Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life
Snider BJ, Norton J, Coats MA, Chakraverty S, Hou CE, et al. ;
Commented by , 17 Jan 2006
Aim of the study
To analyse the neuropathological and genetic features of a family with onset of AD in the third decade of life.
Method
Clinical, genetic and post-mortem neuropathological study of a woman with early onset cognitive symptoms, with similarly affected 1st degree relatives.
Results
The proband had a gradual decline in cognition starting at age 26, characterized by errors in calculations, misplacing things, repeating questions, where she parked her car. Suspiciousness emerged, with word-finding difficulties. Frequent falls occurred.
At age 28 she had generalized tonico-clonic seizures. A nasogastric tube was required at age 30. She was mute, immobile and incontinent from then on until she died at 43 of a pulmonary embolus.
Autopsy showed severe generalized brain atrophy except for the cerebellum. Histology showed severe neuronal loss with extensive plaques and tangles involving the entire neocortex (Braak stages VI-C).
Classic Lewy bodies were seen in the Substantia Nigra as well as diffusely in the cortical and subcortical regions. An older brother and their father developed cognitive symptoms starting at age 27, dying at age 35 and 37 respectively; in both cases the neuropathological diagnosis was AD.
The proband was homozygous for the apolipoprotein E3 allele but showed a single base-pair substitution at codon 170 of the PSEN1 gene; no material from the other two affected family members was available for genetic analysis.
Professor Gauthier's comments
The clinical features of the three patients are consistent with very early onset AD, with an average duration of disease of 11 years before death. In the published literature about such patients, myoclonus, generalized seizures, pyramidal signs are more common than extrapyramidal signs.
Mutations of PSEN1 are the most common abnormalities found in such cases, the one described in this report on codon 170 being a novel one. Lewy bodies have been observed frequently in familial early onset as well as sporadic late-onset AD.
The neuropathology of early-onset and sporadic later-onset AD is this very similar, despite differences in genetic and clinical presentations. Furthermore there is often co-existence of classic AD and Lewy body pathology (this topic is further discussed in "Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium", a CNSforum recommended review article).
The importance of mutations affecting the metabolism of beta-amyloid in the broad context of AD emerging at different ages, and the overlap with Lewy body-related changes will be an important focus of discussion at the 10th International Conference on Alzheimer’s Disease and Related Disorders, July 15-20, Madrid, Spain.