Background:
The PSEN1 c.1292C>A Jalisco founder variant is a recognized cause of autosomal dominant early-onset Alzheimer’s disease in Mexico. Although cognitive impairment is the core phenotype, emerging evidence suggests a broader clinical spectrum that includes seizures and motor manifestations.

Methods:
We retrospectively reviewed three anonymized Mexican patients with genetically confirmed PSEN1 c.1292C>A variant and atypical motor features evaluated at the National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez” over the last five years.

Results:
The three patients showed heterogeneous motor involvement. Case 1 presented a cognitive–parkinsonian phenotype with bradykinesia, rigidity, freezing of gait, dystonic posturing, and pyramidal signs. Case 2 presented an ALS-like motor neuron disease phenotype with progressive weakness, bulbar involvement, fasciculations, active denervation on EMG/NCS, and facilitated bilateral F-waves. Case 3 showed progressive spastic gait, lower-limb weakness, bilateral Babinski signs, and neurophysiological evidence of proprioceptive and corticospinal tract dysfunction.

Conclusion:
The PSEN1 c.1292C>A Jalisco founder variant may present with clinically prominent motor manifestations beyond cognitive impairment. Systematic motor assessment may improve phenotypic characterization, diagnostic suspicion, and genetic counseling.

Key takeaway:
Beyond memory loss, the PSEN1 c.1292C>A Jalisco founder variant may present with a broad motor phenotype, ranging from parkinsonism and spastic gait to ALS-like manifestations.