A Novel Presenilin 1 Mutation in Early-Onset Alzheimer’s Disease With Prominent Frontal Features

Abstract

Familial Alzheimer’s disease (AD) is a rare disorder involving known autosomal dominant mutations in the amyloid precursor protein and presenilin (PSEN) 1 and 2. Here, we present a case of early-onset AD with prominent frontal features associated with a novel deletion of codon 40 in the PSEN1 gene. Serial brain magnetic resonance imaging and ¹⁸F florbetapir imaging show prominent involvement of the frontal lobes, corresponding with the clinical presentation. This case report illustrates a possible link between a novel PSEN1 mutation and frontal variant AD.

Introduction

Early-onset Alzheimer’s disease (EOAD) accounts for approximately 6% to 7% of all AD cases, ¹ with an estimated worldwide prevalence exceeding 1 million. ² Of all EOAD cases, 13% have a well-characterized autosomal dominant inheritance pattern caused by mutations in the amyloid-β precursor protein (AβPP) or presenilin (PSEN) 1 and PSEN2. ¹ Of these, PSEN1, located on the short arm of chromosome 14, is the most common genetic mutation found in approximately 80% of inherited AD (Alzheimer’s Disease and Frontotemporal Dementia Mutation Database [AD&FTDMDB]). ³ Although only an estimated 0.5% of all AD cases have an autosomal dominant transmission pattern using strict criteria, ¹ the discovery of these genes and their detailed characterization continue to provide significant insight into the mechanisms underlying AD.

Presenilin 1 and PSEN2 form the catalytic center of the γ-secretase complex, which cleaves the C-terminal β fragment of AβPP to produce the toxic amyloid β(Aβ) species. ⁴ To date, 187 PSEN1 mutations have been described in AD, encompassing 10 coding exons of the gene. ³ Mutations in PSEN1 show almost complete penetrance by age 60, with some experiencing symptoms before the age of 30. ⁵ Similarly, clinical manifestations are heterogeneous, ranging from typical AD symptoms to seizures, extrapyramidal signs, and prominent frontal features similar to those seen in frontotemporal lobar degeneration (FTLD). ⁵ In this brief report, we present a unique case of AD with clinical features initially mirroring those of behavioral variant frontotemporal dementia (bvFTD). We further demonstrate a novel mutation in the PSEN1 gene.

Case

At age 52, the patient was referred to neurology for evaluation of cognitive difficulties. His symptoms had been slowly progressing and first became noticeable at age 48, 4 years prior to presentation. He worked alongside his wife in human resources and started having trouble with routine tasks such as setting up basic accounts. He was noted to have mild psychomotor slowing and had trouble with word finding and completing full sentences. During this time, he also had a significant change in personality. Although he had always been a gentle and mild mannered person, he now had an increasing frequency of anger outbursts toward his wife. At times he would be mean, abrupt, or rude. His medical history was otherwise unremarkable. He was formally educated up to an associate’s degree, and there was no family history of dementia.

Upon evaluation, he was found to have a striking impairment in executive function. He had great difficulty with go-no-go sequences and had reduced verbal fluency (could only recall 5 words starting with letter “S” in 1 minute). Simple measures of attention seemed unaffected. Questions regarding similarities of objects, such as a chair and a sofa, and other measures demonstrated a significant impairment in abstract reasoning. ⁶ Other features suggestive of frontal lobe dysfunction included a snout reflex and mild difficulty with repetitive alternating graphics. He scored a 4 of 10 on the clock drawing test based on the Sunderland criteria, ⁷ suggesting visual–spatial impairments. His initial Mini-Mental State Examination (MMSE) score was 30. Initial magnetic resonance imaging of the brain showed mild diffuse cortical atrophy abnormal for his age (Figure 1A) but failed to show a pattern suggestive of a particular dementia syndrome. Over the course of 6 years, brain imaging showed progressive atrophy most prominently involving the lateral frontal lobes (Figure 1A-C), in addition to atrophy of the medial temporal lobe structures.

