter involvement is also supported by MRI and neuropathological observations. White matter pathology is also relevant to the pathogenesis of other neurodegenerative diseases. Further study of white matter promises to clarify the origin of dementia in FXTAS.