Presence of Middle Cerebellar Peduncle Sign in FMR1 Premutation Carriers Without Tremor and Ataxia

Abstract

Here we report five cases of male FMR1 premutation carriers who present without clinical symptoms of the fragile X-associated tremor/ataxia syndrome (FXTAS), but who on MRI demonstrate white matter hyperintensities in the middle cerebellar peduncles (MCP sign) and other brain regions, a rare finding. MCP sign is the major radiological feature of FXTAS; it is therefore remarkable to identify five cases in which this MRI finding is present in the absence of tremor and ataxia, the major clinical features of FXTAS. Subjects underwent a detailed neurological evaluation, neuropsychological testing, molecular testing, and MRI evaluation utilizing T2 imaging described here. Additional white matter disease was present in the corpus callosum in four of the five cases. However, all cases were asymptomatic for motor signs of FXTAS.

Cerebellar-cortical function and connectivity during sensorimotor behavior in aging FMR1 gene premutation carriers

“…Our findings of reduced Crus I-extrastriate connectivity are consistent with prior structural MRI and histopathological studies showing white matter degeneration in premutation carriers with and without FXTAS ( Greco et al, 2006 , Hashimoto et al, 2011b , Famula et al, 2018 ). Cortical innervation of cerebellar cortex primarily is translated via pontine nuclei and MCP.…”

“…The MCP is the major cortical-cerebellar input pathway relaying sensory information to cerebellar targets, and hyperintensities of the MCP seen on T2-weighted MR images are a primary radiological sign of the disease ( Jacquemont et al, 2003 , Greco et al, 2006 ). MCP degeneration and more generalized cerebellar atrophy may occur before the onset of tremor, ataxia or other neurological symptoms in premutation carriers ( Brunberg et al, 2002 , Wang et al, 2017 ), and reduced MCP width is seen in both asymptomatic premutation carriers and those with FXTAS ( Famula et al, 2018 , Shelton et al, 2018 ). Further, reductions in extreme capsule pathway connectivity ( Wang et al, 2012 ) and superior cerebellar peduncle (SCP) tract volume are associated with increased CGG repeats and disease risk ( Wang et al, 2013 ), suggesting that white matter pathways integrating sensorimotor brain networks are affected by FXTAS and may show degenerative changes prior to disease onset.…”

“…These findings suggest cerebellar dysfunction during manual motor behavior may represent a quantifiable trait dimension associated with atypical aging in premutation carriers and putative FXTAS risk. It remains unclear whether these findings reflect intrinsic defects of cerebellar function or atypical cerebellar-cortical functional connectivity as implicated by deterioration of cortical-cerebellar tracts, including the MCP and SCP, and findings of generalized white matter pathology in aging premutation carriers ( Brunberg et al, 2002 , Ariza et al, 2016 , Sellier et al, 2017 , Famula et al, 2018 ). Analyses of the relationships between cortical-cerebellar connectivity and precision manual motor control in aging premutation carriers are needed to clarify the functional anatomy of manual motor behavioral differences in premutation carriers and determine functional brain markers associated with the FXTAS prodrome.…”

Ataxia as the Major Manifestation of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Case Series

“…Cases 2 and 3 presented with the MCP sign, and therefore this finding categorized them with a definite FXTAS diagnosis. Although it is considered as a hallmark of FXTAS, the MCP sign is only found in 60% of males [5,33] and it is uncommon in females, with approximately 13% displaying the MCP sign [34,35]. It can rarely be present in asymptomatic carriers [33], and thus it must be interpreted along with clinical manifestations (e.g., cerebellar ataxia, scanning speech, vertigo).…”

“…Although it is considered as a hallmark of FXTAS, the MCP sign is only found in 60% of males [5,33] and it is uncommon in females, with approximately 13% displaying the MCP sign [34,35]. It can rarely be present in asymptomatic carriers [33], and thus it must be interpreted along with clinical manifestations (e.g., cerebellar ataxia, scanning speech, vertigo). White matter lesions are also commonly observed; the presence of such in the splenium of the corpus callosum and in cerebral white matter constitute minor neuroradiological criteria for FXTAS [32].…”