p.L1795F LRRK2 variant is a common cause of Parkinson's disease in Central Europe.

Pathogenic variants in LRRK2 are one of the most common genetic risk factors for Parkinson's disease (PD). Recently, the lesser-known p.L1795F variant was proposed as a strong genetic risk factor for PD, however, further families are currently lacking in literature. A multicentre young onset and familial PD cohort (n = 220) from 9 movement disorder centres across Central Europe within the CEGEMOD consortium was screened for rare LRRK2 variants using whole exome sequencing data. We identified 4 PD cases with heterozygous p.L1795F variant. All 4 cases were characterised by akinetic-rigid PD phenotype with early onset of severe motor fluctuations, 2 receiving LCIG therapy and 2 implanted with STN DBS; all 4 cases showed unsatisfactory effect of advanced therapies on motor fluctuations. Our data also suggest that p.L1795F may represent the most common currently known pathogenic LRRK2 variant in Central Europe compared to the more studied p.G2019S, being present in 1.81% of PD cases within the Central European cohort and 3.23% of familial PD cases. Together with the ongoing clinical trials for LRRK2 inhibitors, this finding emphasises the urgent need for more ethnic diversity in PD genetic research.

An exploration of the genetics of the mutant Huntingtin (mHtt) gene in a cohort of patients with chorea from different ethnic groups in sub-Saharan Africa.

BACKGROUND: Africans are underrepresented in Huntington's disease (HD) research. A European ancestor was postulated to have introduced the mutant Huntingtin (mHtt) gene to the continent; however, recent work has shown the existence of a unique Htt haplotype in South-Africa specific to indigenous Africans. OBJECTIVE: We aimed to investigate the CAG trinucleotide repeats expansion in the Htt gene in a geographically diverse cohort of patients with chorea and unaffected controls from sub-Saharan Africa. METHODS: We evaluated 99 participants: 43 patients with chorea, 21 asymptomatic first-degree relatives of subjects with chorea, and 35 healthy controls for the presence of the mHtt. Participants were recruited from 5 African countries. Additional data were collected from patients positive for the mHtt gene; these included demographics, the presence of psychiatric and (or) cognitive symptoms, family history, spoken languages, and ethnic origin. Additionally, their pedigrees were examined to estimate the number of people at risk of developing HD and to trace back the earliest account of the disease in each region. RESULTS: HD cases were identified in all countries. Overall, 53.4% of patients with chorea were carriers for the mHTT; median tract size was 45 CAG repeats. Of the asymptomatic relatives, 28.6% (6/21) were carriers for the mHTT; median tract size was 40 CAG. No homozygous carries were identified. Median CAG tract size in controls was 17 CAG repeats. Men and women were equally affected by HD. All patients with HD-bar three who were juvenile onset of <21 years-were defined as adult onset (median age of onset was 40 years). HD transmission followed an autosomal dominant pattern in 84.2% (16/19) of HD families. In familial cases, maternal transmission was higher 52.6% (10/19) than paternal transmission 36.8% (7/19). The number of asymptomatic individuals at risk of developing HD was estimated at ten times more than the symptomatic patients. HD could be traced back to the early 1900s in most African sites. HD cases spread over seven ethnic groups belonging to two distinct linguistic lineages separated from each other approximately 54-16 kya ago: Nilo-Sahara and Niger-Congo. CONCLUSION: This is the first study examining HD in multiple sites in sub-Saharan Africa. We demonstrated that HD is found in multiple ethnic groups residing in five sub-Saharan African countries including the first genetically confirmed HD cases from Guinea and Kenya. The prevalence of HD in the African continent, its associated socio-economic impact, and genetic origins need further exploration and reappraisal.

Metabolomic profiling reveals altered phenylalanine metabolism in Parkinson's disease in an Egyptian cohort.

