Expanding the AFG3L2 Spectrum: A Link to Axonal Neuropathy

The AFG3L2 gene encodes a mitochondrial AAA-protease involved in inner mitochondrial membrane (IMM) proteostasis. Heterozygous variants in the AFG3L2 proteolytic domain cause Spinocerebellar Ataxia type 28, heterozygous variants in the AFG3L2 ATPase domain cause Optic Atrophy type 12, while biallelic variants lead to recessive Spastic Ataxia type 5. In this study, we aimed to investigate the link between AFG3L2 haploinsufficiency and Charcot-Marie-Tooth (CMT) phenotypes.

We performed clinical evaluation, genetic analyses, electrophysiology, and functional studies in 1 patient's fibroblasts.

In this study, we report a patient presenting with progressive symmetric distal muscle atrophy, weakness, pes cavus, and sensory deficits at lower limbs, in the absence of cerebellar or pyramidal signs. Electrophysiologic studies confirmed axonal sensorimotor neuropathy. After excluding common CMT-related genes, clinical exome sequencing revealed a heterozygous truncating variant in AFG3L2 [NM_006793.3:c.121C > T; p.(Arg41*)]. In patient's fibroblasts, we observed ∼50% reduction in AFG3L2 protein levels, which is sufficient to hyperactivate the stress-sensitive IMM protease OMA1. Consequently, we detected increased OPA1 processing, mitochondrial shortening, and activation of the integrated stress response.

These findings suggest that AFG3L2 haploinsufficiency can underlie axonal CMT, expanding the clinical spectrum of AFG3L2-related diseases and emphasizing its potential inclusion in CMT diagnostic panels.