Parkinsonism Versus Concomitant Parkinson's Disease in Fragile X–Associated Tremor/Ataxia Syndrome

Abstract

Background Fragile X–associated tremor/ataxia syndrome (FXTAS) is a late‐onset neurodegenerative disorder associated with premutation alleles (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. FXTAS is characterized by the presence of ubiquitin‐positive inclusions in neurons and astrocytes and by cerebellar tremor and ataxia. Parkinsonism has been reported in FXTAS, but most patients lack the characteristic rest tremor and severe rigidity seen in idiopathic Parkinson's disease (PD). Objective To describe the frequency of concomitant PD in FXTAS. Methods We reviewed the medical record of 40 deceased patients diagnosed with FXTAS and performed a pathology analysis to confirm both FXTAS and PD. Results Clinical histories indicated that 5 FXTAS patients were diagnosed with idiopathic PD and 2 with atypical parkinsonian syndrome. After pathological examination, we found that 7 patients in the PD clinical diagnosis group had dopaminergic neuronal loss; however, only 2 of 7 presented Lewy bodies (LBs) in the substantia nigra. Therefore, a total of 5% of the 40 cohort patients met the pathologic criteria for the concomitant diagnosis of FXTAS and PD. In addition, 2 patients not clinically diagnosed with PD also had nigral neuronal loss with LBs in substantia nigra. In total 10% of these 40 patients had LBs. Conclusion This report expands our understanding of clinical symptoms and unusual presentations in patients with FXTAS and the concept that the parkinsonism found in FXTAS is sometimes indistinguishable from PD. We propose that FMR1 should be recognized as one of the exceptional genetic causes of parkinsonism with presynaptic dopaminergic loss and LBs.

Upper and Lower Limb Movement Kinematics in Aging FMR1 Gene Premutation Carriers

“…This aspect of our study design allowed us to assess FXTAS during early or more mild stages, but also suggests that patients’ gait impairments may not have manifested yet at the joint level. Furthermore, musculoskeletal weakness (e.g., reductions in deep tendon reflexes and somatosensation) contributing to the control of lower limb joint movement has been reported primarily in male premutation carriers [ 1 , 35 , 36 , 37 ]. Our sample consisted of 68.4% female carriers, suggesting that neurodegeneration affecting joint movements may be specific to males with FXTAS [ 17 , 27 ].…”

“…Increased reaction times and movement times have also been documented in FMR1 premutation carriers during standardized clinical assessments of manual dexterity [ 70 ]. These results suggest that upper limb atypicalities in aging individuals with FXTAS are characterized by slowed motor behavior, implicating the basal ganglia circuits [ 37 , 71 ]. This proposition is also supported by evidence of dopaminergic cell loss, the existence of Lewy bodies in surviving dopaminergic neurons in the substantia nigra [ 37 , 72 , 73 ], increased iron deposition in neuronal and glial cells of the putamen [ 74 ], and pre- and post-synaptic nigrostriatal dysfunction [ 75 ] in patients with FXTAS.…”

“…Based on previous studies of walking in FMR1 premutation carriers [ 17 , 26 , 27 , 33 ], we hypothesized that individuals with FXTAS would show a reduced stride length, decreased stride velocity, and increased percentage of double support time (i.e., percent of stride time spent with both feet in contact with the ground), as well as increased variability of stride length and cadence relative to healthy controls and asymptomatic carriers. As musculoskeletal weakness has been consistently documented in individuals with FXTAS [ 1 , 34 , 35 , 36 , 37 ], we also predicted that patients would show reduced knee flexion of the swing leg at toe-offs and reduced knee extension and ankle dorsiflexion of the ipsilateral leg at heel strikes. For tests of reaching, we hypothesized that premutation carriers would show jerkier joint movement relative to healthy controls, reflective of reduced multi-joint coordination that is often observed in cerebellar patients [ 30 , 38 , 39 , 40 ].…”

X‐Linked Parkinsonism: Phenotypic and Genetic Heterogeneity

“…50,56,57 Neuropathology Pathological findings from a cohort of 40 subjects with FXTAS showed synuclein and Lewy bodies (LB) pathology in 10% of the cases, of whom two had been diagnosed with PD earlier in life. 37 Furthermore, a presynaptic dopaminergic loss was demonstrated in all cases diagnosed with parkinsonism. Furthermore, high levels of extracellular or intracellular iron deposits within capillaries and parenchyma of the striatum and, to a lesser extent, the cerebellum have been reported.…”

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications

“…FXTAS can coexist with other neurodegenerative diseases. Salcedo-Arellano and colleagues conducted a study to describe the frequency of Parkinson’s disease and concomitant FXTAS [ 151 ]. They reviewed medical records and performed a pathology analysis on 40 deceased patients with a diagnosis of FXTAS.…”