Leveraging genetic diversity to understand monogenic Parkinson's disease's landscape in AfrAbia.

Am J Neurodegener Dis 2023;12(4):108-122 www.AJND.us /ISSN:2165-591X/AJND0151946 Review Article Leveraging genetic diversity to understand monogenic Parkinson’s disease’s landscape in AfrAbia Wael Mohamed Basic Medical Science Department, Kulliyah of Medicine, International Islamic University Malaysia, Kuantan, Pahang, Malaysia Received June 27, 2023; Accepted August 15, 2023; Epub August 15, 2023; Published August 30, 2023 Abstract: Parkinson’s disease may be caused by a single highly deleterious and penetrant pathogenic variant in 5-10% of cases (monogenic). Research into these mutational disorders yields important pathophysiological insights. This article examines the phenotype, genotype, pathophysiology, and geographic and ethnic distribution of genetic forms of disease. Well established Parkinson’s disease (PD) causal variants can follow an autosomal dominant (SNCA, LRRK2, and VPS35) and autosomal recessive pattern of inheritance (PRKN, PINK1, and DJ). Parkinson’s disease is a worldwide condition, yet the AfrAbia population is understudied in this regard. No prevalence or incidence investigations have been conducted yet. Few studies on genetic risk factors for PD in AfrAbia communities have been reported which supported the notion that the prevalence and incidence rates of PD in AfrAbia are generally lower than those reported for European and North American populations. There have been only a handful of documented genetic studies of PD in AfrAbia and very limited cohort and case-control research studies on PD have been documented. In this article, we provide a summary of prior conducted research on monogenic PD in Africa and highlight data gaps and promising new research directions. We emphasize that monogenic Parkinson’s disease is influenced by distinctions in ethnicity and geography, thereby reinforcing the need for global initiatives to aggregate large numbers of patients and identify novel candidate genes. The current article increases our knowledge of the genetics of Parkinson’s disease (PD) and helps to further our knowledge on the genetic factors that contribute to PD, such as the lower penetrance and varying clinical expressivity of known genetic variants, particularly in AfrAbian PD patients. Keywords: AfrAbia, Parkinson’s disease, monogenic, genetics, challenges, gaps, prospects Introduction Parkinson’s disease (PD) affects one percent of the global population. It disproportionately affects the elderly and has severe consequences for their quality of life [1, 2]. It is believed that neuron mortality in vulnerable brain regions (particularly but not exclusively the substantia nigra) and the development of Lewy bodies in the few surviving neurons result from a complex interaction between genetic and environmental factors [3]. Resting tremor, bradykinesia, mood problems, olfactory dysfunction, and cognitive impairment are only some of the motor and non-motor symptoms of PD, a complex, diverse neurodegenerative condition. About 6.1 million individuals worldwide were living with PD in 2016 [4], and this number is anticipated to climb to 17.5 million by 2040 [5] due to an aging global population and greater lifespan. Dopamine replacement therapy (DRT) with levodopa or other dopamine agonists (DA) is the standard treatment for people with Parkinson’s disease [6]. The overwhelming majority of PD cases have no identifiable cause. About 5-10% of all patients suffer from a monogenic form of PD [6, 7]. Almost 100 genetic risk loci have been associated with PD but most of our knowledge is based on EUR population-based studies [6]. High genetic heterogeneity underlies PD, in part due to the multiple rare mutations observed only in a single family or small groups [6]. Despite extensive and ongoing research, the pathogenic pathways underlying Parkinson’s disease needs more explanation and better understanding [7, 8]. Due to the high genetic Monogenic PD in AfrAbia heterogeneity of the disease and the difficulty in interpreting variants of uncertain significance, Next Generation Sequencing (NGS) technologies are widely used in diagnostics, but their application to Parkinson’s disease (PD) is still limited to a small number of patients with a clear family history and a small number of causative mutations. There are presently no disease-modifying therapeutics for PD, even though it is a widespread neurodegenerative condition for which we have only a limited grasp of the molecular and cellular disease foundation. Most cases of Parkinson’s disease have a complicated genetic background. Strong evidence for the function of cholinergic pathway in causing Parkinson’s disease is shown for the first time by mutations in RIC3, a chaperone of neuronal nicotinic acetylcholine receptor subunit-7 (CHRNA7). Intellectual incapacity, stiffness, seizures, myoclonus, dystonia, and a poor response to levodopa are only some of the (atypical) symptoms of early-onset X-linked parkinsonism [9]. CHCHD2, LRP10, TMEM230, UQCRC1, and VPS13C are only a few of the newly discovered genes for which replication studies are necessary to confirm such associations. Some genes (including SNCA and LRRK2) have been related to both Mendelian types of PD and enhanced vulnerability. Mutations in genes like glucocerebrosidase (GBA1) are intermediate between a single gene’s involvement and a predisposition for the disease [10]. Recent hot topics include the investigation of regional and ethnic differences for PD gene mutations, the impact of heterozygous variants in recessive PD genes, the outcomes in individuals who co-inherit mutations in both GBA1 and LRRK2, and the impact of the underlying genetic form on outcomes from deep brain stimulation. The purpose of this review is to increase our knowledge of the significance of genetics in PD and to disseminate that information worldwide so that it may be used. In addition to enhancing our current understanding of known genetic causes, such as reduced penetrance and variable clinical expressivity of known genetic variants in AfrAbia PD patients. It also, establishes an efficient infrastructure to speed up the discovery of novel monogenic causes of parkinsonism. 109 Genetic diversity in AfrAbia Over the last two decades, more than 20 genes responsible for hereditary PD have been identified. At least five genes, including SNCA (PARK1/4), LRRK2 (PARK8), VPS35 (PARK17), DNAJC13, and CHCHD2 [11, 12], have been implicated in autosomal dominant types of PD. LRRK2 is one of the main risk factors for PD in the EUR population. About 1.8% of healthy people, 3.6% of people with sporadic PD, and 10% of those with autosomal dominant familial PD are carriers [13]. So far, scientists have uncovered over 80 variations of the LRRK2 gene [14]. Seven of these variations have been identified as harmful, with the G2019S mutation being the most frequent. This mutation is responsible for 5-6% of familial and 1-2% of sporadic PD cases [13, 15]. It’s interesting to see how the prevalen (...truncated)