Digenic inheritance of mutations in SPG7 and AFG3L2 causes late-onset ataxia with pyramidal signs

In this journal, Estiar et al. (2026) recently described 12 patients with digenic heterozygous variants in SPG7 and AFG3L2 genes, including one patient previously published by Magri et al. (2018). Patients had been identified from exome and genome data of cohorts with motor neuron disorder (MND), ataxia and rare/neurodegenerative diseases, and literature review. In a study that we published in 2023, we reported an additional patient with a deletion affecting the canonical acceptor splice-site c.1454_1462del p.(Arg485_Glu487del) (c.1450-1_1457delGGAGAGGCG) in SPG7 and a missense variant c.2105G > A p.(Arg702Gln) in AFG3L2. The patient had predominantly lower limb ataxia and hyperreflexia with a disease duration of 13 years at the time of assessment. These observations are in line with the clinical features of the patients described by Estiar et al., further supporting a potential role for digenic inheritance involving SPG7 and AFG3L2 in spastic ataxia.