Prodromal Markers of Upper Limb Deficits in FMR1 Premutation Carriers and Quantitative Outcome Measures for Future Clinical Trials in Fragile X-associated Tremor/Ataxia Syndrome Joan A. O’Keefe, PhD, PT,1,2,* Deborah Bang, MS,2 Erin E. Robertson, PhD,1 Alexandras Biskis, BS,1,3 Bichun Ouyang, PhD,2 Yuanqing Liu, MS,2 Gian Pal, MD, MS,2 Elizabeth Berry-Kravis, MD, PhD,2,4 and Deborah A. Hall, MD, PhD2

ABSTRACT: Background: Background Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a rare, late-onset neurodegenerative disorder characterized by tremor and cerebellar gait ataxia, affecting premutation carriers (PMC) of CGG expansions (range, 55–200) in the fragile X mental retardation 1 (FMR1) gene. Discovery of early predictors for FXTAS and quantitative characterization of motor deficits are critical for identifying disease onset, monitoring disease progression, and determining efficacy of interventions. Methods: Methods A total of 39 PMC with FXTAS, 20 PMC without FXTAS, and 27 healthy controls performed a series of upper extremity (UE) motor tasks assessing tremor, bradykinesia, and rapid alternating movements that were quantified using an inertial-based sensor system (Kinesia One; Great Lakes NeuroTechnologies, Cleveland, OH, USA). Sub-scores from the clinician-rated FXTAS Rating Scale were correlated with the severity scores generated by the sensor system to determine its validity in FXTAS. Results: Results PMC with FXTAS had significantly worse postural and kinetic tremor compared with PMC without FXTAS (P = 0.02, 0.03) and controls (P = 0.001, 0.0001), respectively, and slower finger tap (P = 0.001), hand movement (P = 0.0001), and rapid alternating movement speed (P = 0.003) and amplitude (P = 0.04) than controls. PMC without FXTAS had significantly worse right finger tap (P = 0.004), hand movement (P = 0.01), and rapid alternating movement speed (P = 0.003) and amplitude (P = 0.02) than controls. FXTAS Rating Scale subscores significantly correlated with all tremorography scores except for finger taps and left rapid alternating movement. Conclusions: Conclusions These findings support the use of inertial sensor quantification systems as promising measures for preclinical FXTAS symptom detection in PMC, characterization of the natural history of FXTAS, assessment of medication responses, and outcome assessment in clinical trials.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a lateonset, progressive neurodegenerative disorder affecting approximately 40% to 70% of men and 16% to 20% of women carrying a

“premutation” range allele of 55 to 200 CGG repeats in the fragile X mental retardation 1 (FMR1) gene located on the X chromosome.1–4 The mechanisms underlying the


Department of Cell & Molecular Medicine, Rush University Medical Center, Chicago, Illinois, USA; 2Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA; 3Department of Pediatrics, Rush University Medical Center, Chicago, Illinois, USA; 4Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, USA

*Correspondence to: Dr. Joan A. O’Keefe, Department of Cell & Molecular Medicine, Rush University Medical Center, 600 South Paulina Street, Suite 507 Armour Academic Center, Chicago, IL 60612, USA, E-mail: [email protected] Keywords: Fragile X-associated tremor/ataxia syndrome (FXTAS), FMR1 premutation carriers, tremor, bradykinesia, inertial sensor based tremorography. Joan A. O’Keefe and Deborah Bang contributed equally to the work and are cofirst authors. Relevant disclosures and conflicts of interest are listed at the end of this article. Received 2 June 2020; revised 9 July 2020; accepted 13 July 2020. Published online 29 August 2020 in Wiley Online Library ( DOI: 10.1002/mdc3.13045


MOVEMENT DISORDERS CLINICAL PRACTICE 2020; 7(7): 810–819. doi: 10.1002/mdc3.13045 © 2020 International Parkinson and Movement Disorder Society



TABLE 1 Participant demographic and clinical characteristics Variable

Controls, n = 27

PMC Without FXTAS, n = 20

PMC with FXTAS, n = 38

Age, mean  SD Sex FXTAS diagnosis (%, n) Possible Probable Definite FMR1 CGG repeat size, mean  SD FXTAS Rating Scale, mean  SD Total scores, mean  SD Disease duration, mean  SD FMR1 activation ratio, mean  SD

