Early onset familial Alzheimer Disease with spastic paraparesis, dysarthria, and seizures and N135S mutation in PSEN1

Abstract

Objective: Early onset familial Alzheimer disease (EOFAD) can be caused by mutations in genes for amyloid precursor protein, presenilin 1 (PSEN1), or presenilin 2 (PSEN2). There is considerable phenotypic variability in EOFAD, including some patients with spastic paraparesis. The objective is to describe clinical and neuropathologic features of a family with a PSEN1 mutation that has been reported previously, without autopsy confirmation, in a single Greek family whose affected members presented with memory loss in their 30s, as well as variable limb spasticity and seizures.

Methods: We prospectively evaluated 2 children (son and daughter) with EOFAD and reviewed medical records on their mother. Archival material from the autopsy of the mother was reviewed and postmortem studies were performed on the brain of the daughter.

Results: All 3 individuals in this family had disease onset in their 30s, with cognitive deficits in multiple domains, including memory, language, and attention, as well as less common features such as spastic dysarthria, limb spasticity, and seizures. At autopsy both the mother and her daughter had pathologic findings of Alzheimer disease, and histologic evidence of corticospinal tract degeneration. Genetic studies revealed a mutation in PSEN1 leading to an asparagine to serine substitution at amino acid residue 135 (N135S) in presenilin 1.

Conclusions: This is the first description of neuropathologic findings in EOFAD owing to N135S PSEN1 mutation. The clinical phenotype was remarkable for spastic dysarthria, limb spasticity, and seizures, in addition to more typical features of EOFAD.

Figure 1

(A) MRI of the brain of the son (coronal view, T1 sequence) showing left > right hippocampal atrophy. (B) The coronal section of the brain of the daughter shows a similar appearance with mild atrophy that disproportionately affects the medial temporal lobe.

Figure 2

A range of plaque types are detected in the brain of the mother, including some plaques with a so-called “cotton wool appearance (A). Immunostaining for Aβ (B) shows mostly diffuse amyloid deposits, as well as mild focal amyloid angiopathy (inset). A Bielschowsky stain (C) shows neuritic elements in many of the plaques, as well as many cortical neurofibrillary tangles (inset). The tau immunostain (C) shows dystrophic neurites in plaques, but also profusely throughout the cortical gray matter. (A-D, ×400)

Figure 3

Corticospinal tract degeneration in the medullary pyramid (A and C) compared to normal fiber tract in the adjacent medial lemniscus (B and D) on sections immunostained for HLA-DR for activated microglia (C and D) and counterstained with Luxol fast blue for myelin (A and B). Note vacuolated myelin and myelin debris in the cytoplasm of HLA-DR-positive macrophages (A) and well as hypertrophic microglia and macrophages (C) in the pyramid, but absence of these findings in the medial lemniscus (B and D). (A-D, ×400)

Figure 4

The senile plaques in the daughter (A and B) were readily apparent on routine H&E stains due to dense amyloid cores (arrows in A). The Bielschowsky stain shows prominent neuritic elements in many of the senile plaques (B). Inset shows higher magnification of a neuritic plaque. In the hippocampus (C) there are many neuritic plaques and flame-shaped neurofibrillary tangles. In the basal nucleus of Meynert (D) there are many globose neurofibrillary tangles (arrows) with Bielschowsky stain.

Figure 5

Bielschowsky (A) and thioflavin-S (B) stained sections of the basal ganglia show many senile plaques, some of which have dense amyloid cores (inset). (A and B, ×400)

Figure 6

Adjacent sections of cortex (A & B), hippocampus (C & D) and cerebellum (E & F) of the daughter immunostained for Aβ42 (A, C & E) and for Aβ40 (B, D & F). Note numerous cortical, hippocampal and cerebellar plaques, many appearing as diffuse deposits, with Aβ42, but only a few plaques with Aβ40 immunoreactivity. Even in those plaques with both (insets in A and B), there is more Aβ42 immunoreactivity. There is focal amyloid angiopathy in hippocampus and cerebellum. (A, B, E & F ×40; C & D × 100)

Figure 7

The motor cortex (A) and the hypoglossal nucleus (C and D) of the daughter show normal motor neurons (inset in A shows perineuronal vacuolation of Betz cells). Immunohistochemistry for HLA-Dr for activated microglia (B and D) showed microgliosis in the medullary pyramid (B), but not the hypoglossal nucleus (D). (A-D ×400)

Figure 8

A model of the PSEN 1 protein showing 9 transmembrane spanning domains. Codon 135, (filled yellow circle at TM2 interface) which is the mutation in this kindred, has a serine substituted for an asparagine (N135S). The mutation is in the second transmembrane spanning domain, which serves as part of the active site of γ-secretase. Other pathogenic mutations in the second transmembrane spanning domain at codons 139 M, 143 I and 147 T align with codon 135 N on one face of an alpha helix.