Abstract
Dementia is not just a disease of old age. Early-onset dementia affects people younger than 65 and its differential diagnosis is broader than in older people. Nevertheless, although young people are considerably more liable to develop a rare form of dementia, Alzheimer’s disease (AD) remains the most common diagnosis. The aim of this article is to report on an early-onset AD patient associated with the rare pathogenic variant PSEN1 (Leu85Pro) presenting as a possible corticobasal syndrome with asymmetric limb apraxia, parkinsonian signs, and myoclonus.
INTRODUCTION
Early-onset dementia is defined as presenting before 65 years of age. The diagnosis of these cases is habitually a complex undertaking, due to their differential diagnosis, which is far wider than it is in older patients. For that reason, they tend to require a more extensive evaluation, considering both common and rare disorders. However, the most frequent cause of early-onset dementia is Alzheimer's disease (AD), the same as in elderly patients [1].
Early-onset AD accounts for about 6-7% of all cases of AD [2]. The monogenic AD is produced by mutations in three genes that alter amyloid-β protein production or metabolism: amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2). PSEN1 mutations are associated with an earlier age of onset and a more aggressive course compared with APP and PSEN2 mutations. More than 200 pathogenic mutations have been described [3], accounting for up to 50% of early-onset familial AD [4, 5].
We report on a patient with a new phenotype of early-onset AD associated with the rare pathogenic variant PSEN1 (Leu85Pro).
CASE REPORT
A 29-year-old woman was admitted to our hospital due to progressive cognitive decline over the last months. The patient is from Romania although she has been living in Spain for the last 10 years. There is no family history of dementia. Her parents are nonconsanguineous; they are in their sixties and have no evidence of neurological diseases. Pregnancy, childbirth, and psychomotor development were normal. She was a former smoker of 10 packs per year and her personal medical history only includes a left ovarian cyst and subclinical hypothyroidism treated with levothyroxine.
The first symptoms, which appeared a year and a half before admission, consisted of depressed mood and impairment of short-term memory. She was evaluated by a psychiatrist who initiated treatment with a selective serotonin reuptake inhibitor (escitalopram) with which a slight improvement was observed. In the following months, attention difficulties and motor clumsiness were also detected, so she moved to her home country with her parents. During her stay in Romania, the patient developed a progressive language difficulty of non-fluent type, as well as dysarthria and myoclonus. She returned to Spain two months before admission; since that moment her partner referred that despite there was no evident progression in cognitive symptoms, she developed gait instability and difficulty for climbing stairs, sparse language, and the need for assistance in certain basic activities of daily living such as showering and dressing.
On neurological examination, she was alert and cooperative but had difficulty in maintaining attention. The spontaneous language was nearly absent, markedly effortful, showing dysarthria and difficulties when nominating simple objects and obeying simple orders. The patient showed apraxia for imitation of finger gestures and optic ataxia with both hands although markedly asymmetric being more severe in the left side. Examination of the cranial nerves showed no abnormality and there was no weakness, somatosensory or coordination disturbance (however, a cortical sensory deficit could not be evaluated). Deep tendon reflexes were brisk but bilateral flexor plantar response. She had no resting or postural tremor, although slight extrapyramidal rigidity and generalized bradykinesia and hypomimia were present. Her gait was non-specific. Frequent myoclonus in upper extremities was observed. Primitive reflexes were absent.
A comprehensive laboratory assessment was performed (including ACE, copper, ceruloplasmin, and tumor markers) within normal limits. Serology test were all negative (HIV, HBV, HCV, CMV, EBV, HSV, VZV, Toxoplasma, Mycoplasma, Parvovirus B19, Measles, Coxiella, Bartonella, Brucella, Borrelia, T. Pallidum) as well as immunological tests (RF, ANA, ANCAs, antiphospholipid and antithyroid antibodies, onconeuronal antibodies and antibodies against neuronal cell surface or synaptic proteins). Cerebrospinal fluid was also normal, including OCBs, gram stain, culture, 14–3–3 protein, and PCR for T. Whipplei.
The v-EEG showed generalized slowing (theta 6, 7 hz) with frontal intermittent rhythmic delta activity (FIRDA) suggestive of a moderate nonspecific diffuse encephalopathy. Nerve conduction studies, electromyography, visual evoked and motor evoked potentials (MEPs) were normal. Somatosensory evoked potentials from upper extremities were normal, but giant somatosensory evoked potentials from lower extremities were present.
