Genotype-Phenotype Relationships of Presenilin-1 Mutations in Alzheimer's Disease: An Update

Abstract

It is now more than ten years since pathogenic mutations were first described in the gene encoding presenilin 1 (PSEN1) on chromosome 14. Although PSEN1 mutations are "deterministic" for Alzheimer's disease, they are associated with marked heterogeneity in the clinical expression of neurological features. We review recent publications on the clinical neurological phenotype of PSEN1 mutations, many of which now appear only in abstracts or brief communications, perhaps because PSEN1 mutations are no longer regarded as "novel". However, the clinical heterogeneity associated with these mutations prompts important questions about possible genetic and epigenetic factors which may modify disease phenotype. This area, which may also be relevant to neurodegenerative disorders resulting from other genetic mutations, such as those in the tau gene, currently remains ill-understood.

Phenotypic Variability in Autosomal Dominant Familial Alzheimer Disease due to the S170F Mutation of Presenilin-1

“…The PSEN1 S170F mutation was detected by DNA sequencing in 2 patients. This mutation results in an amino acid change from serine (TCT) to phenylalanine (TTT) at codon 170 on exon 6 of the PSEN1 gene encoding the transmembrane domain III of presenilin-1, where many pathogenic mutations are found to cluster [28]. The pathogenic nature of the S170F mutation has been established before in several reported familial as well as sporadic cases: it was first demonstrated in a North American family with 3 affected family members in 2 generations [44], another family from Austria with 5 cases spanning 3 generations [45] as well as single sporadic cases from Great Britain and Poland with de novo mutations [41,42] and 1 patient in Italy with an incomplete family history [43].…”

“…For instance, familial and sporadic AD share the neuropathological hallmarks of AD pathology such as deposition of amyloid plaques and accumulation of neurofibrillary tangles [17], but the pathological results in EOFAD are more variable and frequently include findings such as cotton wool plaques, Lewy bodies, Pick bodies, and pronounced inflammation [20,21,22]. Likewise, the clinical phenotype of PSEN1 mutation carriers is characterized by widespread deficits involving multiple cognitive domains [23,24,25], resembling cognitive changes observed in sporadic AD [26], but atypical findings such as early non-amnestic cognitive, behavioural or motor symptoms are observed more frequently [27,28,29,30,31,32,33,34]. There is, however, considerable intra- and interfamilial variability regarding e.g.…”

“…To account for this diversity of clinical findings genotype-phenotype correlations can be investigated in larger populations of EOFAD patients [25,32,39] or single patients in comparison to previous descriptions of a given mutation [37,38]. The latter is however complicated due to a bias towards the publication of novel mutations whereas the informative value of detailed clinical observations in known mutations is underestimated [3,27,28,29]. Beyond a research-oriented perspective, this is also clinically relevant: familial AD may be overall rare, it is nevertheless underdiagnosed in relation to its assumed prevalence [40], and this may be attributed to its heterogeneous and atypical clinical presentation.…”

Focal Cortical Presentations Genetically Proven Alzheimer Disease

“…Yet, as time passes, most pathological changes associated with dementia have been described: usually tangles, amyloid deposits and lewy bodies. In the Alladi et al study, half of CBS had pathological hallmarks of AD (21) and several mutations of PSEN-1 have been described with clinical extrapyramidal syndromes and myoclonies (29,30).…”

Diagnosis and management of early‐onset dementia

“…Although such cases may present with the typical AD phenotype, there may be additional neurological features along with the cognitive decline, including myoclonus, epileptic seizures, spas- tic paraparesis, parkinsonism, cerebellar ataxia, and behavioural and psychiatric symptoms sometimes akin to those seen in frontotemporal dementia (FTD). 9 FTLDs are generally associated with a younger age at onset than AD, and therefore feature more prominently in the workload of a neurology-led cognitive clinic. FTLDs have disparate clinical phenotypes (behavioural, linguistic, parkinsonian movement disorder, clinical or subclinical motor neurone disease), disparate pathological substrates (tauopathy, TDP-43 proteinopathy, fused in sarcoma protein (FUS)), and various genetic causes, eg mutations in the tau and progranulin genes.…”