Diagnostic Approach of Early-Onset Dementia with Negative Family History: Implications from Two Cases of Early-Onset Alzheimer’s Disease with De Novo PSEN1 Mutation

INTRODUCTION

Early-onset Alzheimer’s disease (EOAD) is defined as AD with onset of symptoms before age 65 and accounts for 5–10% of all the AD cases. In some cases of EOAD, a clear family history can be found compatible with autosomal dominant inheritance. This is referred to as familial AD (FAD). The known responsible genes for FAD include pathogenic mutations in PSEN1, PSEN2, and APP genes. For EOAD cases with unclear family history, most cases are sporadic. However, some cases are positive in genetic findings, that is, either incomplete penetrance or de novo mutation. EOAD with de novo mutation is relatively rare [1, 2], which means the biological parents of EOAD patients are free of both clinical symptoms and pathogenic genetic mutations carried by the patient. Hereby, we report two EOAD cases with clear pathogenic de novo PSEN1 mutations. One case has a very typical AD phenotype featured by progressive cognitive complains, and the other case is characterized by cognitive impairment and parkinsonism. We propose a diagnostic flowchart to facilitate the differentiation of EOAD cases with de novo genetic mutations among the cases of early-onset dementia with negative family history.

METHODS

Case reports and literature review were performed in July 2018. We searched PubMed and identified all the original reports and reviews from January 1, 1990 to July 9, 2018 with the keywords “de novo”, “mutation”, “duplication”, “PSEN1”, “PSEN2”, “APP”, “early-onset”, and “Alzheimer’s Disease”. By secondary analysis, the potential associations between phenotype and genotype were summarized and the implication for diagnostic approach (diagnostic flowchart) of early-onset dementia with negative family history was raised, commented, and revised via electronic meetings.

RESULTS

Case reports

Case 1

A 40-year-old right-handed man came to our memory clinic due to progressive memory decline and slow response over three years. He was a policeman with high education, and had been married. Three years before, he began to suffer language repetition and becoming forgetful. He often lost things and could not find the things he just set aside. He frequently forgot what his relatives just told him. Even though there was a reminder for him, he was still unaware of what to do with slow response. After two years, his memory was more impaired. He was unable to cook because of forgetting to add seasoning. He had difficulty in comprehension and took the wrong train due to the failure of understanding the train schedule. His ability to calculate had declined. He could not concentrate when someone talked to him or correctly respond. He gradually lost the ability to learn new information, which caused some distress. One month before he could not remember his birthday or recognize the time on the watch, without any response to donepezil or memantine therapy. He had a 15-year history of hypertension with themaximum value 160/100 mmHg. He is the only child in his family. Both of his biological parents were healthy and over age 60. In the neurological examination, the problems were only found in cortical function. His verbal fluency was normal. Response was slow and memory was impaired. Calculation, comprehension, and execution were abnormal. Orientation was impaired for time and place, but preserved for persons. As far as the neuropsychological test, the score on the Mini-Mental State Exam (MMSE) was 23, the Montreal Cognitive Assessment (MoCA) 18, the Clinical Dementia Rating (CDR) 0.5 at one year after onset of symptoms, and MMSE 10, MoCA 7, and CDR 2 at three years after onset of symptoms.

The laboratory tests were normal in blood, urine, and stool routines, coagulation function, thyroid function, biochemistry, homocysteine, vitamin B12, folic acid, and tumor biomarkers. Moreover, there were no positive findings in the screening for infectious or toxic etiology. The pressure was 130 mmH₂O measured via lumbar puncture, CSF glucose, Cl, and proteins were 71 mg/dl, 115 mmol/L, and 47 mg/dL, respectively. In addition, immunoglobulin, Anti-NMDA, AQP4-Ab, NMO-IgG, Hu Ri Yo, oligoclonal band, intrathecal IgG synthesis, and myelin basic protein of CSF were in normal range. At three years after onset, brain MRI demonstrated bilateral hippocampal atrophy, mild lateral ventricle enlargement (Fig. 1A), as well as cerebral white matter degeneration (Fig. 1B). PiB-PET showed diffuse increased uptake in the cerebral cortex (Fig. 1C). The milestones of medical history are summarized inTable 1.

Genetic testing was performed: ApoE was ɛ3/3, and a pathogenic missense mutation (g.44635G > A) was found in the PSEN1 gene (G206S). Both of his biological parents were free of this mutation. Therefore, it is a de novo PSEN1 mutation EOAD case.

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Fig.1

In case 1, brain MRI demonstrated cerebral white matter degeneration (A), as well as bilateral hippocampal atrophy and mild lateral ventricle enlargement (B) at three years after onset. PiB-PET illustrated diffusely increased uptake in the cerebral cortex (C). In case 2, brain MRI was read as normal for age at three years after onset (D). FDG-PET demonstrated mild hypermetabolism in bilateral posterior putamen (E). PIB-PET (F) and AV45-PET (G) showed increased uptake in bilateral frontal lobe, posterior cingulate, caudate, putamen and thalamus. DAT-PET suggested reduced distribution of dopamine transporter in the left putamen (H). At five years after onset, EEG suggested mild abnormalities with intermittent slow waves. Brain MRI revealed slight symmetric atrophy in bilateral medial temporal lobe andhippocampus (I).

