Motor progression of Parkinson's disease with the leucine-rich repeat kinase 2 G2019S mutation.

INTRODUCTION: In this retrospective study, we compared motor disease progression in Ashkenazi-Jewish (AJ) Parkinson's disease (PD) patients carrying the LRRK2*G2019S mutation with that of noncarriers. METHODS: Consecutive PD patients were recruited between 2004 and 2011. Disease progression of carriers versus noncarriers was compared using survival analysis, where the end-point was the time from PD onset to reaching Hoehn and Yahr stage 3 (HY3). RESULTS: Overall, 405 AJ PD patients (males = 241[60%]) were genotyped, of whom 60 (males = 30) were LRRK2*G2019S mutation carriers. Time to HY3 did not differ significantly between mutation carriers and noncarriers (hazard ratio = 1.21, 95%CI = 0.83-1.77, P = 0.33). Age at PD onset was younger for carriers than for noncarriers (59.1 ± 9.8 vs. 63.2 ± 12.0 years, respectively; P = 0.005). In both groups, young age at onset was strongly associated with longer time to HY3, (P < 0.001). CONCLUSION: The LRRK2*G2019S mutation status has no discernible effect on the rate of motor disease progression in AJ PD patients.

Clinical Experience With Deferiprone Treatment for Friedreich Ataxia.

Friedreich ataxia is an inherited disorder characterized by degeneration of the peripheral and central nervous system and hypertrophic cardiomyopathy. Homozygous mutations in the frataxine (FXN) gene reduce expression of frataxin and cause accumulation of iron in the mitochondria. Deferiprone, an oral iron chelator, has been shown effective in cell and animal models of Friedreich ataxia. The results of a 6-month randomized, double blind placebo-controlled study suggested that deferiprone 20 mg/kg/day may reduce disease progression. The authors present their experience of 5 Friedreich ataxia patients treated with deferiprone (20 mg/kg/day), in addition to idebenone treatment, followed over a period of 10-24 months, under off-label authorization. The patients were monitored for laboratory parameters, cardiac assessment, neurological evaluations, and quality of life. The authors conclude that combined therapy of a low dose of deferiprone with idebenone is relatively safe, might improve neurological function, and seems to improve heart hypertrophy, warranting further studies.

Correlates of quality of sexual life in male and female patients with Parkinson disease and their partners.

INTRODUCTION: Patients with Parkinson disease (PD) and their partners may experience a worsening of their sexual life. AIM: To assess quality of sexual life (QoSL) in male and female PD patients and their partners. MATERIALS AND METHODS: Medical, demographic and clinical data was collected regarding consecutive PD patients, including depression, and motor symptom rating. Partners' data included the short form-12 health questionnaire (SF-12). All patients and partners filled the 5-item QoSL questionnaire. RESULTS: Data from 89 PD patients (66 men) and 69 spouses (52 women) was analyzed. Male patients rejected sex significantly less than female patients and their sexual desire was higher, but female patients reported higher sexual satisfaction. Patients and partners similarly perceived their relationship which was averagely good. Analysis within couples demonstrated that better QoSL of patients could be predicted by gender (male), better QoSL of their partners and, motor severity, but not the patient's depression, age or use of l-dopa. The partner's QoSL was explained by younger age, and better motor scores of their parkinsonian partner. Treatment of the PD patient with l-dopa or dopamine agonist was associated with worse partner's QoSL. CONCLUSION: Differences in QoSL of male and female PD patients and within couples were found. These findings suggest that focusing on partner's needs may improve QoSL of patients and partners troubled by PD.

Sequence variants in SLC6A3, DRD2, and BDNF genes and time to levodopa-induced dyskinesias in Parkinson's disease.

Levodopa-induced dyskinesias (LID) present a common but elusive complication of levodopa therapy in Parkinson's disease (PD). In order to identify genetic factors associated with LID, 352 (213 males) levodopa-treated Israeli PD patients were genotyped for 34 polymorphisms within three candidate genes affecting dopaminergic activity and synaptic plasticity: dopamine transporter gene (DAT1 or SLC6A3) [14 single nucleotide polymorphisms (SNPs) and 40-bp variable number tandem repeat (VNTR)], DRD2 [11 SNPs and dinucleotide CA short tandem repeat (STR)], and BDNF (7 SNPs). A comparison of patients with and without LID was performed by applying a time-oriented approach, with survival analyses evaluating LID development hazard rate over time [Cox proportional hazards and accelerated failure time (AFT) lognormal models]. Overall, 192 (54.5 %) participants developed LID, with a mean latency of 5.0 (±4.5) years. After adjusting for gender, age at PD onset, duration of symptoms prior to levodopa exposure, and multiple testing correction, one SNP in SLC6A3 (with 81 % genotyping success) was significantly associated with LID latency: the C allele of the rs393795 extended the time to LID onset, time ratio = 4.96 (95 % CI, 2.3-10.9; p = 4.1 × 10(-5)). This finding should be validated in larger, ethnically diverse PD populations, and the biological mechanism should be explored.

