Jean-Philippe Azulay

Biallelic pathogenic expansions of the RFC1 gene are the genetic cause of cerebellar ataxia, neuropathy, and bilateral vestibular areflexia syndrome. Sensory neuropathy is the most common symptom, but the clinical impairments and gateways to RFC1 -related diseases are extremely variable. We genotyped patients with parkinsonism to test the hypothesis that this condition is another such gateway. We screened four cohorts of patients with parkinsonism ( n = 2037) for pathogenic expansions in the RFC1 gene. In patients bearing two pathogenic expansions, we excluded the possibility of other pathogenic variants by exome sequencing. We detected 10/2037 (0.5%) biallelic (AAGGG) _n RFC1 expansions. The initial diagnosis was Parkinson’s disease in five patients, multiple system atrophy in three and atypical parkinsonism in two. Phenotypes perfectly mimicking Parkinson’s disease and multiple system atrophy defined according to the international diagnostic criteria may serve as gateways to some RFC1 -related disorders. These results could modify the diagnostic and management of these two diseases. The diagnosis and follow-up of patients with parkinsonism should include searches for typical features evocative of a RFC1 -relative disease, such as sensory neuropathy or chronic cough. Nerve conduction studies should be conducted in patients with unexplained symptoms of neuropathic pain or sensory neuropathy. We also suggest that RFC1 screening should be performed in patients with atypical parkinsonism or multiple system atrophy with a long survival. Trial Registration Information: The PREDISTIM cohort is registered with ClinicalTrials.gov : NCT02360683 Graphical MSA = multiple system atrophy; PD = Parkinson’s disease; RFC1 = replication factor C subunit 1

Background: Parkinson's disease (PD) patients on dopaminergic drugs may experience non-motor fluctuations (NMFs) which are often heterogeneous and respond variably to treatments. Objective: We evaluated if personality was associated to NMFs and could modulate the NMFs responsiveness to dopaminergic medication and deep brain stimulation of the sub-thalamic nucleus (STN-DBS). Methods: From the PREDISTIM cohort, personality dimensions of 235 PD patients were assessed by the Temperament and Character Inventory (TCI) before STN-DBS (V0). NMFs were evaluated using the NMFs Severity Scale at V0 and one year after STN-DBS (V1). Linear regression models were performed between TCI dimensions and NMFs at V0; and logistic regression models were done between TCI dimensions and 1) groups of dopa-sensitive patients (responders to ON medication at V0) versus non-dopa-sensitive ones, and 2) responders versus non-responders to STN-DBS at V1. Odds ratios (OR) were also calculated. Results: Significant associations were found between two TCI personality dimensions (“Harm Avoidance” and “Self-Directedness”) and severity of NMFs in OFF medication at V0: PD patients with higher Harm Avoidance and lower Self-Directedness scores having more NMFs. TCI personality dimensions were not associated with the dopa-sensitivity while Novelty Seeking was significantly associated with the STN-DBS-responder group for the psychiatric (OR = 1.09 [1.02–1.17]) and for the dysautonomic NMFs (OR = 1.11 [1.04–1.18]). Conclusions: Certain personality dimensions (Harm Avoidance and Self-Directedness) are associated with NMFs severity at baseline, and PD patients with high Novelty Seeking seem to be better candidates for NMFs improvement after STN-DBS.

