Striking phenotypic variation in a family with the P506S UBQLN2 mutation including amyotrophic lateral sclerosis, spastic paraplegia and frontotemporal dementia

TY - JOUR

T1 - Striking phenotypic variation in a family with the P506S UBQLN2 mutation including amyotrophic lateral sclerosis, spastic paraplegia and frontotemporal dementia

AU - Gkazi, Soragia Athina

AU - Troakes, Claire

AU - Topp, Simon

AU - Miller, Jack W.

AU - Vance, Caroline A.

AU - Sreedharan, Jemeen

AU - Al-Chalabi, Ammar

AU - Kirby, Janine

AU - Shaw, Pamela J.

AU - Al-Sarraj, Safa

AU - King, Andrew

AU - Smith, Bradley N.

AU - Shaw, Christopher E.

PY - 2019/1

Y1 - 2019/1

N2 - Analysis of 226 exome-sequenced UK cases of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia identified 2 individuals who harbored a P497H and P506S UBQLN2 mutation, respectively (n = 0.9%). The P506S index case presented with behavioral variant frontotemporal dementia at the age of 54 years then progressed to ALS surviving 3 years. Three sons presented with (1) slowly progressive pure spastic paraplegia with an onset at 25 years and (2) ALS with disease onset of 25 years and survival of 2 years, and (3) ALS presenting symptoms at the age of 26 years, respectively. Analysis of postmortem tissue from the index case revealed frequent neuronal cytoplasmic UBQLN2-positive inclusions in the dentate gyrus and TDP-43-positive neuronal cytoplasmic inclusions in the frontal and temporal cortex and granular cell layer of the dentate gyrus of the hippocampus. Furthermore, a comprehensive analysis of published UBQLN2 mutations demonstrated that only proline-rich domain mutations contribute to a significantly earlier age of onset in male patients (p = 0.0026).

AB - Analysis of 226 exome-sequenced UK cases of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia identified 2 individuals who harbored a P497H and P506S UBQLN2 mutation, respectively (n = 0.9%). The P506S index case presented with behavioral variant frontotemporal dementia at the age of 54 years then progressed to ALS surviving 3 years. Three sons presented with (1) slowly progressive pure spastic paraplegia with an onset at 25 years and (2) ALS with disease onset of 25 years and survival of 2 years, and (3) ALS presenting symptoms at the age of 26 years, respectively. Analysis of postmortem tissue from the index case revealed frequent neuronal cytoplasmic UBQLN2-positive inclusions in the dentate gyrus and TDP-43-positive neuronal cytoplasmic inclusions in the frontal and temporal cortex and granular cell layer of the dentate gyrus of the hippocampus. Furthermore, a comprehensive analysis of published UBQLN2 mutations demonstrated that only proline-rich domain mutations contribute to a significantly earlier age of onset in male patients (p = 0.0026).

KW - Familial amyotrophic lateral sclerosis (FALS)

KW - Frontotemporal dementia (FTD)

KW - Spastic paraplegia (SP)

KW - UBQLN2

UR - http://www.scopus.com/inward/record.url?scp=85055047566&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2018.08.015

DO - 10.1016/j.neurobiolaging.2018.08.015

M3 - Article

SN - 0197-4580

VL - 73

SP - 229.e5-229.e9

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -