Spastic paraplegia preceding PSEN1‐related familial Alzheimer's disease

Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring

Leonidas Stefanis¹  Muhammad Ilyas²  David Murphy³  John Hardy⁴  George Vavougios⁵  Athanasia Alexoudi⁶  Stylianos Gatzonis⁶  Viorica Chelban⁷  Thomas Bourinaris⁷  Chia‐Ju Lee⁷  Jana Vandrovcova⁷  Sondos Alikhwan⁷  Henry Houlden⁷  Nicholas W. Wood⁷  Ingmar Blumcke⁸  Coras Ronald⁸  Lucía Chávez‐Gutiérrez⁹  Maria Szaruga⁹  Sobia Ahsan Halim^1,10  Ahmed Al‐Harrasi^1,10  Chrisoula Kartanou^1,11  Marianthi Breza^1,11  Georgia Karadima^1,11  Georgios Koutsis^1,11 

[1] 1st Department of Neurology School of Medicine Eginition Hospital National and Kapodistrian University of Athens Athens Greece;Centre for Omic Science Islamia College Peshawar Peshawar Pakistan;Department of Clinical and Movement Neurosciences Queen Square Institute of Neurology University College London London UK;Department of Neurodegenerative Disease Reta Lila Weston Laboratories Queen Square Genomics UCL Dementia Research Institute London UK;Department of Neurology Athens Naval Hospital Athens Greece;Department of Neurosurgery Evangelismos Hospital University of Athens Greece;Department of Neuromuscular Disease, Queen Square Institute of Neurology University College London London UK;Institute of Neuropathology Universitätsklinikum Erlangen Erlangen Germany;KU Leuven‐VIB Center for Brain & Disease Research Leuven Belgium;Natural and Medical Sciences Research Center University of Nizwa Pakistan;Neurogenetics Unit 1st Department of Neurology Eginition Hospital School of Medicine National and Kapodistrian University of Athens Athens Greece;

关键词: Alzheimer's disease;    dementia;    hereditary spastic paraplegia;    HSP;    presenilin;    PSEN1;   

DOI  :  10.1002/dad2.12186

来源: DOAJ

【 摘 要 】

Abstract Introduction We investigated the frequency, neuropathology, and phenotypic characteristics of spastic paraplegia (SP) that precedes dementia in presenilin 1 (PSEN1) related familial Alzheimer's disease (AD). Methods We performed whole exome sequencing (WES) in 60 probands with hereditary spastic paraplegia (HSP) phenotype that was negative for variants in known HSP‐related genes. Where PSEN1 mutation was identified, brain biopsy was performed. We investigated the link between HSP and AD with PSEN1 in silico pathway analysis and measured in vivo the stability of PSEN1 mutant γ‐secretase. Results We identified a PSEN1 variant (p.Thr291Pro) in an individual presenting with pure SP at 30 years of age. Three years later, SP was associated with severe, fast cognitive decline and amyloid deposition with diffuse cortical plaques on brain biopsy. Biochemical analysis of p.Thr291Pro PSEN1 revealed that although the mutation does not alter active γ‐secretase reconstitution, it destabilizes γ‐secretase‐amyloid precursor protein (APP)/amyloid beta (Aβn) interactions during proteolysis, enhancing the production of longer Aβ peptides. We then extended our analysis to all 226 PSEN1 pathogenic variants reported and show that 7.5% were associated with pure SP onset followed by cognitive decline later in the disease. We found that PSEN1 cases manifesting initially as SP have a later age of onset, are associated with mutations located beyond codon 200, and showed larger diffuse, cored plaques, amyloid‐ring arteries, and severe CAA. Discussion We show that pure SP can precede dementia onset in PSEN1‐related familial AD. We recommend PSEN1 genetic testing in patients presenting with SP with no variants in known HSP‐related genes, particularly when associated with a family history of cognitive decline.

【 授权许可】

Unknown