New research supports the view that Parkinson’s disease is biologically heterogeneous, with distinct genetic subtypes associated with different disease trajectories and treatment responses.
The review suggests that variants of the GBA1 gene confer a higher risk of developing Parkinson’s disease and result in earlier onset and more aggressive disease course, with more pronounced motor and non-motor symptoms.
The researchers also highlight ongoing studies that show how patients with severe variants may respond worse to particular treatments, particularly device-aided therapies such as deep brain stimulation.
“Our findings add to growing evidence that Parkinson’s disease is not a single condition, but a group of disorders with different underlying causes,” said lead author Dr Elisa Menozzi, a senior research fellow at UCL Queen Square Institute of Neurology.
“By understanding how genetic factors such as GBA1 influence the disease, we move closer to more precise and personalised approaches to diagnosis and treatment,” he added.
The review article, published in The Lancet Neurology [link here], discusses how variants in the GBA1 gene – which encodes the lysosomal enzyme glucocerebrosidase – can increase the risk and severity of both Parkinson’s disease and dementia with Lewy bodies.
GBA1 variants are found in up to 10–15% of European Parkinson’s disease patients and can be classified as mild, severe, risk or unknown, based on the severity of the clinical phenotype.
Severe variants increase the risk of Parkinson’s disease most greatly (e.g. L483P odds ratio (OR) 6.4–30.4 and V433L OR 4.9–6.7), followed by mild (e.g. N409S OR 2.2–7.8) and risk variants (e.g. E365K OR 1.6–5.5).
However, penetrance is low and age-dependent, having been estimated at 1.5–4.7% at 60 years and 7.7–9.1% at age 80 years.
The authors also highlight evidence showing that GBA1-associated Parkinson’s disease has a more severe phenotype than idiopathic disease, particularly when caused by a severe variant, which also leads to earlier onset.
Severe variants also cause more frequent motor complications, particularly fluctuations and dyskinesias, compared to other variants and idiopathic disease.
Patients with GBA1-associated Parkinson’s disease also suffer from more frequent and severe cognitive impairment and have a higher risk of mood disorders and REM sleep behaviour disorder, with severe variants again leading to worse outcomes.
Cohort studies have also indicated greater issues with autonomic control in GBA1-associated disease, particularly orthostatic hypotension and parasympathetic regulation of cardiovascular function.
Carriers of different variants may also respond differently to treatments, with studies suggesting that deep brain stimulation may be less effective and lead to worse side effects in patients with severe GBA1 variants, compared to those with idiopathic disease, while levodopa–carbidopa intestinal gel infusions also appear to be less effective.
Given these differences, “in individuals with early disease onset and marked non-motor impairment, GBA1 genetic screening might be advisable,” the authors suggested.
Synuclein seed amplification assays have shown promise as a biochemical assessment of disease progression, with accelerated seeding kinetics found to be associated with cognitive decline.
The authors also highlight ongoing clinical trials of GBA1-targeted therapies, most notably the pharmacological chaperone ambroxol, which increased concentrations of glucocerebrosidase and total α-synuclein in cerebrospinal fluid and improved motor function at six months in a Phase 2 trial, although larger trials are needed to confirm efficacy.
A gene therapy trial is also underway, while treatments against other GBA1-specific targets, including mTOR complex 1, Prosaposin C and Progranulin, are being investigated.
“GBA1 appears to offer a tractable therapeutic target to modify the pathogenesis of GBA1-Parkinson’s disease,” the authors concluded.
“Several trials involving several treatment strategies are underway, and more studies are planned,” they added.