Category: Clinical Science
At the end of the session, participants will be able to:
- To explore the neuroautopsy findings associated with a novel PFN1 variant of uncertain significance.
- To compare and contrast the in silico modelling methods of predicting pathogenicity of mutations in
familial ALS-implicated genes.
COI Disclosure:
I do not have a relationship with a for-profit and/or a not-for-profit organization to disclose.
Presenter
Dr. Jacob Houpt
Jacob A. Houpt1, Minhal Ahmed2, Michael J. Strong1,2,3, Qi Zhang1
1Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON, Canada.
2Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
3Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Target Audience:
CanMEDS:
Characterization of a novel PFN1 variant associated with a mixed ALS, FTD, and PSP clinical phenotype
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) form a clinicopathological spectrum with diverse genetic causes, among which PFN1 mutations are rare. We report an autopsy case of an 83-year-old woman with a novel heterozygous PFN1 missense variant (c.286G>A; p.Ala96Thr) and a complex multisystem neurological syndrome. The patient presented with progressive dysarthria, dysphagia, asymmetric upper limb weakness with mixed upper and lower motor neuron signs, vertical gaze palsy, eyelid apraxia, retropulsion, and frontotemporal cognitive impairment. Electromyography confirmed multimyotomal denervation. The clinical presentation seemed to be an overlap between ALS, FTD, and progressive supranuclear palsy (PSP), with no single diagnosis accounting for all features. Post-mortem examination revealed widespread TDP-43 inclusions of mixed subtypes (A-D) with a predominance of subtype C, affecting the frontal, temporal, and primary motor cortices, brainstem motor nuclei, and spinal cord anterior horns, with degeneration of corticospinal tracts. Hippocampal sclerosis and age-related tauopathy (PART and ARTAG) were identified as concomitant pathologies. Significant cerebrovascular disease with multifocal infarcts of varying chronicity was also present. TDP-43 inclusions in the basal ganglia and midbrain tegmentum alongside a subacute left medial longitudinal fasciculus infarct likely contributed to the oculomotor findings. While her PFN1 variant was classified as a VUS, in silico analysis using MutationTaster2025 (which evaluates functional consequences of missense variants) predicted a deleterious effect. This contrasted with an overall likely benign composite interpretation, underscoring the limitations of individual algorithmic tools for novel variants. This case illustrates the neuropathological complexity of familial ALS-FTD cases and the interpretive challenges underlying a novel VUS.