Clinical-Genetic Correlations in Familial Alzheimer's Disease Caused by Presenilin 1 Mutations

Abstract

We describe the clinical phenotype of nine kindred with presenile Alzheimer's disease (AD) caused by different presenilin 1 (PS1) point mutations, and compare them with reported families with mutations in the same codons. Mutations were in exon 4 (Phe105Val), exon 5 (Pro117Arg, Glu120Gly), exon 6 (His163Arg), exon 7 (Leu226Phe), exon 8 (Val261Leu, Val272Ala, Leu282Arg), and exon 12 (Ile439Ser). Three of these amino acid changes (Phe105Val, Glu120Gly, and Ile439Ser) had not been previously reported. Distinct clinical features, including age of onset, symptoms and signs associated with the cortical-type dementia and aggressiveness of the disease, characterized the different mutations and were quite homogeneous across family members. Age of onset fell within a consistent range: some mutations caused the disease in the thirties (P117R, L226F, V272A), other in the forties (E120G, H163R, V261L, L282R), and other in the fifties (F105V, I439S). Associated features also segregated with specific mutations: early epileptic activity (E120G), spastic paraparesis (V261L), subcortical dementia and parkinsonism (V272A), early language impairment, frontal signs, and myoclonus (L226F), and late myoclonus and seizures (H163R, L282R). Neurological deterioration was particularly aggressive in PS1 mutations with earlier age of onset such as P117R, L226F, and E120G. With few exceptions, a similar clinical phenotype was found in families reported to have either the same mutation or different amino acid changes in the same codons. This series points to a strong influence of the specific genetic defect in the development of the clinical phenotype.

The Correlation between Genotype and Phenotype of Alzheimer's Disease

“…PSEN-1 mutations show almost complete penetrance by the age of 60 years. However, there are some recorded exceptions such as the p.A79V (78 years) [47,82,104,105], p.H163R (68 years) [101,[106][107][108] and p.L271V mutations (68 years) [109]. The factors that contribute to reduced penetrance are not at present known.…”

“…BPS sufficient to be reported as suggestive of the phenotype of frontotemporal dementia (FTD) has been noted in the patients carrying PSEN-1 mutations including p.L113P [146], p.M139V [111], p.L226F [101,147], p.M233L [148], p.V412I [71] and PSEN-2 mutations including p.T122R and p.Y231C [149]. In one case carrying p.G183V within PSEN-1, the neuropathological appearances were of Pick's disease without AD amyloid plaques [150].…”

“…The reported families that developed myoclonus carrying the PSEN-1 mutations including p.L113Q, p.Y115H [46], p.P117R, p.H163R [101], p.S169P [122,123], p.S169L [90,91], p.S170F [94], p.L235P, p.R269H [98], p.L250V [124], and p.R269G [125]. The epilepsy/seizure-associated PSEN-1 mutations are spread throughout the PSEN-1.…”

“…There are also some family members with the mutation p.P117A [74,75], p.P117L [76][77][78] and p.L173W [79] have recently been recorded with onset at 24 years. Very early onset of cognitive decline, before age 30 years, has been noted with the following PSEN-1 mutations: p.L85P [80], p.T116N [81][82][83][84], p.P117S [77], p.I143T [82,83,[85][86][87], InsFI [82,88], p.L166H [89], p.S169L [90,91], p.S170F [92][93][94], p.G209V [95], p.M233V [96], p.M233I [97], p.L235Pr [98], p.Y256S [99], p.A260V [39,100], p.V272A [84,101], p.L381V [102], p.G384A [85], p.L424R [103], and p.A434C [82]. PSEN-1 mutations show almost complete penetrance by the age of 60 years.…”

“…It was autopsy proved in patients with the dupAPP mutation [24], p.V272A mutation [84,101], ΔT440 mutation [137] in the PSEN-1 gene and p.A85V mutation [138] in the PSEN-2 gene.…”