HELSINKI, FINLAND — , a discovery that experts believe will have important clinical implications in the not-too-distant future.
A variant in PMSF1, a proteasome regulator, was identified in 15 families from 13 countries around the world, with 22 affected individuals.
“These families were ethnically diverse, and in all of them, the variant in PMSF1 correlated with the neurologic phenotype. We know this is very clear cut — the genotype/phenotype correlation — with the patients carrying the missense mutation having ‘mild’ symptoms, while those with the progressive loss-of-function variant had the most severe phenotype,” she noted.
“Our findings unequivocally link defective PSMF1 to early-onset PD and neurodegeneration and suggest mitochondrial dysfunction as a mechanistic contributor,” study investigator Francesca Magrinelli, MD, PhD, of University College London (UCL) Queen Square Institute of Neurology, UCL, London, told delegates at the 2024 Congress of the European Academy of Neurology.
Managing Patient Expectations
Those “mildly” affected had an early-onset Parkinson’s disease starting between the second and fifth decade of life with pyramidal tract signs, dysphasia, psychiatric comorbidity, and early levodopa-induced dyskinesia.
In those with the intermediate type, Parkinson’s disease symptoms start in childhood and include, among other things, global hypokinesia, developmental delay, cerebellar signs, and in some, associated epilepsy.
In most cases, there was evidence on brain MRI of a hypoplasia of the corpus callosum, Dr. Magrinelli said. In the most severely affected individuals, there was perinatal lethality with neurologic manifestations.
While it may seem that the genetics of Parkinson’s disease is an academic exercise for the most part, it won’t be too much longer before it yields practical information that will inform how patients are treated, said Parkinson’s disease expert Christine Klein, MD, of the Institute of Neurogenetics and Department of Neurology, University of Lübeck, Helsinki, Finland.
The genetics of Parkinson’s disease are complicated, even within a single family. So, it’s very important to assess the pathogenicity of different variants, Dr. Klein noted.
“I am sure that you have all had a Parkinson’s disease [gene] panel back, and it says, ‘variant of uncertain significance.’ This is the worst thing that can happen. The lab does not know what it means. You don’t know what it means, and you don’t know what to tell the patient. So how do you get around this?”
Dr. Klein said that before conducting any genetic testing, clinicians should inform the patient that they may have a genetic variant of uncertain significance. It doesn’t solve the problem, but it does help physicians manage patient expectations.
Clinical Relevance on the Way?
While it may seem that all of the identified variants that predict Parkinson’s disease which, in addition to PSMF1, include the well-established LRRK2 and GBA1, may look the same, this is not true when patient history is taken into account, said Dr. Klein.
For example, age-of-onset of Parkinson’s disease can differ between identified variants, and this has led to “a paradigm change” whereby a purely genetic finding is called a disease.
This first occurred in Huntington’s disease, when researchers gave individuals at high genetic risk of developing the illness, but who currently had no clinical symptoms, the label of “Stage Zero disease.”
This is important to note “because if we get to the stage of having drugs that can slow down, or even prevent, progression to Parkinson’s disease, then it will be key to have patients we know are going to develop it to participate in clinical trials for such agents,” said Dr. Klein.
She cited the example of a family that she recently encountered that had genetic test results that showed variants of unknown significance, so Dr. Klein had the family’s samples sent to a specialized lab in Dundee, Scotland, for further analysis.
“The biochemists found that this variant was indeed pathogenic, and kinase-activating, so this is very helpful and very important because there are now clinical trials in Parkinson’s disease with kinase inhibitors,” she noted.
“If you think there is something else [over and above the finding of uncertain significance] in your Parkinson’s disease panel, and you are not happy with the genetic report, send it somewhere else,” Dr. Klein advised.
“We will see a lot more patients with genetic Parkinson’s disease in the future,” she predicted, while citing two recent preliminary clinical trials that have shown some promise in terms of neuroprotection in patients with early Parkinson’s disease.
“It remains to be seen whether there will be light at the end of the tunnel,” she said, but it may soon be possible to find treatments that delay, or even prevent, Parkinson’s disease onset.
Dr. Magrinelli reported receiving speaker’s honoraria from MJFF Edmond J. Safra Clinical Research Fellowship in Movement Disorders (Class of 2023), MJFF Edmond J. Safra Movement Disorders Research Career Development Award 2023 (Grant ID MJFF-023893), American Parkinson Disease Association (Research Grant 2024), and the David Blank Charitable Foundation. Dr. Klein reported being a medical advisor to Retromer Therapeutics, Takeda, and Centogene and speakers’ honoraria from Desitin and Bial.
A version of this article first appeared on Medscape.com.