Introduction: Parkinson's disease (PD) is the most common motor neurodegenerative disease worldwide. Given the complexity of PD etiology and the different metabolic derangements correlated to the disease, metabolomics profiling of patients is a helpful tool to identify patho-mechanistic pathways for the disease development. Dopamine metabolism has been the target of several previous studies, of which some have reported lower phenylalanine and tyrosine levels in PD patients compared to controls. Methods: In this study, we have collected plasma from 27 PD patients, 18 reference controls, and 8 high-risk controls to perform a metabolomic study using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Results: Our findings revealed higher intensities of trans-cinnamate, a phenylalanine metabolite, in patients compared to reference controls. Thus, we hypothesize that phenylalanine metabolism has been shifted to produce trans-cinnamate via L-phenylalanine ammonia lyase (PAL), instead of producing tyrosine, a dopamine precursor, via phenylalanine hydroxylase (PAH). Discussion: Given that these metabolites are precursors to several other metabolic pathways, the intensities of many metabolites such as dopamine, norepinephrine, and 3-hydroxyanthranilic acid, which connects phenylalanine metabolism to that of tryptophan, have been altered. Consequently, and in respect to Metabolic Control Analysis (MCA) theory, the levels of tryptophan metabolites have also been altered. Some of these metabolites are tryptamine, melatonin, and nicotinamide. Thus, we assume that these alterations could contribute to the dopaminergic, adrenergic, and serotonergic neurodegeneration that happen in the disease.

GBA1 rs3115534 Is Associated with REM Sleep Behavior Disorder in Parkinson's Disease in Nigerians.

BACKGROUND: Rapid eye movement (REM) sleep behavior disorder (RBD) is an early feature of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Damaging coding variants in Glucocerebrosidase (GBA1) are a genetic risk factor for RBD. Recently, a population-specific non-coding risk variant (rs3115534) was found to be associated with PD risk and earlier onset in individuals of African ancestry. OBJECTIVES: We aimed to investigate whether the GBA1 rs3115534 PD risk variant is associated with RBD in persons with PD. METHODS: We studied 709 persons with PD and 776 neurologically healthy controls from Nigeria. All DNA samples were genotyped and imputed, and the GBA1 rs3115534 risk variant was extracted. The RBD screening questionnaire (RBDSQ) was used to assess symptoms of possible RBD. RESULTS: RBD was present in 200 PD (28.2%) and 51 (6.6%) controls. We identified that the non-coding GBA1 rs3115534 risk variant is associated with possible RBD in individuals of Nigerian origin (ß, 0.3640; standard error [SE], 0.103, P = 4.093e-04), as well as in all samples after adjusting for PD status (ß, 0.2542; SE, 0.108; P = 0.019) suggesting that although non-coding, this variant may have the same downstream consequences as GBA1 coding variants. CONCLUSIONS: Our results indicate that the non-coding GBA1 rs3115534 risk variant is associated with an increasing number of RBD symptoms in persons with PD of Nigerian origin. Further research is needed to assess if this variant is also associated with polysomnography-defined RBD and with RBD symptoms in DLB. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The non-coding GBA1 rs3115534 variant is associated with REM sleep behavior disorder in Nigerians.

Background: Damaging coding variants in GBA1 are a genetic risk factor for rapid eye movement sleep behavior disorder (RBD), which is a known early feature of synucleinopathies. Recently, a population-specific non-coding variant (rs3115534) was found to be associated with PD risk and earlier disease onset in individuals of African ancestry. Objectives: To investigate whether the GBA1 rs3115534 PD risk variant is associated with RBD. Methods: We studied 709 persons with PD and 776 neurologically healthy controls from Nigeria. The GBA1 rs3115534 risk variant status was imputed from previous genotyping for all. Symptoms of RBD were assessed with the RBD screening questionnaire (RBDSQ). Results: The non-coding GBA1 rs3115534 risk variant is associated with possible RBD in individuals of Nigerian origin (Beta = 0.3640, SE = 0.103, P =4.093e-04), as well as after adjusting for PD status (Beta = 0.2542, SE = 0.108, P = 0.019) suggesting that this variant may have the same downstream consequences as GBA1 coding variants. Conclusions: We show that the non-coding GBA1 rs3115534 risk variant is associated with increased RBD symptomatology in Nigerians with PD. Further research is required to assess association with polysomnography-defined RBD.

