Worldwide distribution of PSEN1 Met146Leu mutation

A large variability for a founder mutation

A. C. Bruni, L. Bernardi, R. Colao, E. Rubino, N. Smirne, F. Frangipane, B. Terni, S. A M Curcio, M. Mirabelli, A. Clodomiro, R. Di Lorenzo, R. Maletta, M. Anfossi, M. Gallo, S. Geracitano, C. Tomaino, M. G. Muraca, A. Leotta, S. G. Lio, L. Pinessi & 15 others I. Rainero, S. Sorbi, L. Nee, G. Milan, S. Pappatà, A. Postiglione, N. Abbamondi, G. Forloni, P. St. George Hyslop, E. Rogaeva, O. Bugiani, G. Giaccone, J. F. Foncin, M. G. Spillantini, G. Puccio

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)798-806
Number of pages9
JournalNeurology
Volume74
Issue number10
DOIs
Publication statusPublished - Mar 2010

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Presenilin-1
Mutation
Alzheimer Disease
Flavin-Adenine Dinucleotide
Prefrontal Cortex
Italy
Confusion
Memory Disorders
Pathologic Processes
Age of Onset
Phenotype
Population

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Bruni, A. C., Bernardi, L., Colao, R., Rubino, E., Smirne, N., Frangipane, F., ... Puccio, G. (2010). Worldwide distribution of PSEN1 Met146Leu mutation: A large variability for a founder mutation. Neurology, 74(10), 798-806. https://doi.org/10.1212/WNL.0b013e3181d52785

Worldwide distribution of PSEN1 Met146Leu mutation : A large variability for a founder mutation. / Bruni, A. C.; Bernardi, L.; Colao, R.; Rubino, E.; Smirne, N.; Frangipane, F.; Terni, B.; Curcio, S. A M; Mirabelli, M.; Clodomiro, A.; Di Lorenzo, R.; Maletta, R.; Anfossi, M.; Gallo, M.; Geracitano, S.; Tomaino, C.; Muraca, M. G.; Leotta, A.; Lio, S. G.; Pinessi, L.; Rainero, I.; Sorbi, S.; Nee, L.; Milan, G.; Pappatà, S.; Postiglione, A.; Abbamondi, N.; Forloni, G.; St. George Hyslop, P.; Rogaeva, E.; Bugiani, O.; Giaccone, G.; Foncin, J. F.; Spillantini, M. G.; Puccio, G.

In: Neurology, Vol. 74, No. 10, 03.2010, p. 798-806.

Research output: Contribution to journalArticle

Bruni, AC, Bernardi, L, Colao, R, Rubino, E, Smirne, N, Frangipane, F, Terni, B, Curcio, SAM, Mirabelli, M, Clodomiro, A, Di Lorenzo, R, Maletta, R, Anfossi, M, Gallo, M, Geracitano, S, Tomaino, C, Muraca, MG, Leotta, A, Lio, SG, Pinessi, L, Rainero, I, Sorbi, S, Nee, L, Milan, G, Pappatà, S, Postiglione, A, Abbamondi, N, Forloni, G, St. George Hyslop, P, Rogaeva, E, Bugiani, O, Giaccone, G, Foncin, JF, Spillantini, MG & Puccio, G 2010, 'Worldwide distribution of PSEN1 Met146Leu mutation: A large variability for a founder mutation', Neurology, vol. 74, no. 10, pp. 798-806. https://doi.org/10.1212/WNL.0b013e3181d52785
Bruni AC, Bernardi L, Colao R, Rubino E, Smirne N, Frangipane F et al. Worldwide distribution of PSEN1 Met146Leu mutation: A large variability for a founder mutation. Neurology. 2010 Mar;74(10):798-806. https://doi.org/10.1212/WNL.0b013e3181d52785
Bruni, A. C. ; Bernardi, L. ; Colao, R. ; Rubino, E. ; Smirne, N. ; Frangipane, F. ; Terni, B. ; Curcio, S. A M ; Mirabelli, M. ; Clodomiro, A. ; Di Lorenzo, R. ; Maletta, R. ; Anfossi, M. ; Gallo, M. ; Geracitano, S. ; Tomaino, C. ; Muraca, M. G. ; Leotta, A. ; Lio, S. G. ; Pinessi, L. ; Rainero, I. ; Sorbi, S. ; Nee, L. ; Milan, G. ; Pappatà, S. ; Postiglione, A. ; Abbamondi, N. ; Forloni, G. ; St. George Hyslop, P. ; Rogaeva, E. ; Bugiani, O. ; Giaccone, G. ; Foncin, J. F. ; Spillantini, M. G. ; Puccio, G. / Worldwide distribution of PSEN1 Met146Leu mutation : A large variability for a founder mutation. In: Neurology. 2010 ; Vol. 74, No. 10. pp. 798-806.
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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.",
author = "Bruni, {A. C.} and L. Bernardi and R. Colao and E. Rubino and N. Smirne and F. Frangipane and B. Terni and Curcio, {S. A M} and M. Mirabelli and A. Clodomiro and {Di Lorenzo}, R. and R. Maletta and M. Anfossi and M. Gallo and S. Geracitano and C. Tomaino and Muraca, {M. G.} and A. Leotta and Lio, {S. G.} and L. Pinessi and I. Rainero and S. Sorbi and L. Nee and G. Milan and S. Pappat{\`a} and A. Postiglione and N. Abbamondi and G. Forloni and {St. George Hyslop}, P. and E. Rogaeva and O. Bugiani and G. Giaccone and Foncin, {J. F.} and Spillantini, {M. G.} and G. Puccio",
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T1 - Worldwide distribution of PSEN1 Met146Leu mutation

T2 - A large variability for a founder mutation

AU - Bruni, A. C.

AU - Bernardi, L.

AU - Colao, R.

AU - Rubino, E.

AU - Smirne, N.

AU - Frangipane, F.

AU - Terni, B.

AU - Curcio, S. A M

AU - Mirabelli, M.

AU - Clodomiro, A.

AU - Di Lorenzo, R.

AU - Maletta, R.

AU - Anfossi, M.

AU - Gallo, M.

AU - Geracitano, S.

AU - Tomaino, C.

AU - Muraca, M. G.

AU - Leotta, A.

AU - Lio, S. G.

AU - Pinessi, L.

AU - Rainero, I.

AU - Sorbi, S.

AU - Nee, L.

AU - Milan, G.

AU - Pappatà, S.

AU - Postiglione, A.

AU - Abbamondi, N.

AU - Forloni, G.

AU - St. George Hyslop, P.

AU - Rogaeva, E.

AU - Bugiani, O.

AU - Giaccone, G.

AU - Foncin, J. F.

AU - Spillantini, M. G.

AU - Puccio, G.

PY - 2010/3

Y1 - 2010/3

N2 - 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.

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