Background: The Fragile X premutation, 55 to 200 CGG repeats in FMR1, can cause neurodevelopmental disorders, neuropsychiatric disorders and in aging it can cause the  Fragile X-associated Tremor Ataxia Syndrome (FXTAS),  a neurodegenerative disorder. The premutation is associated with elevation of FMR1 mRNA which causes RNA toxicity characterized by oxidative stress, mitochondrial dysfunction and early neuronal and astroglial cell death. Sulforaphane (SFN) is a sulfur containing compound, found in cruciform vegetables including broccoli, cauliflower and Brussel sprouts, that activates the Nrf-2 pathway which in turn stimulates the production of antioxidant enzymes and also enhances mitochondrial biogenesis.

Methods: 15 premutation carriers with FXTAS were given oral sulforaphane titrated up to 6 tablets per day of Avmacol (1275 mg/day) in the first 2 weeks and then treated for 6 months at their maximal tolerated dosage. Baseline measures included quantitative assessment of tremor (Kinesia One) and ataxia (GaitRite), neuropsychological measures (MoCA,CANTAB,BDS2), emotional measures (SCL-90R) and molecular biomarkers including FMRP levels.  Eleven patients completed the 6 month trial and outcome measures. One patient dropped out early and 3 were unable to return for the follow-up assessment.

Results: No significant changes were seen in the tremor and ataxia measures but the Spatial Working Memory   errors improved from 22.6 (SD 4.74) to 18.2 (SD 6.37) (p=0.048) and the MoCA improved from 25.5 to 27.25 (p=0.099).  A surprising finding was improved levels of FMRP in 4 patients and these correlated with improvements on the neuropsychological measures.

Conclusion: Sulforaphane was well tolerated and safe but there were no significant benefits to the tremor and ataxia. FMRP levels increased in 4 patients who had stage 2 and 3 FXTAS and the increase in FMRP, which was almost twice baseline in two patients, correlated with improvements in neurocognitive measures. A controlled trial is warranted.

Keywords: Sulforaphane, FMRP, FXTAS, neurocognitive, premutation