AFG3L2 – Spastic Ataxia 5

AFG3L2 encodes a mitochondrial ATP-dependent metalloprotease (m-AAA) essential for maintaining inner membrane proteostasis. Biallelic AFG3L2 variants cause spastic ataxia 5 (SPAX5), an autosomal recessive neurodegenerative disorder characterized by early‐onset spasticity, ataxia, and additional neurological features. Based on three unrelated probands with confirmed biallelic variants ([PMID:22022284]; [PMID:37025825]; [PMID:34333379]), segregation in two affected siblings ([PMID:22022284]), and consistent functional data demonstrating impaired m-AAA activity and mitochondrial network defects, the gene–disease relationship is classified as Moderate by ClinGen criteria.

Genetic Evidence

Inheritance is autosomal recessive. Three unrelated families presented with biallelic AFG3L2 mutations: two siblings homozygous for c.1847A>G (p.Tyr616Cys) ([PMID:22022284]), one Chinese child with compound heterozygous c.1834G>T (p.Glu612Ter) and c.2176-6T>A ([PMID:37025825]), and one late‐onset case harboring c.[1894C>T];[2167G>A] (p.Arg632Ter; p.Val723Met) ([PMID:34333379]). Segregation analysis in the consanguineous family confirmed cosegregation in two affected siblings.

Variant spectrum includes missense changes (p.Tyr616Cys, p.Val723Met), nonsense alleles (p.Glu612Ter, p.Arg632Ter), and splice‐region variants (c.2176-6T>A). The p.Tyr616Cys change recurs in multiple families, suggesting a potential mutational hotspot in the proteolytic domain.

Functional Evidence

Yeast complementation assays and patient fibroblast analyses of the p.Tyr616Cys variant revealed defective oligomerization of AFG3L2 complexes, impaired mitochondrial network integrity, and reduced respiratory chain components ([PMID:22022284]). In vitro fibroblast studies from patients carrying compound heterozygous alleles demonstrated altered mitochondrial morphology, decreased TOMM70 and complex V protein levels ([PMID:37025825]), and fragmented mitochondrial networks with impaired Ca²⁺ buffering capacity. These concordant assays support a loss-of-function mechanism.

Integration and Conclusion

Collectively, genetic and experimental data demonstrate that biallelic AFG3L2 mutations disrupt m-AAA protease function, leading to mitochondrial dysfunction and the SPAX5 phenotype. While additional rare alleles and broader phenotypic variability are reported, current evidence meets ClinGen Moderate thresholds for clinical validity. AFG3L2 genetic testing should be considered in patients with early‐onset spastic ataxia and mitochondrial‐like features, guiding diagnosis, carrier screening, and potential future therapeutic interventions.

Key Take-home: Biallelic loss-of-function and hypomorphic AFG3L2 variants consistently cause autosomal recessive spastic ataxia 5 with mitochondrial dysfunction, supporting its clinical utility in diagnostic and research settings.

References

• PLoS genetics • 2011 • Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. PMID:22022284
• Heliyon • 2023 • Novel compound heterozygous mutations in the AFG3L2 gene in a Chinese child with microcephaly, early-onset seizures, and cerebral atrophy. PMID:37025825
• Journal of the neurological sciences • 2021 • Expanding the phenotype of AFG3L2 mutations: Late-onset autosomal recessive spinocerebellar ataxia. PMID:34333379

Evidence Based Scoring (AI generated)