Evaluating the performance of polygenic risk profiling across diverse ancestry populations in Parkinson's disease.

Objective: This study aims to address disparities in risk prediction by evaluating the performance of polygenic risk score (PRS) models using the 90 risk variants across 78 independent loci previously linked to Parkinson's disease (PD) risk across seven diverse ancestry populations. Methods: We conducted a multi-stage study, testing PRS models in predicting PD status across seven different ancestries applying three approaches: 1) PRS adjusted by gender and age; 2) PRS adjusted by gender, age and principal components (PCs); and 3) PRS adjusted by gender, age and percentage of population admixture. These models were built using the largest four population-specific summary statistics of PD risk to date (base data) and individual level data obtained from the Global Parkinson's Genetics Program (target data). We performed power calculations to estimate the minimum sample size required to conduct these analyses. A total of 91 PRS models were developed to investigate cumulative known genetic variation associated with PD risk and age of onset in a global context. Results: We observed marked heterogeneity in risk estimates across non-European ancestries, including East Asians, Central Asians, Latino/Admixed Americans, Africans, African admixed, and Ashkenazi Jewish populations. Risk allele patterns for the 90 risk variants yielded significant differences in directionality, frequency, and magnitude of effect. PRS did not improve in performance when predicting disease status using similar base and target data across multiple ancestries, demonstrating that cumulative PRS models based on current known risk are inherently biased towards European populations. We found that PRS models adjusted by percentage of admixture outperformed models that adjusted for conventional PCs in highly admixed populations. Overall, the clinical utility of our models in individually predicting PD status is limited in concordance with the estimates observed in European populations. Interpretation: This study represents the first comprehensive assessment of how PRS models predict PD risk and age at onset in a multi-ancestry fashion. Given the heterogeneity and distinct genetic architecture of PD across different populations, our assessment emphasizes the need for larger and diverse study cohorts of individual-level target data and well-powered ancestry-specific summary statistics. Our current understanding of PD status unraveled through GWAS in European populations is not generally applicable to other ancestries. Future studies should integrate clinical and *omics level data to enhance the accuracy and predictive power of PRS across diverse populations.

Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study.

BACKGROUND: An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations. METHODS: We performed a genome-wide association study (GWAS) in people of African and African admixed ancestry with and without Parkinson's disease. Individuals were included from several cohorts that were available as a part of the Global Parkinson's Genetics Program, the International Parkinson's Disease Genomics Consortium Africa, and 23andMe. A diagnosis of Parkinson's disease was confirmed clinically by a movement disorder specialist for every individual in each cohort, except for 23andMe, in which it was self-reported based on clinical diagnosis. We characterised ancestry-specific risk, differential haplotype structure and admixture, coding and structural genetic variation, and enzymatic activity. FINDINGS: We included 197 918 individuals (1488 cases and 196 430 controls) in our genome-wide analysis. We identified a novel common risk factor for Parkinson's disease (overall meta-analysis odds ratio for risk of Parkinson's disease 1·58 [95% CI 1·37-1·80], p=2·397 × 10-14) and age at onset at the GBA1 locus, rs3115534-G (age at onset ß=-2·00 [SE=0·57], p=0·0005, for African ancestry; and ß=-4·15 [0·58], p=0·015, for African admixed ancestry), which was rare in non-African or non-African admixed populations. Downstream short-read and long-read whole-genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. The identified signal seems to be associated with decreased glucocerebrosidase activity. INTERPRETATION: Our study identified a novel genetic risk factor in GBA1 in people of African ancestry, which has not been seen in European populations, and it could be a major mechanistic basis of Parkinson's disease in African populations. This population-specific variant exerts substantial risk on Parkinson's disease as compared with common variation identified through GWAS and it was found to be present in 39% of the cases assessed in this study. This finding highlights the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson's disease field moves towards targeted treatments in clinical trials. The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towards gaining insights into novel genetic determinants underlying the causes of Parkinson's disease. This finding opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk of Parkinson's disease. FUNDING: The Global Parkinson's Genetics Program, which is funded by the Aligning Science Across Parkinson's initiative, and The Michael J Fox Foundation for Parkinson's Research.

