Mucuna pruriens to treat Parkinson's disease in low-income countries: Recommendations and practical guidelines from the farmer to clinical trials. Paving the way for future use in clinical practice.

Parkinson's disease (PD) is a progressive and disabling neurodegenerative disease that rapidly worsens and results in premature mortality if left untreated. Although levodopa is the gold standard treatment for PD globally, its accessibility and affordability are severely limited in low- and middle-income countries worldwide. In this scenario, Mucuna pruriens (MP), a leguminous plant growing wild in tropical regions, emerges as a potential alternative or adjunct to levodopa-based medications due to its cost-effectiveness and global natural availability. Recent studies have demonstrated that MP can significantly ameliorate motor symptoms, although tolerability may vary. The proposition that MP could play a pivotal role in providing affordable and symptomatic relief for PD in low- and middle-income countries is grounded in its promising therapeutic profile, yet caution is warranted until more comprehensive data on the long-term safety and efficacy of MP become available. This manuscript summarizes the knowledge gained about MP by the authors, focusing on how to cultivate, store, and provide it to patients in the safest and most effective way in clinical trials. We aim to increase clinical trials investigating its safety and efficacy in PD, before promoting individual use of MP on a global scale, particularly in countries where availability and affordability of levodopa-based medications is still limited.

Development and Validation of a Prognostic Model to Predict Overall Survival in Multiple System Atrophy.

Background: Multiple system atrophy (MSA) is a devastating disease characterized by a variable combination of motor and autonomic symptoms. Previous studies identified numerous clinical factors to be associated with shorter survival. Objective: To enable personalized patient counseling, we aimed at developing a risk model of survival based on baseline clinical symptoms. Methods: MSA patients referred to the Movement Disorders Unit in Innsbruck, Austria, between 1999 and 2016 were retrospectively analyzed. Kaplan-Meier curves and multivariate Cox regression analysis with least absolute shrinkage and selection operator penalty for variable selection were performed to identify prognostic factors. A nomogram was developed to estimate the 7 years overall survival probability. The performance of the predictive model was validated and calibrated internally using bootstrap resampling and externally using data from the prospective European MSA Study Group Natural History Study. Results: A total of 210 MSA patients were included in this analysis, of which 124 patients died. The median survival was 7 years. The following clinical variables were found to significantly affect overall survival and were included in the nomogram: age at symptom onset, falls within 3 years of onset, early autonomic failure including orthostatic hypotension and urogenital failure, and lacking levodopa response. The time-dependent area under curve for internal and external validation was >0.7 within the first 7 years of the disease course. The model was well calibrated showing good overlap between predicted and actual survival probability at 7 years. Conclusion: The nomogram is a simple tool to predict survival on an individual basis and may help to improve counseling and treatment of MSA patients.

Onset and mortality of Parkinson's disease in relation to type II diabetes.

OBJECTIVES: There is growing evidence that Parkinson's disease and diabetes are partially related diseases; however, the association between the two, and the impact of specific treatments, are still unclear. We evaluated the effect of T2D and antidiabetic treatment on age at PD onset and on all-cause mortality. RESEARCH DESIGN AND METHODS: The standardized rate of T2D was calculated for PD patients using the direct method and compared with subjects with essential tremor (ET) and the general Italian population. Age at onset and survival were also compared between patients without T2D (PD-noT2D), patients who developed T2D before PD onset (PD-preT2D) and patients who developed T2D after PD onset (PD-postT2D). RESULTS: We designed a retrospective and prospective study. The T2D standardized ratio of PD (N = 8380) and ET (N = 1032) patients was 3.8% and 6.1%, respectively, while in the Italian general population, the overall prevalence was 5.3%. In PD-preT2D patients, on antidiabetic treatment, the onset of PD was associated with a + 6.2 year delay (p < 0.001) while no difference was observed in PD-postT2D. Occurrence of T2D before PD onset negatively affected prognosis (adjusted hazard ratio = 1.64 [95% CI 1.33-2.02]; p < 0.001), while no effect on survival was found in PD-postT2D subjects (hazard ratio = 0.86, [95% CI 0.53-1.39]; p = 0.54). CONCLUSIONS: T2D, treated with any antidiabetic therapy before PD, is associated with a delay in its onset. Duration of diabetes increases mortality in PD-preT2D, but not in PD-postT2D. These findings prompt further studies on antidiabetic drugs as a potential disease-modifying therapy for PD.

