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

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 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.

Keywords: MDSGene; Parkinson's disease; atypical parkinsonism; genetics; red flags; systematic review.

FIG. 1.

Empirical distribution of the age at onset for ATP13A2, DNAJC6, FBXO7, SYNJ1, VPS13C, and DCTN1.

FIG. 2.

Clinical and genetic findings in patients with ATP13A2 mutations according to MDSGene. (A) Reported signs and symptoms are sorted according to their frequency in ATP13A2 mutation carriers (limited to signs and symptoms with a frequency of at least 25%). (B) Schematic representation of the ATP13A2 gene (upper scheme) and protein (lower scheme) with mutations listed in MDSGene. Splice-site mutations are not depicted in the protein because of unpredictable effect.

FIG. 3.

(A) Reported signs and symptoms in PD patients with DCTN1 mutations. Signs and symptoms are listed according to their frequency (limited to signs and symptoms with a frequency of at least 25%). (B) Schematic representation of the DCTN1 gene (upper scheme) and protein (lower scheme) and mutations listed in MDSGene.

FIG. 4.

Relative importance of the 67 clinical variables for classification performance to distinguish the 6 forms of monogenic atypical parkinsonism. The first 10 clinical features contribute 86.5% of the classification accuracy.

FIG. 5.

Comparison of the ranges and medians of AAOs in years. Colored lines, ranges (no range for VPS13C available); dots, median; red, AAO for monogenic atypical parkinsonism; gray, monogenic recessive PD; blue, monogenic dominant PD; boxed, nonmonogenic atypical parkinsonism.