Introduction In advanced Parkinson's disease (aPD), ‘ON-time’ indicates periods of better symptom control, with ‘good ON-time (GOT)’ indicating control without troublesome dyskinesia. Despite its importance, the impact of increased ‘GOT’ on aPD outcomes is understudied. This study aims to evaluate the clinical, humanistic, and economic value of incremental hourly increases in ‘GOT’ for people with aPD. Methods The study analyzed data from people with aPD across seven countries, using the Adelphi Parkinson's Disease Specific Program survey (2017–2020). ‘GOT’ (calculated from self-reported ON/OFF-time and the proportion of troublesome dyskinesia time) was normalized to a 16-h day. Outcomes included symptom control, medication use, falls, activities of daily living (ADLs), quality of life (QoL), and healthcare resource utilization (HRU). Regression models evaluated relationships between incremental ‘GOT’ hours and outcomes. Results Of 802 patients (mean [standard deviation; SD] age, 76.1 [8.9] years; male, 60.3%) included in the analysis, mean (SD) ‘GOT’ was 13.1 (2.7) hours/day. Hourly increases in ‘GOT’ were associated with lower likelihood of reporting uncontrolled motor (odds ratio [OR] 0.79; 95% confidence interval (CI) [0.62, 1.01]) and non-motor symptoms (OR 0.88; 95% CI [0.80, 0.96]), taking ≥ 2 PD medication classes (OR 0.91; 95% CI [0.86, 0.97]) and lower fall risk (incidence rate ratio 0.91; 95% CI [0.87, 0.95]). Hourly increases in ‘GOT’ were significantly associated with reduced humanistic burden (greater ADL independence, OR 1.19; 95% CI [1.04 1.37]) and improved QoL (for Parkinson’s Disease Questionnaire [PDQ]-39: coefficient − 1.49; 95% CI [− 2.46, − 0.52]) and with reduced economic burden, with annual total HRU cost-savings of $8602.24 (95% CI − $12,192.70 to $5011.77). Conclusions In this multi-country, real-world study of people with aPD, hourly increases in ‘GOT’ were associated with improved clinical outcomes, greater humanistic value, and reduced economic burden. Interventions that maximize improvement of ‘GOT’ should be considered for people with aPD adequately controlled on current therapy.

Background Parkinson’s disease is now one of the fastest-growing neurodegenerative disorders in the developed world, with an increasing prevalence and associated socioeconomic costs. Progression of the disease leads to a gradual deterioration in patients’ quality of life, despite optimal treatment, and both medical and societal needs increase, often with the assistance of paid and/or unpaid caregivers. Objective We aimed to quantify the incremental economic burden of Parkinson’s disease by disease severity in a real-world setting across differing geographic regions. Methods Demographics, clinical characteristics, health status, patient quality of life, caregiver burden, and healthcare resource utilization data were drawn from the Adelphi Parkinson’s Disease Specific Program™, conducted in the USA, five European countries, and Japan. Results A total of 563 neurologists provided data for 5299 individuals with Parkinson’s disease; 61% were male, with a mean age of 64 years. Approximately 15% of individuals were deemed to have advanced disease, with significantly more comorbidities, and a poorer quality of life, than those with non-advanced disease. Overall, the mean annual healthcare resource utilization increased significantly with advancing disease, and resulted in a three-fold difference in the USA and Europe. The main drivers behind the high economic burden included hospitalizations, prescription medications, and indirect costs. Conclusions People with Parkinson’s disease, and their caregivers, incur a higher economic burden as their disease progresses. Future interventions that can control symptoms or slow disease progression could reduce the burden on people with Parkinson’s disease and their caregivers, whilst also substantially impacting societal costs.

Mitochondrial disorders are characterized by a huge clinical, biochemical, and genetic heterogeneity, which poses significant diagnostic challenges. Several studies report that more than 50% of patients with suspected mitochondrial disease could have a non-mitochondrial disorder. Thus, only the identification of the causative pathogenic variant can confirm the diagnosis. Herein, we describe the diagnostic journey of a family suspected of having a mitochondrial disorder who were referred to our Genetics Department. The proband presented with the association of cerebellar ataxia, COX-negative fibers on muscle histology, and mtDNA deletions. Whole exome sequencing (WES), supplemented by a high-resolution array, comparative genomic hybridization (array-CGH), allowed us to identify two pathogenic variants in the non-mitochondrial SYNE1 gene. The proband and her affected sister were found to be compound heterozygous for a known nonsense variant (c.13258C>T, p.(Arg4420Ter)), and a large intragenic deletion that was predicted to result in a loss of function. To our knowledge, this is the first report of a large intragenic deletion of SYNE1 in patients with cerebellar ataxia (ARCA1). This report highlights the interest in a pangenomic approach to identify the genetic basis in heterogeneous neuromuscular patients with the possible cause of mitochondrial disease. Moreover, even rare copy number variations should be considered in patients with a phenotype suggestive of SYNE1 deficiency.