Genome-wide Association Identifies Novel Etiological Insights Associated with Parkinson's Disease in African and African Admixed Populations.

Background: Understanding the genetic mechanisms underlying diseases in ancestrally diverse populations is a critical step towards the realization of the global application of precision medicine. The African and African admixed populations enable mapping of complex traits given their greater levels of genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. Methods: Here we perform a comprehensive genome-wide assessment of Parkinson's disease (PD) in 197,918 individuals (1,488 cases; 196,430 controls) of African and African admixed ancestry, characterizing population-specific risk, differential haplotype structure and admixture, coding and structural genetic variation and polygenic risk profiling. Findings: We identified a novel common risk factor for PD and age at onset at the GBA1 locus (risk, rs3115534-G; OR=1.58, 95% CI = 1.37 - 1.80, P=2.397E-14; age at onset, BETA =-2.004, SE =0.57, P = 0.0005), that was found to be rare in non-African/African admixed populations. Downstream short- and long-read whole genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. However, we identified that this signal mediates PD risk via expression quantitative trait locus (eQTL) mechanisms. While previously identified GBA1 associated disease risk variants are coding mutations, here we suggest a novel functional mechanism consistent with a trend in decreasing glucocerebrosidase activity levels. Given the high population frequency of the underlying signal and the phenotypic characteristics of the homozygous carriers, we hypothesize that this variant may not cause Gaucher disease. Additionally, the prevalence of Gaucher's disease in Africa is low. Interpretation: The present study identifies a novel African-ancestry genetic risk factor in GBA1 as a major mechanistic basis of PD in the African and African admixed populations. This striking result contrasts to previous work in Northern European populations, both in terms of mechanism and attributable risk. This finding highlights the importance of understanding population-specific genetic risk in complex diseases, a particularly crucial point as the field moves toward precision medicine in PD clinical trials and while recognizing the need for equitable inclusion of ancestrally diverse groups in such trials. Given the distinctive genetics of these underrepresented populations, their inclusion represents a valuable step towards insights into novel genetic determinants underlying PD etiology. This opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk. Evidence Before this Study: Our current understanding of Parkinson's disease (PD) is disproportionately based on studying populations of European ancestry, leading to a significant gap in our knowledge about the genetics, clinical characteristics, and pathophysiology in underrepresented populations. This is particularly notable in individuals of African and African admixed ancestries. Over the last two decades, we have witnessed a revolution in the research area of complex genetic diseases. In the PD field, large-scale genome-wide association studies in the European, Asian, and Latin American populations have identified multiple risk loci associated with disease. These include 78 loci and 90 independent signals associated with PD risk in the European population, nine replicated loci and two novel population-specific signals in the Asian population, and a total of 11 novel loci recently nominated through multi-ancestry GWAS efforts.Nevertheless, the African and African admixed populations remain completely unexplored in the context of PD genetics. Added Value of this Study: To address the lack of diversity in our research field, this study aimed to conduct the first genome-wide assessment of PD genetics in the African and African admixed populations. Here, we identified a genetic risk factor linked to PD etiology, dissected African-specific differences in risk and age at onset, characterized known genetic risk factors, and highlighted the utility of the African and African admixed risk haplotype substructure for future fine-mapping efforts. We identified a novel disease mechanism via expression changes consistent with decreased GBA1 activity levels. Future large scale single cell expression studies should investigate the neuronal populations in which expression differences are most prominent. This novel mechanism may hold promise for future efficient RNA-based therapeutic strategies such as antisense oligonucleotides or short interfering RNAs aimed at preventing and decreasing disease risk. We envisage that these data generated under the umbrella of the Global Parkinson's Genetics Program (GP2) will shed light on the molecular mechanisms involved in the disease process and might pave the way for future clinical trials and therapeutic interventions. This work represents a valuable resource in an underserved population, supporting pioneering research within GP2 and beyond. Deciphering causal and genetic risk factors in all these ancestries will help determine whether interventions, potential targets for disease modifying treatment, and prevention strategies that are being studied in the European populations are relevant to the African and African admixed populations. Implications of all the Available Evidence: We nominate a novel signal impacting GBA1 as the major genetic risk factor for PD in the African and African admixed populations. The present study could inform future GBA1 clinical trials, improving patient stratification. In this regard, genetic testing can help to design trials likely to provide meaningful and actionable answers. It is our hope that these findings may ultimately have clinical utility for this underrepresented population.

