AUTHOR=Vázquez-Costa Juan Francisco , Payá-Montes María , Martínez-Molina Marina , Jaijo Teresa , Szymanski Jazek , Mazón Miguel , Sopena-Novales Pablo ,  ENoD Consortium , Pérez-Tur Jordi , Sevilla Teresa , Morte Beatriz , Carmona Rosario , Perez-Florido Javier , Aquino Virginia , Ortuño Francisco , Lopez-Lopez Daniel , Bostelmann Gerrit , Dopazo Joaquin , Pérez-Jurado Luis Alberto 

TITLE=Presenilin-1 Mutations Are a Cause of Primary Lateral Sclerosis-Like Syndrome

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 14 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2021.721047

DOI=10.3389/fnmol.2021.721047

ISSN=1662-5099

ABSTRACT=Background and purpose
Primary lateral sclerosis (PLS) is a progressive upper motor neuron (UMN) disorder. It is debated whether PLS is part of the amyotrophic lateral sclerosis spectrum, or a syndrome encompassing different neurodegenerative diseases. Recently, new diagnostic criteria for PLS have been proposed. We describe four patients of two pedigrees, meeting definite PLS criteria and harbouring two different mutations in PSEN1.
Methods
Patients underwent neurological and neuropsychological examination, magnetic resonance imaging (MRI), 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), amyloid‐related biomarkers, and next‐generation sequencing (NGS) testing.
Results
Four patients, aged 25 to 45 years old, presented with a progressive UMN syndrome meeting clinical criteria of definite PLS. Cognitive symptoms and signs were mild or absent during the first years of the disease, but appeared or progressed later in the disease course. Brain MRI showed microbleeds in two siblings, but iron-related hypointensities in the motor cortex were absent. Brain FDG-PET showed variable areas of hypometabolism, including the motor cortex and frontotemporal lobes. Amyloid deposition was confirmed with either cerebrospinal fluid or imaging biomarkers. Two heterozygous likely pathogenic mutations in PSEN1 (p.Pro88Leu and p.Leu166Pro) were found in the NGS testing.
Conclusion
Clinically defined PLS is a syndrome encompassing different neurodegenerative diseases. NGS testing should be part of the diagnostic work-up in PLS patients, at least in those with red flags such as early onset, cognitive impairment and/or family history of neurodegenerative diseases.