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.
| Original language | English |
|---|---|
| Journal | Journal of Neuromuscular Diseases |
| Volume | 8 |
| Issue number | 3 |
| Pages (from-to) | 341-356 |
| Number of pages | 16 |
| ISSN | 2214-3599 |
| DOIs | |
| Publication status | Published - 2021 |
Funding
K.L. received funding from the German Research Foundation, the International Parkinson’s disease and Movement Disorder Society (MDS), and the Damp foundation. She is further an active member of the Global Parkinson’s Genetics Program (GP2) initiative. N.B. served as a consultant for Centogene. NB is funded by the DFG (BR4328.2-1/2-2, GRK1957), the Collaborative Center for X-linked Dystonia-Parkinsonism and the Else-Kröner Fresenius-Stiftung (HA17 2017). Several conclusions can be drawn from this systematic review on treatment of monogenic PD with dominant mutations in SNCA, LRRK2, or VPS35 or with recessive mutations in Parkin, PINK1, and DJ1. First, there is no treatment that is harmful to one genetic form but beneficial in another one. Second, the report of detailed treatment data including dose and response quantification is rare. Third, based on the available data from about half of >2,000 mutation carriers, it can be concluded that most patients, independent of the genetic cause, respond well to levodopa. The percentage of good responders seems to be lowest for DJ1 and SNCA mutation carriers, respectively. Thus, levodopa is the most efficient and most frequently prescribed drug in monogenic PD as is for idiopathic PD. Fourth, accordingly, brain surgery is rather rarely applied and reported. Fifth, there is a wide spectrum of (additional) non-levodopa drugs that often show an additive beneficial effect. Sixth, reported outcomes on brain surgery comprise good outcome in all mutation carriers This work was funded by the German Research Foundation (FOR2488) and the Damp foundation. L.O. is the recipient of a stipend for her medical thesis (“Excellenzstipendium”) from the University of Lübeck.
