Based on phenotypic variability, it has been suggested that AIFM-related diseases have differing pathogenic mechanisms.34 In Cowchock syndrome, the p.E493V mutation alters the redox properties of the mutated protein, resulting in increased apoptosis.13 In COXPD6, in comparison, the R201del mutation reduces activity of respiratory chain complexes I–V and increases caspase-independent programmed cell death.11 Most of the 11 mutations identified in this study are located in the NADH and second FAD domains of AIFM1, which are essential for FAD-dependent NADH oxidoreductase. Here, AIFM1 is linked to X-linked Charcot-Marie-Tooth disease type 4.