Authors :
Danielle Andrade, MD, MSc, FRCPC – Institute of Medical Science, University of Toronto
Anne S. Bassett, CM, MD, FRCPC – The Dalglish Family 22q Clinic, Department of Mental Health and Division of Cardiology, and Toronto General Hospital Research Institute, Toronto, Ontario, Canada
Quratulain Zulfiqar Ali, MD, MSc (c) – University of Toronto, University Health Network
Presenting Author: Victor Lira, MD, CSCN (EEG). MSc (c) – University of Toronto, University Health Network
Nikolai Gil Reyes, MD – Edmond J. Safra Program in Parkinson's Disease and Morton and Gloria Shulman Movement Disorders Centre, Krembil Research Institute, Toronto Western Hospital, University of Toronto, Toronto, Canada
M. Carmela Tartaglia, MD – Division of Neurology, Department of Medicine, Toronto Western Hospital, Krembil Neuroscience Centre, University of Toronto, Toronto, Canada
Alfonso Fasaho, MD, PhD, FAAN – Edmond J. Safra Program in Parkinson's Disease and Morton and Gloria Shulman Movement Disorders Centre, Division of Neurology, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada,
Gabor G. Kovacs, MD, PhD, FRCPC – Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Laboratory Medicine Program & Krembil Brain Institute, Toronto Ontario, Canada.
Rationale:
Dravet syndrome (DS) is a developmental and epileptic encephalopathy associated with pathogenic variants in the SCN1A gene in over 80% of cases. Despite high mortality, 80-90% of patients survive childhood. As such, the adult manifestations of this condition are not well understood. Increasing accessibility of genetic testing has meant that more adults are diagnosed with DS due to SCN1A pathogenic variants (SCN1A-DS), thereby increasing the chances of improved understanding of aging within a molecularly defined group. This, in addition to the imminent availability of precision therapies, it is imperative to understand the natural history of DS, to determine and evaluate therapeutic goals. There are only a few adult cases with detailed neuropathological examination reported in the literature and here we report the postmortem findings of a 55-year-old woman with DS due to a confirmed SCN1A pathogenic variant leading to Nav1.1 loss-of-function. Clinically, she developed pharmacoresistant seizures, intellectual disability, progressive ataxia, parkinsonism, and cognitive decline.
Methods:
Histopathological analysis was carried out using formalin-fixed, paraffin-embedded, 4.5-μm-thick sections from various regions of the brain. Histological examination was performed using Luxol fast blue-hematoxylin and eosin (LFB-H&E) and Periodic-Acid-Schiff staining (PAS). Immunohistochemistry (IHC) was performed using the following primary antibodies: phosphorylated-tau, Aβ, a-synuclein, p62, and phosphorylated (p)-TDP-43. Subsequently, all sections were counterstained with haematoxylin.
Results:
Neuropathological examination revealed a striking excess and several layers of corpora amylacea (wasteosomes) covering the whole convexity of the brain. In addition, abundant p62-positive gray matter neuritic profiles were found mostly in limbic regions and in the white matter in neocortical regions. Pericellular TMEM106B-positive deposits were also observed. There was severe Purkinje cell loss in some lobes of the cerebellum together with variable neuronal loss in the substantia nigra, neocortex, and hippocampus. No a-synuclein, amyloid-b, or phospho-TDP-43 pathology was present. Immunostaining for phosphorylated tau revealed neurofibrillary pathology consistent with Braak stage I (left) –II (right) (Figure 1).
Conclusions:
In summary, our study reveals pathological alterations suggestive of chronic glymphatic insufficiency, impaired autophagy and some degree of neuronal loss without misfolded protein deposits. These findings are suggestive of an accelerated aging and neurodegenerative process in this adult with DS.
Funding: None