Familial British dementia
by André Delacourte
Familial British dementia (FBD) and Familial Danish dementia (FDD) are early-onset autosomal dominant disorders characterised by progressive cognitive impairment, spasticity, and cerebellar ataxia.
Hippocampal neurofibrillar degeneration and widespread parenchymal and vascular amyloid deposits are the main neuropathological lesions.
Familial cerebral amyloid angiopathy-British type for FBD. Heredopathia ophthalmo-oto-encephalica for FDD.
Symptoms and course
FBD is characterised by an impaired recognition and recall memory progressing to dementia, progressive spastic tetraparesis and cerebellar ataxia. The average age of onset is usually 60 years old.
FDD is characterised by cataracts, deafness, progressive ataxia and dementia. The average age of onset is usually 60 years old.
Causes and risk factors
Pure familial disease, with genetic defects on BRI gene provoking the production of an abnormal protein fragment that accumulate in the brain tissue.
Familial British dementia (FBD) and familial Danish dementia (FDD) are associated with a stop codon mutation in the BRI gene located on chromosome 13, resulting in the production of an amyloidogenic fragment, amyloid-Bri (ABri) for FBD and Adan for FDD.
Patients with FBD have a single nucleotide substitution at codon 267 in the BRI2 gene, resulting in an arginine replacing the stop codon and a longer open reading frame of 277 amino acids instead of 266.
Patients with FDD have a presence of a 10-nt duplication (795-796insTTTAATTTGT) between codons 265 and 266, one codon before the normal stop codon 267. The decamer duplication mutation produces a frame-shift in the BRI sequence generating a larger-than-normal precursor protein, of which the amyloid subunit (designated ADan) comprises the last 34 C-terminal amino acids.
Six patients affected in England, and 52 persons at risk in one wellcharacterised family (Mead S. et al, 2000).
Familial British dementia with amyloid angiopathy: early clinical, neuropsychological and imaging findings.
Familial cluster. Early clinical signs : impaired recognition and recall memory, abnormal MRI of the brain, consisting of deep white-matter hyperintensity (T(2)-weighted scans) and lacunar infarcts, but no intracerebral haemorrhage.
The corpus callosum can be severely atrophic. Cataracts and deafness for FDD. Genetic analysis to demonstrate the gene defect on BRI gene.
Ongoing research/Clinical trials
These pathologies could beneficiate of the research on proteopathies (most neurodegenerative disorders are characterised by an aggregation of specific proteins in the brain tissue that could have neurotoxic effects).
- S. Mead, M. James-Galton, T. Revesz, R. B. Doshi, G. Harwood, E. L. Pan, J. Ghiso, B. Frangione, and G. Plant, Familial British dementia with amyloid angiopathy: Early clinical, neuropsychological and imaging findings, Brain, May 1, 2000; 123(5): 975 - 991.
- Vidal, R., B. Frangione, et al. (1999). A stop-codon mutation in the BRI gene associated with familial British dementia. Nature 399(6738): 776-81.
- Vidal, R., T. Revesz, et al. (2000). A decamer duplication in the 3' region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred. Proc Natl Acad Sci U S A 97(9): 4920-5.
Last Updated: Friday 09 October 2009