Figure 1.

Progressive atrophy and fibrillar amyloid β (Aβ) deposition in a patient with prominent frontal features associated with a novel mutation in PSEN1. MRI at clinical presentation (A), and 3 years later (B), and CT scan 6 years later (C) indicates progressive cortical atrophy prominently affecting the dorsolateral frontal lobes. ¹⁸F florbetapir imaging shows increased Aβ neuritic plaque accumulation and loss of gray-white matter differentiation on axial images of the frontal lobe (D), mid brain (E), and temporal lobe (F) regions. Quantitative analysis indicates prominent Aβ deposition in the frontal lobes. PSEN indicates presenilin; MRI, magnetic resonance imaging; CT, computed tomography.

Because of his prominent frontal dysfunction, he was initially diagnosed with FTLD, bvFTD type. A standard laboratory panel for treatable causes of dementia was unrevealing. Genetic tests for progranulin, APP, PSEN1, and PSEN2 were obtained, and he was shown to have a novel PSEN1 deletion of codon 40 (118-120delD, coding exon 4, position 73 637 535-73 637 537; Athena Diagnostics [Worcester, MA, USA]). He was carefully followed after his initial diagnosis and developed an amnestic syndrome and other features consistent with a diagnosis of probable AD. A brain ¹⁸F florbetapir positron emission tomography (PET) scan of the brain was obtained, demonstrating the presence of fibrillary Aβ (Figure 1D-F). The Aβ deposition was most prominent in the frontal lobes bilaterally by quantitative analysis.

Discussion

This report documents a case of frontal variant AD ⁸ associated with a novel mutation in PSEN1. Although cerebrospinal fluid biomarkers p-τ, total τ, and Aβ were not obtained, progressive neurocognitive symptoms with a positive ¹⁸F florbetapir brain PET scan establish a diagnosis of probable AD with a relatively high degree of certainty. ⁹ Of particular interest is the association between certain mutations in PSEN1 and clinical AD symptoms overlapping with FTD. In a study of autosomal dominant AD, Wallon et al reported 8 families with distinct PSEN1 mutations, all initially presenting with symptoms suggestive of frontal lobe dysfunction. ¹⁰ In the case presented here, progressive cortical atrophy and Aβ deposition were most prominent in the dorsolateral frontal lobes (Figure 1D-F). Interestingly, 2 of the previously reported AD cases involving the PSEN1 p.Leu113Pro mutation were also associated with prominent frontal lobe Aβ plaque deposition. ¹⁰ Although fibrillar Aβ is not strongly correlated with the severity of clinical symptoms, ¹¹ prominent frontal lobe pathology, including atrophy, may nevertheless help explain why the presenting symptoms primarily involve frontal lobe dysfunction in a subgroup of patients with AD.

We cannot fully rule out the possibility that this novel mutation represents a random, nonpathologic event. Certain features do support a pathologic nature of the mutation. His age of onset falls within the range of PSEN1 mutations reported with familial AD, and 14 other pathologic mutations specifically locate to exon 4, of which 11 are associated with an established dominant inheritance pattern. ³ However, the deletion of codon 40 described here does not result in a frame shift and is not predicted to be pathogenic by the Protein Variation Effect Analyzer (PROVEAN). ¹² Moreover, a point mutation in codon 35 of exon 4 (position 73 637 521, G >A), a highly conserved amino acid across mammalian species, ¹³ has been noted in both sporadic AD and healthy controls, suggesting a nonpathologic polymorphism ^14,15 Codon 40 is less conserved, ¹³ and no variants have been observed in this codon in large population studies published to date, in 1000 genomes, or in the NHLBI Exome Sequencing Project Exome Variant Database. Further genetic analysis of other family members was not possible in the case reported here, and thus future studies will be required to fully determine inheritance pattern and pathologic characteristics of this novel PSEN1 variant in AD.