Abstract #6

Presenter

Madison Gray is currently a PGY5 resident in Neuropathology at Western University in London, Ontario. He completed medical school at the University of Ottawa and a PhD focused on cerebellar development at SickKids and the University of Toronto. His clinical interests include perinatal and forensic neuropathology. Current research focuses on identifying synaptic cues that promote multisensory integration in the developing cerebellum and identifying connectional changes resulting from perinatal brain injury.

Authors

Madison T. Gray ¹, Elizabeth Finger ², Lee Cyn Ang ^1,2

¹ Department of Pathology and Laboratory Medicine

² Department of Clinical Neurological Sciences, Schulich School of Medicine, Western University, London, ON, Canada

CanMEDS:
Medical Expert (the integrating role), Scholar

Progressive Supranuclear Palsy: A Novel Phenotype Of Germline Sqstm1 (p62) Mutation

A woman presented at age 61 with anhedonia and emotional lability with an MMSE of 28/30. Two years after presentation, she developed disinhibition ― notably inappropriate giggling ― as well as a wide-based gait.  Five years after initial presentation, there was the development of ocular abnormalities including saccadic intrusions and upgaze limitation. Fine motor movements were slower and less elegant on the left. The patient passed away in a nursing home seven years after presentation. 

Family history was notable for a father and paternal grandmother who were prone to giggle and have angry outbursts. Neither carried a formal neurological diagnosis. Antemortem genetic testing in our patient revealed a c.1211T>C(p. Met404Thr) mutation in SQSTM1(p62).

At autopsy, there was moderate frontotemporal atrophy. Histological sections showed atrophy and gliosis of the subthalamic nucleus. Grumose degeneration of the dentate nucleus was also present. p62 and phosphorylated-tau(AT8) immunostaining demonstrated globose tangles most prominent in substantia nigra, pontine nuclei, and inferior olive. Neurofibrillary tangles were rare in cortex and basal ganglia where tufted astrocytes and coiled bodies predominated. No abnormal beta-amyloid, TDP-43, or alpha-synuclein staining was present. This was consistent with a pathological diagnosis of progressive supranuclear palsy (PSP).

Mutations of SQSTM1(p62) have been associated with FTLD/ALS, and inclusion body myositis-like myopathy, and familial Paget disease of bone. Here, we report (to our knowledge) the first case of SQSTM1 mutation presenting with pathologically-confirmed PSP. The mutation in this case (p.Met404Thr) has been reported to impair ubiquitin binding and has not previously been associated with neurodegenerative disease.