SNCA: Major genetic modifier of age at onset of Parkinson's disease

Age at onset serves as a predictor of progression and mortality in sporadic Parkinson's disease (PD). Therefore, the identification of genetic modifiers for age at onset might lead to a better understanding of disease pathogenesis. We performed multivariate linear regression analysis in 1396 sporadic PD patients assessing 21 single‐nucleotide polymorphisms (SNPs) that have been previously suggested to be associated with sporadic PD. Moreover, a cumulative risk score was assigned to each patient and correlated with age at onset. We identified the rs356219 risk allele in the SNCA gene as significantly contributing to earlier age at onset. Neither one of the other 21 SNPs tested in this analysis nor the cumulative number of risk alleles showed a significant impact on PD onset. Because sequence variants in the SNCA gene are not only associated with autosomal dominantly inherited PD and increased susceptibility for sporadic PD but also have been found to modify the phenotype such as age at onset in both sporadic and various monogenic forms of PD, this gene serves as an outstanding target for further research on PD pathogenesis, which in return might provide potential therapeutic options. © 2013 Movement Disorder Society     

LRRK2 exon 41 mutations in sporadic Parkinson disease in Europeans

BACKGROUND: Mutations in leucine-rich repeat kinase 2 gene (LRRK2), particularly the G2019S mutation in exon 41, have been detected in familial and sporadic Parkinson disease (PD) cases. OBJECTIVES: To assess the frequency of LRRK2 exon 41 mutations in a series of sporadic PD cases from Europe and to determine the clinical features of LRRK2 mutation carriers. DESIGN: We analyzed European cases of sporadic PD for the presence of LRRK2 exon 41 mutations. These mutations were screened by denaturing high-performance liquid chromatography, and abnormal chromatograph traces were investigated by direct sequencing to determine the exact nature of the variants. Early-onset sporadic PD cases were also screened for parkin mutations. The haplotypes associated with the G2019S mutation were determined. The clinical characteristics of patients carrying LRRK2 mutations were detailed. SETTING: French Network for the Study of Parkinson Disease Genetics. Patients Three hundred twenty patients with apparently sporadic PD from Europe. MAIN OUTCOME MEASURES: Results of genetic analyses. RESULTS: We found the G2019S mutation in 6 patients and identified 2 new variants (Y2006H and T2031S) in 1 patient each. Their clinical features were similar to those of typical PD. All G2019S mutation carriers shared a common haplotype. CONCLUSIONS: The G2019S mutation is almost as frequent in sporadic cases (1.9%) as in previously reported familial cases (2.9%) in Europe and occurs in the same common founder. We identified 2 novel variants. Although the phenotype of LRRK2 mutation carriers closely resembles that of typical PD, the age at onset was younger (29 years in 1 patient) than previously described, and 3 patients were improved by deep brain stimulation.     

The motor phenotype of Parkinson's disease in relation to age at onset

Background: Parkinson's disease (PD) is heterogeneous and age at onset may define variation in clinical phenotype. Most previous studies have used various age cut‐offs and have been based on clinical case series. Methods: We have studied the association between clinical features and age of onset in 358 community‐based and regional patients with PD. Results: Tremor at presentation is twice as common in those with onset over 64 years as compared to those with onset under 45 (early onset PD ‐ EOPD) and becomes more common with increasing age at onset (p values for trend ≤ 0.004). Dystonia affects 60% of those with EOPD, shows a curvilinear relationship with age at onset (cubic versus linear p=0.01) with highest risk in patients whose disease began before 48 years. In this study age at onset was a strong predictor of the development of dyskinesias, with younger age associated with a higher risk of dyskinesias. Following multivariable analysis, allowing for possibly confounding factors (disease duration, L‐DOPA dosage, L‐DOPA treatment duration) younger age at onset, (less than 55 years) predicted the development of L‐DOPA induced dyskinesia (odds ratio <45 years 2.1, 95% CI 1.0, 4.8; odds ratio < 55 years 3.8, 95% CI 1.8, 8.0). Only 2/70 (2.9%) EOPD patients carried pathogenic parkin or PINK1 mutations and the clinical differences between early and late onset disease were not explained by the presence of mutations in these genes. Discussion: This study highlights the clinical differences between early and late onset PD, which have important implications for diagnosis and management. © 2011 Movement Disorder Society     

Clinical heterogeneity in Parkinson's disease revisited: a latent profile analysis

