Objective: To describe an atypical late-onset, bulbar-predominant neurodegenerative presentation associated with a heterozygous truncating AFG3L2 variant and contextualize this phenotype within the expanding spectrum of AFG3L2-related disease.

Background: Spinocerebellar ataxia type 28 (SCA28) is a rare autosomal dominant ataxia caused by pathogenic variants in AFG3L2, which encodes a mitochondrial m-AAA protease involved in mitochondrial protein quality control. It typically presents in young adulthood with progressive gait ataxia, dysarthria, ophthalmoparesis, and corticospinal tract signs. Phenotypic variability is increasingly recognized. Most reported pathogenic variants are missense mutations clustered in the proteolytic domain of AFG3L2, whereas truncating variants are uncommon and their contribution to dominant disease remains uncertain.

Method: N/A

Results: A 78-year-old man presented with progressive dysarthria and dysphagia, prompting evaluation for neuromuscular junction dysfunction and paraneoplastic etiologies, which was unrevealing. He was empirically started on riluzole and referred for evaluation of bulbar-onset motor neuron disease. Electrodiagnostic testing showed no evidence of motor neuron or neuromuscular junction pathology. At age 80, examination demonstrated impaired smooth pursuit, ophthalmoparesis not fully corrected by vertical vestibulo-ocular reflex, weakness of the orbicularis oculi and buccinators, severe hypomimia and dysarthria, normal strength, tone, and reflexes, mild left dyscoordination, and gait normal for age. Brain MRI showed global atrophy with prominent cerebellar vermian involvement. Genetic testing identified a heterozygous likely pathogenic truncating AFG3L2 variant (c.2104C>T; p.Arg702Ter).

Conclusion: Although this truncating variant has not previously been linked to autosomal dominant SCA28, the overlapping phenotype raises the possibility that such variants could contribute to disease in a dominant fashion if supported by additional genetic or functional evidence. This case highlights the expanding spectrum of AFG3L2-related disease and underscores the importance of considering genetic ataxias in patients presenting with progressive bulbar symptoms even when classic gait ataxia is minimal or absent.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/late-onset-bulbar-predominant-neurodegeneration-associated-with-a-truncating-afg3l2-variant-expanding-the-clinical-spectrum-of-afg3l2-related-disease/