Adult-onset KMT2B-related dystonia.

KMT2B-related dystonia (DYT-KMT2B, also known as DYT28) is an autosomal dominant neurological disorder characterized by varying combinations of generalized dystonia, psychomotor developmental delay, mild-to-moderate intellectual disability and short stature. Disease onset occurs typically before 10 years of age. We report the clinical and genetic findings of a series of subjects affected by adult-onset dystonia, hearing loss or intellectual disability carrying rare heterozygous KMT2B variants. Twelve cases from five unrelated families carrying four rare KMT2B missense variants predicted to impact protein function are described. Seven affected subjects presented with adult-onset focal or segmental dystonia, three developed isolated progressive hearing loss, and one displayed intellectual disability and short stature. Genome-wide DNA methylation profiling allowed to discriminate these adult-onset dystonia cases from controls and early-onset DYT-KMT2B patients. These findings document the relevance of KMT2B variants as a potential genetic determinant of adult-onset dystonia and prompt to further characterize KMT2B carriers investigating non-dystonic features.

Long-term safety, discontinuation and mortality in an Italian cohort with advanced Parkinson's disease on levodopa/carbidopa intestinal gel infusion.

INTRODUCTION: Levodopa/carbidopa intestinal gel (LCIG) is an effective treatment in patients with advanced Parkinson's disease (PD) with consolidated evidence of clinical efficacy. However, only few studies have assessed long-term safety, causes of discontinuation, mortality, and relative predictors. METHODS: We conducted a retrospective analysis of 79 PD patients treated with LCIG between 2005 and 2020 in two Italian Neurological Centers, recording all adverse events (AEs), including weight loss (WL). Kaplan-Meier curve was used to estimate the time to discontinuation and survival. Cox proportional hazard model was employed to identify predictors of discontinuation and mortality, while Pearson's correlation was used to analyze predictors of WL. RESULTS: The average follow-up was 47.7 ± 40.5 months and the median survival from disease onset was 25 years. There were three cases of polyradiculoneuropathy Guillain-Barre syndrome-like, all occurred in the early years of LCIG treatment. Twenty-five patients died (32%), 18 on LCIG (including one suicide) and seven after discontinuation. The mean WL was 3.62 ± 7.5 kg, which correlated with levodopa dose at baseline (p = 0.002), levodopa equivalent daily dose (LEDD) baseline (p = 0.017) and off-duration (p = 0.0014), but not dyskinesia. Peristomal complications emerged as a negative predictor of discontinuation (p = 0.008). CONCLUSIONS: LCIG has a relatively satisfactory long-term safety profile and efficacy and a relatively low rate of discontinuation. Peristomal complications may represent a predictor of longer duration of therapy. According to the mortality analysis, LCIG patients show a long lifespan. Delaying the initiation of LCIG does not affect the sustainability of LCIG therapy.

Negative symptoms in Huntington's disease.