Objective – The heterogeneity of Parkinson’s disease (PD) is increasingly recognized, and several attempts have been made to subclassify subjects on clinical or cognitive features. We explored the utility of latent profile analysis (LPA) as a means of classifying patients with PD on clinical features and test validity of these subclasses against neuropsychological data. Methods – LPA utilizing clinical variables while controlling for age was applied to a cohort of 71 outpatients with PD. The resultant subgroups were validated via comparison to 30 control subjects on neuropsychological tests of executive, memory, and visuospatial functions. Results – The LPA resulted in a three‐class solution identifying a ‘younger onset, mild motor impairment group’, a ‘moderate motor impairment group’, and an ‘old onset, fast progression group’. The groups were distinguishable on cognitive variables with the ‘younger onset mild motor impairment subgroup’ displaying deficits pertaining verbal acquisition, visuospatial construction, and set maintenance. The ‘moderate motor impairment group’ exhibited widespread cognitive impairment, and the ‘old onset, fast disease progression group’ had extensive cognitive impairment but outperformed the former group on verbal acquisition and visuospatial function. Conclusion – LPA holds promise in PD research as it uncovered three PD subtypes distinguished by motor symptoms and disease progression and validated by cognitive variables.     

MDR1 variants and risk of Parkinson disease

The multidrug resistance protein 1 (MDR1 or ABCB1) gene encodes a P-glycoprotein that protects the brain against neurotoxicants. Certain MDR1 genetic variants are known to compromise the function of this transporter and may thus be associated with Parkinson disease (PD). We therefore conducted a large case-control study investigating the potential relationship between MDR1 variants and PD. We determined the frequency of three MDR1 variants in 599 European PD patients and controls and further stratified the population by ethnicity, age at onset, and exposure to pesticides. We detected no relevant association in either the entire sample, or when separately investigating by ethnic origin or age at onset. However, the distribution of c.3435C/T differed significantly between PD patients exposed to pesticides compared to those non-exposed (odds ratio = 4.74; confidence interval = [1.009; 22.306]); p = 0.047), suggesting that common MDR1 variants might influence the risk to develop PD in conjunction with exposure to pesticides.     

Familial associations of Alzheimer disease and essential tremor with Parkinson disease

Background: We constructed a cohort of first‐degree relatives of participants in a population‐based case–control study of Parkinson disease (PD) and compared the occurrence of Alzheimer disease (AD) and essential tremor (ET) in relatives of PD cases and controls. Methods: We relied on proband interviews to assess family history in 372 probands with incident PD confirmed by a movement disorder specialist and 404 controls from three rural California counties. Results: Overall, for the 2980 first‐degree relatives of PD cases, the risk of AD was not increased compared with the 2981 relatives of controls. But relatives of younger onset PD cases (≤60 years of age) were three times more likely to have received an AD diagnosis [hazard ratios (HR): 2.86; 95%CI: 1.44, 5.71]. Our data also suggest that some relatives of PD probands might be at a slightly increased risk of receiving an ET diagnosis, especially relatives of tremor dominant cases (HR: 1.69; 95%CI 0.99, 2.88), younger onset cases (HR: 2.03; 95%CI 0.93, 4.44), and male relatives (HR: 2.31; 95%CI 1.13, 4.73). In addition, fathers of cases were almost 15 years younger than fathers of controls when diagnosed with ET. Results were stable in sensitivity analyses. Conclusion: Our study suggests a familial susceptibility to AD amongst first‐degree relatives of younger onset PD cases.     

Novel and reported variants in Parkinson's disease genes confer high disease burden among Indians

BackgroundGenetic heterogeneity in Parkinson's disease (PD) has been unambiguously reported across different populations. Assuming a higher genetic load, we tested variant burden in PD genes to an early onset PD cohort from India.MethodsWhole exome sequencing was performed in 250 PD patients recruited following MDS-UPDRS criteria. The number of rare variants in the 20 known PD genes per exome were used to calculate average rare variant burden with the 616 non-PD exomes available in-house as a comparison group. SKAT-O test was used for gene level analysis.Results80 patients harboured rare variants in 20 PD genes, of which six had known pathogenic variants accounting for 2.4% of the cohort. Of 80 patients, 12 had homozygous and nine had likely compound heterozygous variants in recessive PD genes and 59 had heterozygous variants in only dominant PD genes. Of the 16 novel variants of as yet unknown significance identified, four homozygous across ATP13A2, PRKN, SYNJ1 and PARK7; and 12 heterozygous among LRRK2, VPS35, EIF4G1 and CHCHD2 were observed. SKAT-O test suggested a higher burden in GBA (p_unadjusted = 0.002). Aggregate rare variant analysis including 75 more individuals with only heterozygous variants in recessive PD genes (excluding GBA), with an average of 0.85 protein-altering rare variants per PD patient exome versus 0.51 in the non-PD group, revealed a significant enrichment (p < 0.0001).ConclusionThis first study in an early onset PD cohort among Indians identified 16 novel variants in known genes and also provides evidence for a high genetic burden in this ethnically distinct population.     

