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

Autores de IIS La Fe

• Juan Francisco Vázquez Costa

  Autor

• Marina Martínez Molina

  Autor

• Teresa Jaijo Sanchís

  Autor

• Miguel Mazón Momparler

  Autor

• Pablo Sopena Novales

  Autor

• 

  Jordi Perez Tur

  Autor

• 

  Teresa Sevilla Mantecón

  Autor

Participantes ajenos a IIS La Fe

• Paya-Montes, M
• Szymanski, J
• Consortium, E

Grupos

• Biomedicina Molecular, Celular y Genómica

  

  Leader

  José María Millán Salvador

• Núcleo de investigación traslacional integrado Urológico de Valencia (NITIUV)

  

  Leader

  César David Vera Donoso

• Patología Neuromuscular y Ataxias

  

  Investigador Principal

  Teresa Sevilla Mantecón

• Unidad mixta de investigación en enfermedades raras (CIPF)

  

  Leader

  José María Millán Salvador

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 (ALS) 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 harboring two different mutations in presenilin 1 (PSEN1).</p> Methods Patients underwent neurological and neuropsychological examination, MRI, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), amyloid-related biomarkers, and next-generation sequencing (NGS) testing.</p> Results Four patients, aged 25-45 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 year 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 (CSF) or imaging biomarkers. Two heterozygous likely pathogenic mutations in PSEN1 (p.Pro88Leu and p.Leu166Pro) were found in the NGS testing.</p> Conclusion Clinically defined PLS is a syndrome encompassing different neurodegenerative diseases. The NGS testing should be part of the diagnostic workup in patients with PLS, at least in those with red flags, such as early-onset, cognitive impairment, and/or family history of neurodegenerative diseases.</p>

Keywords

• primary lateral sclerosis; progressive spastic paraparesis; Alzheimer's disease; PSEN1 mutation; motor neuron disease