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Table 1

Milestones of medical history in two EOAD cases with de novo PSEN1 mutation

	Duration	Initial Findings	Duration	First visit Findings	Duration	Second visit Findings	Duration	Last visit Findings
Case 1	0 y	Language repetition and forgetful (lost things and could not find the things he just set aside)	1 y	MMSE 23, MoCA 18, CDR 0.5; Normal brain MRI	2 y	MMSE 18, MoCA 14; unable to cook because of forgetting to add seasoning; had difficulty in comprehension and took the wrong train due to the failure of understanding the train schedule	3 y	MMSE 10, MoCA 7, CDR 2; Brain MRI: bilateral hippocampal atrophy, mild lateral ventricle enlargement, cerebral white matter degeneration; PiB-PET: diffusely increased uptake in cerebral cortex
Case 2	0 y	Forget his menu of breakfast and appointment with his girlfriend but was still competent for daily life and work	3 y	Parkinsonism in the right limb; normal brain MRI; PIB-PET and AV45-PET: increased bilateral frontal and subcortical uptake; DAT-PET: reduced dopamine transporter in left putamen	4 y	MMSE 24, MoCA 19	5 y	MMSE21, MoCA 18, CDR 1; Brain MRI: slight symmetric atrophy in bilateral medial temporal lobe and hippocampus; FDG-PET: cortical hypometabolism

y, years after onset.

Case 2

A 30-year-old right-handed man was admitted to our memory clinic with very early-onset progressive cognitive decline for five years and parkinsonism for two years. He initially began to forget his menu of breakfast and appointment with his girlfriend but was still competent for daily life and work. Three years later, he resigned from the work as laborer and presented facial hypomimia and hypokinesia and rigidity in the right limbs. Bilateral parkinsonian signs were DOPA-responsive (levodopa) and gradually developed with walking difficulties. When he visited our clinic, he was unable to independently walk and lost himself sometimes. There was nearly no response to memantine therapy. He experienced generalized tonico-clonic seizures twice when he was four to five years old. He denied family history of dementia or parkinsonism. His biological parents and his sister were healthy. His uncle (father’s younger brother) suffered epilepsy in his 50s, but was free of cognitive decline and parkinsonism.

Neurological examinations showed impairment of short-term memory and orientations in time and place, masked face and nuchal dystonia with anticollis. Muscle strength was normal, but muscle tone in limbs was increased. Deep tendon reflexes were brisk, with bilateral positive Babinski’s sign. Retropulsion test was positive. In neuropsychological tests, the scores were MMSE 24 and MoCA 19 at four years after onset of symptoms; and MMSE 21, MoCA 18, and CDR 1 at the first visit to our memory clinic five years after onset of symptoms.

The laboratory tests for blood, urine, and stool routines, biochemistry, homocysteine, vitamin B12, thyroid function, folic acid, and tumor biomarkers were all normal. Hyperhomocystinemia was found. The concentration of serum copper and ceruloplasmin were in normal range, as well as the level of plasma amino acids and urinary organic acids. HIV screen was negative. No abnormalities were found in the CSF (glucose 64 mg/dl, Cl 125 mmol/L, proteins 31 mg/dL, negative oligoclonal band and syphilis antibody). At three years after onset, brain MRI was read as normal for age (Fig. 1D). FDG-PET revealed mild hypermetabolism in bilateral posterior putamen (Fig. 1E). PIB-PET (Fig. 1F) and AV45-PET (Fig. 1G) showed increased uptake in bilateral frontal lobe, posterior cingulate, caudate, putamen, and thalamus. DAT-PET suggested reduced distribution of dopamine transporter in the left putamen (Fig. 1H). At five years after onset, EEG suggested mild abnormalities with intermittent slow waves. Brain MRI revealed slight symmetric atrophy in bilateral medial temporal lobe and hippocampus (Fig. 1I). Hypometabolism was obvious in bilateral posterior parietal cortex and right medial temporal lobe via FDG-PET. The milestones of medical history are summarized in Table 1.

Whole exome sequencing was performed for the patient and his parents. Inspection of the variants revealed only one pathogenic mutation. Subsequent DNA sequencing of PSEN1 exon 7 revealed heterozygous ATG to GTG mutation at codon 233, which results a Met to Val substitution (M233V). The parents did not carry this mutation, which suggested a de novo mutation in the patient. APOE polymorphism showed homozygosity for ɛ3 allele. Paternity was confirmed by microsatellite typing.

