We highlight the association of PLS with PSEN1 mutations and describe 3 patients with PLS and dementia that were misdiagnosed as ALS/Dementia.

PLS and HSP are rare manifestations of pyramidal tract dysfunction. Whereas PLS is usually associated with pure upper motor neuron dysfunction, HSP may have other manifestations such as peripheral neuropathy, hydrocephalus, etc., leading to classifying HSP as simple or complicated.  They are both characterized by a slowly progressive spastic paraparesis, with upper extremities and bulbar region traditionally spared in HSP. Moreover, PLS might be associated with cognitive decline and dementia, often frontotemporal dementia.

Case series of 3 patients seen at the University of California Irvine ALS Center with PSEN1 mutations, dementia and primary lateral sclerosis.

We report three male patients, aged 40-44 years, with previously described pathogenic mutations in the PSEN1 gene (A431E in patients 1 and 2 and L381V in patient 3). Patients 1 and 2 were Mexican-American brothers (from Michoacán, the state neighboring Jalisco in Mexico), while case 3 was a Vietnamese man. Patients 1 and 2 presented with frontotemporal dementia as an initial symptom but developed marked spastic quadriparesis (legs>arms). Both developed bulbar dysfunction and spastic anarthria. Patient 3 had a cognitive problem since childhood, then developed progressive spastic quadriparesis and bulbar dysfunction (dysphagia and spastic anarthria). Additional features were myoclonus in patient 1, sympathetic storming in patient 3, and pseudobulbar affect in Patient 1 and 2. MRI showed mild global cerebral atrophy in all 3 cases.

We conclude that PLS is associated with PSEN1 mutations in certain patients; given the early upper extremity and bulbar involvement this is unlikely to be HSP. It is important to screen PLS patients or ALS/Dementia patients in ALS clinics for PSEN1 mutations, especially from at risk regions, such as Jalisco or Michoacán, Mexico.