Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family

Abstract

Objective: To report, for the first time, a large autosomal dominant Alzheimer disease (AD) family in which the APP A713T mutation is present in the homozygous and heterozygous state. To date, the mutation has been reported as dominant, and in the heterozygous state associated with familial AD and cerebrovascular lesions. Methods:The family described here has been genealogically reconstructed over 6 generations dating back to the 19th century. Plasma b-amyloid peptide was measured. Sequencing of causative AD genes was performed.Results: Twenty-one individuals, all but 1 born from 2 consanguineous unions, were studied: 8 were described as affected through history, 5 were studied clinically and genetically, and 8 were asymptomatic at-risk subjects. The A713T mutation was detected in the homozygous state in 3 patients and in the heterozygous state in 8 subjects (6 asymptomatic and 2 affected).Conclusions: Our findings, also supported by the b-amyloid plasma assay, confirm (1) the pathogenic role of the APP A713T mutation, (2) the specific phenotype (AD with cerebrovascular lesions) associated with this mutation, and (3) the large span of age at onset, not influenced by APOE, TOMM40, and TREM2 genes. No substantial differences concerning clinical phenotype were evidenced between heterozygous and homozygous patients, in line with the classic definition of dominance. Therefore, in this study, AD followed the classic definition of a dominant disease, contrary to that reported in a previously described AD family with recessive APP mutation. This confirms that genetic AD may be considered a disease with dominant and recessive traits of inheritance. Neurology ® 2015;84:2266-2273 GLOSSARY Ab 5 b-amyloid; AD 5 Alzheimer disease; ADL 5 activities of daily living; AMC 5 affected mutation carrier; APP 5 amyloid precursor protein; ASMC 5 asymptomatic mutation carrier; CVL 5 cerebrovascular lesion; FDG 5 fluorodeoxyglucose; HIS 5 Hachinski Ischemic Score; IADL 5 instrumental activities of daily living; MMSE 5 Mini-Mental State Examination; NMC 5 non-mutation carrier; PolyPhen-2 5 Polymorphism Phenotyping 2; PSEN1 5 presenilin 1; PSEN2 5 presenilin 2; SIFT 5 sorting intolerant from tolerant.

Molecular genetics of early‐onset Alzheimer's disease revisited

“…For clarity, a general g-secretase cleavage site is reported. severely affected [54,55]. The major implication of these findings is that the homozygous state of autosomal dominant mutations in AD is not lethal as initially hypothesized.…”

“…PSEN mutations are commonly inherited in an autosomal dominant manner, but de novo mutations in PSEN1 have been described in EOAD patients with disease onset as early as 28 years [52,53]. Two families have been described that segregate dominant EOAD mutations in a homozygous state, a Italian family with the APP mutation p.A713T [54] and a Colombian family with the PSEN1 mutation p.E280A [55]. In both families, the homozygous carriers did not seem to be more web 4C=FPO web 4C=FPO In red are the two recessive pathogenic mutations, in gray the nonpathogenic mutations.…”

Low Florbetapir PET Uptake and Normal Aβ1-42 Cerebrospinal Fluid in an APP Ala713Thr Mutation Carrier

“…The potential AD pathogenicity of APP Ala713Thr (g.275329G>A) variant is confirmed by segregation of the mutation with the disease [8,9,28,29], absence of the mutation in control subjects [8,9,28], and results of bioinformatics analysis [30].…”

“…Despite these considerations, asymptomatic subjects of heterozygous carriers have been reported [8,9]; since these cases were mainly younger than 65 years [8] or than the average age at onset of respective affected family members [9], they cannot be considered spared from the disease. Moreover, an incomplete penetrance of the mutation may be supposed in order to explain this phenomenon, as other genetic or environmental factors could be necessary for the expression/unexpression of AD phenotype [7].…”

“…Among APP mutations, the APP Ala713Thr was considered by some authors as a possible nonpathogenic polymorphism [7]; more recently, the variant has been associated with autosomal dominant familial AD (FAD) with cerebrovascular lesions in Calabrian families [8,9], and no relevant differences in clinical phenotype were found between heterozygous and homozygous patients, according to the definition of dominance [9].…”