Authors: Joan A. O’Keefe, Deborah Bang, Erin E. Robertson, Alexandras Biskis, Bichun Ouyang, Yuanqing Liu, Gian Pal, Elizabeth Berry-Kravis, and Deborah A. Hall

Summary

Dr. Joan O’Keefe and the study team at Rush University are very interested in Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative condition affecting some individuals who are Fragile X premutation carriers.

FXTAS symptoms include tremor and cerebellar gait ataxia. The cerebellum is the part of the brain that is responsible for the control of gait, balance, and motor coordination. Cerebellar gait ataxia makes it challenging to control gait, which may result in unsteady walking or movement. There are no proven treatments for FXTAS available to date. As treatments become available, early symptom detection will be important for early intervention and management. Discovering early predictors for FXTAS and being able to measure and better characterize the motor deficits that are part of FXTAS are critical for identifying FXTAS onset, monitoring progression, and determining the effectiveness of interventions.

Prodromal — or the period before the first signs of observable symptoms — symptoms of FXTAS have been previously reported in premutation carriers without FXTAS, including slowing of movements and reaction times and challenges with balance and gait. The Kinesia One inertial sensor-based system has been shown to be a valid and reliable method of measuring tremor and bradykinesia (slowness of movement) in other conditions, including Parkinson’s disease and essential tremor. The Rush team aimed to use this device to

  1. characterize the severity of tremor subtypes and bradykinesia in premutation carriers with FXTAS, and
  2. determine whether this technology could detect early signs of motor dysfunction in premutation carriers without FXTAS.

A total of 39 premutation carriers with FXTAS, 20 premutation carriers without FXTAS, and 27 controls performed a series of upper extremity (arms) motor tasks assessing tremor, bradykinesia, and rapid alternating movements that were measured using the Kinesia One system. Scores from the clinician‐rated FXTAS Rating Scale were correlated or associated with the severity scores generated by the sensor system to determine the system’s validity in FXTAS.

Premutation carriers with FXTAS had significantly worse postural and kinetic tremor (tremors while maintaining a posture and during motion, respectively) compared with premutation carriers without FXTAS and controls, as well as slower finger tap, hand movement, and rapid alternating movement speed and amplitude (maximum distance moved) than controls. Premutation carriers without FXTAS had significantly worse finger tap, hand movement, and rapid alternating movement speed and amplitude than controls. FXTAS Rating Scale subscores significantly correlated with most tremorography scores.

Why This Matters

The Kinesia One inertial sensor system was able to accurately identify and measure key upper extremity (UE) motor differences in individuals with and without FXTAS compared to controls. The significant findings related to the differences in speed and execution of motor functions were noteworthy in premutation carriers without FXTAS, suggesting these findings could potentially represent prodromal signs of FXTAS. This means this system could potentially predict FXTAS onset in premutation carriers who are not showing signs of FXTAS on a neurological exam, which would help with determining earlier interventions. These findings also support the use of inertial sensor quantification systems as promising measures for characterization of the natural history of FXTAS and outcome assessment in clinical trials.

Next Steps

More research will need to be done to learn more about the clinical onset of FXTAS in premutation carriers. Longitudinal studies will be important to confirm whether these findings are indeed predictive for the development of FXTAS. Research that includes neuroimaging like MRI to understand how different parts of the brain are involved and associated with the development of various FXTAS symptoms like tremor, slow movement, and changes in coordination, will also be important.

O’Keefe, J. A., Bang, D., Robertson, E. E., Biskis, A., Ouyang, B., Liu, Y., Pal, G., Berry-Kravis, E., & Hall, D. A. (2020). 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. Movement disorders clinical practice, 7(7), 810–819. https://doi.org/10.1002/mdc3.13045↗

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