A whole-body CT was normal, except for the already known ovarian cyst. Brain MRI showed a symmetric mild diffuse cortical and subcortical atrophy with subtle parietal predominance (Fig. 1). 123I-FP-CIT SPECT (DaTSCAN) showed absent dopaminergic presynaptic transport in both putamen and reduced in right caudate nuclei (Fig. 2A). 2-[18F] Fluoro-2-Deoxy-D-Glucose PET (FDG PET) demonstrated severe bilateral temporoparietal hypometabolism with intense metabolic activity in the occipital cortex (Fig. 2B). Finally, 11C-Pittsburgh Compound-B (PiB PET) showed diffuse cortical retention of the radiotracer, in addition to the basal ganglia (Fig. 2C).
MRI (A-sagittal FLAIR; B-axial FLAIR): symmetric mild diffuse cortical and subcortical atrophy with subtle parietal predominance.
A) DaTSCAN: absent dopaminergic presynaptic transport in both putamen and reduced activity in right caudate nuclei; B) FDG PET: severe bilateral temporo-parietal hypometabolism with intense metabolic activity in the occipital cortex; C) PiB PET: diffuse cortical retention in cortex and in basal ganglia.
She received a five-day intravenous immunoglobulin-compassionate treatment with no improvement.
Based on the results of both PET scans, the AD biomarker profile in the cerebrospinal fluid was analyzed showing reduced amyloid-Aβ42 levels (254.5 pg/ml), increased total tau (565 pg/ml), and within range phosphorylated tau levels (65.76 pg/ml). Gene sequencing of PSEN1 revealed a point mutation in exon 4 at codon 254 (T to C) changing from leucine to proline at position 85 (Leu85Pro). Another variant of uncertain pathogenicity was identified (p.Pro45Gln) in SPAST gene.
The patient was last time evaluated six months after admission; a marked disease progression was observed; she was mute, her left limb was dystonic and apraxic, and her gait was unstable.
DISCUSSION
The (Leu85Pro) mutation in the PSEN1 gene is a rare pathogenic variant associated with early-onset AD as demonstrated by Ataka et al. [6]. These authors described the case of a 27-year-old Japanese man who presented a complex visual problem, as well as impairment of memory and spastic gait. 99Tc-SPECT and FDG PET showed bilateral hypoperfusion and hypometabolism in the occipital and temporal lobes with a marked increase in Aβ42 production, thus compatible with a visual variant of AD.
Our case is, to date, the second one reported with this mutation and a clinical description available and shows a different phenotype. She started at the age of 27 with progressive cognitive decline with predominant involvement of language, asymmetric limb apraxia, parkinsonian signs, and myoclonus. A remarkable difference between our case and the previously reported is the absence of a spastic gait and other pyramidal features except for mild hyperreflexia, otherwise possible in a young woman; further, the MEPs were normal.
Our patient presented a predominantly posterior form of AD. According to the last proposed clinical phenotypes by Armstrong et al. [7], she fulfills criteria for a possible corticobasal syndrome (CBS). The description of this new phenotype argues for the involvement of other genetic and/or epigenetic factors modulating the phenotype of AD associated with PSEN1 mutations, as has been discussed elsewhere [8, 9]. Although AD pathology is not uncommon among patients with sporadic CBS, this phenotype is unusual in genetic AD and, to date, there are only three mutations described in the PSEN1 gene with a similar presentation [10, 11].
In contrast to the first reported case, FDG PET showed hypermetabolism in the occipital cortex. There is not a definite explanation for this finding. Our patient has neither prominent visual symptoms nor suspected visual seizures. Nevertheless, a possible hypothesis is that, due to lack of collaboration, she remained with open eyes through the whole test (despite protocol prompts to keep them closed). The pattern of PiB retention (cortex and striatum) is consistent with a typical AD-pattern [12].
We could assess her parents and one sister; the rest of the family members are living in Romania. All three were asymptomatic; only her sister agreed to perform the genetic study and the PSEN1 mutation was ruled out. Although incomplete penetrance or different paternity is possible, we hypothesize that most likely the mutation occurred de novo in our patient, as it happened in the Japanese case.
It seems interesting that this mutation was also found in a family of four affected siblings and two non-demented individuals [13], in spite just one being a carrier (there is no clinical description). Therefore, again a de novo mutation could explain that pedigree structure.
The absence of family history, the aggressive course, and the very early onset of cognitive decline led us to focus the diagnostic workup on rapidly progressive dementias, mainly prionopathies and autoimmune disorders. Due to the negative results of all tests, we decided to rule out an atypical form of AD by PiB PET. The positivity of AD biomarkers gave us the diagnostic clue that was confirmed with the genetic analysis. This case emphasizes the utility of AD biomarkers in the assessment of young, atypical rapidly progressive dementia patients.
DISCLOSURE STATEMENT
Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/19-0107r2).