To report a case of Charcot-Marie-Tooth (CMT) disease associated with a heterozygous pathogenic variant in ATP1A1, presenting with atypical features including cognitive impairment and visual snow syndrome.

Charcot-Marie-Tooth disease is typically characterized by progressive distal muscle weakness and sensory loss. While ATP1A1 variants have been linked to various neurological disorders, such as alternating hemiplegia of childhood and CAPOS syndrome (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss), their association with CMT remains rare and poorly understood. This case highlights an unusual presentation of CMT with an ATP1A1 pathogenic variant. 

Case report.

A 19-year-old male with a family history of polyneuropathy presented with pes cavus, distal weakness, and sensory loss. The clinical picture evolved to include cognitive impairment and visual snow syndrome, prompting extensive neurological workup including brain and orbital Magnetic resonance imaging (MRI), dilated eye exam, and Electroencephalography (EEG), all of which were unremarkable. Examination revealed muscle atrophy, bilateral foot drop, hyporeflexia, decreased distal sensation, and a steppage gait.  Electromyography (EMG) confirmed a length-dependent sensorimotor polyneuropathy with mixed axonal and demyelinating features. Exome sequencing identified a heterozygous pathogenic variant in ATP1A1: c.1645G>A p.(G549R), inherited from his father who exhibited milder intellectual disability, suggesting variable expressivity. 

This case significantly expands the phenotypic spectrum of ATP1A1-related CMT, demonstrating a unique combination of polyneuropathy with cognitive, and visual manifestations. The mixed axonal and demyelinating features further distinguish this presentation from prior ATP1A1-related CMT which have often described primarily axonal features. These findings underscore the importance of considering ATP1A1 variants in atypical CMT cases, especially those with multisystem involvement. The observed intrafamilial variability highlights the challenges in genetic counseling and prognostication for ATP1A1-related disorders. Further research is crucial to elucidate the full spectrum of ATP1A1-associated phenotypes and to understand the underlying pathophysiological mechanisms that bridge peripheral and central nervous system involvement.