We present an atypical and exceptionally early-onset case of CLN5 whose clinical and molecular phenotype may be modified by a variably penetrant mutation, p.Gly517Val, in the linker region of the mtDNA polymerase POLG1. Functional in vitro analysis of relative mtDNA copy number and mitochondrial membrane potential supports the pathogenicity of the POLG1 change and suggest a possible genetic interaction between an NCL-related gene and another involved in mitochondrial homeostasis. The gene discussed is POLG; the disease is neuronal ceroid lipofuscinosis 5.