BACKGROUND: Apathy is the commonest psychiatric manifestation in Huntington's disease (HD). We investigated negative psychiatric symptoms-as determined by the Scale for the Assessment of Negative Psychiatric Symptoms (SANS)-in early and intermediate HD patients, hypothesizing that such symptoms would be prominent and constitute a more comprehensive and clinically relevant assessment than apathy alone. We also assessed relations between negative symptoms and disease stage, mood, motor, and cognitive disturbances. METHODS: Thirty-five stage 1 and twenty-nine stage 2 consecutive adult HD outpatients were administered SANS; the Scale for the Assessment of Positive Psychiatric Symptoms (SAPS); the motor section of the Unified Huntington's Disease Rating Scale (UHDRS); Total Functional Capacity (TFC); and instruments to assess cognition, anxiety, and depression. RESULTS: The groups had similar age, education, and CAG length. Scores on the Hamilton depression and anxiety scales, and SAPS were similar. Negative symptoms were pervasive in the entire series. Illness duration, UHDRS, TFC, cognition, and SANS scores were significantly worse in stage 2. Mini Mental State Examination (MMSE) and SAPS scores were significantly (multiple regression) associated with SANS score, while Hamilton depression and UHDRS scores were not. SANS score was also associated with stage after removing the cognition-related domains of alogia and attention. CONCLUSIONS: Negative symptoms are pervasive in HD but more severe in stage 2. The associations of SANS with MMSE and SAPS suggest impaired cognition and thinking as important in generating negative symptoms. SANS appears useful for revealing a wide range of negative symptoms in HD.

Natural history of motor symptoms in Parkinson's disease and the long-duration response to levodopa.

The natural pattern of progression of Parkinson's disease is largely unknown because patients are conventionally followed on treatment. As Parkinson's disease progresses, the true magnitude of the long-duration response to levodopa remains unknown, because it can only be estimated indirectly in treated patients. We aimed to describe the natural course of motor symptoms by assessing the natural OFF in consecutive Parkinson's disease patients never exposed to treatment (drug-naïve), and to investigate the effects of daily levodopa on the progression of motor disability in the OFF medication state over a 2-year period. In this prospective naturalistic study in sub-Saharan Africa, 30 Parkinson's disease patients (age at onset 58 ± 14 years, disease duration 7 ± 4 years) began levodopa monotherapy and were prospectively assessed using the Unified Parkinson's disease Rating Scale (UPDRS). Data were collected at baseline, at 1-year and 2-years follow-up. First-ever levodopa intake induced a significant improvement in motor symptoms (natural OFF versus ON state UPDRS-III 41.9 ± 15.9 versus 26.8 ± 15.1, respectively; P < 0.001). At 1-year follow-up, OFF state UPDRS-III score after overnight withdrawal of levodopa was considerably lower than natural OFF (26.5 ± 14.9; P < 0 .001). This effect was not modified by disease duration. At the 2-year follow-up, motor signs after overnight OFF (30.2 ± 14.2) were still 30% milder than natural OFF (P = 0.001). The ON state UPDRS-III at the first-ever levodopa challenge was similar to the overnight OFF score at 1-year follow-up and the two conditions were correlated (r = 0.72, P < 0.001). Compared to the natural progression of motor disability, levodopa treatment resulted in a 31% lower annual decline in UPDRS-III scores in the OFF state (3.33 versus 2.30 points/year) with a lower model's variance explained by disease duration (67% versus 36%). Using the equation regressed on pretreatment data, we predicted the natural OFF at 1-year and 2-year follow-up visits and estimated that the magnitude of the long-duration response to levodopa ranged between 60% and 65% of total motor benefit provided by levodopa, independently of disease duration (P = 0.13). Although levodopa therapy was associated with motor fluctuations, overnight OFF disability during levodopa was invariably less severe than the natural course of the disease, independently of disease duration. The same applies to the yearly decline in UPDRS-III scores in the OFF state. Further research is needed to clarify the mechanisms underlying the long-duration response to levodopa in Parkinson's disease. Understanding the natural course of Parkinson's disease and the long-duration response to levodopa may help to develop therapeutic strategies increasing its magnitude to improve patient quality of life and to better interpret the outcome of randomized clinical trials on disease-modifying therapies that still rely on the overnight OFF to define Parkinson's disease progression.

Skin Biopsy May Help to Distinguish Multiple System Atrophy-Parkinsonism from Parkinson's Disease With Orthostatic Hypotension.

