Efforts to model POLR3-HLD in vivo using constitutive patient-derived mutations in POLR3A and POLR3B have been unsuccessful, owing either to a lack of phenotype or embryonic lethality.16,17 Recently, Merheb et al.18 developed an Olig2 conditional knock-in mouse model using a constitutively lethal double mutation in Polr3a. This evidence concerns the gene POLR3A and leukodystrophy.