Dynamic interaction of genetic risk factors and cocaine abuse in the background of Parkinsonism - a case report.

Parkinsonism is a complex multifactorial neurodegenerative disorder, in which genetic and environmental risk factors may both play a role. Among environmental risk factors cocaine was earlier ambiguously linked to Parkinsonism. Former single case reports described Parkinsonism in chronic cocaine users, but an epidemiological study did not confirm an increased risk of Parkinson's disease. Here we report a patient, who developed Parkinsonism in young age after chronic cocaine use, in whom a homozygous LRRK2 risk variant was also detected.The patient was investigated because of hand tremor, which started after a 1.5-year period of cocaine abuse. Neurological examination suggested Parkinsonism, and asymmetrical pathology was confirmed by the dopamine transporter imaging study. The genetic investigations revealed a homozygous risk allele in the LRRK2 gene. After a period of cocaine abstinence, the patient's symptoms spontaneously regressed, and the dopamine transporter imaging also returned to near-normal.This case report suggests that cocaine abuse indeed might be linked to secondary Parkinsonism and serves as an example of a potential gene-environmental interaction between the detected LRRK2 risk variant and cocaine abuse. The reversible nature of the DaTscan pathology is a unique feature of this case, and needs further evaluation, whether this is incidental or can be a feature of cocaine related Parkinsonism

The Role of Genetic Testing in the Clinical Practice and Research of Early-Onset Parkinsonian Disorders in a Hungarian Cohort: Increasing Challenge in Genetic Counselling, Improving Chances in Stratification for Clinical Trials

The genetic analysis of early-onset Parkinsonian disorder (EOPD) is part of the clinical diagnostics. Several genes have been implicated in the genetic background of Parkinsonism, which is clinically indistinguishable from idiopathic Parkinson’s disease. The identification of patient’s genotype could support clinical decision-making process and also track and analyse outcomes in a comprehensive fashion. The aim of our study was to analyse the genetic background of EOPD in a Hungarian cohort and to evaluate the clinical usefulness of different genetic investigations. The age of onset was between 25 and 50 years. To identify genetic alterations, multiplex ligation-dependent probe amplification (n = 142), Sanger sequencing of the most common PD-associated genes (n = 142), and next-generation sequencing (n = 54) of 127 genes which were previously associated to neurodegenerative disorders were carried out. The genetic analysis identified several heterozygous damaging substitutions in PD-associated genes (C19orf12, DNAJC6, DNAJC13, EIF4G1, LRRK2, PRKN, PINK1, PLA2G6, SYNJ1). CNVs in PRKN and SNCA genes were found in five patients. In our cohort, nine previously published genetic risk factors were detected in three genes (GBA, LRRK2, and PINK1). In nine cases, two or three coexisting pathogenic mutations and risk variants were identified. Advances of sequencing technologies make it possible to aid diagnostics of PD by widening the scope of analysis to genes which were previously linked to other neurodegenerative disorders. Our data suggested that rare damaging variants are enriched versus neutral variants, among PD patients in the Hungarian population, which raise the possibility of an oligogenic effect. Heterozygous mutations of multiple recessive genes involved in the same pathway may perturb the molecular process linked to PD pathogenesis. Comprehensive genetic assessment of individual patients can rarely reveal monogenic cause in EOPD, although it may identify the involvement of multiple PD-associated genes in the background of the disease and may facilitate the better understanding of clinically distinct phenocopies. Due to the genetic complexity of the disease, genetic counselling and management is getting more challenging. Clinical geneticist should be prepared for counselling of patients with coexisting disease-causing mutations and susceptibility factors. At the same time, genomic-based stratification has increasing importance in future clinical trials

The European challenges of funding orphan medicinal products

Funding of orphan medicinal products (OMPs) is an increasing challenge in the European Union (EU).To identify the different methods for public funding of OMPs in order to map the availability for rare disease patients, as well as to compare the public expenditures on OMPs in 8 EU member states.Information on the reimbursement status of 83 OMPs was collected in 8 countries by distinguishing standard and special reimbursements. In two consecutive years, the total public expenditures on OMPs were calculated by using annual EUR exchange rates. Annual total public expenditures were calculated per capita, and as a proportion of GDP, total public pharmaceutical and healthcare budgets. Differences between countries were compared by calculating the deviations from the average spending of countries.In 2015 29.4-92.8% of the 83 OMPs were available with any kind of public reimbursement in participant countries including special reimbursement on an individual basis. In Austria, Belgium and France more OMPs were accessible for patients with public reimbursement than in Bulgaria, Czech Republic, Hungary and Poland. Standard reimbursement through retail pharmacies and/or hospitals was applied from 0 to 41% of OMPs. The average annual total public expenditure ranged between 1.4-23.5 €/capita in 2013 and 2014. Higher income countries spent more OMPs in absolute terms. Participant countries spent 0.018-0.066% of their GDPs on funding OMPs. Average expenditures on OMPs were ranged between 2.25-6.51% of the public pharmaceutical budget, and 0.44-0.96% of public healthcare expenditures.Standard and special reimbursement techniques play different roles in participant countries. The number of accessible OMPs indicated an equity gap between Eastern and Western Europe. The spending on OMPs as a proportion of GDP, public pharmaceutical and healthcare expenditure was not higher in lower income countries, which indicates substantial differences in patient access to OMPs in favour of higher-income countries. Equity in access for patients with rare diseases is an important policy objective in each member state of the EU; however, equity in access should be harmonized at the European level

Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

Differences in the molecular structure of the blood-brain barrier in the cerebral cortex and white matter: an in silico, in vitro, and ex vivo study

The blood-brain barrier (BBB) is the main interface controlling molecular and cellular traffic between the central nervous system (CNS) and the periphery. It consists of cerebral endothelial cells (CECs) interconnected by continuous tight junctions, and closely associated pericytes and astrocytes. Different parts of the CNS have diverse functions and structures and may be subject of different pathologies, in which the BBB is actively involved. It is largely unknown, however, what are the cellular and molecular differences of the BBB in different regions of the brain. Using in silico, in vitro, and ex vivo techniques we compared the expression of BBB-associated genes and proteins (i.e., markers of CECs, brain pericytes, and astrocytes) in the cortical grey matter and white matter. In silico human database analysis (obtained from recalculated data of the Allen Brain Atlas), qPCR, Western blot, and immunofluorescence studies on porcine and mouse brain tissue indicated an increased expression of glial fibrillary acidic protein in astrocytes in the white matter compared with the grey matter. We have also found increased expression of genes of the junctional complex of CECs (occludin, claudin-5, and alpha-catenin) in the white matter compared with the cerebral cortex. Accordingly, occludin, claudin-5, and alpha-catenin proteins showed increased expression in CECs of the white matter compared with endothelial cells of the cortical grey matter. In parallel, barrier properties of white matter CECs were superior as well. These differences might be important in the pathogenesis of diseases differently affecting distinct regions of the brain

Prediction of Relapse After Anti–Tumor Necrosis Factor Cessation in Crohn's Disease: Individual Participant Data Meta-analysis of 1317 Patients From 14 Studies

Background & Aims: Tools for stratification of relapse risk of Crohn's disease (CD) after anti–tumor necrosis factor (TNF) therapy cessation are needed. We aimed to validate a previously developed prediction model from the diSconTinuation in CrOhn's disease patients in stable Remission on combined therapy with Immunosuppressants (STORI) trial, and to develop an updated model. Methods: Cohort studies were selected that reported on anti-TNF cessation in 30 or more CD patients in remission. Individual participant data were requested for luminal CD patients and anti-TNF treatment duration of 6 months or longer. The discriminative ability (concordance-statistic [C-statistic]) and calibration (agreement between observed and predicted risks) were explored for the STORI model. Next, an updated prognostic model was constructed, with performance assessment by cross-validation. Results: This individual participant data meta-analysis included 1317 patients from 14 studies in 11 countries. Relapses after anti-TNF cessation occurred in 632 of 1317 patients after a median of 13 months. The pooled 1-year relapse rate was 38%. The STORI prediction model showed poor discriminative ability (C-statistic, 0.51). The updated model reached a moderate discriminative ability (C-statistic, 0.59), and included clinical symptoms at cessation (hazard ratio [HR], 2.2; 95% CI, 1.2–4), younger age at diagnosis (HR, 1.5 for A1 (age at diagnosis ≤16 years) vs A2 (age at diagnosis 17 - 40 years); 95% CI, 1.11–1.89), no concomitant immunosuppressants (HR, 1.4; 95% CI, 1.18–172), smoking (HR, 1.4; 95% CI, 1.15–1.67), second line anti-TNF (HR, 1.3; 95% CI, 1.01–1.69), upper gastrointestinal tract involvement (HR, 1.3 for L4 vs non-L4; 95% CI, 0.96–1.79), adalimumab (HR, 1.22 vs infliximab; 95% CI, 0.99–1.50), age at cessation (HR, 1.2 per 10 years younger; 95% CI, 1–1.33), C-reactive protein (HR, 1.04 per doubling; 95% CI, 1.00–1.08), and longer disease duration (HR, 1.07 per 5 years; 95% CI, 0.98–1.17). In subanalysis, the discriminative ability of the model improved by adding fecal calprotectin (C-statistic, 0.63). Conclusions: This updated prediction model showed a reasonable discriminative ability, exceeding the performance of a previously published model. It might be useful to guide clinical decisions on anti-TNF therapy cessation in CD patients after further validation. © 2021 AGA Institut