The LRRK2 G2019S mutation status does not affect the outcome of subthalamic stimulation in patients with Parkinson's disease.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established therapy for advanced Parkinson's disease (PD). The most common genetic mutation associated with PD identified to date is the G2019S mutation of the LRRK2 gene, which is highly prevalent in the Ashkenazi Jewish population. The effect of STN-DBS surgery in patients carrying this mutation has not been systematically studied. We therefore performed a case-control study to evaluate the impact of the G2019S mutation status on the outcomes of bilateral STN-DBS. METHODS: The study sample included 39 Jewish PD patients with bilateral STN-DBS. Thirteen patients (5 females) were G2019S mutation heterozygous. The control group consisted of 26 PD patients with bilateral STN-DBS, negative for the mutation, matched (2:1) for gender, age at PD onset, and disease duration at surgery. Clinical data including the Unified PD Rating Scale scores (UPDRS), levodopa equivalent daily dose (LEDD), and clinical global impression of change (CGIC) concerning both motor and neuropsychiatric outcome- were available at 3 time points (preoperative baseline, 6-12 months and 3 years postoperatively). RESULTS: Implementing a linear mixed model, a significant improvement (p < 0.05) was found for the whole group concerning reduction in motor UPRDS (off state) and LEDD pre- vs. postoperatively, as expected. No difference in clinical outcome was found between carriers and matched non-carriers at baseline or at postoperative follow-up (up to 3 years). CONCLUSIONS: In our study, STN-DBS outcomes were not influenced by the LRRK2 G2019S mutation, and thus knowledge of carrier status may not be relevant to the considerations of patient selection for surgery.

Dyskinesias in patients with Parkinson's disease: effect of the leucine-rich repeat kinase 2 (LRRK2) G2019S mutation.

BACKGROUND: While Parkinson's disease (PD) phenotype in leucine-rich repeat kinase 2 gene (LRRK2)-associated and sporadic PD seems similar, there is paucity of data on the possible effect of mutations in LRRK2 on response to and complications of dopaminergic therapy. OBJECTIVE: To assess the impact of the LRRK2 Gly2019Ser (G2019S) carrier status on the time to the onset of levodopa-induced dyskinesias (LID). METHODS: Consecutive PD patients treated with levodopa were genotyped for the LRRK2 G2019S mutation. The relationship between mutation carrier status and the time to LID onset was explored after matching carriers to non-carriers for age at PD onset, gender, and time from PD diagnosis to levodopa initiation, using Kaplan-Meier curves and the Cox proportional hazards model, using LID onset as an end-point. RESULTS: Overall, 349 Israeli PD patients [222 Ashkenazi-Jewish (AJ), 60.5% males, mean age at diagnosis: 60.6 ± 13.2 years] participated in the study. Of these, 33 patients (9.5%, 30 AJ) carried the LRRK2 G2019S mutation. The prevalence of LID was non-significantly higher among carriers (22/33, 66.7%) than non-carriers (168/316, 53.2%, p = 0.15). The mean duration of therapy from levodopa initiation to the development of LID or last follow-up (in cases who were LID-free) was 5.1 ± 5.4 years for carriers and 4.4 ± 4.0 years in non-carriers (p = 0.47) and the survival curves in carriers and matched non-carriers were not significantly different (Cox proportional hazards test and log-rank test; p = 0.79). CONCLUSIONS: The LRRK2 G2019S mutation status has no discernable effect on the prevalence of LID or on LID latency in Israeli levodopa-treated PD patients.

Gender effect on time to levodopa-induced dyskinesias.

Levodopa-induced dyskinesias (LID) are commonly observed during long-term treatment of patients with Parkinson's disease (PD). The impact of non-pharmacological factors on the latency to LID appearance is not known. The aim of the paper was to identify factors associated with time to appearance of LID. Consecutive PD patients treated with levodopa (n = 155) were included in this historical prospective analysis and LID and non-LID groups were compared. The relationship between possible risk factors and the time of LID onset was explored using the Kaplan-Meier method and the Cox multivariate regression model, controlling for the confounding effects of gender, age of disease onset, time to initiation of levodopa treatment, and history of smoking. Patients with LID (57.4%) were significantly younger at disease onset and had a slightly longer latency from diagnosis to levodopa treatment than those without; disease duration and age had no effect on LID appearance. Female gender was associated with a shorter time to LID and the median time to LID was 6 years for males and 4 years for females (p = 0.004). In the multivariate survival analysis a younger age of onset of PD and a longer time from diagnosis to levodopa treatment initiation were also associated with a shorter time to LID appearance (p = 0.030 and 0.036, respectively). Female gender is associated with a significantly shorter latency to LID appearance. Younger age at PD diagnosis and a longer time until starting levodopa are associated with both higher likelihood to develop LID, and a shorter latency until LID were observed.