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MDS 2021 | GBA-associated PD: stratifying patients based on GBA variants

Glucocerebrosidase (GBA) mutations represent the largest known genetic risk factor for the development of Parkinson’s disease (PD), with 15 – 20% of patients with PD carrying a heterozygous GBA mutation. Enza Maria Valente, MD, PhD, IRCCS Mondino Foundation & University of Pavia, Pavia, Italy, outlines the clinical features of GBA-associated PD and the current research efforts to improve our understanding of the various phenotypes associated with different GBA variants. As not all individuals with a GBA mutation will develop PD, efforts are ongoing to understand how to predict disease onset in asymptomatic carriers. Several markers of disease conversion have been assessed. Additionally, there is also heterogeneity within individuals who do convert to GBA-associated PD. As larger cohorts have been assessed, there is increasing evidence to support a stratification of these patients based on the specific GBA variant present. Prof. Valente discusses the need to detailed characterization of genotype-phenotype correlations to enable accurate prognostication and to discover therapeutic strategies that may specifically tackle the pathogenetic mechanism underlying GBA dysfunction in order to prevent or delay disease progression. This interview took place during the 2021 International Congress of Parkinson’s Disease and Movement Disorders.

Transcript (edited for clarity)

Thank you very much for this opportunity. This is really an important and very hot topic in Parkinson’s disease genetics nowadays. As you know, GBA, it’s really the most important genetic factor predisposing to Parkinson’s disease that we know so far. It reaches a prevalence that can be up to 15 to 20% of patients with PD may carry a heterozygous GBA variant. Because it is so common, which is something unusual for a genetic factor, there is a major research effort in trying to understand better the progression of the disease, the phenotypes associated to the variants, GBA variants, and also trying to discover efficient therapeutic strategies that may specifically tackle the pathogenetic mechanism underlying this GBA dysfunction, in order to prevent or delay the progression of the disease in these patients...

Thank you very much for this opportunity. This is really an important and very hot topic in Parkinson’s disease genetics nowadays. As you know, GBA, it’s really the most important genetic factor predisposing to Parkinson’s disease that we know so far. It reaches a prevalence that can be up to 15 to 20% of patients with PD may carry a heterozygous GBA variant. Because it is so common, which is something unusual for a genetic factor, there is a major research effort in trying to understand better the progression of the disease, the phenotypes associated to the variants, GBA variants, and also trying to discover efficient therapeutic strategies that may specifically tackle the pathogenetic mechanism underlying this GBA dysfunction, in order to prevent or delay the progression of the disease in these patients.

GBA variants are heterozygous variants, so they are transmitted to about 50% of offspring. This is also very important in terms of genetic counseling, because the offspring of patients who carry a variant have themselves a 50% chance of having inherited this variant. Of course, this doesn’t mean that they will develop the disease for sure, because this is only a risk factor. We know that there are many healthy individuals carrying heterozygous, GBA variants, and never developing the disease throughout their life, but still it is important to know. This cohort of asymptomatic carriers really represent a very important group of people because they have a higher risk of developing the disease and there is also a lot of research effort in the direction of identifying markers of disease conversion, so how many of them will eventually develop PD, and there are some early biomarkers that can predict that some of them will become affected while some others will not. And if not, are there any protective mechanisms that prevent diseases to develop? So, research is very hot on this.

Another very important aspect is the phenotype of course, as you asked me about the clinical features. Overall, it was only discovered that the presence of GBA variants is associated with a Parkinson’s disease phenotype, which seems a little bit more aggressive than idiopathic PD in terms of an earlier age of onset, and definitely a higher occurrence of non-motor features such as cognitive dysfunction and eventually dementia in some cases, or autonomic dysfunction or psychiatric disturbances and so on. Now with more and more studies, and now that very large cohorts of patients have been studied in the world, it is becoming evident that there is a stratification based on the type of variants that patients have.

So now what the researchers are trying to do, and there are big consortia in the world, trying to put cases together to start the larger cohorts. It is not just important to say ‘GBA positive’ or ‘GBA negative’, but it also very important to see which specific mutation and variant the patient carries, because some mild variants are associated with a milder phenotype, while the presence of different types of variants that affect more the enzymatic activity of the gene, such as those that were called severe variants or complex alleles, seem to be associated with more severe presentation and earlier presentation of the disease.

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