Uncovering the genetic basis of Parkinson’s disease worldwide
The session kicked off with Shen’s lecture “Uncovering the genetic basis of Parkinson’s disease worldwide.” He started his talk by showing clinical vignettes of multiethnic Malaysian patients having young-onset Parkinson’s disease (PD)1,2 and posing the question to the audience: “Younger PD patients have a slower disease progression - True or false?” These patients had quite markedly divergent clinical outcomes, e.g., with the severe group developing severe parkinsonism and motor response complications as well as dementia, responding poorly to deep brain stimulation, and having early mortality.1,2
Shen revealed that one important explanation was the difference in their underlying genetics, in these cases reflecting GBA1-vs. PRKN-related PD.1-7 The ancestries of these patients (Chinese, Indian and Malays) are also highly relevant globally, with China and India being (by far) the two most populous countries in the world (home to almost 2.9 billion people), not counting the extensive diaspora of Chinese and Indians globally, and Malays comprising ~200 million individuals living in Southeast Asia. Shen went on to discuss the common monogenic forms of PD, their global distributions (and mutational spectrum, e.g., the “severe” GBA1 p.L483P/ L444P variant being the most common variant in East Asians), and their characteristic clinical features.1-9
The need to prioritize diversity in genetics research by studying underrepresented populations10,11 was again highlighted by the example of a very high rate of PRKN (accounting for >50% of early-onset PD) among the indigenous population in the Malaysian state of Sabah.1,3 Other well-known pockets of high prevalence of monogenic PD include North African Arab-Berbers and Spanish Basques, with LRRK2 p.G2019S and p.R1441G, respectively.3,8,9 Common genetic risk variants contributing to sporadic PD were also discussed,3,8,13 including the Asian LRRK2 variants p.G2385R and p.R1628P,14,15 as well as other population-specific variants such as the recent finding of GBA1 rs3115534-G in ~40% of Nigerian PD patients.12
The latter highlights the importance of regional and global collaborations, e.g., via the Global Parkinson’s Genetics Program (GP2) and International Parkinson Disease Genomics Consortium (IPDGC).13,16,17 The role of genetics (which serve as the earliest definable upstream cause or predisposition to PD) was placed in the context of recent proposals for biological classification of PD, which will likely result in a major paradigm shift in PD research.18 Shedding light on disease mechanisms, PD genetics will be increasingly relevant in the era of molecularly-based therapies (targeting disease processes, rather than merely symptoms).19
Shen also emphasized the role of the modifiers of disease development and progression, including environmental factors and gene-environment interactions/epigenetics.3,20,21 A call was made for the field to work towards ensuring that the fruits of research efforts are fairly distributed globally (e.g., in access to new genotype-based therapies), providing benefit to patients and their families around the world.14,18,22 Finally, tribute was paid to the numerous pioneers and contributors to the PD genetics field.
The challenges of managing and researching PD in Africa
Next, Oluwadamilola (“Lara”) spoke about “The challenges of managing and researching PD in Africa.” She started by asking “Why should there be a focus on PD in Africa?” and explained that the increasing global burden of PD is expected to impact Africa disproportionately in the coming decades due to large population increases, ageing, and reducing “competition” from communicable diseases.23 The rich ancestral diversity24 and special populations in Africa also offer valuable opportunities for discoveries, e.g., in PD genetics12 or disease manifestations.25
In terms of the challenges to PD management in Africa, Lara referred to the overarching themes highlighted recently by a group of global experts and stakeholders in PD coming together under the umbrella of the World Health Organization (WHO).22
All these interact to result in delayed diagnosis, misdiagnosis, and delayed or lack of access to treatment.
A major contributor to the wide treatment gap in the continent is reduced access to effective medications. Although levodopa is on the WHO Model Lists of Essential Medicines, it is not available or accessible in some countries, particularly in Sub-Saharan Africa (SSA).22,25 Two studies in Kenya and Nigeria found that, in contrast to other parts of the world, anticholinergics and ergot dopamine agonists were more available and affordable than levodopa.28,29 The main findings from a continent-wide survey were that PD therapies and services were, to a large extent, unavailable and unaffordable in most African regions, especially in SSA (and less so in Northern and Southern Africa), and variation even within countries (e.g., urban vs. rural).30
The situation with research in Africa mirrors the clinical situation, with a lack of funding, infrastructure, and workforce (e.g., a major lack of movement disorders postgraduate training), resulting in mostly small hospital‐based studies and few population‐level (including epidemiological) studies.10,31 Most of the research therefore ends up with low visibility on account of publication in low-impact journals.32 Lara highlighted the issue of mistrust that can hinder international collaboration, and the need for cultural and linguistic adaptions to research protocols (e.g., sometimes the need for familial involvement in the consent process).
The talk finished on a positive note by highlighting the many efforts currently being made in education and training of healthcare professionals by the MDS, and the great collaborative work being done within the GP2, IPDGC, and the Transforming Parkinson's Care in Africa (TraPCAf) network.12,16,23