The clinical diversity in our two half-siblings was as remarkable as to suggest that differential segregation of other gene variants could influence phenotypic expression. A prioritized variant found by in-silico data mining was in HDAC6. A hemizygous HDAC6P856S change, found in Pt2, and absent in Pt1, was associated with decreased tubulin-specific deacetylase activity [22]. Through deacetylation of α-tubulin, HSP90, and other substrates, and binding to ubiquitinated proteins that are then transported into, and degraded by, the aggresome, HDAC6 plays a role in a number of important homeostatic and signaling pathways, including axonal transport, redox signaling, misfolded-protein response, and autophagy [25,26]. Interestingly, the RNA-binding modulator factors TDP-43 and FUS/TLS, whose mutations are associated with familial amyotrophic lateral sclerosis (ALS), have HDAC6 mRNA as a specific substrate [27]. A Drosophila model in which TDP-43 is silenced shows decreased HDAC6 expression, [28] and HDAC6 overexpression is able to rescue the phenotype of a Drosophila model of spinobulbar muscular atrophy [6].