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.

Precision Medicine in Parkinson’s Disease: From Genetic Risk Signals to Personalized Therapy

“…In addition, the coexistence of atypical non-dopaminergic signs (89% with postural instability and 83% with dystonic/pyramidal features), precluded a complete motor response to dopaminergic therapy [ 48 ]. Over et al reported similar results in a more recent study [ 272 ]. Among 82 out of 146 SNCA carriers for whom treatment information was available, 79.3% of patients displayed a good response on relative low mean doses of Levodopa, nearly 10% showed a moderate response to higher doses, and 11% had a minimal response [ 272 ].…”

“…Among 82 out of 146 SNCA carriers for whom treatment information was available, 79.3% of patients displayed a good response on relative low mean doses of Levodopa, nearly 10% showed a moderate response to higher doses, and 11% had a minimal response [ 272 ]. In both studies, no obvious differences emerged according to mutation type, but good levodopa responsiveness was more frequently observed in SNCA duplication and triplication carriers compared to p.G51D mutation carriers, despite a higher rate of motor and non-motor adverse events (dystonia, dyskinesias, hallucinations, psychosis) [ 48 , 272 ].…”

“…As regards non-levodopa medications, dopamine agonists, COMT inhibitors, MAO-B inhibitors, anticholinergic medications, or NMDA antagonists evidenced benefit in most patients [ 272 ]. Both dopaminergic and non-dopaminergic drugs (e.g., amantadine, anticholinergics, tricyclic antidepressants) contribute to non-motor symptoms worsening, due to potential exacerbation of psychiatric disorders, impulse control disorders, autonomic dysfunction, and cognitive decline, commonly in SNCA carriers.…”

“…Limited data are available on the relationship between SNCA mutation and response to device-aided therapies. To date, literature reported eight patients carrying SNCA mutations received either bilateral subthalamic nucleus deep brain stimulation (STN-DBS) ( n = 5), bilateral Globus Pallidus internus (GPi) DBS (GPi-DBS) ( n = 1), or thalamotomy/pallidotomy brain surgery ( n = 2) [ 270 , 272 , 273 , 274 , 275 , 276 , 277 , 278 , 279 , 280 ]. All patients displayed a beneficial motor response to DBS, sustained over a follow-up period ranging from 1 months to 4 years [ 270 , 272 , 273 , 274 , 275 , 276 , 277 , 278 , 279 , 280 ].…”

The Genetics of Parkinson’s Disease and Implications for Clinical Practice

“…Indeed the heritability of impulse control disorder was estimated at 57%, suggesting a predominant genetic component [ 197 ]. In contrast, in a retrospective study of people with PD looking at the time to develop L-DOPA induced motor complications, addition of genotype to clinical data did not lead to any improvement in the model [ 198 ].…”