Expanding the AFG3L2 Spectrum: A Link to Axonal Neuropathy.

Area of Science:

• Genetics
• Neuroscience
• Mitochondrial Biology

Background:

• The AFG3L2 gene encodes a mitochondrial AAA-protease crucial for inner mitochondrial membrane (IMM) proteostasis.
• Variants in AFG3L2 are linked to various neurological disorders, including Spinocerebellar Ataxia type 28, Optic Atrophy type 12, and Spastic Ataxia type 5.

Purpose of the Study:

• To investigate the potential association between AFG3L2 haploinsufficiency and Charcot-Marie-Tooth (CMT) disease phenotypes.
• To explore the molecular mechanisms underlying AFG3L2-related neuropathies.

Main Methods:

• Clinical evaluation, genetic analysis (clinical exome sequencing), and electrophysiology were performed on a patient with neuropathy.
• Functional studies using patient-derived fibroblasts assessed AFG3L2 protein levels, OMA1 protease activity, OPA1 processing, mitochondrial morphology, and integrated stress response activation.

Main Results:

• A patient presented with axonal sensorimotor neuropathy consistent with CMT, but without cerebellar or pyramidal signs.
• Clinical exome sequencing identified a heterozygous truncating variant in AFG3L2 (c.121C > T; p.(Arg41*)).
• Patient fibroblasts showed reduced AFG3L2 protein levels, leading to OMA1 hyperactivation, increased OPA1 processing, mitochondrial shortening, and integrated stress response activation.

Conclusions:

• AFG3L2 haploinsufficiency is a potential cause of axonal Charcot-Marie-Tooth disease.
• This finding expands the clinical spectrum of AFG3L2-related disorders.
• AFG3L2 should be considered for inclusion in diagnostic panels for CMT.