As previously reported, standard investigations appear to be unyielding in patients with GNAO1-related disease. Two of our patients had low levels of CSF 5-methyltetrahydrofolate, although this was not consistently seen in the cohort. Brain MRI (figure 2) showed a combination of minor features in most, including a thin corpus callosum with dilated ventricles in 4, as previously reported8 as well as hypoplastic caudate nuclei in 3 and a diffuse astrocytoma (WHO grade II) in the oldest patient (patient 5). The latter finding raises concerns about the possible role of the Gly40Arg mutation in tumorigenesis, in view of the reported role of GNAO1 in promoting oncogenic transformation.19,21 A somatic GNAO1 mutation (p.Arg243Hys) has been identified in breast carcinomas where it promotes oncogenic transformation by rendering the Gα subunit constitutively activated and enhancing signaling pathways responsible for neoplastic transformation.21 Although GNAO1 was identified as part of the human plasma proteome, its high abundance was suggested to promote cancer cell viability via proapoptotic protein interference.20 Larger series and longer follow-up data will be fundamental to determine whether patients carrying specific GNAO1 mutations are at higher risk of developing tumors.
