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      Deep brain stimulation for monogenic Parkinson’s disease: a systematic review

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          Abstract

          Deep brain stimulation (DBS) is an effective treatment for Parkinson’s disease (PD) patients with motor fluctuations and dyskinesias. The key DBS efficacy studies were performed in PD patients with unknown genotypes; however, given the estimated monogenic mutation prevalence of approximately 5–10%, most commonly LRRK2, PRKN, PINK1 and SNCA, and risk-increasing genetic factors such as GBA, proper characterization is becoming increasingly relevant. We performed a systematic review of 46 studies that reported DBS effects in 221 genetic PD patients. The results suggest that monogenic PD patients have variable DBS benefit depending on the mutated gene. Outcome appears excellent in patients with the most common LRRK2 mutation, p.G2019S, and good in patients with PRKN mutations but poor in patients with the more rare LRRK2 p.R1441G mutation. The overall benefit of DBS in SNCA, GBA and LRRK2 p.T2031S mutations may be compromised due to rapid progression of cognitive and neuropsychiatric symptoms. In the presence of other mutations, the motor changes in DBS-treated monogenic PD patients appear comparable to those of the general PD population.

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          The online version of this article (10.1007/s00415-019-09181-8) contains supplementary material, which is available to authorized users.

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          PINK1 mutations are associated with sporadic early-onset parkinsonism.

          Tamara Ialongo, Sergio Salvi, Alberto Albanese … (2004)
          We have recently reported homozygous mutations in the PINK1 gene in three consanguineous families with early-onset parkinsonism (EOP) linked to the PARK6 locus. To further evaluate the pathogenic role of PINK1 in EOP and to draw genotype-phenotype correlates, we performed PINK1 mutation analysis in a cohort of Italian EOP patients, mostly sporadic, with onset younger than 50 years of age. Seven of 100 patients carried missense mutations in PINK1. Two patients had two PINK1 mutations, whereas in five patients only one mutation was identified. Age at onset was in the fourth-fifth decade (range, 37-47 years). The clinical picture was characterized by a typical parkinsonian phenotype with asymmetric onset and rare occurrence of atypical features. Slow progression and excellent response to levodopa were observed in all subject. Two of 200 healthy control individuals also carried one heterozygous missense mutation. The identification of a higher number of patients (5%) than controls (1%) carrying a single heterozygous mutation, along with previous positron emission tomography studies demonstrating a preclinical nigrostriatal dysfunction in PARK6 carriers, supports the hypothesis that haploinsufficiency of PINK1, as well as of other EOP genes, may represent a susceptibility factor toward parkinsonism. However, the pathogenetic significance of heterozygous PINK1 mutations still remains to be clarified.
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            Large-scale screening of the Gaucher's disease-related glucocerebrosidase gene in Europeans with Parkinson's disease.

            , Alexis Brice, Suzanne Lesage … (2011)
            Pathogenic variants in the glucocerebrosidase gene (GBA) encoding the enzyme deficient in Gaucher's disease (GD) are associated with Parkinson's disease (PD). To investigate the sequence variants, their association with PD and the related phenotypes in a large cohort of European, mostly French, patients and controls, we sequenced all exons of GBA in 786 PD patients from 525 unrelated multiplex families, 605 patients with apparently sporadic PD and 391 ethnically matched controls. GBA mutations were significantly more frequent (odds ratio=6.98, 95% confidence interval 2.54-19.21; P=0.00002) in the PD patients (76/1130=6.7%) than in controls (4/391=1.0%) and in patients with family histories of PD (8.4%) than in isolated cases (5.3%). Twenty-eight different mutations were identified in patient and control groups, including seven novel variants. N370S and L444P accounted for 70% of all mutant alleles in the patient group. PD patients with GBA mutations more frequently had bradykinesia as the presenting symptom and levodopa-induced dyskinesias. The phenotype was similar in patients with one, two or complex GBA mutations, although the two patients with c.1263del+RecTL and N370S/RecΔ55 mutations had signs of GD. Segregation analyses in 21 multiplex families showed that 17% of the affected relatives did not carry GBA mutations found in the given family, indicating heterogeneity of the aetiology, but 46% of the unaffected relatives were GBA mutation carriers. These genotype and clinical analyses on the largest homogeneous sample of European patients studied to date confirmed that GBA mutations are the most common genetic risk factor for PD, particularly in familial forms.
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              alpha-Synuclein gene duplication is present in sporadic Parkinson disease.