BACKGROUND: The differential diagnosis between multiple system atrophy parkinsonism type (MSA-P) and Parkinson's disease with orthostatic hypotension (PD+OH) is difficult because the 2 diseases have a similar clinical picture. The aim of this study is to distinguish MSA-P from PD+OH by immunostaining for abnormal phosphorylated α-synuclein at serine 129 (p-syn) in cutaneous nerves. METHOD: We recruited 50 patients with parkinsonism and chronic orthostatic hypotension: 25 patients fulfilled the diagnostic criteria for MSA-P and 25 patients for PD+OH. The patients underwent a skin biopsy from the cervical area, thigh, and leg to analyze somatic and autonomic skin innervation and p-syn in skin nerves. RESULTS: Intraneural p-syn positivity was found in 72% of patients with MSA-P, mainly in distal skin sites. More important, p-syn deposits in MSA-P differed from PD+OH because they were mainly found in somatic fibers of subepidermal plexi, whereas scant autonomic fiber involvement was found in only 3 patients. All patients with PD+OH displayed widely distributed p-syn deposits in the autonomic skin fibers of proximal and distal skin sites, whereas somatic fibers were affected only slightly in 4 patients with PD+OH. Skin innervation mirrored p-syn deposits because somatic innervation was mainly reduced in MSA-P. Sympathetic innervation was damaged in PD+OH but fairly preserved in MSA-P. CONCLUSIONS: The p-syn in cutaneous nerves allows the differentiation of MSA-P from PD+OH; MSA-P mainly shows somatic fiber involvement with relatively preserved autonomic innervation; and by contrast, PD+OH displays prevalent abnormal p-syn deposits and denervation in autonomic postganglionic nerves. © 2020 International Parkinson and Movement Disorder Society.

Benign versus malignant Parkinson disease: the unexpected silver lining of motor complications.

OBJECTIVE: We sought to evaluate demographic, clinical, and habits/occupational variables between phenotypic extremes in Parkinson's disease (PD). METHODS: Databases from nine movement disorders centers across seven countries were retrospectively searched for subjects meeting criteria for very slowly progressive, benign, PD (bPD) and rapidly progressive, malignant, PD (mPD). bPD was defined as Hoehn and Yahr (H&Y) stage ≤ 3, normal cognitive function, and Schwab and England (S&E) score ≥ 70 after ≥ 20 years of PD (≥ 10 years if older than 60 at PD onset); mPD as H&Y > 3, S&E score < 70, and cognitive impairment within 10 years from PD onset. We performed between-group analysis of demographic, habits/occupational, and clinical features at baseline and follow-up and unsupervised data-driven analysis of the clinical homogeneity of bPD and mPD. RESULTS: At onset, bPD subjects (n = 210) were younger, had a single limb affected, lower severity and greater asymmetry of symptoms, and lower prevalence of depression than mPD (n = 155). bPD was associated with active smoking and physical activity, mPD with agricultural occupation. At follow-up, mPD showed higher prevalence of depression, hallucinations, dysautonomia, and REM behaviour disorder. Interestingly, the odds of mPD were significantly reduced by the presence of dyskinesia and wearing-off. Data-driven analysis confirmed the independent clustering of bPD and mPD, with age at onset emerging as a critical discriminant between the two groups (< 46-year-old vs. > 68-year-old). CONCLUSIONS: Phenotypic PD extremes showed distinct demographic, clinical, and habits/occupational factors. Motor complications may be conceived as markers of therapeutic success given their attenuating effects on the odds of mPD.

Mitochondrial dysfunction in fibroblasts of Multiple System Atrophy.

