Adolescent-onset spastic paraplegia associated with a TUBB4A p.Gly96Arg variant: insights from diffusion tensor tractography

Adolescent-onset spastic paraplegia may present with heterogeneous underlying pathophysiology, including both axonal and myelin-related mechanisms. We report a 53-year-old woman with progressive spastic paraplegia beginning in adolescence who was found to harbor a pathogenic TUBB4A p.Gly96Arg variant. Brain magnetic resonance imaging showed diffuse white-matter abnormalities and thinning of the corpus callosum, without basal ganglia or cerebellar atrophy, mimicking hereditary spastic paraplegia. Compared with three older healthy controls, diffusion tensor imaging (DTI)-based tractography showed lower fractional anisotropy and higher apparent diffusion coefficient across the corpus callosum, corticospinal tract, and middle cerebellar peduncle. Mean tract length was shorter in the corpus callosum but near the control means in the corticospinal tract and middle cerebellar peduncle, while streamline-count deviations also varied by tract. In this genetically confirmed case, DTI-based tractography provided supportive, hypothesis-generating characterization of white matter microstructural involvement. However, these observations do not establish an underlying pathological mechanism or an independent differential diagnostic role for DTI.