Abstract

Variation in the genetic risk(s) of developing Parkinson's disease (PD) undoubtedly contributes to the subsequent phenotypic heterogeneity. Although patients with PD who undergo deep brain stimulation (DBS) are a skewed population, they represent a valuable resource for exploring the relationships between heterogeneous phenotypes and PD genetics. In this series, 94 patients who underwent DBS were screened for mutations in the most common genes associated with PD. The consequent genetic subgroups of patients were compared with respect to phenotype, levodopa (l-dopa), and DBS responsiveness. An unprecedented number (29%) of patients tested positive for at least 1 of the currently known PD genes. Patients with Parkin mutations presented at the youngest age but had many years of disease before needing DBS, whereas glucocerebrosidase (GBA) mutation carriers reached the threshold of needing DBS earlier, and developed earlier cognitive impairment after DBS. DBS cohorts include large numbers of gene positive PD patients and can be clinically instructive in the exploration of genotype-phenotype relationships.

Highlights

  • Tremor was seen in all subgroups, and the proportion of tremor compared with akinesia/rigidity or axial features was similar in each group.UPDRS, Unified Parkinson’s Disease Rating Scale; SD, standard deviation; GBA, glucosidase beta acid; LRRK2, leucine-rich repeat kinase 2

  • The results from this study confirm that patients who undergo deep brain stimulation (DBS) surgery are a valuable resource for identifying genetic forms of Parkinson’s disease (PD)

  • The use of DBS cohorts facilitates the rapid identification of mutation-positive patients for study, patients who have major cognitive or psychiatric problems or a relative lack of L-dopa response are excluded; the relevance of such data to the broader population of PD patients is partially limited

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Summary

Patients and Methods

All patients were followed at the National Hospital for Neurology and Neurosurgery, Queen Square and underwent DBS between 2002 and 2011. A subset of 37 patients with >5 years of follow-up post-DBS underwent repeat cognitive assessment and had the mean annual change on the DRS-2 between baseline and follow-up calculated. Multiplex ligation-dependent probe amplification (MLPA) was performed according to manufacturer’s instructions using the P051 Salsa MLPA Parkinson probe set (MRC Holland, Amsterdam, the Netherlands). This set includes probes that detect exonic rearrangements in PARK1 (synuclein alpha [SNCA]; exons 1–6), PARK2 (Parkin: exons 1–12), PARK6 (phosphatase and tensin homolog-induced putative kinase 1 [PINK1]; exons 1–8), PARK7 (DJ1; coding exons 3, 5, 6, and 7), PARK8 (leucine-rich repeat kinase 2 [LRRK2]; exons 1, 2, 10, 15, 27, 41, and 49), the Ala30Pro mutation in PARK 1 (SNCA), and the Gly2019Ser mutation in PARK8 (LRRK2). Kruskal Wallis and nonparametric post hoc comparisons were used as appropriate

Results
Third-degree relative 1 Second-degree relative
Discussion

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