De Novo PS1 Mutation (Pro436Gln) in a Very Early-Onset Posterior Variant of Alzheimer’s Disease Associated with Spasticity: A Case Report

INTRODUCTION

Early-onset autosomal dominant Alzheimer’s disease (AD) represents around 0.5%of all AD cases, and many of these familial cases carry mutations in the presenilin 1 (PS1), presenilin 2 (PS2), and amyloid precursor protein (APP) genes [1]. Of these, PS1 mutations are the most common cause of early-onset AD, with more than 300 mutations reported worldwide (http://www.alzforum.org/mutations) [2].

AD is also a common cause of early-onset dementia in sporadic cases. Though de novo PS1 mutations are a rare finding in truly sporadic cases [3], a few cases have been reported, most with a very early onset [4 –8]. One of the largest cohort studies to date identified nine de novo PS1 mutations in 129 sporadic cases with onset before age 51 years [9].

We report a young man with very early-onset AD associated with a de novo Pro436Gln PS1 mutation. The clinical phenotype was remarkable in that he presented a posterior cortical syndrome with severe visual agnosia and mild limb spasticity with brisk reflexes. This report, together with two previous cases with the same mutation, further indicates that this variant has a very strong impact on the clinical phenotype, in particular as regards the association with spasticity.

MATERIALS AND METHODS

This is a case report of a sporadic AD case with onset in his twenties studied and diagnosed at the Dementia Care Unit of Hospital Fundación Jiménez Díaz (Madrid). The patient was an only child of a family with no history of dementia; his nonconsanguineous parents remain healthy in their early seventies.

The patient underwent a wide cognitive assessment including the Mini-Mental State Examination, verbal fluency tasks, the Boston Diagnostic Aphasia Examination, the Hopkins Verbal Learning Test, the Trail Making Test (part A), the Digit Symbol test, the copy and recall of the Rey-Osterrieth Complex Figure, and the WAIS-IV battery (see Table 1). He also underwent a brain magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT) imaging with fluorodeoxyglucose (FDG), and analysis of cerebrospinal fluid (CSF) AD biomarkers using the Lumipulse G600II chemiluminescent immunoassay (Fujirebio Iberia, Barcelona, Spain). Finally, amyloid PET imaging with ¹⁸F-florbetaben tracer (Neuraceq, Alliance Medical Radiopharmacy Ltd, UK) was performed and, for research purposes, the procedure was repeated with ¹⁸F-flutemetamol (Vizamyl, GE Healthcare, Norway). Amyloid PET results were visually evaluated by a physician trained in the radiopharmaceutical-specific qualitative rating methodology provided by the manufacturers.

In the light of the results of the CSF biomarker study and amyloid PET findings, a genetic analysis including the PS1, PS2, APP, and APOE genes was conducted. A DNA sample was amplified by PCR to analyze all coding regions of the genes, with the exception of APP, in which only exons 16 and 17 were examined. DNA of both parents was also analyzed after informed consent was provided.

Finally, we compare the clinical features of our case with two previously reported independent cases carrying the same mutation.

RESULTS

A 32-year-old male was referred to our clinic due to slowly progressive cognitive and functional decline over the preceding six years. He had no relevant medical history. Pregnancy, birth, and psychomotor development had been normal. He had average academic performance through primary and secondary education, and afterwards had gone on to earn a two-year professional degree in economics.

Starting at age 21 years, his parents noted that the patient had certain learning difficulties, though his general physician did not find them important. However, he was unable to further his education. At 26 years of age, he underwent a psychiatric assessment due to anxiety, apathy, and increasing learning difficulties. He struggled to cope with his work duties as a hospital janitor, becoming very anxious on his way to work every morning. After resigning from this position, the patient remained unemployed, developed social inhibition, and had limited daily activities. Treatment with antidepressants resulted in no improvement. At 30 years of age, he began reporting difficulties with vision. One year later he could not read fluently, had spatial disorientation, and experienced difficulty recognizing numbers, letters, objects, and faces. He could not operate his mobile phone. There were no specific complaints regarding memory or language.

On neurological examination, the patient presented hyperreflexia and mild spasticity, predominantly in the lower limbs, and he had developed a subtle spastic gait. He had Hoffman sign in the right hand and a neutral right plantar reflex, while the left was flexor. He also had transient distal myoclonus of the upper limbs. There were no cerebellar signs or parkinsonism. A summary of the formal neuropsychologic evaluation appears in Table 1. He exhibited mild memory deficits, though the most significant features were severe visual agnosia (Boston Naming Test score, 31/60, due not to naming deficits but rather an inability to recognize the figures), visuoconstructive apraxia (by way of example, his score on the Rey Complex Figure copy was 3/36 after 6 min, percentile < 3, Fig. 1), and near total alexia. The WAIS-IV battery showed average performance on the vocabulary, information, and similarities subtests, though profound impairment was found for all visual tasks. Apraxia tests prompting the patient to imitate hand and finger gestures evidenced impairment, and the patient presented optic ataxia.

