Parkinson's Disease in Central Asian and Transcaucasian Countries: A Review of Epidemiology, Genetics, Clinical Characteristics, and Access to Care

Our understanding of Parkinson’s disease (PD) has significantly accelerated over the last few years, but predominant advances have been made in developed, Western countries. Little is known about PD in the Central Asian (CA) and Transcaucasian (TC) countries. Here, we review the clinical characteristics, treatments used, epidemiology, and genetics of PD in CA and TC countries via a methodological search in MEDLINE, EMBASE, Scopus, Web of Science, and Google Scholar databases. For the acquisition of PD care-related data, the search was extended to the local web resources. Our findings showed that PD prevalence in the region is averaging 62 per 100,000 population. The mean age of onset is 56.4 ± 2.8 in females and 63.3 ± 3.5 in males. Large-scale national studies on PD prevalence from the region are currently lacking. A limited number of genetic studies with small cohorts and inconclusive results were identified. The G2019S LRRK2 mutation, the commonest mutation in PD worldwide, was found in 5.7% of patients with idiopathic PD and 17.6% of familial cases in 153 Uzbek patients. Our review highlighted systematic deficiencies in PD health care in the region including lacks of neurologists specializing in PD, delays in PD diagnosis, absence of specialized PD nurses and PD rehab services, limited access to PD medications and surgery, and the unavailability of PD infusion therapies. Overall, this article demonstrated the paucity of data on this common neurological disorder in CA and TC countries and identified a number of healthcare areas that require an urgent consideration. We conclude that well-designed large-scale epidemiological, genetic, and clinical studies are desperately needed in this region. Healthcare professionals, local and national institutions, and stakeholders must come together to address deficiencies in PD healthcare systems in CA and TC countries

A glimpse of the genetics of young-onset Parkinson's disease in Central Asia

Background: Knowledge of the genetic background of many human diseases is currently lacking from genetically undiscovered regions, including Central Asia. Kazakhstan is the first Central Asian country where the genetic studies of Parkinson's disease (PD) have been emerging since it had become a member of the International Parkinson Disease Genomics Consortium. Here we report on the results of whole‐exome sequencing (WES) in 50 young‐onset PD (YOPD) cases from Kazakhstan. / Methodology: WES was performed on 50 unrelated individuals with YOPD from Kazakhstan. Exome data were screened for novel/ultra‐rare deleterious variants in known and candidate PD genes. Copy number variants and small indels were also called. / Results: Only three cases (6%) were found to be positive for known PD genes including two unrelated familial PD cases with LRRK2 p.(Arg1441Cys) and one case with a homozygous pathogenic PRKN p.(Arg84Trp) variant. Four cases had novel and ultra‐rare variants of uncertain significance in LRRK2, DNAJC13, and VPS35. Novel deleterious variants were found in candidate Mendelian PD genes including CSMD1, TNR, EIF4G1, and ATP13A3. Eight cases harbored the East Asian‐specific LRRK2 p.(Ala419Val) variant. Conclusions The low diagnostic yield in our study might imply that a significant proportion of YOPD cases in Central Asia remains unresolved. Therefore, a better understanding of the genetic architecture of PD among populations of Central Asian ancestry and the pathogenicity of numerous rare variants should be further investigated. WES is a valuable technique for large‐scale YOPD genetic studies in Central Asia

Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome

Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development

Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease.

Importance: Pathogenic variants in LRRK2 are a relatively common genetic cause of Parkinson disease (PD). Currently, the molecular mechanism underlying disease is unknown, and gain and loss of function (LOF) models of pathogenesis have been postulated. LRRK2 variants are reported to result in enhanced phosphorylation of substrates and increased cell death. However, the double knockout of Lrrk2 and its homologue Lrrk1 results in neurodegeneration in a mouse model, suggesting that disease may occur by LOF. Because LRRK2 inhibitors are currently in development as potential disease-modifying treatments in PD, it is critical to determine whether LOF variants in LRRK2 increase or decrease the risk of PD. Objective: To determine whether LRRK1 and LRRK2 LOF variants contribute to the risk of developing PD. Design, Setting, and Participants: To determine the prevailing mechanism of LRRK2-mediated disease in human populations, next-generation sequencing data from a large case-control cohort (>23 000 individuals) was analyzed for LOF variants in LRRK1 and LRRK2. Data were generated at 5 different sites and 5 different data sets, including cases with clinically diagnosed PD and neurologically normal control individuals. Data were collected from 2012 through 2017. Main Outcomes and Measures: Frequencies of LRRK1 and LRRK2 LOF variants present in the general population and compared between cases and controls. Results: Among 11 095 cases with PD and 12 615 controls, LRRK1 LOF variants were identified in 0.205% of cases and 0.139% of controls (odds ratio, 1.48; SE, 0.571; 95% CI, 0.45-4.44; P = .49) and LRRK2 LOF variants were found in 0.117% of cases and 0.087% of controls (odds ratio, 1.48; SE, 0.431; 95% CI, 0.63-3.50; P = .36). All association tests suggested lack of association between LRRK1 or LRRK2 variants and PD. Further analysis of lymphoblastoid cell lines from several heterozygous LOF variant carriers found that, as expected, LRRK2 protein levels are reduced by approximately half compared with wild-type alleles. Conclusions and Relevance: Together these findings indicate that haploinsufficiency of LRRK1 or LRRK2 is neither a cause of nor protective against PD. Furthermore, these results suggest that kinase inhibition or allele-specific targeting of mutant LRRK2 remain viable therapeutic strategies in PD

Bi-allelic variants in <em>SPATA5L1</em> lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss.

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype

Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.The article is available via Open Access. Click on the 'Additional link' above to access the full-text.Published version, accepted version (6 month embargo), submitted versio