Novel neuropathological observations in an adult with Dravet syndrome.

Abstract

Dravet syndrome (DS) is a developmental and epileptic encephalopathy associated with pathogenic variants in the SCN1A gene. The neuropathological features of adult DS remain poorly understood. 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. 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 and prominent immunoreactivity for aquaporin 4 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 α-synuclein, amyloid-β, or phospho-TDP-43 pathology was present. Immunostaining for phosphorylated tau revealed neurofibrillary pathology consistent with Braak stage I (left) -II (right). In summary, our study reveals pathological alterations suggestive of chronic glymphatic insufficiency, impaired autophagy, and some degree of neuronal loss without currently known misfolded protein deposits. These findings are suggestive of an accelerated aging and neurodegenerative process in this adult with DS.