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Genotype–Phenotype Relations for the Atypical Parkinsonism Genes : MDSGene Systematic Review

Wittke, Christina ; Petkovic, Sonja ; Dobricic, Valerija ; Schaake, Susen ; Arzberger, Thomas ; Compta, Yaroslau ; Englund, Elisabet LU orcid ; Ferguson, Leslie W. ; Gelpi, Ellen and Roeber, Sigrun , et al. (2021) In Movement Disorders 36(7). p.1499-1510
Abstract

This Movement Disorder Society Genetic mutation database Systematic Review focuses on monogenic atypical parkinsonism with mutations in the ATP13A2, DCTN1, DNAJC6, FBXO7, SYNJ1, and VPS13C genes. We screened 673 citations and extracted genotypic and phenotypic data for 140 patients (73 families) from 77 publications. In an exploratory fashion, we applied an automated classification procedure via an ensemble of bootstrap-aggregated (“bagged”) decision trees to distinguish these 6 forms of monogenic atypical parkinsonism and found a high accuracy of 86.5% (95%CI, 86.3%–86.7%) based on the following 10 clinical variables: age at onset, spasticity and pyramidal signs, hypoventilation, decreased body weight, minimyoclonus, vertical gaze... (More)

This Movement Disorder Society Genetic mutation database Systematic Review focuses on monogenic atypical parkinsonism with mutations in the ATP13A2, DCTN1, DNAJC6, FBXO7, SYNJ1, and VPS13C genes. We screened 673 citations and extracted genotypic and phenotypic data for 140 patients (73 families) from 77 publications. In an exploratory fashion, we applied an automated classification procedure via an ensemble of bootstrap-aggregated (“bagged”) decision trees to distinguish these 6 forms of monogenic atypical parkinsonism and found a high accuracy of 86.5% (95%CI, 86.3%–86.7%) based on the following 10 clinical variables: age at onset, spasticity and pyramidal signs, hypoventilation, decreased body weight, minimyoclonus, vertical gaze palsy, autonomic symptoms, other nonmotor symptoms, levodopa response quantification, and cognitive decline. Comparing monogenic atypical with monogenic typical parkinsonism using 2063 data sets from Movement Disorder Society Genetic mutation database on patients with SNCA, LRRK2, VPS35, Parkin, PINK1, and DJ-1 mutations, the age at onset was earlier in monogenic atypical parkinsonism (24 vs 40 years; P = 1.2647 × 10−12) and levodopa response less favorable than in patients with monogenic typical presentations (49% vs 93%). In addition, we compared monogenic to nonmonogenic atypical parkinsonism using data from 362 patients with progressive supranuclear gaze palsy, corticobasal degeneration, multiple system atrophy, or frontotemporal lobar degeneration. Although these conditions share many clinical features with the monogenic atypical forms, they can typically be distinguished based on their later median age at onset (64 years; IQR, 57–70 years). In conclusion, age at onset, presence of specific signs, and degree of levodopa response inform differential diagnostic considerations and genetic testing indications in atypical forms of parkinsonism.

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Contribution to journal
publication status
published
subject
keywords
atypical parkinsonism, genetics, MDSGene, Parkinson's disease, red flags, systematic review
in
Movement Disorders
volume
36
issue
7
pages
12 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85102736763
  • pmid:34396589
ISSN
0885-3185
DOI
10.1002/mds.28517
language
English
LU publication?
yes
id
3f0e31bc-ea40-4074-b178-cf4e7654bd42
date added to LUP
2021-12-09 15:30:53
date last changed
2024-06-15 22:22:03
@article{3f0e31bc-ea40-4074-b178-cf4e7654bd42,
  abstract     = {{<p>This Movement Disorder Society Genetic mutation database Systematic Review focuses on monogenic atypical parkinsonism with mutations in the ATP13A2, DCTN1, DNAJC6, FBXO7, SYNJ1, and VPS13C genes. We screened 673 citations and extracted genotypic and phenotypic data for 140 patients (73 families) from 77 publications. In an exploratory fashion, we applied an automated classification procedure via an ensemble of bootstrap-aggregated (“bagged”) decision trees to distinguish these 6 forms of monogenic atypical parkinsonism and found a high accuracy of 86.5% (95%CI, 86.3%–86.7%) based on the following 10 clinical variables: age at onset, spasticity and pyramidal signs, hypoventilation, decreased body weight, minimyoclonus, vertical gaze palsy, autonomic symptoms, other nonmotor symptoms, levodopa response quantification, and cognitive decline. Comparing monogenic atypical with monogenic typical parkinsonism using 2063 data sets from Movement Disorder Society Genetic mutation database on patients with SNCA, LRRK2, VPS35, Parkin, PINK1, and DJ-1 mutations, the age at onset was earlier in monogenic atypical parkinsonism (24 vs 40 years; P = 1.2647 × 10<sup>−12</sup>) and levodopa response less favorable than in patients with monogenic typical presentations (49% vs 93%). In addition, we compared monogenic to nonmonogenic atypical parkinsonism using data from 362 patients with progressive supranuclear gaze palsy, corticobasal degeneration, multiple system atrophy, or frontotemporal lobar degeneration. Although these conditions share many clinical features with the monogenic atypical forms, they can typically be distinguished based on their later median age at onset (64 years; IQR, 57–70 years). In conclusion, age at onset, presence of specific signs, and degree of levodopa response inform differential diagnostic considerations and genetic testing indications in atypical forms of parkinsonism.</p>}},
  author       = {{Wittke, Christina and Petkovic, Sonja and Dobricic, Valerija and Schaake, Susen and Arzberger, Thomas and Compta, Yaroslau and Englund, Elisabet and Ferguson, Leslie W. and Gelpi, Ellen and Roeber, Sigrun and Giese, Armin and Grossman, Murray and Irwin, David J. and Meissner, Wassilios G. and Nilsson, Christer and Pantelyat, Alexander and Rajput, Alex and van Swieten, John C. and Troakes, Claire and Respondek, Gesine and Weissbach, Anne and Madoev, Harutyun and Trinh, Joanne and Vollstedt, Eva Juliane and Kuhnke, Neele and Lohmann, Katja and Dulovic Mahlow, Marija and Marras, Connie and König, Inke R. and Stamelou, Maria and Bonifati, Vincenzo and Lill, Christina M. and Kasten, Meike and Huppertz, Hans Jürgen and Höglinger, Günter and Klein, Christine}},
  issn         = {{0885-3185}},
  keywords     = {{atypical parkinsonism; genetics; MDSGene; Parkinson's disease; red flags; systematic review}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{1499--1510}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Movement Disorders}},
  title        = {{Genotype–Phenotype Relations for the Atypical Parkinsonism Genes : MDSGene Systematic Review}},
  url          = {{http://dx.doi.org/10.1002/mds.28517}},
  doi          = {{10.1002/mds.28517}},
  volume       = {{36}},
  year         = {{2021}},
}