To describe a unique case of progressive cognitive, behavioral, and motor decline associated with a novel homozygous variant in FA2H, suggestive of possible SPG35, highlighting important imaging findings.

Mutations in FA2H are implicated in spastic paraplegia type 35 (SPG35), a rare autosomal recessive neurodegenerative disorder involving sphingolipid metabolism. Clinical presentations often include spasticity, ataxia, cognitive impairment, and motor dysfunction, but functional neuroimaging findings have not been well described.

We evaluated a 50-year-old woman with a 9-year history of progressive cognitive decline, behavioral changes, upward gaze palsy, and gait imbalance. Family history revealed a sister with longstanding gait impairment and a niece with early gait disturbances. Clinical, neuroimaging, electrophysiological, and genetic evaluations were performed, including brain MRI, FDG PET, 24-hour ambulatory EEG, and whole-genome sequencing (WGS).

Neuroimaging demonstrated marked cerebellar atrophy on MRI and isolated cerebellar hypometabolism on FDG PET. EEG revealed intermittent focal slowing and epileptiform discharges over the frontal centrotemporal (left more than right) regions. Laboratory evaluations excluded metabolic, and infectious causes. WGS identified a homozygous FA2H variant of uncertain significance (c.32_34del, p.F11del). While this variant has not been classified as pathogenic, its role in sphingolipid metabolism may contribute to the observed phenotype.

This case expands the clinical spectrum of possible FA2H-related disease and suggests cerebellar dysfunction as a key feature. To our knowledge, this is the first reported case of isolated cerebellar hypometabolism on FDG PET in suspected SPG35. Recognition of such imaging patterns may help refine diagnosis in atypical neurodegenerative presentations and support ongoing efforts to establish genotype–phenotype correlations in FA2H-associated disorders.