New Parkinson's Disease Gene Discovered
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A new gene for early-onset Parkinson's disease (PD) has been identified, 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, United Kingdom, told delegates at the Congress of the European Academy of Neurology 2024.
Those "mildly" affected had an early-onset PD 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, PD 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, Magrinelli said. In the most severely affected individuals, there was perinatal lethality with neurologic manifestations.
While it may seem that the genetics of PD 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 PD expert Christine Klein, MD of the Institute of Neurogenetics and Department of Neurology, University of Lubeck, Helsinki, Finland, said at the conference.
The genetics of PD are complicated, even within a single family. So, it's very important to assess the pathogenicity of different variants, Klein noted.