65.37  9.07 12 men, 15 women (44% men)

53.0  9.04a***,b** 2 men, 18 women (10% men)

68.05  8.9 23 men, 16 women (59% men)

32.36  5.3

96  25.5

13%, 5 45%, 17 42%, 16 86.69  17.12

12.5  7.16 N/A N/A

6.2  4.8 N/A 46.15  24.9

37.91  25.65a*,c* 7.7  5.2 years 44.6  17.0


Significantly different from controls. Significantly different from FXTAS. c Significantly different from PMC without FXTAS. *P < 0.05; **P < 0.01; ***P < 0.001. Abbreviations: PMC, premutation carriers; FXTAS, fragile X-associated tremor/ataxia syndrome; SD, standard deviation. b

neurodegeneration of FXTAS are thought to be attributed to a toxic gain of function as a result of (1) increased FMR1 mRNA transcription and sequestration of RNA binding proteins contributing to protein aggregation and inclusion formation in neurons and astrocytes and (2) CGG repeat-associated non-AUG translation, which generates toxic polyglycine peptides also found in the inclusions in neurons.5–7 Mitochondrial dysfunction and antisense transcripts to FMR1 may also contribute to the pathogenesis of FXTAS.7–9 Clinical features include kinetic tremor, cerebellar gait ataxia, psychiatric issues, and executive dysfunction/cognitive decline in premutation carriers (PMC) with onset generally beginning after 50 years of age.10,11 Kinetic tremor and cerebellar ataxia are the core motor features of the disease, although parkinsonism may be present in a significant number of individuals with FXTAS.12–18 To date, there are no disease-modifying therapies available for FXTAS, which causes significant disability and increased morbidity and mortality.19 However, as treatments become available, early symptom detection will be critical for earlier intervention and timely management. Prodromal symptoms of FXTAS have been previously reported in PMC without FXTAS including manual slowing of movement and prolonged reaction times,20 deficits in postural response latencies and the sensorimotor control of balance,21 increased gait variability,22 and reduced stride length during gait23 and delayed step reaction times24 when dual tasking. The Kinesia One inertial sensor-based system (Great Lakes NeuroTechnologies, Cleveland, OH, USA) has been shown to be a valid and reliable method of measuring UE tremor and bradykinesia in Parkinson’s disease (PD) and essential tremor. Our group recently demonstrated its ability to distinguish the tremor and bradykinesia profiles between patients with FXTAS, PD, and essential tremor.25 Therefore, the primary objectives of this study were to use the Kinesia Oneinertial sensor system to (1) characterize the severity of tremor subtypes and bradykinesia in PMC with FXTAS and (2) determine whether this technology can detect early signs of motor dysfunction in PMC without FXTAS.

Methods Study Participants PMC participants with and without FXTAS were recruited from the FXTAS and Fragile X Clinics at Rush University Medical Center and from recruitment advertisements from the National Fragile X Foundation. Inclusion criteria for FXTAS participants were (1) FMR1 CGG repeat size of 55 to 200; (2) a diagnosis of possible, probable, or definite FXTAS according to wellestablished clinical and radiological criteria1,13; and (3) mild to severe tremor. Inclusion criteria for PMC participants without FXTAS were (1) FMR1 CGG repeat size of 55 to 200 and (2) a diagnosis of no FXTAS made by a movement disorder specialist (D.A.H.) after administration of a neurological examination. None of the PMC participants without FXTAS had magnetic resonance imaging. Exclusion criteria were (1) a history of stroke or traumatic brain injury with focal neurological deficit or any other neurological or muscular disease, (2) a significant seizure disorder, or (3) clinical diagnosis of dementia. Healthy control participants were recruited from Rush University Medical Center or the community or were friends or family members of the enrolled PMC participants. Inclusion criteria for controls were (1) a normal neurological examination and (2)

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RESEARCH ARTICLE CLINICAL PRACTICE Prodromal Markers of Upper Limb Deficits in FMR1 Premutation Carriers and Quantitative Outcome Measures for Future...
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