To describe a patient with late-onset ataxia and heterozygous variants in SPG7 and AFG3L2, and relate the case to previously reported patients with the same variant combination.
Approach:
Genetic analysis: Whole-exome sequencing and screening of ataxia-related genes identified heterozygous AFG3L2 c.2105G>A, p.(Arg702Gln), and an SPG7 deletion, NM_003119.4 c.1450-1_1457delGGAGAGGCG, also designated c.1454_1462del, p.(Arg485_Glu487del).
Clinical assessment: The patient was assessed after 13 years of disease and again at 15 years; the case was considered alongside reports of patients carrying variants in both genes.
Key Findings:
Ataxia began at approximately age 45. At assessment after 13 years of disease, the patient had predominantly lower-limb cerebellar ataxia, hyperreflexia, and a SARA score of 8; sensory testing remained normal.
Bilateral sensorineural hearing loss was present at the initial assessment. At 15 years of disease, follow-up identified ptosis requiring surgery and progressive oculomotor dysfunction. Orthostatic hypotension was also reported.
The AFG3L2 variant had also been reported in a French family. The SPG7 deletion was predicted to alter splicing, but this effect was not directly tested in the patient.
Two heterozygous pathogenic POLG variants were found in cis and were considered unlikely to account for the phenotype.
Interpretation:
The authors proposed a possible digenic effect involving SPG7 and AFG3L2, which they said was strongly corroborated by the patients reported by Estiar et al.; they could not establish the effect definitively in this case. They proposed that the variants may disrupt the m-AAA protease complex and mitochondrial proteostasis, but this mechanism was not directly demonstrated in the patient.
Limitations:
The digenic effect could not be definitively established in the original report.
The proposed effects of the variants on splicing, protein structure, nucleotide binding, and complex function rely on predictions and models rather than direct functional evidence.
Conclusion:
This case adds clinical and genetic observations consistent with an association between combined SPG7 and AFG3L2 variants and late-onset ataxia with pyramidal signs; a digenic causal effect in this patient remains unproven.