The effect of onset age on the clinical features of Parkinson's disease

Many clinicians view age at onset as an important determinant of clinical phenotype in Parkinson's disease (PD) and this has been reinforced by the identification of Mendelian genes that account for some cases of younger onset PD. A systematic review of OVID Medline for articles relevant to the relationship between clinical features and age at onset in PD published in English between 1950–2007 was performed. There are very few prospective community based studies which focus on the relationship between age at onset and the features of PD and a variety of case definitions are used in the literature. Most studies of young onset PD are based on specialist clinic referral series. The available evidence suggests that PD patients with a younger age at onset have: (i) a slower disease progression, (ii) an increased rate of dystonia at onset and during treatment, (iii) a lower rate of dementia and (iv) an increased rate of dyskinesias in response to l -DOPA treatment. The majority of the available studies do not report patient genotype data, but it is probably that the clinical heterogeneity of PD will be further refined with detailed clinico-genetic studies.     

Clinical features and gene analysis in Korean patients with early-onset Parkinson disease

BACKGROUND: Systematic analysis of clinical features and gene mutations has not been performed in Korean patients with early-onset Parkinson disease (PD). OBJECTIVE: To investigate the clinical characteristics and genetic background of Korean patients with early-onset PD. DESIGN: Clinical and genetic study. SETTING: University hospital. PATIENTS: Ninety-four patients with early-onset PD (mean +/- SD age at onset, 39.8 +/- 7.3 years) of 1100 patients with PD. INTERVENTIONS: Analysis of clinical characteristics and mutation analysis of the parkin and PTEN-induced kinase (PINK1) genes by direct sequencing and gene-dosage analysis using the multiplex ligation-dependent probe amplification technique. MAIN OUTCOME MEASURES: The correlation between age at onset and clinical characteristics and the clinical features of patients with onset before age 30 years vs patients with onset after age 30 years. RESULTS: Because age at onset was younger, levodopa-induced dyskinesia and off-dystonia were more frequently observed (P=.008). Patients affected before age 30 years showed more frequent levodopa-induced dyskinesia and off-dystonia (P=.002). We identified 3 patients (5%) with parkin gene mutations but none with the PINK1 mutation. CONCLUSIONS: Earlier onset of levodopa-induced dyskinesia and off-dystonia were characteristic features of early-onset PD, especially before an onset age of 30 years. However, parkin gene mutations were less frequent in these patients than in Japanese groups reported elsewhere.     

VPS35 mutation in Japanese patients with typical Parkinson's disease

Vacuolar protein sorting 35 (VPS35) was recently reported to be a pathogenic gene for late‐onset autosomal dominant Parkinson's disease (PD), using exome sequencing. To date, VPS35 mutations have been detected only in whites with PD. The aim of the present study was to determine the incidence and clinical features of Asian PD patients with VPS35 mutations. We screened 7 reported nonsynonymous missense variants of VPS35, including p.D620N, known as potentially disease‐associated variants of PD, in 300 Japanese index patients with autosomal dominant PD and 433 patients with sporadic PD (SPD) by direct sequencing or high‐resolution melting (HRM) analysis. In addition, we screened 579 controls for the p.D620N mutation by HRM analysis. The p.D620N mutation was detected in 3 patients with autosomal dominant PD (1.0%), in 1 patient with SPD (0.23%), and in no controls. None of the other reported variants of VPS35 were detected. Haplotype analysis suggested at least 3 independent founders for Japanese patients with p.D620N mutation. Patients with the VPS35 mutation showed typical tremor‐predominant PD. We report Asian PD patients with the VPS35 mutation. Although VPS35 mutations are uncommon in PD, the frequency of such mutation is relatively higher in Japanese than reported in other populations. In VPS35, p.D620N substitution may be a mutational hot spot across different ethnic populations. Based on the clinical features, VPS35 should be analyzed in patients with PD, especially autosomal dominant PD or tremor‐predominant PD. © 2012 Movement Disorder Society     

