Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype.
ABSTRACT Eleven early-onset dementia families, all with affected individuals who have either presented clinical symptoms of early onset familial Alzheimer's disease (EOFAD) or have been confirmed to have EOFAD by autopsy, and two early onset cases with biopsy-confirmed AD pathology, were screened for missense mutations in the entire coding region of presenilin-1 (PS-1) and -2 (PS-2) genes. Missense mutations were detected by direct sequence analysis of PCR products amplified from genomic DNA templates of affected individuals. Three pedigrees were attributable to known mutations in the PS-1 gene: P264L, E280A and the splice acceptor site (G to T) mutation, which results in the deletion of residues 290-319 of PS-1 (PS-1 delta 290-319). In a fourth pedigree, a novel PS-1 mutation was identified in exon 7 (M233T), which is homologous to a pathogenic PS-2 mutation (M239V), and is characterized by a very early average age of onset (before the age of 35). In one early onset case, another novel PS-1 mutation was identified in exon 8 (R278T). Of the five remaining families and the other early onset case, none have missense mutations in the PS-1 or PS-2 genes, or in exon 16 and 17 of the APP gene. Moreover, two of the PS-1 mutations, PS-1 delta 290-319 and R278T, are associated with the co-presentation of familial spastic paraparesis (FSP) in some of the affected family members. Our data raise the possibility that the phenotypic spectrum associated with PS-1 mutations may extend beyond typical FAD to include FSP, a disease heretofore unsuspected to bear any relationship to FAD. In addition, our data suggest that other novel EOFAD loci, in addition to APP and the presenilin genes, are involved in the aetiology of up to 50% of EOFAD cases.
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ABSTRACT: Genetic analyses of patients with neurodegenerative disorders have identified multiple genes that need to be investigated for the presence of damaging variants. However, mutation analysis by Sanger sequencing is costly and time consuming. We tested the utility of a recently designed semi-custom genome-wide array (NeuroX; Illumina, Inc) tailored to study neurodegenerative diseases (e.g., mutation screening). We investigated 192 patients with 4 different neurodegenerative disorders for the presence of rare damaging variations in 77 genes implicated in these diseases. Several causative mutations were identified and confirmed by Sanger sequencing, including PSEN1 p.M233T responsible for Alzheimer's disease in a large Italian family, as well as SOD1 p.A4V and p.I113T in patients with amyotrophic lateral sclerosis. In total, we identified 78 potentially damaging rare variants (frequency <1%), including ABCA7 p.L400V in a family with Alzheimer's disease and LRRK2 p.R1514Q in 6 of 98 patients with Parkinson's disease (6.1%). In conclusion, NeuroX appears to be helpful for rapid and accurate mutation screening, although further development may be still required to improve some current caveats.Neurobiology of Aging 08/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.07.038 · 4.85 Impact Factor
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ABSTRACT: In recent years, galanthamine isolated from several members of the Amaryllidaceae (Leucojum spp., Narcissus species, Galanthus spp.) has become an important therapeutic options used to slow down the process of neurological degeneration in Alzheimer’s disease. This review traces aspects of the history of its development from little known observational studies in the Caucasus Mountains (Southern Russia), to the use of this drug in Eastern European countries (esp. Bulgaria) in the treatment of poliomyelitis and ultimately to the recent introduction onto Western markets in the treatment of Alzheimer’s disease. Of note, little is known about the early history of the drug’s development and the review also points to other gaps in our knowledge about the ethnopharmacology, pharmacology and clinical use of galanthamine.Journal of Ethnopharmacology 06/2004; 92(2-3):147-162. DOI:10.1016/S0378-8741(04)00073-X · 2.94 Impact Factor
Article: The genetics of Alzheimer’s disease[Show abstract] [Hide abstract]
ABSTRACT: Alzheimer's disease (AD) is a complex and heterogeneous neurodegenerative disorder, classified as either early onset (under 65 years of age), or late onset (over 65 years of age). Three main genes are involved in early onset AD: amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2). The apolipoprotein E (APOE) E4 allele has been found to be a main risk factor for late-onset Alzheimer's disease. Additionally, genome-wide association studies (GWASs) have identified several genes that might be potential risk factors for AD, including clusterin (CLU), complement receptor 1 (CR1), phosphatidylinositol binding clathrin assembly protein (PICALM), and sortilin-related receptor (SORL1). Recent studies have discovered additional novel genes that might be involved in late-onset AD, such as triggering receptor expressed on myeloid cells 2 (TREM2) and cluster of differentiation 33 (CD33). Identification of new AD-related genes is important for better understanding of the pathomechanisms leading to neurodegeneration. Since the differential diagnoses of neurodegenerative disorders are difficult, especially in the early stages, genetic testing is essential for diagnostic processes. Next-generation sequencing studies have been successfully used for detecting mutations, monitoring the epigenetic changes, and analyzing transcriptomes. These studies may be a promising approach toward understanding the complete genetic mechanisms of diverse genetic disorders such as AD.Clinical Interventions in Aging 04/2014; 9:535-551. DOI:10.2147/CIA.S51571 · 1.82 Impact Factor