Larner, A. J. & Doran, M. Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin-1 gene. J. Neurol. 253, 139-158

Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery Fazakerley, Liverpool, UK.
Journal of Neurology (Impact Factor: 3.38). 03/2006; 253(2):139-58. DOI: 10.1007/s00415-005-0019-5
Source: PubMed


It is now 10 years since the first report of mutations in the presenilin genes that were deterministic for familial autosomal dominant Alzheimer's disease. The most common of these mutations occurs in the presenilin-1 gene (PSEN1) located on chromosome 14. In the ensuing decade, more than 100 PSEN1 mutations have been described. The emphasis of these reports has largely been on the novelty of the mutations and their potential pathogenic consequences rather than detailed clinical, neuropsychological, neuroimaging and neuropathological accounts of patients with the mutation. This article reviews the clinical phenotypes of reported PSEN1 mutations, emphasizing their heterogeneity, and suggesting that other factors, both genetic and epigenetic,must contribute to disease phenotype.

1 Follower
12 Reads
  • Source
    • "Additionally she had prominent myoclonic jerks and increased muscle tone, which are infrequently seen at her stage of disease and which seldom involve all extremities. Published phenotype descriptions are almost exclusively characterized as spastic paraparesis (reviewed by Larner and Doran [3]). Finally, her speech abnormality was atypical as well, more closely resembling a classic expressive aphasia than the variant aphasias usually described in AD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Early onset dementias have variable clinical presentations and are often difficult to diagnose. We established a family pedigree that demonstrated consistent recurrence of very early onset dementia in successive generations. In order to refine the diagnosis in this family, we sequenced the exomes of two affected family members and relied on discrete filtering to identify disease genes and the corresponding causal variants. Among the 720 nonsynonymous SNPs shared by two affected members, we found a C to T transition that gives rise to a Thr147Ile missense substitution in the PS1 protein. The presence of this same mutation in a French early-onset Alzheimer's disease family, other affected members of the family, and the predicted high pathogenicity of the substitution strongly suggest that it is the causal variant. In addition to exceptionally young age of onset, we also observed significant limb spasticity and early loss of speech, concurrent with progression of dementia in affected family members. These findings extend the clinical presentation associated with the Thr147Ile variant. Lastly, one member with the Thr147Ile variant was treated with the PKC epsilon activator, bryostatin, in a compassionate use trial after successful FDA review. Initial improvements with this treatment were unexpectedly clear, including return of some speech, increased attentional focus, ability to swallow, and some apparent decrease in limb spasticity. Our findings confirm the role of the PS1 Thr147Ile substitution in Alzheimer's disease and expand the clinical phenotype to include expressive aphasia and very early onset of dementia.
    Journal of Alzheimer's disease: JAD 03/2015; 46(2). DOI:10.3233/JAD-150051 · 4.15 Impact Factor
  • Source
    • "In addition to cognitive symptoms, some unusual clinical features may be present early in the course of the disease, in particular myoclonus and seizures [69]. Despite almost all of these symptoms having been reported in sporadic AD patients, extrapyramidal signs, behavioral and psychiatric symptoms (agitation, depression, delusion, and hallucinations), aphasia, and cerebellar signs are significantly more frequent in PSEN1 mutation carriers [70, 71]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is the most common progressive neurodegenerative disease and the most common form of dementia in the elderly. It is a complex disorder with environmental and genetic components. There are two major types of AD, early onset and the more common late onset. The genetics of early-onset AD are largely understood with mutations in three different genes leading to the disease. In contrast, while susceptibility loci and alleles associated with late-onset AD have been identified using genetic association studies, the genetics of late-onset Alzheimer's disease are not fully understood. Here we review the known genetics of early- and late-onset AD, the clinical features of EOAD according to genotypes, and the clinical implications of the genetics of AD.
    BioMed Research International 05/2014; 2014:291862. DOI:10.1155/2014/291862 · 3.17 Impact Factor
  • Source
    • "In addition to typical memory impairment, it is widely known that atypical symptoms such as behaviour disturbance, movement disorders, pyramidal tract signs, myoclonus or seizures frequently occur in familial Alzheimer's disease with PSEN1 or APP mutations (Rossor et al., 1993; Cabrejo et al., 2006; Larner and Doran, 2006, 2009). We observed a significantly higher frequency of pyramidal signs and dysarthria as well as potentially increased incidence of seizures and myoclonus, but not extrapyramidal signs, during their disease course, compared to sporadic Alzheimer's disease adjusted by Braak neurofibrillary tangles stage (Supplementary material and Supplementary Table 6). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies suggest that subcortical structures, including striatum, are vulnerable to amyloid-β accumulation and other neuropathological features in familial Alzheimer's disease due to autosomal dominant mutations. We explored differences between familial and sporadic Alzheimer's disease that might shed light on their respective pathogenic mechanisms. To this end, we analysed 12 brain regions, including neocortical, limbic and subcortical areas, from post-mortem brains of familial Alzheimer's disease (n = 10; age at death: 50.0 ± 8.6 years) with mutations in amyloid precursor protein (APP) or presenilin 1 (PSEN1), sporadic Alzheimer's disease (n = 19; age at death: 84.7 ± 7.8 years), neurologically normal elderly without amyloid-β accumulation (normal ageing; n = 13, age at death: 82.9 ± 10.8 years) and neurologically normal elderly with extensive cortical amyloid-β deposits (pathological ageing; n = 15; age at death: 92.7 ± 5.9 years). The levels of amyloid-β40, amyloid-β42, APP, apolipoprotein E, the synaptic marker PSD95 (now known as DLG4), the astrocyte marker GFAP, other molecules related to amyloid-β metabolism, and tau were determined by enzyme-linked immunosorbent assays. We observed that familial Alzheimer's disease had disproportionate amyloid-β42 accumulation in subcortical areas compared with sporadic Alzheimer's disease, whereas sporadic Alzheimer's disease had disproportionate amyloid-β42 accumulation in cortical areas compared to familial Alzheimer's disease. Compared with normal ageing, the levels of several proteins involved in amyloid-β metabolism were significantly altered in both sporadic and familial Alzheimer's disease; however, such changes were not present in pathological ageing. Among molecules related to amyloid-β metabolism, the regional distribution of PSD95 strongly correlated with the regional pattern of amyloid-β42 accumulation in sporadic Alzheimer's disease and pathological ageing, whereas the regional distribution of APP as well as β-C-terminal fragment of APP were strongly associated with the regional pattern of amyloid-β42 accumulation in familial Alzheimer's disease. Apolipoprotein E and GFAP showed negative regional association with amyloid-β (especially amyloid-β40) accumulation in both sporadic and familial Alzheimer's disease. Familial Alzheimer's disease had greater striatal tau pathology than sporadic Alzheimer's disease. In a retrospective medical record review, atypical signs and symptoms were more frequent in familial Alzheimer's disease compared with sporadic Alzheimer's disease. These results suggest that disproportionate amyloid-β42 accumulation in cortical areas in sporadic Alzheimer's disease may be mediated by synaptic processes, whereas disproportionate amyloid-β42 accumulation in subcortical areas in familial Alzheimer's disease may be driven by APP and its processing. Region-specific amyloid-β42 accumulation might account for differences in the relative amounts of tau pathology and clinical symptoms in familial and sporadic Alzheimer's disease.
    Brain 03/2014; 137(5). DOI:10.1093/brain/awu046 · 9.20 Impact Factor
Show more