Cerebral Amyloid Angiopathy, Itm2b-Related, 2

A number sign (#) is used with this entry because of evidence that the disorder is caused by mutation in the ITM2B gene (603904), which is also the site of mutation in familial British dementia (FBD; 176500).

Clinical Features

Stromgrem et al. (1970) described this syndrome in 9 persons in 5 generations of a Danish family. Intention tremor was present. Paranoid psychosis or increasing dementia occurred in late life. Posterior polar cataracts appeared between ages 20 and 30, and deafness which appeared about the same time became severe by age 45. In a follow-up, Stromgrem (1981) presented a pedigree with affected persons in 5 sibships of 4 generations but no male-to-male transmission. The brain was examined in 1 case; 'the dominating pathological feature was an accumulation of large quantities of cholesterol and cholesterol compounds freely in the tissue and, to a lesser degree, in glial cells, walls and lumina of vessels.' Stromgrem (1982) reported that further cases had appeared in the family in the 2.5 years since he prepared the follow-up.

Cataracts seem to be the first manifestation of familial Danish dementia, starting before the age of 30, whereas impaired hearing usually develops 10 to 20 years later. Cerebellar ataxia occurs shortly after the age of 40, followed by paranoid psychosis and dementia 10 years later. Most patients die in their fifth to sixth decade of life. Neuropathologically, the disease is characterized by a uniform diffuse atrophy of all parts of the brain; a very severe chronic diffuse encephalopathy, mostly in the cerebellum, the cerebral cortex, and the white matter; and the presence of extremely thin and almost completely demyelinated cranial nerves. A widespread amyloid angiopathy is present in the blood vessels of the cerebrum, choroid plexus, cerebellum, spinal cord, and retina. The presence of plaques and neurofibrillary tangles is the major histopathologic finding in the hippocampus, whereas the cerebral white matter also shows some ischemic lesions (Vidal et al., 2000).

Molecular Genetics

Vidal et al. (2000) reported the isolation and biochemical characterization of a de novo-created amyloid protein and the identification of the genetic defect in the ITM2B gene (603904.0002) that results in dementia in the Danish kindred originally reported by Stromgrem et al. (1970).

Pathogenesis

Like Alzheimer disease (AD; 104300), FBD and FDD are associated with amyloid deposition and neurodegeneration in the central nervous system. In addition, proteins of the complement system and their proinflammatory activation products, which are among the inflammatory markers associated with lesions characteristic of AD, are also associated with FBD and FDD. Rostagno et al. (2002) showed that parenchymal plaques and cerebrovascular amyloid deposits in FBD and FDD brain sections contained complement activation products of the classical and alternative pathways, including iC3b, C4d, Bb, and C5b-9. Hemolytic studies of amyloid peptides from FBD (ABri) and FDD (ADan) showed specific binding to C1q and activation of both the classical (70-75% of activation) and alternative pathways (25-30% of activation), at levels comparable to those generated by beta-amyloid 1-42 in AD. Rostagno et al. (2002) suggested that the chronic inflammatory response generated by amyloid peptides may be a contributing factor to the pathogenesis of FBD, FDD, and AD.

Animal Model

Coomaraswamy et al. (2010) developed transgenic mice expressing the Danish mutant form of ITM2B (603904.0002). Immunohistochemical analysis detected the Danish amyloid (ADan) peptide at 2 months of age in hippocampus and meningeal vessels. By 18 months, ADan deposition was detected throughout the brain, with the majority of ADan deposits associated with the vasculature. In larger vessels, ADan was confined to the vessel wall with a sheet-like appearance. In smaller vessels, ADan often completely obstructed the vessel lumen. ADan appeared to be integrated into the endothelial and vascular basement membrane and led to abnormal thickening of the membrane, with destruction of vessel wall integrity and loss of vascular smooth muscle cells with age. ADan lesions evoked a neuroinflammatory response and were associated with microhemorrhage, neuritic dystrophy, and behavioral changes, including impaired function in the Morris water maze and increased anxiety in the open field.