Reply: Glial mitochondropathy in infantile neuroaxonal dystrophy: pathophysiological and therapeutic implications

Sir, Mitochondrial dysfunction is increasingly being recognized as a therapeutic target in PLA26G-associated neurodegeneration (PLAN). We demonstrated in Drosophila and in human PLA2G6 mutant fibroblasts that loss of normal PLA2G6 activity is associated with increased mitochondrial lipid peroxidation and mitochondrial dysfunction. Furthermore, we identified the therapeutic benefits of deuterated polyunsaturated fatty acids (D-PUFAs) in PLAN, through inhibition of lipid peroxidation. D-PUFAs ameliorated the locomotor deficits in flies lacking the fly orthologue of PLA2G6 ( iPLA2-VIA ), and reversed the mitochondrial abnormalities in patient fibroblasts harbouring pathogenic mutations in PLA2G6 (Kinghorn et al. , 2015). In their Letter to the Editor, Farrar et al. (2016) report abnormal mitochondrial morphology at the ultrastructural level in muscle and cutaneous nerves, as well as in cutaneous Schwann cells of a patient with infantile neuroaxonal dystrophy (INAD) associated with homozygous PLA2G6 mutations. They also observed a selective loss of complex IV of the respiratory chain in skeletal muscle, and they report elevated urine catecholamine levels and serum neuronal specific enolase in their patient. This study is thus supportive of the abnormal mitochondrial morphology observed in the CNS of Drosophila and mouse models of PLA2G6 deficiency (Beck et al. , 2011; Kinghorn et al. , 2015; Kinghorn and Castillo-Quan, 2016). It also provides evidence for the involvement of peripheral nerves outside of the CNS, and that mitochondrial pathology extends beyond neurons to glia. The next step will be to …