In LS-related CRCs, the concurrent coupled loss of MLH1 and PMS2 or MSH2 and MSH6 expression is generally linked to alterations in the MLH1 and MSH2 genes, respectively, while the loss of all four MMR proteins, defined as null IHC staining phenotype, has been only rarely reported [18,24,25]. This evidence concerns the gene MSH6 and Leigh syndrome.