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    • "Microangiopathic leukoencephalopathy with white matter lacunar infarcts Guerreiro et al., 2008 S130L 2 3, 1 69.0 (n = 3) 65–81 Not found in 110 healthy controls and 100 patients with familial Alzheimer's disease. Does not Tedde et al., 2003; Walker et al., 2005; Tomaino et al., 2007; (continued) "
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    ABSTRACT: Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11 Volga German families, 101 who are likely to have the same N141I mutation in presenilin 2 (54 genotyped confirmed). We have also assessed the detailed neuropathologic findings in 18 autopsies from these families and reviewed the world's literature on other presenilin 2 mutations; presenting a novel mutation that is predicted to lead to a premature truncation codon. Seven presenilin 2 mutations reported in the literature have strong evidence for pathogenicity whereas others may be benign polymorphisms. One hundred and one affected persons, with sufficient historical information from the Volga German pedigrees (N141I mutation), had a mean onset age of 53.7 years+/-7.8 (range 39-75) and mean age at death of 64.2 years+/-9.8 (range 43-88). These figures overlap with and generally fall between the results from the subjects in our centre who have late onset familial Alzheimer's disease or mutations in presenilin 1. Seizures were noted in 20 (30%) of 64 subjects with detailed medical records. Two mutation carriers lived beyond age 80 without developing dementia, representing uncommon examples of decreased penetrance. Two persons had severe amyloid angiopathy and haemorrhagic stroke. Eighteen cases had detailed histopathology available and analysed at our institution. Braak stage was five or six, amyloid angiopathy and neuritic plaques were common and more than 75% had Lewy bodies in the amygdala. TAR DNA-binding protein-43 inclusions were uncommon. In addition, a 58-year-old female with a 2 year course of cognitive decline and no family history of dementia has abnormal fludeoxyglucose-positron emission tomography imaging and a novel 2 base pair deletion in presenilin 2 at nucleotide 342/343, predicted to produce a frame-shift and premature termination. We conclude that mutations in presenilin 2 are rare with only seven being well documented in the literature. The best studied N141I mutation produces an Alzheimer's disease phenotype with a wide range of onset ages overlapping both early and late onset Alzheimer's disease, often associated with seizures, high penetrance and typical Alzheimer's disease neuropathology. A novel premature termination mutation supports loss of function or haploinsufficiency as pathogenic mechanisms in presenilin 2 associated Alzheimer's disease.
    Brain 04/2010; 133(Pt 4):1143-54. DOI:10.1093/brain/awq033 · 9.20 Impact Factor
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    ABSTRACT: Autosomal dominant early-onset Alzheimer disease (EOAD) is a heterogeneous condition that has been associated with mutations in 3 different genes: the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes. Most cases are due to mutations in the PSEN1 gene, whereas mutations in the APP and PSEN2 genes are rare. Mutation analysis of the APP, PSEN1 and PSEN2 genes was performed. We herein report the case of a German EOAD patient with a family history of dementia and a missense mutation at codon 141 (N141I) of the PSEN2 gene. To our knowledge, this is the first German EOAD patient without a Volga-German ancestry and a positive family history for dementia carries the mutation PSEN-2 N141I. The patient came to our clinic for the first time when she was 47 years old. During the following 3 years, her Mini-Mental State Examination (MMSE) score dropped from 28 to 0. Mild cognitive impairment (MCI) was an early symptom that was already present during the first consultation. The concentration in cerebrospinal fluid (CSF) of tau-protein (1151 pg/ml) was increased, whereas the concentration of beta-amyloid protein (Abeta1-42) was decreased (335 pg/ml). Magnetic resonance imaging (MRI) revealed only slight changes in the early stage of the disease and positron emission tomography with (18F) fluoro-2-deoxy-D-glucose (18F-FDG PET) demonstrated glucose reduction left parietal and in the precuneus region. Follow-up MRI and 18F-FDG PET studies showed progression of atrophy of the left entorhinal cortex with relative sparing of the hippocampus and progressive hypometabolism of both temporoparietal lobes and left frontal lobe.
    European journal of medical research 01/2009; 13(12):579-84. · 1.50 Impact Factor
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    BMC Geriatrics 01/2010; DOI:10.1186/1471-2318-10-S1-A90 · 1.68 Impact Factor
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