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

Liu, Jia; Wang, Qianqian; Jing, Donglai; Gao, Ran; Zhang, Jing; Cui, Chunlei; Qiao, Huanyu; Liang, Zhigang; Wang, Chaodong; Rosa‐Neto, Pedro; Wu, Liyong; Jia, Jianping; Gauthier, Serge

doi:10.3233/jad-181108

Cited by 19 publications

(9 citation statements)

References 21 publications

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“…We report a case presenting with levodopa-responsive EOP and MCI with a de novo mutation (p.M233V) in PSEN1. This mutation has been previously reported in patients with complex phenotypes, including cognitive impairment, movement disorders, and neuropsychiatric disorders [4][5][6][7]. In most of these cases, the initial symptom was cognitive impairment (one with combined cerebellar manifestation), while our patient was characterized by a combination of parkinsonism and cognitive impairment.…”

Section: Discussionsupporting

confidence: 49%

A heterozygous de novo PSEN1 mutation in a patient with early-onset parkinsonism

et al. 2021

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Background Mutations in presenilin 1 (PSEN1) are the most common known genetic cause of early-onset Alzheimer's disease. Patients with PSEN1 mutations exhibit broad phenotypes. Here, we report clinical, neuroimaging and genetic findings in a patient with a de novo mutation in PSEN1 (c.697A > G, p.M233V) presenting with early-onset parkinsonism as the initial and primary symptom. Methods We recruited a family with one affected patient with early-onset parkinsonism. The patient underwent comprehensive neurological examination and imaging evaluation. Whole genome sequencing was performed for the proband. ResultsThe patient presented with parkinsonism and mild cognitive impairment. He had a good response to levodopa. Brain MRI evaluation showed atrophy of the bilateral frontotemporal lobe and hippocampus. 18 F-fluorodeoxyglucose-positron emission tomography (PET) and 11 C-2β-carbomethoxy-3β-(4-fluorophenyl) tropane-PET showed decreased metabolism and dopamine transporter distribution in the bilateral putamen and caudate nucleus. 11 C-Pittsburgh compound B -PET showed β-amyloid protein deposition. Genetic analysis identified a heterozygous de novo variant in PSEN1 (c.697A > G, p.M233V). Conclusions Screening for PSEN1 variations should be considered in patients with levodopa-responsive early-onset parkinsonism.

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Section: Discussionsupporting

confidence: 49%

A heterozygous de novo PSEN1 mutation in a patient with early-onset parkinsonism

et al. 2021

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“…We report a case of a 35-year-old woman with significant deterioration in psychomotor functioning, depression, and catatonic features, who was found to have the early-onset dementia-causing PSEN1 mutation. Early-onset AD occurs prior to 65 years of age [ 2 , 3 ]. Pathologically, it is characterized by the accumulation of intracytoplasmic neurofibrillary tangles and amyloid deposition in the parenchyma and blood vessels [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

Early-Onset Alzheimer’s Disease Masquerading as Catatonia

Alakkas

Meyer

Debbold

et al. 2020

Case Reports in Neurological Medicine

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A 35-year-old woman with a history of sexual trauma was brought in by her family for further evaluation of depressive symptoms and progressive decline in activities of daily living. She was admitted to the inpatient psychiatric unit for the treatment of suspected catatonia. After failure to respond to standard medical treatment, she received an extensive workup, which ultimately revealed a PSEN1 mutation consistent with early-onset Alzheimer’s disease. Diagnosis was challenging because of her young age, lack of reliable family history, and reports of recent sexual abuse by her biological father. This case is a cautionary reminder for clinicians that end stages of dementia can present similar to catatonia with mutism, lack of spontaneous movement, and refusal to eat. The clues to the diagnosis were profound cortical atrophy and lack of improvement with optimal medical management.

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“…Mutations in this gene can be associated with onset of AD as early as the late 20s, with most people with pathogenic mutations developing AD before the age of 60 years 45,46 . Although most cases are familial, de novo PSEN1 pathogenic variants have also been found in people with sporadic EOAD, where further testing showed that neither parent had the variant, and therefore, it likely occurred for the first time in the affected individual at conception 8–18,47 …”

Section: Admentioning

confidence: 99%

Genetic testing in dementia‐A medical genetics perspective

Huq

Sexton

Lacaze

et al. 2021

Int J Geriat Psychiatry

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Objective When a genetic cause is suspected in a person with dementia, it creates unique diagnostic and management challenges to the treating clinician. Many clinicians may be unaware of the practicalities surrounding genetic testing for their patients, such as when to test and what tests to use and how to counsel patients and their families. This review was conducted to provide guidance to clinicians caring for patients with dementia regarding clinically relevant genetics. Methods We searched PubMed for studies that involved genetics of dementia up to March 2020. Patient file reviews were also conducted to create composite cases. Results In addition to families where a strong Mendelian pattern of family history is seen, people with younger age of onset, especially before the age of 65 years were found to be at an increased risk of harbouring a genetic cause for their dementia. This review discusses some of the most common genetic syndromes, including Alzheimer disease, frontotemporal dementia, vascular dementia, Parkinson disease dementia/dementia with Lewy bodies and some rarer types of genetic dementias, along with illustrative clinical case studies. This is followed by a brief review of the current genetic technologies and a discussion on the unique genetic counselling issues in dementia. Conclusions Inclusion of genetic testing in the diagnostic pathway in some patients with dementia could potentially reduce the time taken to diagnose the cause of their dementia. Although a definite advantage as an addition to the diagnostic repository, genetic testing has many pros and cons which need to be carefully considered first.

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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

Cited by 19 publications

References 21 publications

A heterozygous de novo PSEN1 mutation in a patient with early-onset parkinsonism

A heterozygous de novo PSEN1 mutation in a patient with early-onset parkinsonism

Early-Onset Alzheimer’s Disease Masquerading as Catatonia

Genetic testing in dementia‐A medical genetics perspective

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