Fragile X-associated tremor ataxia syndrome with co-occurrent progressive supranuclear palsy-like neuropathology

Co-occurrence of multiple neuropathologic changes is a common phenomenon, most prominently seen in Alzheimer’s disease (AD) and Parkinson’s disease (PD), complicating clinical diagnosis and patient management. Reports of co-occurring pathological processes are emerging in the group of genetically defined repeat-associated non-AUG (RAN)-translation related diseases. Here we report a case of Fragile X-associated tremor-ataxia syndrome (FXTAS) with widespread and abundant nuclear inclusions of the RAN-translation related FMRpolyG-peptide. In addition, we describe prominent neuronal and glial tau pathology representing changes seen in progressive supranuclear palsy (PSP). The highest abundance of the respective pathological changes was seen in distinct brain regions indicating an incidental, rather than causal correlation.


Introduction
Fragile X-associated tremor-ataxia syndrome (FXTAS) was first discovered in 2001 and has emerged as a unique late onset ataxia with often characteristic imaging features [9,11,17]. FXTAS is caused by a premutation expansion in the trinucleotide CGG repeat (50-200 repeats) in the fragile X mental retardation 1 (FMR1) gene. Patients typically present from 60 to 65 years of age with tremor and/or gait ataxia and a spectrum of associated neurologic and medical symptoms [9]. Diagnostic criteria also include pathognomonic neuroimaging and neuropathological findings [1,8,10]. The intranuclear sequestration of proteins by expanded CGG repeats in FMR1 mRNA has been suggested as a triggering pathogenic event [7]. In addition, non-AUG-initiated (RAN) translation of the expanded CGG repeats into a polyglycine-containing peptide (FMRpolyG) that is prone to aggregate has been implicated in neurotoxicity [2,3,15,18]. These aberrant protein inclusions can also trigger the aggregation of other proteins. Indeed, there have been reports of the co-occurrence of FXTAS with Lewy body dementia (LBD) and Alzheimer's disease (AD) [16]. We now report a patient with FXTAS and neuropathological evidence of co-occurring progressive supranuclear palsy (PSP).

Case presentation
A 65-year-old Caucasian male was followed in the ataxia clinic at the Center for Movement Disorders and Neurorestoration at the University of Florida who had a 10-year history of gradually progressive bilateral upper extremity postural tremor and action myoclonus, bradykinesia, memory impairment, and an unsteady gait with frequent forward falls. On exam he had no vision abnormalities or gaze palsies and normal muscle strength with intact sensation, but limited cervical rotation due to neck muscle stiffness. MRI revealed FLAIR and T2 hyperintensities in the middle cerebellar peduncles extending into the deep white matter of the cerebellum as well as generalized atrophy. Given that the patient's clinical presentation and imaging were suggestive of FXTAS, further genetic testing was completed which showed 96 CGG trinucleotide repeats in the FMR1 gene. By age 68, he had diffuse myoclonus and a severely ataxic gait requiring the use of a wheelchair, inability to perform activities-of-daily-living due to impairment of executive functioning, dysarthria, dysmetria, hypomimia, incontinence, and constipation. He died at the age of 69.
Central nervous system autopsy was performed with post-mortem interval of 3 h. The brain weighed 1235 g and gross examination revealed gray discoloration of the cerebellar peduncles and deep cerebellar white matter. There was mild hypopigmentation of the substantia nigra.

Discussion and conclusions
Patients with FXTAS may occasionally present with PSPlike clinical findings [5], and a recent case report showed co-occurrence of FXTAS with PSP neuropathological findings [14]. We have expanded upon these findings and report a case of abundant FXTAS pathology with cooccurring PSP-like tau pathology. Clinically, the patient had symptoms of FXTAS with tremor and ataxia with the addition of PSP-like symptoms of bradykinesia, postural instability, dysarthria, and executive dysfunction. However, there was no evidence of truncal rigidity or supranuclear gaze palsy [6]. Neuropathological study revealed classic changes of FXTAS including white matter pallor and spongiosis in the cerebellum and cerebrum along with widespread intranuclear ubiquitin, p62, and FMRpolyG positive inclusions [7,8,12]. Additionally, the patient had tau pathology including globose NFTs in the substantia nigra, locus coeruleus, medulla, and basal ganglia with tufted astrocytes and oligodendroglial coiled bodies composed of 4-repeat tau, which are consistent with PSP neuropathology, and given the overall low abundance possibly reflecting "incidental PSP" [4]. Cross-seeding of misfolded proteins has been suggested as a possible mechanism for the co-occurrence of multiple pathologies in neurodegenerative diseases [13], but whether our case reflects the incidental co-occurrence of two distinct neurodegenerative processes or is the consequence of a cross-talk between two distinct neurodegenerative processes cannot be determined with certainty. The fact that the highest abundance of the respective neuropathological changes was detected in non-overlapping brain regions may favor two independent processes.
Abbreviations AD: Alzheimer's disease; FXTAS: Fragile X-associated tremor-ataxia syndrome; LBD: Lewy body dementia; NFT: Neurofibrillary tangle; PD: Parkinson's disease; PSP: progressive supranuclear palsy; RAN: Repeat-associated non-AUG Authors' contributions SP, MAW and ATY confirmed neuropathologic diagnosis. SP, ATY, ANS and BG co-wrote the manuscript. JA and SHS provided the clinical information. AK and PKT provided RAN-translation antibodies and critical discussion. All authors read and approved the final manuscript.

Funding
This study was supported by the 1Florida ADRC, funded by NIH/NIA grant #P50 AG047266-01A1; AK and PKT were supported by NIH/NINDS grant R01NS086810.
Availability of data and materials All data generated or analysed during this study are included in this published article.
Ethics approval and consent to participate Staining of human tissue samples was performed with approval of the University of Florida institutional review board.

Consent for publication
Informed consent was obtained according to guidelines of the University of Florida institutional review board.

Competing interests
The authors declare that they have no competing interests.