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

Abstract

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.

Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer’s Disease

“…In the majority of PSEN1 mutations, the initial symptoms may be cognitive decline, and Parkinsonism occurs in later disease stages. However, Parkinsonism could also be an initial symptom in cases of several PSEN1 mutations, mutations such as Arg41Ser, Gly217Asp and Val272Ala [50][51][52]. A patient with PSEN1 Arg41Ser developed a tremor and bradykinesia and was diagnosed with PD.…”

“…The mechanism of how PSEN1 may be involved in Parkinsonism remain unclear. It may be possible that amyloid deposition may impact dopamine transport, particularly the presynaptic dopaminergic pathway [52].…”

A Novel Pathogenic PSEN1 Variant in a Patient With Dystonia-Parkinsonism Without Dementia

“…Motor impairment has been reported in the early stages of the disease and may even precede cognitive decline in a small subset of patients [ 5 ]. Few cases have been reported of PSEN1 mutation carriers with parkinsonism as an isolated presenting feature without dementia or significant cognitive decline over time [ 6 - 8 ]. Here, we report a male patient with adult-onset dystonia-parkinsonism with positive AD biomarkers carrying a novel PSEN1 frameshift variant.…”

“…Classic AD biomarkers (18FDG-PET, 18F-flutemetamol PET-CT, and CSF biomarkers) were inconclusive [ 7 ]. Finally, Chen et al [ 8 ] described a patient with levodopa-responsive parkinsonism, mild cognitive impairment, and positive PiB-PET, harboring a de novo PSEN1 variant. Data from previous case reports concerning cognitive functions and AD biomarker findings are not consistent.…”

Early‐Onset Dementia‐Parkinsonism with Rapid Development of Motor Fluctuations and Dyskinesia Due to PSEN1 G206V Pathogenic Variant

“…2,3 Furthermore, some of the cases with parkinsonism have been reported to be levodopa-responsive and to develop early motor fluctuations and dyskinesias. 4 However, PSEN1 variants are seldom considered in the assessment of patients with early-onset parkinsonism. 5 We describe the case of a patient with a mixed clinical phenotype of early-onset dementia and parkinsonism with motor complications due to a pathogenic variant in the PSEN1 gene.…”