Differential genetic susceptibility in diphasic and peak‐dose dyskinesias in Parkinson's disease

To examine whether there is a differential genetic susceptibility in the diphasic and peak‐dose forms of levodopa‐induced dyskinesias (LID) in patients with Parkinson's disease (PD). The study cohort comprised 503 unrelated Korean PD patients who were treated with levodopa and had a disease duration of at least 5 years. The presence of LID was identified during a routine follow‐up and special care was taken to separate the two distinct forms of LID into diphasic and peak‐dose dyskinesias (PDSK). Genotyping was performed in the 503 patients and in 559 healthy controls to search for polymorphisms of DRD3 p.S9G, DRD2 Taq1A, GRIN2B c.2664C>T, c.366C>G, c.‐200T>G, and the promoter region of SLC6A4. A total of 229 patients expressed LID (peak‐dose in 205, diphasic in 57, and both in 33). The presence of diphasic dyskinesia (DDSK) was exclusively associated with the DRD3 p.S9G variant after adjusting for gender, age at PD onset, Hoehn & Yahr stage, and duration of levodopa treatment. Carrying the AA genotype was likely to shorten the onset of DDSK according to the duration of levodopa therapy (P = 0.02). The presence of PDSK was not significantly associated with any of the six genetic variants studied. There may be a genetic susceptibility in the development of DDSK in PD patients on chronic levodopa therapy, and its underlying pathophysiological mechanism might be distinct from that of PDSK. © 2010 Movement Disorder Society     

Association study of Parkin gene polymorphisms with idiopathic Parkinson disease

BACKGROUND: Previously, we detected linkage of idiopathic Parkinson disease (PD) to the region on chromosome 6 that contains the Parkin gene (D6S305; logarithm of odds score, 5.47) in families with at least one individual with age at onset younger than 40 years (families with early-onset disease). Further study demonstrated the presence of Parkin mutations in this data set. However, previous case-control studies have reported conflicting results regarding the role of more common Parkin polymorphisms as susceptibility alleles for idiopathic PD. OBJECTIVE: To investigate the association of 7 previously studied Parkin single-nucleotide polymorphisms (SNPs) throughout the promoter and most of the open reading frame with PD in a large cohort of patients with primarily late-onset PD. METHODS: One promoter, 3 intronic, and 3 exonic Parkin SNPs were genotyped in 1580 individuals belonging to 397 families, and their association with PD was evaluated using family-based association tests. RESULTS: No significant association (P>.05) between PD and any Parkin SNP allele or genotype was detected. Haplotype analysis and stratification by age at onset or family history also failed to produce significant results. CONCLUSIONS: These results suggest that these common variants of Parkin are not associated with PD in white patients, although Parkin mutations are known to cause early- and late-onset PD.     

Autosomal dominant Parkinson's disease in a large German pedigree

Brüggemann N, Külper W, Hagenah J, Bauer P, Pattaro C, Tadic V, Lohnau T, Winkler S, Tönnies H, Sprenger A, Pramstaller P, Rolfs A, Siebert R, Riess O, Vieregge P, Lohmann K, Klein C. Autosomal dominant Parkinson’s disease in a large German pedigree.
Acta Neurol Scand: 2012: 126: 129–137.
© 2011 John Wiley & Sons A/S. Objective – While several genes have been identified to cause Parkinson′s disease (PD), monogenic forms explain only a small proportion of cases. We report clinical and genetic results in a large family with late‐onset autosomal dominant PD. Methods – Thirty‐eight family members of a five‐generation Northern German PD family underwent a detailed neurologic examination, and transcranial sonography was performed in fifteen of them. Comprehensive mutation analysis of known PD‐causing genes and a genome‐wide linkage analysis were performed. Results – Late‐onset definite PD was found in five subjects with a mean age at onset of 63 years. Another six individuals presented either with probable/possible PD or with subtle parkinsonian signs. Six members with a mean age of 79 years had an essential tremor phenotype. Mode of PD inheritance was compatible with autosomal dominant transmission. One of three examined patients with definite PD demonstrated an increased area of substantia nigra hyperechogenicity upon transcranial sonography. Comprehensive linkage and mutational analysis excluded mutations in known PD‐causing genes. Genome‐wide linkage analysis suggested a putative disease gene in an 11.3‐Mb region on chromosome 7p15–21.1 with a multipoint LOD score of 2.0. Conclusions – The findings in this family further demonstrate genetic heterogeneity in familial autosomal dominant late‐onset PD.     

