Open-Label Trial of Sulforaphane in Premutation Carriers With FXTAS

Primary measures are performed on PBMCs. Mitochondrial mass and membrane potential will use selected floors and either plate readers or analytical flow cytometry.

Using PMBCs we will observe in changes in ATP production of various segments of the electron transport chain by utilizing different substrates and coupling between electron transport and ATP production.

Observing levels in potential molecular biomarkers that affect mitochondrial dysregulation. GRP78 is a master controller of the mitochondrial ER stress response. It helps improve Ca2+ transfer and mitochondrial function. Its level will be measured via ELISA

Observing levels in potential molecular biomarkers that affect mitochondrial dysregulation. CHOP is a common downstream indicator of mitochondrial ER stress signals. It helps improve Ca2+ transfer and mitochondrial function. Its level will be measured via ELISA

Observing levels in potential molecular biomarkers that affect mitochondrial dysregulation. Bax/Bcl-2 is a common measure of mitochondrial dysfunction. It helps improve Ca2+ transfer and mitochondrial function. It will be measure via Elisa.

The standardized neurological examination including frontal release signs, snout, jaw jerk, and palmomental reflex; sensory examination of pinprick and vibration sense; and assessment of alternating movements and cranial nerves. These measures constitute the FXTAS Rating Scale (FXTAS-RS).

The measurements will include anatomic volume for quantifying atrophy. We have developed a robust and efficient method for accurate segmentation of the cerebellum and brainstem and have applied this method to segment the hippocampus, amygdala, basal ganglia, and corpus callosum accurately. We will continue using this method for quantifying volumes of the white matter in individual lobes and subcortical structures, including the corpus callosum, midbrain, pons, and cerebellar white matter, and calibrating iron depositions in subcortical nuclei (i.e., dentate nucleus, substantia nigra, putamen, and globus pallidus)

The measurements will include FLAIR hyperintensity volume for subcortical lesions. Subcortical hyperintensities will be segmented automatically using Lesion Prediction Algorithm (LPA) from SPM12, which also co-registers FLAIR images to T1 images. To calculate regional FLAIR hyperintensity volume, we will threshold the generated lesion probability maps at 0.7 and superimpose subcortical and white matter masks to the probability maps using fslmaths from FSL.

The upper extremity function fine motor scale measures the neurological quality of life related to one's ability to carry out various activities involving digital, manual, and reach-related functions ranging from fine motor to self-care. The assessment is administered as a self-report questionnaire and responses are recorded on a scale of 1 (unable to do) to 5 (without any difficulty). The assessment will be administered at baseline and at 6 months and any changes in scaled responses will measure changes in neurological quality of life related to the upper extremity functioning.

The lower extremity function mobility scale measures the neurological quality of life related to one's ability to carry out various activities involving the trunk region and increasing degrees of bodily movement, ambulation, balance, and endurance. The assessment is administered as a self-report questionnaire and response are recorded on a scale of 1 (unable to do/can't do) to 5 (without any difficulty/no difficulty). The assessment will be administered at baseline and 6 months and any changes in scaled responses will measure change in neurological quality of life related to the lower extremity functioning.

The Symptom Checklist-90-Revised (SCL-90-R) is a 90 item self-report psychometric questionnaire created to capture a broad range of psychological problems and has been shown to be sensitive in capturing emotional issues in carriers both with and without FXTAS.

For the NIH Toolbox Grip Strength Test, participants squeeze the Jamar Plus Digital dynamometer as hard as they can for a count of three. The dynamometer provides a digital reading of force in pounds.

Gait variability will be measured using the GAITRite in which participants will traverse the GAITRite walkway across 6 walking trials for each condition with minimal interruption.

The Purdue Pegboard test will measure abnormalities in dexterity, tremor, and bradykinesia.

Participants will perform pre-defined tasks for the Kinesia One test (e.g., finger to nose, finger tapping, wrist rotation, holding arms extended, arms resting on the legs, and hand grasps).

The Montreal Cognitive Assessment (MoCA) will be administered at baseline and 6 months and the MoCA is scored on a scale of 0-30 points. Changes in the participant's score from the MoCA administered at baseline and the MoCA administered at 6 months will measure whether there are changes in cognitive dysfunction.

The Mini Mental State Exam (MMSE) will be administered at baseline and 6 months. MMSE is scored on a scale of 0-30 points. Changes in participant's score from MMSE administered at baseline and MMSE administered at 6 months will measure whether there are changes in mild cognitive dysfunction.

The Behavioral Dysfunction Scale 2 (BDS-2) is a 9-item assessment of simple motor tasks that scores the participant's completion of each item/task on a scale of 0 (patient demonstrates a complete lack of insight into the accuracy of his or her performance and fails to recognize that errors are being made) to 3 (patient demonstrates good performance with no errors). The BDS-2 is administered at baseline and 6 months and changes in participant scores will measure changes in executive function deficits.

The Controlled Oral Word Association Test (COWAT) measures executive functioning deficits using verbal fluency and word retrieval tasks. One's score is calculated by the total number of words listed (1 word = 1 point) Changes in the participant's score from the COWAT administered at baseline and the COWAT administered at 6 months will measure changes in executive function deficits.

The Stocking of Cambridge subtest from the CANTAB assessment will be administered to measure deficits in frontal executive planning.

The Spatial Working Memory and Paired Associates Learning subtest from the CANTAB assessment will be used to measure hippocampus-mediated memory deficits

The Choice Reaction Time subtest from the CANTAB assessment will be used to measure motor changes and bradykinesia.

Cognitive ability will be measured using the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV).