Familial British dementia FBD and familial encephalopathy with neuronal dementia with neuroserpin deposits

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Recently, two very rare forms of inherited dementia (Familial British dementia and familial encepha-lopathy with neuroserpin inclusion bodies (FEN1B)) have been described which support the emerging concept that many of the inherited dementias are disorders of protein processing in which there is either intracellular or extracellular toxic accumulation of misfolded/misprocessed proteins, a theme common to all of the diseases discussed here.

Familial British dementia is characterized by spasticity, ataxia, and later progressive dementia accompanied by widespread demyelination, with distinctive perivascular fibrous deposits that are clearly different from the plaques of AD. A T—>A transversion mutation in the stop codon of the BRI

gene on chr 13 causes the addition of several amino acids at the C-terminus of the BRI protein (Vidal et al., 1999). While the normal function of the BRI protein is unknown, the presence of the extra C-terminal amino acids causes the protein to be misprocessed by a Furin-mediated cleavage. This causes the accumulation of a 34 amino acid C-terminal derivative termed the ABRI peptide that assembles into toxic amyloid deposits through mechanisms which remain to be elucidated (Kim etal., 1999).

Missense mutations in neuroserpin, a neuron-specific serine protease inhibitor (serpin), have been described in two pedigrees with a familial dementia (Davis etal., 1999). In these families with FEN1B the mutant neuroserpin forms typical serpin loop-sheet polymers that assemble into fibrous aggregates which appear as 5—50 mm PASpositive eosinophilic inclusions called ''Collins bodies'' in the deep layers of the cerebral cortex, subcortical nuclei and substantia nigra.

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