Risk factors for progression in Parkinson's disease

Using case-control methodology, we assessed prevalence and duration of exposure to putative risk factors for rapid progression of Parkinson's disease (PD) in patients not taking levodopa or direct dopamine agonists. We identified 31 patients termed "rapidly progressive" who were stage I or II (Hoehn and Yahr) on their first visit to our center and who progressed to stage III during the study period; we pair-matched this group with 31 "slowly progressive" patients who had the same symptom duration and the same Hoehn and Yahr stage at study entry, but whose parkinsonism did not progress to stage III during the study. Only age of PD onset was associated with different rates of PD progression; older patients at PD onset progressed more rapidly than younger patients.     

Myopathy causing camptocormia in idiopathic Parkinson's disease: A multidisciplinary approach

Extreme forward flexion of the spine, named camptocormia (CC), and head drop syndrome (HD) may be among the most disabling symptoms in Parkinson's disease (PD). This study aims to eludicate the etiology of PD‐associated CC and HD via a multidisciplinary approach (clinical examination, electromyography, MRI, genetic analysis, muscle morphology) centering on the histology of the paraspinal muscles. We studied 17 patients with the clinical diagnosis of PD and CC or head drop syndrome and six controls. We performed muscle biopsies of paraspinal muscles and deep neck extensor muscles. Mean age at onset of postural abnormality was 66 years and mean latency between onset of parkinsonian symptoms to first signs of CC or head drop was 7 years. The electromyogram of paraspinal muscles was abnormal in 13–14 patients. Histopathology revealed chronic myopathic changes in 14 of 17 biopsies, consisting of abnormal variation in fiber size, increase in internal nuclei, and increase in connective tissue, myofibrillar disarray and similarities to protein surplus myopathies. Interestingly, heterozygous variants in the Parkin gene were found in 2 of 9 investigated patients. We conclude that CC and HD in PD are predominantly myopathic. Aberrant protein aggregation may link PD and CC. © 2009 Movement Disorder Society     

Functional decline in Parkinson disease

OBJECTIVES: To determine the overall rate of functional decline and to assess the progression of different signs of Parkinson disease (PD). PATIENTS AND METHODS: Patients with clinically diagnosed PD followed up for at least 3 years were included in this study. Demographic and clinical data (including the Unified Parkinson's Disease Rating Scale [UPDRS]) were analyzed by the multivariate unbalanced repeated-measurements design using the mixed-effects model to study the association between different symptoms and various demographic variables. Regression models helped estimate the rates of progression of the disease in relationship to the various components of the UPDRS. Patients were categorized as having tremor-dominant or postural instability-gait difficulty-dominant PD and the 2 categories were compared for progression of their total UPDRS scores. DESIGN: A multivariate mixed-effects model was used to study the relationship between the different symptoms and various demographic variables. Nonparametric statistical tests were used to compare the progression of symptoms in the "on" (good function) state and the "off" (poor function) state groups for 2 age-at-onset categories (< or =57 and >57 years). RESULTS: Data from 1731 visits on 297 patients (181 men) followed up for an average of 6.36 years (range, 3-17 years) were analyzed. The annual rate of decline in the total UPDRS scores was 1.34 when assessed during the on state and 1.58 when assessed during the off state. Patients with an older age at onset had more rapid progression of PD than those with a younger age at onset. Furthermore, the older-onset group had statistically significantly more progression in mentation, freezing, and parts I (mentation) and II (activities of daily living) UPDRS subscores. Handwriting was the only component of the UPDRS score that did not notably deteriorate during the observation period. Regression analysis of 108 patients whose symptoms were rated during their off state showed a faster rate of cognitive decline as age at onset increased. The slopes (ie, the annual rates of decline) of progression in the UPDRS scores, when adjusted for age at the initial visit, were steeper for the postural instability--gait difficulty--dominant group compared with the tremor-dominant group. CONCLUSION: Based on longitudinal follow-up data, our findings provide evidence for a variable course of progression of the different PD symptoms, thus implying different biochemical or degenerative mechanisms for the various clinical features associated with PD.     

