ATP1A3 potentially causes hereditary spastic paraplegia: A case report of a patient presenting with lower limb spasticity and intellectual disability

Sodium/potassium (Na+/K+) ATPase is a heteromeric protein complex responsible for maintaining the Na+/K+ electrochemical gradient across the neuronal plasma membrane. The α3 isoform of the Na+/K+ ATPase, encoded by ATP1A3, acts as a rescue pump and is predominantly present in the neurons of the central nervous system. The de novo variants of ATP1A3 cause several distinct neurological syndromes. We presented the case of a boy with no family history of neurological diseases who was harboring a de novo pathogenic variation, NM_152296:c.974G > T, p.Gly325Val, in ATP1A3. He presented with a rare spastic paraplegia of the lower extremities, autism spectrum disorder, and intellectual disability. Previous studies have demonstrated the ATP1A3 variant p.Gly325 to be pathogenic for dystonia, face dysmorphia, encephalopathy, brain magnetic resonance imaging abnormalities, and no hemiplegia. A recent study has revealed, for the first time, the development of spastic paraplegia as a manifestation of the de novo ATP1A3 p.Pro775Leu pathogenic variant. In this case report, we concluded that another de novo pathogenic variation in ATP1A3, p.Gly325Val, manifests as spastic paraplegia and intellectual disability in the index patient. These results suggest that ATP1A3 is a novel causative gene of hereditary spastic paraplegia.