Worldwide distribution of PSEN1 Met146Leu mutation: a large variability for a founder mutation

Abstract

Objective: Large kindreds segregating familial Alzheimer disease (FAD) offer the opportunity of studying clinical variability as observed for presenilin 1 (PSEN1) mutations. Two early-onset FAD (EOFAD) Calabrian families with PSEN1 Met146Leu (ATG/CTG) mutation constitute a unique population descending from a remote common ancestor. Recently, several other EOFAD families with the same mutation have been described worldwide.

Methods: We searched for a common founder of the PSEN1 Met146Leu mutation in families with different geographic origins by genealogic and molecular analyses. We also investigated the phenotypic variability at onset in a group of 50 patients (mean age at onset 40.0 +/- 4.8 years) by clinical, neuropsychological, and molecular methodologies.

Results: EOFAD Met146Leu families from around the world resulted to be related and constitute a single kindred originating from Southern Italy before the 17th century. Phenotypic variability at onset is broad: 4 different clinical presentations may be recognized, 2 classic for AD (memory deficits and spatial and temporal disorientation), whereas the others are expressions of frontal impairment. The apathetic and dysexecutive subgroups could be related to orbital-medial prefrontal cortex and dorsolateral prefrontal cortex dysfunction.

Conclusions: Genealogic and molecular findings provided evidence that the PSEN1 Met146Leu families from around the world analyzed in this study are related and represent a single kindred originating from Southern Italy. The marked phenotypic variability might reflect early involvement by the pathologic process of different cortical areas. Although the clinical phenotype is quite variable, the neuropathologic and biochemical characteristics of the lesions account for neurodegenerative processes unmistakably of Alzheimer nature.

Figure 1 Pedigree Extended pedigree representing known affected subjects of all families with Met146Leu mutation and magnification of Naples family pedigree. E = explanted brain; PH = patients hospitalized in psychiatric hospital.

Figure 2 Neuropathology (A–F) Neuropathologic changes were represented by parenchymal Aβ deposits (A, frontal cortex; D, putamen; F, inferior olive: anti-Aβ42 antibody), neurofibrillary tangles and neuropil threads (B, frontal cortex; E, putamen: AT8 antibody), congophilic angiopathy (C, temporal cortex, anti–Aβ40 antibody). (G–H) Immunohistochemical staining showing Tau immunoreactivity in the brain of patients 1768 (G, cortex: RD3 antibody) and 1772 (H, cortex: RD4 antibody). (I) Sarcosyl-insoluble tau from parietal (lane 1), temporal (lane 2), and frontal (lane 3) cortex of the patient appears as 3 major bands at 72, 68, and 64 kDa and a minor band at 60 kDa after immunoblotting with antiserum BR133. Sarcosyl-insoluble tau from AD brain is shown as comparison (lane 4). The human recombinant Tau is reported as marker (lane 5). Bar in A = 25 μm, same magnification in A, B, D, E, and F. Bar in C = 50 μm. Bar in G, H = 30 μm.

Figure 3 Imaging Axial slices of [¹⁸F]FDG-PET scans of control (C) (male, 38 years) and patient (P). Images were normalized in the Montreal Neurological Institute (MNI) space using SPM2 (Wellcome Department of Imaging Neuroscience, London, UK). The images show relative tracer distribution. Compared to control, the patient shows a clear severe metabolic deficit in the temporoparietal, superior parietal, and posterior cingulate cortices. Slight hypometabolism is evident in the mesial temporal and prefrontal cortex. C: Results of SPM analysis highlight the location of hypometabolic deficit in our patient as compared to controls (p < 0.02 uncorrected) (patients vs 14 healthy controls, age range of controls: 27–70, age was considered in the statistical model of SPM as nuisance covariate).