Worldwide distribution of PSEN1 Met146Leu mutation: a large variability for a founder mutation.
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.
Bruni
A C
AC
Centro Regionale di Neurogenetica, Azienda Sanitaria Provinciale Catanzaro, Viale A. Perugini, 88046 Lamezia Terme (CZ), Italy. bruni@arn.it
Bernardi
L
L
Colao
R
R
Rubino
E
E
Smirne
N
N
Frangipane
F
F
Terni
B
B
Curcio
S A M
SA
Mirabelli
M
M
Clodomiro
A
A
Di Lorenzo
R
R
Maletta
R
R
Anfossi
M
M
Gallo
M
M
Geracitano
S
S
Tomaino
C
C
Muraca
M G
MG
Leotta
A
A
Lio
S G
SG
Pinessi
L
L
Rainero
I
I
Sorbi
S
S
Nee
L
L
Milan
G
G
Pappatà
S
S
Postiglione
A
A
Abbamondi
N
N
Forloni
G
G
St George Hyslop
P
P
Rogaeva
E
E
Bugiani
O
O
Giaccone
G
G
Foncin
J F
JF
Spillantini
M G
MG
Puccio
G
G
D000328:Adult; D000544:Alzheimer Disease / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics* / Q000266:history; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D005192:Family Health; D005260:Female; D019788:Fluorodeoxyglucose F18; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D014943:Global Health; D049670:History, 17th Century; D049674:History, 21st Century; D006801:Humans; D007391:International Cooperation; D007558:Italy; D007930:Leucine / Q000235:genetics*; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000235:genetics; D008715:Methionine / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D049268:Positron-Emission Tomography; D053764:Presenilin-1 / Q000235:genetics*
C508853:PSEN1 protein, human; D053764:Presenilin-1; D019788:Fluorodeoxyglucose F18; D008715:Methionine; D007930:Leucine