Abstract
ABSTRACT
Pathogenic variants in ATP1A3 are classically associated with alternating hemiplegia of childhood, CAPOS syndrome, and rapid‐onset dystonia‐parkinsonism. However, the phenotypic spectrum of ATP1A3‐related disease has expanded considerably in recent years, including atypical presentations with spasticity and hereditary spastic paraplegia‐like phenotypes. We describe a 43‐year‐old woman who developed a progressive upper motor neuron syndrome characterized by spastic paraparesis, generalized hyperreflexia, bilateral Babinski signs, inexhaustible ankle clonus, spastic dysarthria, dysphagia, and mild cerebellar involvement. Extensive metabolic, autoimmune, infectious, neurophysiological, neuroimaging, and genetic investigations failed to identify an alternative diagnosis. Targeted next‐generation sequencing identified a heterozygous ATP1A3 NM_152296.4:c.2984G>A, p.(Arg995His). Familial segregation analysis demonstrated a confirmed de novo occurrence with biological parentage verification. The variant affects a highly conserved residue within the transmembrane M8 domain, is absent from population databases, and is predicted to be deleterious by multiple in silico tools. According to ACMG/AMP criteria, the variant fulfilled PM2 and PP3 and is currently classified as a variant of uncertain significance (VUS). This case suggests a possible expansion of the phenotypic spectrum of ATP1A3‐related disease and represents, to our knowledge, the first reported adult‐onset primary lateral sclerosis‐like phenotype associated with an ATP1A3 variant. These findings suggest that ATP1A3 should be considered in the genetic evaluation of unexplained adult‐onset upper motor neuron syndromes.