LAUSR

do not fit test results, particularly when positive tests show poor correlation with phenotype, and occasionally are found in asymptomatic patients. In line with this, Balint et al brings about a very relevant topic: the antibodies of unknown significance (AUS). In 2018, the same author performed a very interesting analogy on the functional connections between genetics and neuroimmunology. Many different techniques are used to detect antibodies. Screening tests include indirect immunofluorescence and immunohistochemistry, using slices of rodent brain tissue and Western blot, where denatured proteins are detected. Usually it requires confirmation through specific test systems such as cell-based assays, which overexpress the antigen of interest. Besides the aforementioned analogies between VUS and AUS, we have to consider that there are several relevant differences in clinical practice that are still a challenge for general neurologists and movement disorders experts considering this topic. First, considering that VUS are related to Mendelian disorders, trio sequencing is a feasible way to define pathogenicity, and this is not possible for AUS. Furthermore, the number of VUS is extremely higher than that of AUS, and of course, it demands a careful interpretation because a genetic counseling is necessary. In addition, several genetic disorders are related to metabolic changes, and the levels of enzymatic activities may provide functional information, which is frequently not possible in immune-mediated disorders. In general, degenerative progression may work as a marker for genetic diseases, and improvement with immunotherapy may reinforce autoimmune disorders. Laboratories specialized in functional studies are still scarce in clinical practice for genetics and immune-mediated disorders, and as a consequence, it limits establishing a connection between a VUS or AUS and the clinical phenotype. Future proposal classifications are necessary for AUS, to reach more than 20 years of studies on the guidelines and classification for VUS. And finally, it is mandatory to highlight that, in spite of considerable discussion on functional studies for VUS and AUS, the main practical convergence point for the genetic and autoimmune investigation is the clear correlation with the clinical phenotype, to avoid false-positive diagnosis.