Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson's disease susceptibility genes. In our discovery cohort, the majority of Parkinson's disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson's disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility.
Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.
Background and Aims
Subcutaneous (SC) vedolizumab presents the opportunity for inflammatory bowel disease (IBD) patients to manage their treatment at home. There is currently no data on the process of transitioning patients established on intravenous (IV) to SC as part of routine clinical care. The aim of this programme is to evaluate the clinical and biochemical outcomes of switching a cohort of IBD patients established on IV vedolizumab to SC 12 weeks following the transition.
Methods
178 adult patients were offered the opportunity to transition to SC vedolizumab. Patients who agreed were reviewed prior to switching and at week 12 (W12) after their first SC dose. Evaluation outcomes included disease activity scores, the IBD-Control patient-reported outcome measures (PROMs) and faecal calprotectin (FCP). Reasons for patients declining or accepting transitioning, pharmacokinetics, adverse drug reactions and risk factors for a poor outcome in SARS-CoV-2 infection were also assessed.
Results
124 patients agreed to transition, of which 106 patients had been on IV vedolizumab for at least 4 months. There were no statistically significant differences in disease activity scores or IBD-Control PROMs between baseline and W12. A statistically significant increase in FCP was observed (31µg/g vs. 47µg/g; p=0.008), although this was unlikely to be clinically relevant. The most common adverse drug reaction reported was injection site reactions (15%). Based on this cohort of patients, an expected reduction of £572,000 per annum is likely to be achieved.
Conclusions
Transitioning patients established on IV vedolizumab to SC appears to be safe and effective, with high patient satisfaction and multiple benefits for the health service.
Background: Accurate diagnosis of the cause of parkinsonism during life can be difficult, particularly at presentation, but few studies have described changes in clinical diagnosis over time and the effect of applying strict research criteria. Methods: Incident patients with a possible/probable diagnosis of degenerative or vascular parkinsonism had a standardised assessment at diagnosis and at yearly intervals thereafter at which the most likely clinical diagnosis was recorded without strict application of research criteria. Four years after the beginning of the incident period, formal research criteria were applied retrospectively using patient records at baseline and the latest yearly follow-up.
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