NEUROSERPIN MUTATION CAUSES ELECTRICAL STATUS EPILEPTICUS OF SLOW-WAVE SLEEP

Conformational diseases result from cellular dysfunctions induced by aberrant aggregation of proteins. They are caused either by excess of secretion of a normal protein, or more frequently, by mutation in a protein, as in prion diseases. Recently, one of them, familial encephalopathy with neuroserpin inclusion bodies (FENIB, OMIM #604218), an autosomal dominant dementia, was recognized. It is caused by mutations in PI12 (proteinase inhibitor 12, SERPINI1 or neuroserpin, OMIM #602445), a neuron-specific serine proteinase inhibitor (serpin).^1,2 Neuroserpin was first identified in culture medium of chicken axons, then in human neurons.³ It plays roles in synapses and vessel permeability, and is known to be associated with learning, memory, and behavior. It belongs to the serpin super-family, members of which display at least 30% amino acid sequence homology with their archetype, alpha-1-antitrypsin.

Mutated neuroserpin progressively polymerizes in neuronal endoplasmic reticulum, inducing cognitive impairment and sometimes myoclonic epilepsy. Neuropathology is characterized by neuronal intra-cytoplasmic rounded inclusions, homogeneously pale to intensely pink with eosin, and PAS positive after diastase treatment (Collins bodies). Four different mutations have been described in six families affected by FENIB: two in exon 2 (S49P and S52R) and two in exon 9 (H338R and G392E). Known mutations in serpins are localized in the mobile regions of the molecule (exon 2 and 9). They result in proteins …