              Y Min, David Ahn, B. C. Jeon … (2008)
              alpha-Synuclein gene (SNCA) multiplication was found in familial Parkinson disease (PD). We examined SNCA multiplication in patients with familial and sporadic PD and multiple system atrophy (MSA). We screened 1,106 patients with parkinsonism (PD = 906, MSA = 200) for SNCA multiplication by multiplex PCR. Fluorescent in situ hybridization was done to confirm the multiplication. [(123)I]N-omega-Fluoropropyl-2 beta-carbomethoxy-3beta-(4-iodophenyl)-tropane ([(123)I]FP-CIT) SPECT was done in the patients with SNCA multiplication and their family members. Three patients were identified as having SNCA duplication. One patient had a positive family history, and two patients were sporadic. Each patient had asymptomatic carriers in their families. The familial case had early onset parkinsonism with rapidly progressive course, cognitive impairment, and dysautonomia. Sporadic cases were more typical of PD. [(123)I]FP-CIT SPECT was abnormal in the patients and normal in the asymptomatic carriers. SNCA multiplication is present in sporadic Parkinson disease (PD) and needs to be screened. Low penetrance, clinical heterogeneity, and normal dopamine transporter imaging in asymptomatic carriers may suggest the presence of other genetic modifiers or environmental triggers that play a role in the pathogenesis of PD due to SNCA duplication.
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                Author and article information

                Contributors
                Tomi Kuusimäki:
                ORCID: http://orcid.org/0000-0002-4829-7275
                tomi.kuusimaki@utu.fi
                Journal
                Journal ID (nlm-ta): J Neurol
                Journal ID (iso-abbrev): J. Neurol
                Title: Journal of Neurology
                Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )
                ISSN (Print): 0340-5354
                ISSN (Electronic): 1432-1459
                Publication date (Electronic): 18 January 2019
                Publication date PMC-release: 18 January 2019
                Publication date (Print): 2020
                Volume: 267
                Issue: 4
                Pages: 883-897
                Affiliations
                [1 ]GRID grid.410552.7, ISNI 0000 0004 0628 215X, Division of Clinical Neurosciences, , Turku University Hospital, ; Hämeentie 11, POB 52, 20521 Turku, Finland
                [2 ]GRID grid.1374.1, ISNI 0000 0001 2097 1371, Department of Neurology, , University of Turku, ; Turku, Finland
                [3 ]GRID grid.15485.3d, ISNI 0000 0000 9950 5666, Department of Neurology, , Helsinki University Hospital, ; Helsinki, Finland
                [4 ]GRID grid.7737.4, ISNI 0000 0004 0410 2071, Department of Clinical Neurosciences (Neurology), , University of Helsinki, ; Helsinki, Finland
                [5 ]GRID grid.5608.b, ISNI 0000 0004 1757 3470, Department of Neurosciences, , University of Padua, ; Padua, Italy
                Author information
                http://orcid.org/0000-0002-4829-7275
                Article
                Publisher ID: 9181
                DOI: 10.1007/s00415-019-09181-8
                PMC ID: 7109183
                PubMed ID: 30659355
                SO-VID: c2f3bf46-1262-4f05-8db9-d136c4a51027
                Copyright © © The Author(s) 2019
                License:

                OpenAccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Date received : 11 November 2018
                Date revision received : 29 December 2018
                Date accepted : 2 January 2019
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © Springer-Verlag GmbH Germany, part of Springer Nature 2020

                ScienceOpen disciplines: Neurology
                Keywords: parkinson’s disease,monogenic,genetic,deep brain stimulation
                Data availability:
                ScienceOpen disciplines: Neurology
                Keywords: parkinson’s disease, monogenic, genetic, deep brain stimulation

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