In contrast to other neurological conditions defined by profound cIV impairment, such as rapidly progressive SURF1-deficient LS,4 the clinical course of APOPT1-associated encephalopathy appears to be highly variable in severity. Although some individuals developed severe neurological signs at an early age, with motor impairment evolving into spastic quadriparesis, epilepsy, and severe cognitive impairment (e.g., individual S1), others showed an intermediate phenotype with severe motor impairment but mild or absent cognitive involvement, and in one case the neurological examination was virtually normal at 14 years of age (individual S2), despite the presence of some posterior white matter abnormalities. Strikingly, in all affected individuals who underwent electromyography and nerve conduction velocity studies, evidence of a peripheral neuropathy was also found, even in absence of clinical signs. Remarkably, severely affected individual S1 and subclinically affected individual S2 are siblings, sharing the same homozygous mutation, which predicts the synthesis of a truncated protein, again supporting the wide clinical variability of this condition. Irrespective of the severity of the onset and initial evolution, in all cases both the MRI lesions and the clinical progression stabilize, determining a chronic, long-surviving clinical course, in contrast with the rapidly downhill, often fatal outcome of other early-onset COX-defective encephalopathies. All our APOPT1 mutant subjects are alive, some in their teens, with the oldest one being in her third decade. In some cases stabilization and improvement (individuals S1 and S6) coincided with the starting of vitamin and/or CoQ10-based treatment, and in individual S2 the administration of a vitamin cocktail since the first months of life may have helped to prevent the development of clinical symptoms. Nevertheless the efficacy of these therapies remains unproven, since other subjects (individuals S3, S4, and S5) showed stabilization with no specific treatment (Table 1).