Multiple System Atrophy is a severe neurodegenerative disorder which is characterized by a variable clinical presentation and a broad neuropathological spectrum. The pathogenic mechanisms are almost completely unknown. In the present study, we established a cellular model of MSA by using fibroblasts' primary cultures and performed several experiments to investigate the causative mechanisms of the disease, with a particular focus on mitochondrial functioning. Fibroblasts' analyses (7 MSA-P, 7 MSA-C and 6 healthy controls) displayed several anomalies in patients: an impairment of respiratory chain activity, in particular for succinate Coenzyme Q reductase (p < 0.05), and a reduction of complex II steady-state level (p < 0.01); a reduction of Coenzyme Q10 level (p < 0.001) and an up-regulation of some CoQ10 biosynthesis enzymes, namely COQ5 and COQ7; an impairment of mitophagy, demonstrated by a decreased reduction of mitochondrial markers after mitochondrial inner membrane depolarization (p < 0.05); a reduced basal autophagic activity, shown by a decreased level of LC3 II (p < 0.05); an increased mitochondrial mass in MSA-C, demonstrated by higher TOMM20 levels (p < 0.05) and suggested by a wide analysis of mitochondrial DNA content in blood of large cohorts of patients. The present study contributes to understand the causative mechanisms of Multiple System Atrophy. In particular, the observed impairment of respiratory chain activity, mitophagy and Coenzyme Q10 biosynthesis suggests that mitochondrial dysfunction plays a crucial role in the pathogenesis of the disease. Furthermore, these findings will hopefully contribute to identify novel therapeutic targets for this still incurable disorder.

Skin Nerve Phosphorylated α-Synuclein Deposits in Parkinson Disease With Orthostatic Hypotension.

This study aimed to investigate phosphorylated α-synuclein (p-syn) in autonomic skin nerves of Parkinson disease (PD) patients with and without orthostatic hypotension (OH). We studied 28 PD patients with normal corrected Mini-Mental State Examination including 14 patients with neurogenic OH (PD + OH) and 14 matched patients did not complain of OH (PD - OH); 7 of whom were re-evaluated over a follow-up period (4 ± 2 years). Skin biopsy was performed in proximal and distal sites. PD + OH patients showed a higher p-syn deposition than PD - OH, with widespread autonomic cholinergic and adrenergic skin nerve involvement. Over the follow-up period, PD - OH patients showed an increase in motor dysfunction scores without autonomic symptoms and a slight increase of skin p-syn deposition but still lower than PD + OH, mainly restricted to adrenergic fibers of skin vessels (SV). In summary, PD + OH patients showed a wide involvement of p-syn deposits in autonomic cholinergic and adrenergic skin nerves compared with PD - OH, and PD - OH patients showed a lower load of skin p-syn restricted to adrenergic fibers of SV still persisting over the follow-up period. The data supported a different pathogenesis between PD + OH and PD - OH and may help to identify a specific diagnostic trait for PD + OH.

Quantitative gait analysis in parkin disease: Possible role of dystonia.

INTRODUCTION: Parkin disease (PARK2, OMIM 602544) is an autosomal-recessive early-onset parkinsonism characterized by an early occurrence of lower limb dystonia. The aim of this study was to analyze spatiotemporal, kinematic, and kinetic gait parameters in patients with parkin disease in the OFF and ON conditions compared to healthy age-matched controls. METHODS: Fifteen patients with parkin disease and 15 healthy age-matched controls were studied in a gait analysis laboratory with an integrated optoelectronic system. Spatiotemporal, kinematic, and kinetic gait parameters at a self-selected speed were recorded in the OFF and ON conditions. A jerk index was computed to quantify the possible reduction of smoothness of joint movements. RESULTS: Compared to controls, parkin patients had, either in the OFF or in the ON conditions, significant reduction of walking velocity, increased step width, and decreased percentage of double support. Kinematic analysis in both conditions showed: increased ankle dorsiflexion and knee flexion at the initial contact; maximal flexion and increased range of motion in mid stance; increased hip flexion and max extension in stance at pelvis; and increased mean tilt antiversion. Kinetics showed increased hip and knee power generation in stance in either condition. The jerk index was increased at all joints both in OFF and ON. There were no correlations between individual gait parameters and clinical ratings. CONCLUSION: Parkin patients have an abnormal gait pattern that does not vary between the OFF and the ON conditions. Variations recorded with instrumented analysis are more evident for kinematic than kinetic parameters at lower limbs. Severity of dystonia does not correlate with any individual kinematic parameter. © 2016 International Parkinson and Movement Disorder Society.

Mutational analysis of COQ2 in patients with MSA in Italy.