Blood lysosphingolipids accumulation in patients with parkinson's disease with glucocerebrosidase 1 mutations

Introduction: Glucocerebrosidase 1 mutations, the most common genetic contributor to Parkinson's disease (PD), have been associated with decreased glucocerebrosidase enzymatic activity in PD patients with glucocerebrosidase 1 mutations (glucocerebrosidase 1–PD). However, it is unknown whether this decrease in enzymatic activity leads to lysosphingolipid accumulations. Methods: The levels of hexosylsphingosines, globotriaosylsphingosine, sphingomyelin, and sphingomyelin‐509 were measured in dried blood spots from glucocerebrosidase 1–PD patients (n = 23), sporadic PD patients (n = 105), Gaucher disease patients (n = 32), and controls (n = 88) by liquid chromatography‐tandem mass spectrometry. Results: Glucocerebrosidase 1–PD patients had increased hexosylsphingosine levels when compared with sporadic PD patients (P < .001) and controls (P < .0001). Hexosylsphingosine levels were increased in glucocerebrosidase 1 mutation carriers of glucocerebrosidase 1 (L444P; N370S; n = 11, P = .001) and glucocerebrosidase 1 polymorphic variants (E326K, T369M) associated with PD (n = 12, P = .04) when compared with controls. Conclusions: Lysosphingolipid accumulations in PD patients who bear glucocerebrosidase 1 mutations suggest that substrate reduction therapy might be viewed as a possible strategy for glucocerebrosidase 1–PD treatment. © 2018 International Parkinson and Movement Disorder Society     

Imaging nigral pathology and clinical progression in Parkinson's disease

The pattern of dopamine cell loss in Parkinson's disease (PD) is known to be prominent in the ventrolateral and caudal substantia nigra (SN), but less severe in the dorsal and rostral region. Both diffusion tensor imaging (DTI) and R2* relaxometry of the SN have been reported as potential markers for PD, but their relative ability to mark disease progression and differences in pathophysiological bases remains unclear. High‐resolution T2‐weighted, R2*, and DTI were obtained from 28 controls and 40 PD subjects [15 early stage [disease duration ≤1 year], 14 mid stage [duration 2–5 years], and 11 late stage [duration >5 years]). Fractional anisotropy and R2* values in both rostral and caudal SN were obtained for all subjects, and clinical measures (e.g., disease duration, levodopa‐equivalent daily dosage, and “off”‐drug UPDRS motor score) were obtained for Parkinson's subjects. There was no correlation between fractional anisotropy and clinical measures, whereas R2* was strongly associated with disease progression. Compared to controls, fractional anisotropy in caudal SN was significantly decreased in PD patients of all stages, whereas in rostral SN, it was decreased significantly only in the late‐stage group. R2* in both SN regions was significantly increased in the mid‐ and late‐stage, but not early‐stage, of PD subjects. These findings suggest that fractional anisotropy changes may mark early pathological changes in caudal SN, whereas the changes in R2* may more closely track PD's clinical progression after symptom onset. © 2012 Movement Disorder Society     

Timing matters: Otological symptoms and Parkinson's disease

IntroductionOtological symptoms contribute to the disability of established Parkinson's disease (PD). We sought to evaluate whether prodromal onset may affect PD progression.MethodsA retrospective cohort design was used to compare time to advanced disease, defined as a Hoehn & Yahr stage ≥3 in consecutive PD patients with history of auditory and/or vestibular symptoms appearing before versus after PD onset. Time from PD onset to H&Y ≥ 3 was determined using Cox proportional hazards, with adjusted results summarized as hazards ratio (HR).ResultsAfter adjusting for age at PD onset, there was a lower risk of progression to advanced disease in patients with prodromal otological symptoms compared to those with otological symptoms after PD onset (HR = 0.34; 95%CI: 0.15–0.75, p = 0.008). This association remained significant after adjusting for age at PD onset and MDS-UPDRS III (HR = 0.25; 95% CI: 0.10–0.63, p = 0.003) and propensity score-adjusted analysis (HR = 0.46; 95% CI: 0.24–0.91, p = 0.025).ConclusionProdromal otological symptoms might be associated with a reduced risk of motor progression in PD.     

The MC1R melanoma risk variant p.R160W is associated with Parkinson disease

Epidemiological studies have reported the co‐occurrence of Parkinson disease (PD) and melanoma. Common genetic variants in the MC1R (melanocortin 1 receptor) gene, which determines skin and hair color, are associated with melanoma. Here we investigated whether genetic variants in MC1R modulate the risk of PD by sequencing the entire gene in 870 PD patients and 736 controls ascertained from Spain. We found that the MC1R variant p.R160W (rs1805008) is marginally associated with PD (odds ratio = 2.10, gender‐ and age‐adjusted p = 0.009, Bonferroni‐corrected p = 0.063). Our results suggest that MC1R genetic variants modulate the risk of PD disease in the Spanish population. Ann Neurol 2015;77:889–894