This work presents two patients with severe encephalopathy and severe mtDNA depletion in muscle associated with novel variants in FBXL4; S1 harboring two variants in compound heterozygosis c.[858+5G>C];[1510T>C] and S2 harboring one variant in homozygosis c.[851delC];[851delC]. Here, FBXL4 is linked to Encephalopathy.