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Fig. 1

MRI imaging, including a posterior view of a 3D reconstruction, showing severe parieto-occipital atrophy. FDG-PET reveals hypometabolism in the same region. On the right, model of the Rey Complex Figure test (top), his copy after six minutes (middle picture), and his delayed recall after five minutes (bottom).

A comprehensive assessment including blood test (with copper, ceruloplasmin, tumor markers, and immunological tests) and full-body CT scan were normal. An EEG revealed slowed waves (5–7 Hz) in the parieto-occipital regions. Nerve conduction studies, electromyogram, and somatosensory evoked potentials were normal. A spinal MRI scan was also normal.

A neuroimaging study of the patient is shown in Figs. 1 2. A brain MRI, including spectroscopy and diffusion tensor imaging, revealed marked bilateral parieto-occipital atrophy with decreased fiber density. Consistently, brain FDG-PET demonstrated moderate-severe hypometabolism in the parieto-occipital cortex. CSF biomarkers were suggestive of AD with decreased Aβ₄₂ concentration (230 pg/ml; normal > 725), decreased Aβ_42/40 ratio (0.046; > 0.068), normal total tau (320 pg/ml; < 410), and increased phospho-tau (62 pg/ml; < 59). Finally, both amyloid PET scans were clearly positive, evidencing Aβ neuritic plaques throughout the cortex with the highest burden detected in the posterior cortex (Fig. 2).

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Fig. 2

Amyloid PET studies identified amyloid-β neuritic plaques in cortical areas, with higher burden in the posterior cortex. Standardized uptake value ratios (SUVR) were calculated using the pons as the reference región.

Sequencing of the PS1 gene revealed a pathogenic mutation in c.1307C > A (Fig. 3) resulting in a change from proline to glutamine at codon 436 (p.Pro436Gln, P436Q) located in the transmembrane domain 9 of exon 12. The APOE genotype was 3/3. A genetic study of the parents confirmed parenthood, though neither carried the PS1 mutation.

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Fig. 3

A) Integrative Genomics Viewer (IGV) visualization of the heterozygous variant c.1307C > A (p.Pro436Gln) in the PS1 gene (NM_000021). B) Sanger chromatogram of the variant detected in the patient, absent in the unaffected parents.

DISCUSSION

We report an extensive study of a sporadic, very early-onset AD case caused by a de novo Pro436Gln mutation in PS1, in which the main features included the unusual association of posterior cortical syndrome and spasticity.

Two previous cases with this mutation have been reported. The first, from Australia, involved a patient with a positive family history of presenile dementia [10]. The clinical information for this case is sparse, but the age at onset was very similar to our case (late twenties, diagnosed at 34 years), and dementia was also associated with abnormal gait, brisk reflexes, and bilateral extensor plantar responses.

The second is an interesting case from the United Kingdom in which the mutation was detected de novo in DNA isolated from the cerebral cortex but not in peripheral lymphocytes, indicating mosaicism [11].The degree of mosaicism was estimated at 8%in lymphocytes and 14%in the cerebral cortex. Symptoms first manifested at age 42 years as a progressive parkinsonian syndrome, mild spastic paraparesis, and dementia. Neuropathologic findings were remarkable for numerous cotton-wool type Aβ plaques, a type of senile plaques that has been clinically correlated with spastic paraparesis [2]. The daughter of this case had the mutation detectable in lymphocytes and developed progressive cerebellar syndrome with spastic paraparesis and dementia at age 27 years, supporting a clear gene dosage effect on age of presentation.

Therefore, the Pro436Gln mutation shows a very strong impact on the clinical phenotype as regards age at onset and presence of spasticity. This clinical feature appears in association with approximately twenty specific PS1 mutations distributed across all exons, although a cluster of mutations associated with spasticity is found in exon 8 and in variants resulting in the skipping of exon 9. Patients carrying these mutations show a consistent pathological phenotype with Aβ plaques of the cotton-wool type, white matter abnormalities, and degeneration of the corticospinal tract [2].The strong correlation of the specific PS1 mutation with certain clinical features has been reported for many mutations [12]. However, there is insufficient information regarding the cognitive phenotype of the earlier Pro436Gln cases to ascertain whether a posterior cortical syndrome is also a particular feature of this mutation.

This report further emphasizes that PS1 mutations should be screened for in patients with sporadic, very early-onset dementia, as de novo mutations may occur. In fact, the rate of mutations in sporadic AD cases with age at onset below 51 years is estimated at 14%[13]. Particularly, de novo PS1 mutations were demonstrated in 7%of sporadic AD cases from a large French cohort with onset before age 51 years [9]. Several of the reported cases with de novo mutations had an age at onset even younger than 30 years [4 , 8]. This finding, however, is probably biased as more extensive screening studies are conducted in younger patients. In our case, CSF AD biomarkers offered valuable diagnostic information and guided genetic analyses.