ClinVar Genomic variation as it relates to human health

In a patient with early-onset familial Alzheimer disease (104300), Kamino et al. (1992) identified an A-to-G transition in the APP gene, resulting in a glu693-to-gly (E693G) substitution. The mutation is referred to as E22G in the processed beta-amyloid protein. The proband was from a family with early-onset familial Alzheimer disease spanning 3 generations. He had onset of disease at age 56 years, and postmortem examination found neuritic amyloid plaques and tau-positive neurofibrillary tangles. Moderate to severe amyloid was deposited in the cortical and leptomeningeal arteries. The mutation was not identified in 126 other FAD families. Other mutations of codon 693 cause hereditary cerebral hemorrhage and amyloidosis (see 609095) of the Dutch type (E693Q; 104760.0001) and Italian type (E693K; 104760.0014). Miravalle et al. (2000) referred to the E693G mutation as the 'Arctic mutation.' Nilsberth et al. (2001) identified the E693G mutation in affected members of a large Swedish family with AD. Mutation carriers had decreased levels of plasma beta-amyloid-40 and -42. Cells transfected with the mutation showed increased rates and amounts of protofibril formation. Nilsberth et al. (2001) postulated that the pathogenic mechanism for AD in patients with the E693G mutation may involve rapid beta-amyloid protofibril formation leading to accelerated buildup of insoluble beta-amyloid intra- and/or extracellularly. In vitro, the Arctic mutant form of A-beta forms protofibrils and fibrils at higher rates and in larger quantities than wildtype A-beta. In transgenic mice that expressed the Arctic mutant in neurons, Cheng et al. (2004) found that amyloid plaques formed faster and were more extensive compared to control mice. Cheng et al. (2004) concluded that the Arctic mutation is highly amyloidogenic in vivo. Basun et al. (2008) restudied the clinical features of the American and Swedish families with the E693G mutation reported by Kamino et al. (1992) and Nilsberth et al. (2001), respectively. They noted that the American family was descended from Swedish immigrants. Affected individuals typically presented between age 52 and 65 years, with slow deterioration of cognitive function typical of AD, as well as some additional symptoms such as disorientation, dysphasia, and dyspraxia. None of the patients had a history of cerebrovascular events. Neuropathologic examination of 2 patients showed severe congophilic angiopathy of multiple vessels, amyloid plaques in a ring form without a core, neurofibrillary tangles, and neuronal loss. The amyloid plaques were strongly immunopositive for beta-amyloid-40 and -42, showed neuritic features, and were negative for Congo red. (less)

In a patient with early-onset familial Alzheimer disease (104300), Kamino et al. (1992) identified an A-to-G transition in the APP gene, resulting in a glu693-to-gly (E693G) substitution. The mutation is referred to as E22G in the processed beta-amyloid protein. The proband was from a family with early-onset familial Alzheimer disease spanning 3 generations. He had onset of disease at age 56 years, and postmortem examination found neuritic amyloid plaques and tau-positive neurofibrillary tangles. Moderate to severe amyloid was deposited in the cortical and leptomeningeal arteries. The mutation was not identified in 126 other FAD families. Other mutations of codon 693 cause hereditary cerebral hemorrhage and amyloidosis (see 609095) of the Dutch type (E693Q; 104760.0001) and Italian type (E693K; 104760.0014). Miravalle et al. (2000) referred to the E693G mutation as the 'Arctic mutation.' Nilsberth et al. (2001) identified the E693G mutation in affected members of a large Swedish family with AD. Mutation carriers had decreased levels of plasma beta-amyloid-40 and -42. Cells transfected with the mutation showed increased rates and amounts of protofibril formation. Nilsberth et al. (2001) postulated that the pathogenic mechanism for AD in patients with the E693G mutation may involve rapid beta-amyloid protofibril formation leading to accelerated buildup of insoluble beta-amyloid intra- and/or extracellularly. In vitro, the Arctic mutant form of A-beta forms protofibrils and fibrils at higher rates and in larger quantities than wildtype A-beta. In transgenic mice that expressed the Arctic mutant in neurons, Cheng et al. (2004) found that amyloid plaques formed faster and were more extensive compared to control mice. Cheng et al. (2004) concluded that the Arctic mutation is highly amyloidogenic in vivo. Basun et al. (2008) restudied the clinical features of the American and Swedish families with the E693G mutation reported by Kamino et al. (1992) and Nilsberth et al. (2001), respectively. They noted that the American family was descended from Swedish immigrants. Affected individuals typically presented between age 52 and 65 years, with slow deterioration of cognitive function typical of AD, as well as some additional symptoms such as disorientation, dysphasia, and dyspraxia. None of the patients had a history of cerebrovascular events. Neuropathologic examination of 2 patients showed severe congophilic angiopathy of multiple vessels, amyloid plaques in a ring form without a core, neurofibrillary tangles, and neuronal loss. The amyloid plaques were strongly immunopositive for beta-amyloid-40 and -42, showed neuritic features, and were negative for Congo red. (less)