MAPT allele and haplotype frequencies in Nigerian Africans: Population distribution and association with Parkinson's disease risk and age at onset.

INTRODUCTION: The association between MAPT and PD risk may be subject to ethnic variability even within populations of similar geographical origin. Data on MAPT haplotype frequencies, and its association with PD risk in black Africans are lacking. We aimed to determine the frequencies of MAPT haplotypes and their role as risk factors for PD and age at onset in Nigerians. METHODS: The haplotype and genotype frequencies of MAPT rs1052553 were analysed in 907 individuals with PD and 1022 age-matched healthy controls from the Nigeria Parkinson's Disease Research network cohort. Clinical data related to PD included age at study, age at onset (AAO), and disease duration. RESULTS: The frequency of the H1 haplotype was 98.7% in PD, and 99.1% in controls (p = 0.19). The H2 haplotype was present in - 1.3% of PD and 0.9% of controls (p = 0.24). The most frequent MAPT genotype was H1H1 (PD - 97.5%, controls - 98.2%). The H1 haplotype was not associated with PD risk after accounting for gender and AAO (Odds ratio for H1/H1 vs H1/H2 and H2/H2: 0.68 (95% CI:0.39-1.28); p = 0.23). CONCLUSIONS: Our findings support previous studies that report a low frequency of the MAPT H2 haplotype in black ancestry Africans but document its occurrence in Nigerians. The MAPT H1 haplotype was not associated with an increased risk or age at onset of PD in this cohort.

MAPT allele and haplotype frequencies in Nigerian Africans: population distribution and association with Parkinson's disease risk and age at onset.

Background: The microtubule-associated protein tau ( MAPT ) gene is critical because of its putative role in the causal pathway of neurodegenerative diseases including Parkinson's disease (PD). However, there is a lack of clarity regarding the link between the main H1 haplotype and risk of PD. Inconsistencies in reported association may be driven by genetic variability in the populations studied to date. Data on MAPT haplotype frequencies in the general population and association studies exploring the role of MAPT haplotypes in conferring PD risk in black Africans are lacking. Objectives: To determine the frequencies of MAPT haplotypes and explore the role of the H1 haplotype as a risk factor for PD risk and age at onset in Nigerian Africans. Methods: The haplotype and genotype frequencies of MAPT rs1052553 were analysed using PCR-based KASP™ in 907 individuals with PD and 1,022 age-matched neurologically normal controls from the Nigeria Parkinson's Disease Research (NPDR) network cohort. Clinical data related to PD included age at study, age at onset, and disease duration. Results: The frequency of the main MAPT H1 haplotype in this cohort was 98.7% in individuals with PD, and 99.1% in healthy controls (p=0.19). The H2 haplotype was present in 41/1929 (2.1%) of the cohort (PD - 1.3%; Controls - 0.9%; p=0.24). The most frequent MAPT genotype was H1H1 (PD - 97.5%, controls - 98.2%). The H1 haplotype was not associated with PD risk after accounting for gender and age at onset (Odds ratio for H1/H1 vs H1/H2 and H2/H2: 0.68 (95% CI:0.39-1.28); p=0.23). Conclusions: Our findings support previous studies that report a low frequency of the MAPT H2 haplotype in black ancestry Africans, but document its occurrence in the Nigerian population (2.1%). In this cohort of black Africans with PD, the MAPT H1 haplotype was not associated with an increased risk or age at onset of PD.

Underrepresented Populations in Parkinson's Genetics Research: Current Landscape and Future Directions.

