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From the Departments of Neurological Sciences (Drs. Filla, De Michele, Volpe, and Bonavita), Departments of Molecular and Cellular Biology and Pathology and CEOS (Drs. Cocozza and Ruggiero, and I. Castaldo), Federico II University, Naples; Neurogenetic Center (Dr. Bruni), Lametia Terme; Telethon Institute of Genetics and Medicine and SCRI-San Raffaele Hospital (A. Patrignani and Dr. Casari), Milan, Italy; and Department of Pathology (Dr. Masters), Melbourne University, Australia.
Address correspondence and reprint requests to Dr. Alessandro Filla, Dipartimento di Scienze Neurologiche, Università "Federico II", via Pansini 5, 80131 Napoli, Italy; e-mail: afilla{at}unina.it
Objective: To perform a clinical and molecular study of a large autosomal dominant family with a complex neurologic syndrome that comprises early-onset dementia, extrapyramidal and cerebellar features, and epilepsy.
Background: Early-onset forms of dementia often are caused by genetic factors. Mutations of three different genes—amyloid precursor protein (APP), presenilin 1 (PS-1), presenilin 2 (PS-2)—have been found in early-onset autosomal dominant forms of AD, of the human microtubule associated-protein tau gene (MAPT) in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), of the BRI gene in familial British dementia, of the PI12 gene in familial encephalopathy with neuroserpin inclusion bodies. Linkage to chromosome 3 has been found in familial nonspecific dementia (FND) and linkage to chromosome 20 has been found in Huntington disease (HD)-like neurodegenerative disease. Dementia may be a feature of other neurodegenerative diseases such as HD, dentatorubro-pallidoluysian atrophy (DRPLA), diseases caused by mutations of the prion protein gene (PRNP), spinocerebellar ataxias (SCA), and familial parkinsonism.
Methods: A southern Italian family with autosomal dominant dementia-plus was observed. The family includes 57 individuals in 5 generations (14 affected, 7 personally observed). The authors performed linkage analysis to APP, PS-1, PS-2, FTDP-17, BRI, PI12, FND, HD-like, SCA4, SCA5, SCA10, SCA11, SCA13, PARK1, PARK2, PARK3 loci; direct mutation analysis of HD, DRPLA, SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, and PRNP genes; and sequencing of the PRNP open reading frame.
Results: Linkage to the examined loci was excluded. All of the direct mutation analyses were negative excluding mutations in the examined genes.
Conclusions: This family has a peculiar phenotype and molecular analyses excluded genes known to cause hereditary dementias.
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