Therapies for Genetic Forms of Parkinson's Disease: Systematic Literature Review

Abstract

Parkinson's disease (PD) is a disabling neurological condition characterized by the loss of dopaminergic neurons. Currently, the treatment for PD is symptomatic and compensates for the endogenous loss of dopamine production. In cases where the pharmacological therapy is only partly beneficial or results in major wearing-off complications, surgical interventions such as deep brain stimulation may be an alternative treatment. The disease cause often remains unknown, but in some patients, a monogenic cause can be identified. Mutations in at least six genes, LRRK2, SNCA, and VPS35 (dominant forms) or Parkin/PRKN, PINK1, and DJ1/PARK7 (recessive forms) have been unequivocally linked to PD pathogenesis. We here systematically screened 8,576 publications on these monogenic PD forms. We identified 2,226 mutation carriers from 456 papers. Levodopa was the most widely applied treatment; only 34 patients were indicated to be untreated at the time of reporting. Notably, detailed treatment data was rarely mentioned including response quantification (good, moderate, minimal) in 951 and/or dose in 293 patients only. Based on available data, levodopa showed an overall good outcome, especially in LRRK2, VPS35, Parkin, and PINK1 mutation carriers ("good" response in 94.6-100%). Side effects of levodopa therapy were reported in ∼15-40%of levodopa-treated patients across genes with dyskinesias as the most frequent one. Non-levodopa medication was indicated to be administered to <200 patients with mainly good outcome. Only a few reports were available on outcomes of brain surgery. Here, most mutation carriers showed a good response. Importantly, none of the available treatments is harmful to one genetic form but effective in another one. In the light of different medication schemes, the progressive nature of PD, and side effects, an improvement of therapeutic options for PD is warranted including a treatabolome database to guide clinicians in treatment decisions. Further, novel disease-cause-modifying drugs are needed.

Keywords: MDSGene; Treatabolome; deep brain stimulation; genetic Parkinson’s disease; levodopa; systematic literature review; treatment.

Fig. 1

Flow chart of systematic literature review. The flow diagram shows the steps and respective numbers of papers.

Fig. 2

Results of the systematic literature review for SNCA mutation carriers. A) The chart shows information on carriers of SNCA mutations with levodopa treatment, respective response and side effects, subdivided by different mutations. B) Information on brain surgery and response.

Fig. 3

Results of the systematic literature review for LRRK2 mutation carriers. A) The chart shows information on carriers of LRRK2 mutations with levodopa treatment, respective response and side effects, subdivided by the most frequent mutations. B) Information on brain surgery and response.

Fig. 4

Results of the systematic literature review for VPS35 mutation carriers. A) The chart shows information on carriers of VPS35 mutations with levodopa treatment, respective response and side effects, subdivided by the most frequent mutations. B) Information on brain surgery and response. *: Other side effects have not been reported.

Fig. 5

Results of the systematic literature review for Parkin mutation carriers. A) The chart shows information on carriers of Parkin mutations with levodopa treatment, respective response and side effects, subdivided by type of mutation. B) Information on brain surgery and response.

Fig. 6

Results of the systematic literature review for PINK1 mutation carriers. A) The chart shows information on carriers of PINK1 mutations with levodopa treatment, respective response and side effects, subdivided by the most frequent mutations. B) Information on brain surgery and response. *: Other side effects have not been reported.

Fig. 7

Results of the systematic literature review for DJ1 mutation carriers. A) The chart shows information on carriers of DJ1 mutations with levodopa treatment, respective response and side effects. Due to the low number of recurrent mutations, no subdivision for the most frequent mutations has been included. B) No patient with brain surgery has been reported.