BACKGROUND: Human genetics research lacks diversity; over 80% of genome-wide association studies have been conducted on individuals of European ancestry. In addition to limiting insights regarding disease mechanisms, disproportionate representation can create disparities preventing equitable implementation of personalized medicine. OBJECTIVE: This systematic review provides an overview of research involving Parkinson's disease (PD) genetics in underrepresented populations (URP) and sets a baseline to measure the future impact of current efforts in those populations. METHODS: We searched PubMed and EMBASE until October 2021 using search strings for "PD," "genetics," the main "URP," and and the countries in Latin America, Caribbean, Africa, Asia, and Oceania (excluding Australia and New Zealand). Inclusion criteria were original studies, written in English, reporting genetic results on PD from non-European populations. Two levels of independent reviewers identified and extracted information. RESULTS: We observed imbalances in PD genetic studies among URPs. Asian participants from Greater China were described in the majority of the articles published (57%), but other populations were less well studied; for example, Blacks were represented in just 4.0% of the publications. Also, although idiopathic PD was more studied than monogenic forms of the disease, most studies analyzed a limited number of genetic variants. We identified just nine studies using a genome-wide approach published up to 2021, including URPs. CONCLUSION: This review provides insight into the significant lack of population diversity in PD research highlighting the immediate need for better representation. The Global Parkinson's Genetics Program (GP2) and similar initiatives aim to impact research in URPs, and the early metrics presented here can be used to measure progress in the field of PD genetics in the future. © 2022 International Parkinson and Movement Disorder Society.

Spectrum of movement disorders: Experience of a one and half year of existence of the first specialized center in Senegal.

BACKGROUND: Movement disorders have different prevalence in different regions and they are little studied in Africa. OBJECTIVES: Evaluate the prevalence and determine the spectrum of movement disorders in the first specialized center in Senegal. METHODS: It was a prospective study over on 18 months in adult outpatient clinic. Demographic, clinical, paraclinical data, including genetic test in collaboration with the Queen Square Institute of Neurology at UCL were collected. RESULTS: One hundred and thirty four patients were followed up, representing a prevalence of 4.7%. Men represented 56% for a sex ratio of 1.3. The mean age of population was 47.7 ± 18 years with limits ranging from 16 to 81 years. Eighty-one patients (60.4%) had hyperkinetic and 53 patients (39.6%) had hypokinetic movements. Twenty-nine patients (21.6%) had tremors and 18 (13.4%) had dystonic movements. Ataxia and choreic movements were respectively in 11 (8.2%) and 10 patients (7.5%). Twenty-four patients (17.9%) were from a first-degree consanguineous. A genetic test on saliva samples was done in 16 patients (11.9%) and confirmed Huntington's disease in 8 patients of 6 families. Parkinson disease was the most frequent etiology (32.8%) followed by essential tremor (12.7%) and psychogenic tremor in 7.5%. Stroke accounted for 6% of the causes of MD (tremor, ballism, dystonia, ataxia and parkinsonism) and no etiology was found in 9%. CONCLUSION: The spectrum of movement disorders is very heterogeneous with a non-negligible frequency and diverse etiologies in neurological practice in Senegal.

Prevalence of Fabry Disease among Patients with Parkinson's Disease.

BACKGROUND: An increased prevalence of Parkinson's disease (PD) disease has been previously reported in subjects with Fabry disease (FD) carrying alpha-galactosidase (GLA) mutations and their first-line relatives. Moreover, decreased alpha-galactosidase A (AGLA) enzymatic activity has been reported among cases with PD compared to controls. OBJECTIVE: The aim of our study was to determine the prevalence of FD among patients with PD. METHODS: We recruited 236 consecutive patients with PD from February 2018 to December 2020. Clinical and sociodemographic data, including the MDS-UPDRS-III scores and HY stage (the Hoehn and Yahr scale), were collected, and in-depth phenotyping was performed in subjects with identified GLA variants. A multistep approach, including standard determination of AGLA activity and LysoGb3 in males, and next-generation based GLA sequencing in all females and males with abnormal AGLA levels was performed in a routine diagnostic setting. RESULTS: The mean age of our patients was 68.9 ± 8.9 years, 130 were men (55.1%), and the mean disease duration was 7.77 ± 5.35 years. Among 130 men, AGLA levels were low in 20 patients (15%), and subsequent Lyso-Gb3 testing showed values within the reference range for all tested subjects. In 126 subsequently genetically tested patients, four heterozygous p.(Asp313Tyr) GLA variants (3.2%, MAF 0.016) were identified; all were females. None of the 4 GLA variant carriers identified had any clinical manifestation suggestive of FD. CONCLUSIONS: The results of this study suggest a possible relationship between FD and PD in a small proportion of cases. Nevertheless, the GLA variant found in our cohort is classified as a variant of unknown significance. Therefore, its pathogenic causative role in the context of PD needs further elucidation, and these findings should be interpreted with caution.

WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia.

INTRODUCTION: Sixteen subjects with biallelic WARS2 variants encoding the tryptophanyl mitochondrial aminoacyl-tRNA synthetase, presenting with a neonatal- or infantile-onset mitochondrial disease, have been reported to date. Here we present six novel cases with WARS2-related diseases and expand the spectrum to later onset phenotypes including dopa-responsive early-onset parkinsonism and progressive myoclonus-ataxia. METHODS: Six individuals from four families underwent whole-exome sequencing within research and diagnostic settings. Following the identification of a genetic defect, in-depth phenotyping and protein expression studies were performed. RESULTS: A relatively common (gnomAD MAF = 0.0033) pathogenic p.(Trp13Gly) missense variant in WARS2 was detected in trans in all six affected individuals in combination with different pathogenic alleles (exon 2 deletion in family 1; p.(Leu100del) in family 2; p.(Gly50Asp) in family 3; and p.(Glu208*) in family 4). Two subjects presented with action tremor around age 10-12 years and developed tremor-dominant parkinsonism with prominent neuropsychiatric features later in their 20s. Two subjects presented with a progressive myoclonus-ataxia dominant phenotype. One subject presented with spasticity, choreo-dystonia, myoclonus, and speech problems. One subject presented with speech problems, ataxia, and tremor. Western blotting analyses in patient-derived fibroblasts showed a markedly decreased expression of the full-length WARS2 protein in both subjects carrying p.(Trp13Gly) and an exon-2 deletion in compound heterozygosity. CONCLUSIONS: This study expands the spectrum of the disease to later onset phenotypes of early-onset tremor-dominant parkinsonism and progressive myoclonus-ataxia phenotypes.

A Cross-Sectional Comprehensive Assessment of the Profile and Burden of Non-motor Symptoms in Relation to Motor Phenotype in the Nigeria Parkinson Disease Registry Cohort.

BACKGROUND: Data on non-motor symptoms (NMS) in black Africans with Parkinson's disease (PD) are sparse. OBJECTIVE: To describe the profile of NMS in the Nigeria PD Registry (NPDR) cohort and explore the relationship between NMS and PD motor phenotype. METHODS: We conducted a cross-sectional study of the frequency and burden of NMS, based on the non-motor symptoms scale (NMSS) and the Chaudhuri method respectively in our cohort. Baseline demographics, disease characteristics (Hoehn and Yahr stage, MDS-UPDRS total score and Part III motor score), motor phenotype (based on Stebbin et al's algorithm), and levodopa equivalent daily dose (LEDD) were documented. RESULTS: Data are presented for 825 PD whose mean age at study was 63.7 ± 10.1 years, female sex-221 [26.8%] while median PD duration was 36 months. PD phenotypes included tremor-dominant 466 (56.5%), postural instability and gait disorder (PIGD) 259 (31.4%), and indeterminate 100 (12.1%). 82.6% were on treatment (median LEDD of 500 mg/24 hours). 804 (97.5%) endorsed at least 1 NMS. The median NMSS score was 26.0 while subscores for urinary and sexual function domains were significantly higher in males (P < 0.05). PIGD-PD had more frequent NMS and higher frequency of severe/very severe NMSS burden (P = 0.000 for both). Nocturia and fatigue were the most prevalent NMS overall and across motor subtypes. PIGD phenotype and total UPDRS scores were the independent determinants of NMSS scores (P = 0.000). CONCLUSION: The profile and burden of NMS, and association with motor subtype in our black African cohort is largely similar to descriptions from other populations.