AR and X-linked disease: This aspect is particularly relevant for chronic, slow-progressive diseases such as SBMA that require long-term treatment regimes for three reasons: (i) any therapy is more likely to work if started at puberty, concomitant with or before symptoms appear; (ii) any therapy suppressing mutant AR will enhance AR LOF, an aspect that cannot be neglected in an X-linked disease affecting males; and (iii) SBMA patients show signs of androgen insensitivity syndrome, so a therapy that will be administered for the entire life of the patient must take this into account.