COQ2 mutations have been implicated in the etiology of multiple system atrophy (MSA) in Japan. However, several genetic screenings have not confirmed the role of its variants in the disease. We performed COQ2 sequence analysis in 87 probable MSA. A homozygous change p.A43G was found in an MSA-C patient. Cosegregation analysis and the evaluation of CoQ10 content in muscle and fibroblasts did not support the pathogenic role of this variant.

Botulinum neurotoxins for the treatment of focal dystonias: Review of rating tools used in clinical trials.

Botulinum neurotoxins (BoNTs) are used to achieve therapeutic benefit in focal dystonia. An expert panel recently reviewed published evidence on the efficacy of BoNTs for the treatment of focal dystonias and produced recommendations for clinical practice. Another panel reviewed the clinimetric properties of rating scales for dystonia and produced recommendations for current usage and future directions. Considering that the strength of evidence derives not only from the quality of the study design, but also from usage of validated outcome measures, we combined the information provided by these two recent reviews and assessed the appropriateness of the rating instruments used in clinical trials on BoNT treatment in focal dystonia. Data sources included all the publications on BoNT treatment for focal dystonias reviewed by the recent evidence-based analysis. We reviewed all rating instruments used to assess primary and secondary outcome following BoNT treatment. The publications were allocated into five topics according to the focal dystonia type reviewed in the meta-analysis: blepharospasm, oromandibular dystonia, cervical dystonia, upper limb dystonia, and laryngeal dystonia. For each topic, papers were divided, according to the terminology used in the meta-analysis, into placebo-controlled, active comparator and methodological or uncontrolled. For each topic we identified the rating tools used in each study class and annotated which were the mostly used in each focal dystonia type. Outcome measures included tools related to motor and non-motor features, such as pain and depression, and functional as well as health-related quality of life features. Patient- and investigator-reported outcomes were also included. Rating instruments were classified as recommended, suggested, listed or not included, based on recommendations produced by the rating scale task force. Both primary and secondary outcome measures were assessed. As a final step we compared current practice, as summarized by the meta-analysis, with the recommendations of the rating scales panel. For blepharospasm, three placebo-controlled trials used suggested scales, one active-comparator study used a recommended scale and three active-comparator studies used suggested scales. For oromandibular dystonia, one placebo-controlled study used a suggested scale. For cervical dystonia, six placebo-controlled trials used a recommended scale, four active-comparator trials used a recommended scale and one active-comparator study used a suggested scale. For upper limb and laryngeal dystonia, no trial used validated instruments. Appropriately designed studies should be based on recommended rating instruments. Therapeutic trials not using clinimetrically tested rating measures do not provide sufficient information on efficacy of BoNT treatment, even if the study design is robust. Further research is needed to develop and validate new tools to assess all types of focal dystonia and to apply them in prospective placebo-controlled clinical trials.

Translation and linguistic validation of the Composite Autonomic Symptom Score COMPASS 31.

The aim of our study was to translate and to do a linguistic validation of the Composite Autonomic Symptom Score COMPASS 31. COMPASS 31 is a self-assessment instrument including 31 items assessing six domains of autonomic functions: orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor functions. This questionnaire has been created by the Autonomic group of the Mayo Clinic from two previous versions: the Autonomic Symptom Profile (ASP) composed of 169 items and the following COMPASS with 72 items selected from the ASP. We translated the questionnaire by means of a standardized forward and back-translation procedure. Thirty-six subjects, 25 patients with autonomic failure of different aethiologies and 11 healthy controls filled in the COMPASS 31 twice, 4 ± 1 weeks apart, once in Italian and once in English in a randomized order. The test-retest showed a significant correlation between the Italian and the English versions as total score. The evaluation of single domains by means of Pearson correlation when applicable or by means of Spearman test showed a significant correlation between the English and the Italian COMPASS 31 version for all clinical domains except the vasomotor one for the lack of scoring. The comparison between the patients with autonomic failure and healthy control groups showed significantly higher total scores in patients with respect to controls confirming the high sensitivity of COMPASS 31 in revealing autonomic symptoms.

Causes of withdrawal of duodenal levodopa infusion in advanced Parkinson disease.

