Frequency of Hereditary and GBA1‐Related Parkinsonism in Latin America: A Systematic Review and Meta‐Analysis

Abstract

BackgroundIdentifying hereditary parkinsonism is valuable for diagnosis, genetic counseling, patient prioritization in trials, and studying the disease for personalized therapies. However, most studies were conducted in Europeans, and limited data exist on admixed populations like those from Latin America.ObjectivesThis study aims to assess the frequency and distribution of genetic parkinsonism in Latin America.MethodsWe conducted a systematic review and meta‐analysis of the frequency of parkinsonian syndromes associated with genetic pathogenic variants in Latin America. We defined hereditary parkinsonism as those caused by the genes outlined by the MDS Nomenclature of Genetic Movement Disorders and heterozygous carriers of GBA1 pathogenic variants. A systematic search was conducted in PubMed, Web of Science, Embase, and LILACS in August 2022. Researchers reviewed titles and abstracts, and disagreements were resolved by a third researcher. After this screening, five researchers reanalyzed the selection criteria and extracted information based on the full paper. The frequency for each parkinsonism‐related gene was determined by the presence of pathogenic/likely pathogenic variants among screened patients. Cochran's Q and I2 tests were used to quantify heterogeneity. Meta‐regression, publication bias tests, and sensitivity analysis regarding study quality were also used for LRRK2‐, PRKN‐, and GBA1‐related papers.ResultsWe included 73 studies involving 3014 screened studies from 16 countries. Among 7668 Latin American patients, pathogenic variants were found in 19 different genes. The frequency of the pathogenic variants in LRRK2 was 1.38% (95% confidence interval [CI]: 0.52–2.57), PRKN was 1.16% (95% CI: 0.08–3.05), and GBA1 was 4.17% (95% CI: 2.57–6.08). For all meta‐analysis, heterogeneity was high and publication bias tests were negative, except for PRKN, which was contradictory. Information on the number of pathogenic variants in the other genes is further presented in the text.ConclusionsThis study provides insights into hereditary and GBA1‐related parkinsonism in Latin America. Lower GBA1 frequencies compared to European/North American cohorts may result from limited access to gene sequencing. Further research is vital for regional prevalence understanding, enabling personalized care and therapies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Towards a Global View of Parkinson's Disease Genetics

“…Monogenic forms of PD only account for 5 to 15% of PD cases. 42 Nextgeneration sequencing techniques widely integrated in research have identified a multitude of genetic variants potentially associated with PD across >80 genes, albeit most of them lack replication in subsequent studies. 43 Despite these advancements, unraveling the genetic mechanisms contributing to the heterogeneity of PD phenotypes remains a daunting challenge, especially as we extend our exploration to other ancestral backgrounds.…”

“…The frequency of homozygous or compound heterozygous PRKN mutations varies, showing rates ranging from <2% to approximately 13% in early-onset PD cohorts of European [94][95][96][97][98] and Latin American descent. 42,[99][100][101] This variability is attributed to differences in case detection, ancestry, and the proportion of familial cases and consanguinity. In Asian and North African populations, PRKN gene mutations contribute to early-onset PD, accounting for approximately 3 to 7% of cases.…”

“…As shown by Kasten et al in the MDSGene Systematic Review, there is a significant degree of missing phenotypic data across publications, encompassing both non-motor symptoms and cardinal motor features. 106 Despite significant advances in genetic research, 5,42 this gap is even more pronounced in studies regarding underrepresented populations, highlighting an urgent need for expanded research efforts to uncover phenotypic variability of these mutations in diverse ethnic backgrounds.…”

“…113 The frequency of GBA1 mutations in PD varies considerably across ethnicities, with up to 20% prevalence in Ashkenazi Jewish patients, 111 contrasting with 4 to 5% found in Asian and Latin American studies. 42,114,115 The spectrum of GBA1 variants across populations is also highly variable, with specific mutations conferring differing levels of risk. 116 For example, the p.N409S mutation, prevalent in European and Ashkenazi Jewish populations, is associated with a milder PD phenotype, whereas the p.L483P mutation is linked to a more severe PD phenotype.…”