Diagnostic flowchart

We propose a diagnostic flowchart for patients with early-onset progressive cognitive decline, and lack of a family history compatible with an autosomal dominant pattern (Fig. 2). The age of onset is usually under 50. Therefore, a limit of age under 50 should be proposed, with the presence of clinical features, such as myoclonus, seizures, extrapyramidal signs, ataxia, and spastic paraparesis. After the initial neurological examination, laboratory tests, and anatomical neuroimaging are done, the etiology should be determined as originating from the primary central nervous system (CNS) or systemic etiology (e.g., hypothyroidism, diabetes) [10]. Primary CNS etiology can be classified as primarily neurodegenerative (e.g., AD, FTD, etc.) or not (e.g., NMDA encephalitis, general paresis of insane, multiple sclerosis, etc.). The primarily neurodegenerative population can be further divided into amyloid positive or negative based on CSF or PET findings. The population with amyloid positivity is most likely EOAD with three kinds of hereditary possibilities: de novo genetic changes, sporadic cases, and incomplete penetrance (including censoring effect masking family history) [1, 11].

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Fig.2

Diagnostic flowchart for early-onset dementia. Gray background means the diagnostic flow of the two cases reported. The content within red dotted box means probably early-onset Alzheimer’s disease. CNS, central nervous system; CSF, cerebrospinal fluid; EOAD, early-onset Alzheimer’s disease; PET, positron emission tomography.

DISCUSSION

Both of our EOAD cases had cognitive decline as presenting phenotype, and were confirmed by gene testing as de novo PSEN1 mutation. Neither of the two mutations (G206S and M233V) are novel. Indeed, PSEN1 G206S mutation is pathogenic and has been reported in three families. This earliest report could be traced back to the year 2001 by Rogaeva et al. [12]. A large pedigree with 15 affected members by this mutation was then reported. All affected members met NINCDS-ADRDA criteria for probable or definite AD. The age of onset of symptoms was very early, ranging from 30 to 35 in this pedigree [13]. An affected family from Korea with four patients has been reported with early-onset before 40 years [14], with the proband showing bilateral frontotemporal and parietal hypometabolism on PET and diffuse brain atrophy with enlarged ventricles on CT. To our knowledge, the patient we report in this paper is the first Chinese EOAD case with de novo PSEN1 G206S mutation. The age of onset and clinical manifestations are comparable to previous reports. Disease progression is featured by cognitive decline and relatively faster progression than usual sporadic cases. We speculate that the genotype PSEN1 G206S mutation is probably correlated to the phenotype of EOAD with pure cognitive problems.

The PSEN1 M233V mutation was first detected two decades before in a family with four affected members from four generations with an autosomal dominant pattern and very early-onset [15]. Interestingly, the prominent symptoms of patients were parkinsonism and epilepsy rather than cognitive decline. After the proband passed away at age 34, autopsy was undertaken: amyloid plaques were observed in the cortex and striatum with nigral and cortical Lewy bodies [16], which can explain parkinsonism, dementia, and epilepsy [17]. Until this year, the same mutation was reported in three affected members from a Canadian-Vietnamese family, displaying cognitive decline, psychiatric symptoms, epilepsy, and a variety of atypical motor findings like ataxia, dystonia, and rigidity [18]. All the patients were early-onset before their 20s and brain MRI exhibited cerebral atrophy. This mutation has been proven to impair the carboxypeptidase-like γ-cleavage, which would lead to reduced Aβ₄₀, increased Aβ₄₂ and Aβ₄₂/Aβ₄₀ ratio [19]. The case we reported here is probably the first Chinese EOAD case with PSEN1 M233V mutation, as well as the first worldwide case with de novo PSEN1 M233V mutation. In which, the onset age was 25 years old and clinical symptoms were parkinsonism, dementia, and epilepsy. Therefore, this phenotype is most probably correlated to the genotype PSEN1 M233V.

Although EOAD with de novo mutation is not common, sporadic cases with early-onset cognitive issue should be considered for this possibility. Individuals with mutations in PSEN2 or APP are usually onset after 40 years old [20]. Therefore, the very-early onset cases (before 35 years old) should be screened for PSEN1 mutations first. Concerning the clinical symptoms in PSEN1 mutations, myoclonus, seizures, extrapyramidal signs, psychiatric symptoms, aphasia, visual agnosia, and ataxia are reported. Moreover, stroke-like episodes or vascular events can be present, especially in PSEN1 mutations beyond codon 200 [21]. Due to the variant phenotype, the differential diagnosis is sometimes puzzling, including frontotemporal dementia, Creutzfeldt-Jakob disease, progressive spastic paraparesis, recessive hereditary ataxias, etc. All the cases share the same features such as early-onset, similar symptoms, and unclear family history (recessive inheritance, incomplete penetrance or sporadic case). For instance, hereditary leukoencephalopathy with axonal spheroids is gradually recognized in recent years with autosomal dominant inheritance and early-onset. However, we ever reported two sporadic cases with novel mutations [22], in which cognitive and extrapyramidal disorders, seizures and psychiatric symptoms can be seen. Based on the above, specific exams are required. PIB-PET or AV45-PET can demonstrate the presence of amyloid plaques with more specificity in EOAD. When it is positive, genetic test is the next step for screening. Even though more than 90 distinct PSEN1 mutations have been found from the familiar and sporadic cases, definite pathogenicity is only confirmed in 77% mutations [3]. Therefore, not all mutations have clinical significance and the pathogenic mutations should be identified.