OBJECTIVE: We performed a real-life observation of patients with Parkinson disease (PD) who received duodenal levodopa infusion (DLI) to determine which adverse events caused treatment discontinuation and when such events occurred. METHODS: All consecutive patients with PD treated at the Carlo Besta Neurological Institute were included. The patients were evaluated at baseline and after DLI at regular intervals. Their motor condition was assessed and adverse events were recorded. RESULTS: Thirty-five patients with PD (15 men and 20 women) were included. They received DLI implants between October 2007 and September 2013. Four patients died of causes unrelated to the procedure. At the end of the study, 21 patients (60%) were still on treatment. DLI provided efficacious motor control in all patients. Discontinuation was most frequently caused by device- or infusion-related adverse events. Ten patients of the remaining 31 discontinued DLI. There were 2 main causes of withdrawal: stoma infection (4 patients), and worsening of dyskinesias not manageable with infusion reduction (3 patients). In most patients, discontinuations occurred during the first year after implant. Risk of discontinuation was related to age at implant, but no other demographic or clinical variables. CONCLUSIONS: We identified 2 main causes leading to DLI withdrawal during the first year postimplant and suggest adopting measures to prevent such occurrences. Elderly patients are at higher risk of treatment discontinuation.

Genome-wide association study in musician's dystonia: a risk variant at the arylsulfatase G locus?

Musician's dystonia (MD) affects 1% to 2% of professional musicians and frequently terminates performance careers. It is characterized by loss of voluntary motor control when playing the instrument. Little is known about genetic risk factors, although MD or writer's dystonia (WD) occurs in relatives of 20% of MD patients. We conducted a 2-stage genome-wide association study in whites. Genotypes at 557,620 single-nucleotide polymorphisms (SNPs) passed stringent quality control for 127 patients and 984 controls. Ten SNPs revealed P < 10(-5) and entered the replication phase including 116 MD patients and 125 healthy musicians. A genome-wide significant SNP (P < 5 × 10(-8) ) was also genotyped in 208 German or Dutch WD patients, 1,969 Caucasian, Spanish, and Japanese patients with other forms of focal or segmental dystonia as well as in 2,233 ethnically matched controls. Genome-wide significance with MD was observed for an intronic variant in the arylsulfatase G (ARSG) gene (rs11655081; P = 3.95 × 10(-9) ; odds ratio [OR], 4.33; 95% confidence interval [CI], 2.66-7.05). rs11655081 was also associated with WD (P = 2.78 × 10(-2) ) but not with any other focal or segmental dystonia. The allele frequency of rs11655081 varies substantially between different populations. The population stratification in our sample was modest (λ = 1.07), but the effect size may be overestimated. Using a small but homogenous patient sample, we provide data for a possible association of ARSG with MD. The variant may also contribute to the risk of WD, a form of dystonia that is often found in relatives of MD patients.

Different mutations at V363 MAPT codon are associated with atypical clinical phenotypes and show unusual structural and functional features.

Microtubule-associated protein tau gene (MAPT) is one of the major genes linked to frontotemporal lobar degeneration, a group of neurodegenerative diseases clinically, pathologically, and genetically heterogeneous. In particular, MAPT mutations give rise to the subgroup of tauopathies. The pathogenetic mechanisms underlying the MAPT mutations so far described are the decreased ability of tau protein to promote microtubule polymerization (missense mutations) or the altered ratio of tau isoforms (splicing mutations), both leading to accumulation of hyperphosphorylated filamentous tau protein. Following a genetic screening of patients affected by frontotemporal lobar degeneration, we identified 2 MAPT mutations, V363I and V363A, leading to atypical clinical phenotypes, such as posterior cortical atrophy. We investigated in vitro features of the recombinant mutated tau isoforms and revealed unusual functional and structural characteristics such as an increased ability to promote microtubule polymerization and a tendency to form oligomeric instead of filamentous aggregates. Thus, we disclosed a greater than expected complexity of abnormal features of mutated tau isoforms. Overall our findings suggest a high probability that these mutations are pathogenic.