To present a case of Hereditary Spastic Paraplegia (HSP) 46 with distinct imaging and clinical findings, with two novel variants in GBA2, previously classified as variants of undetermined significance (VUS).

HSP is an uncommon cause of lower extremity spasticity and weakness. There have been many genetic etiologies identified with various clinical features. HSP 46 is an autosomal recessive, slowly progressive form of HSP caused by biallelic pathogenic variants in GBA2.

A 21-year-old man presented with progressive lower extremity weakness and ambulatory dysfunction. Symptom onset was in second grade, when he was found to have difficulty walking and inversion of the right foot. His ambulatory dysfunction continued to progress. Extensive serologic testing was negative, as was MRI of his spinal cord. Brain MRI demonstrated thinning of the corpus collosum. Examination approximately 12 years after his initial presentation was notable for diffuse hyperreflexia, bilateral lower extremity spasticity, and bilateral Hoffmann and Babinski signs. He had excessive lower extremity circumduction in swing phase, hyperextension at the knees, and internal rotation at the hips; consistent with a scissoring gait. There were no cranial neuropathies, sensory deficits, or cerebellar ataxia. The family history was negative. Genetic testing via whole-exome sequencing demonstrated compound heterozygous GBA2 variants, both classified as VUS: c.1820 A>G (p.N607S) and c.472 G>A (p.G158R).

Considering the distinctive clinical features, MRI finding of dysgenesis of the corpus collosum, and absence of an alternative explanation, we propose that the GBA2 variants found in this patient may be causative. Functional studies and/or messenger ribonucleic acid sequencing may confirm our hypothesis.