Genotype–Phenotype Relations for the Atypical Parkinsonism Genes: MDSGene Systematic Review
Mov Disord. 2021-03-19; 36(7): 1499-1510
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Wittke C(#)(1), Petkovic S(#)(1), Dobricic V(#)(1), Schaake S(#)(1);
MDS‐endorsed PSP Study Group; Respondek G(2)(3), Weissbach A(1), Madoev H(1),
Trinh J(1), Vollstedt EJ(1), Kuhnke N(1), Lohmann K(1), Dulovic Mahlow M(1),
Marras C(4), König IR(5), Stamelou M(6)(7)(8), Bonifati V(9), Lill CM(1), Kasten
M(#)(1)(10), Huppertz HJ(#)(11), Höglinger G(#)(3)(12), Klein C(1).
Collaborators: Arzberger T, Compta Y, Englund E, Ferguson LW, Gelpi E, Roeber S,
Giese A, Grossman M, Irwin DJ, Meissner WG, Nilsson C, Pantelyat A, Rajput A,
van Swieten JC, Troakes C.
(1)Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
(2)Department of Neurology, Technische Universität München, Munich, Germany.
(3)German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
(4)Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
(5)Institute of Medical Biometry and Statistics, University of Luebeck, Luebeck,
(6)Parkinson’s Disease and Movement Disorders Department, HYGEIA Hospital,
(7)School of Medicine, European University of Cyprus, Nicosia, Cyprus.
(8)Neurology Clinic, Philipps-University, Marburg, Germany.
(9)Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The
(10)Department of Psychiatry and Psychotherapy, University of Luebeck, Luebeck,
(11)Swiss Epilepsy Center, Klinik Lengg AG, Zurich, Switzerland.
(12)Department of Neurology, Hannover Medical School, Hannover, Germany.
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. © 2021 International Parkinson
and Movement Disorder Society.
© 2021 International Parkinson and Movement Disorder Society.
Conflict of interest statement: Relevant conflicts of interest/financial
disclosures: There are no conflicts of interest.