LRRK2 variant tied to slower worsening of tremors, study finds
G2385R variant also differed from idiopathic disease in daytime sleepiness
Parkinson’s disease patients carrying the G2385R mutation in the LRRK2 gene, a known risk factor for the disease, show a slower worsening of tremors and less daytime sleepiness than those idiopathic Parkinson’s, whose disease has no identified cause, a study from China reports.
The study also found that two other LRRK2 mutations, likewise known to increase Parkinson’s risk, had no substantial influence on disease symptoms relative to idiopathic Parkinson’s patients. People with these LRRK2 gene mutations also had rates of survival similar to idiopathic disease patients.
“Our extended longitudinal follow-up of LRRK2-PD [LRRK2-associated Parkinson’s] in the Chinese population provided valuable insights, further confirming the clinical characteristics of the three LRRK2 variants,” the researchers wrote.
The study, “Clinical features and progression of Parkinson’s disease with LRRK2 variants: A prospective study,” was published in the Annals of Clinical and Translational Neurology. It was led by the Parkinson’s Disease & Movement Disorders Multicenter Database and Collaborative Network in China.
LRRK2 mutations are a common genetic risk factor for Parkinson’s
Parkinson’s is best known for such disease motor symptoms as tremors and rigidity, yet patients also experience nonmotor symptoms such as sleep and memory problems. Parkinson’s causes are complex, and include a combination of genetic and environmental factors.
Mutations in the LRRK2 gene are one of the most common genetic risk factors for both familial and sporadic disease forms. The G2385R, R1628P, and A419V variants are common in China, where they have been linked to a higher risk of developing Parkinson’s.
Previous studies suggest that certain LRRK2 mutations may be associated with differences in age at Parkinson’s onset, symptoms, and rates of disease progression relative to idiopathic Parkinson’s. However, some data inconsistencies are seen among the studies.
Furthermore, “comprehensive clinical investigations of LRRK2-PD with the A419V and R1628P variants, especially A419V, remain scarce,” the researchers wrote.
To better understand how Parkinson’s manifests in the presence of the G2385R, R1628P, and A419V mutations, the researchers drew on data from the Chinese Parkinson’s Disease With LRRK2 Variants Registry (NCT03523104).
Among the 2,056 patients whose data were analyzed, recruited to the registry between February 2017 and December 2020, were 649 people carrying mutations in the LRRK2 gene, and 1,407 with idiopathic Parkinson’s.
A total of 304 patients carried the G2385R mutation, 220 had the R1628P mutation, 105 carried the A419V mutation, and 20 patients carried at least two LRRK2 mutations. All were followed for an average of 5.6 years.
Tremor worsened at slower rate with LRRK2 than idiopathic Parkinson’s
Results showed that age at disease onset and disease duration were similar between the two groups, but the proportion of men was lower with LRRK2-Parkinson’s that idiopathic disease (46.2% vs. 52.6%).
At registry’s entry, LRRK2-Parkinson’s patients had significantly less severe tremors than idiopathic patients, based on tremor scores of the Unified Parkinson’s Disease Rating Scale (UPDRS) part 3, in which higher scores indicate more severe symptoms (mean of 3.27 vs. 3.71 points).
Those carrying the G2385R variant showed a lower level of tremor severity, with a mean score of 3.18 points.
No significant group differences were seen in terms of other motor symptoms or disease severity scales.
“Follow-up data indicated that significant differences in tremor scores … persisted between LRRK2-PD and [idiopathic Parkinson’s] patients,” the researchers wrote, adding that tremor worsening was significantly slower in LRRK2-Parkinson’s patients, particularly in those with the G2385R mutation.
No significant differences in tremor progression were seen between patients carrying the R1628P or A419V mutations and those with idiopathic disease.
Excessive daytime sleepiness also less common with LRRK2 variant
At entry to the registry, excessive daytime sleepiness was significantly less common in patients with LRRK2 mutations than in idiopathic Parkinson’s patients (29.7% vs. 36.6%), particularly for those with R1628P (28.2%) or G2385R (28.6%) mutations.
Other nonmotor symptoms did not differ significantly between the groups.
Follow-up data again confirmed that differences in excessive daytime sleepiness persisted, with LRRK2-Parkinson’s patients experiencing such sleepiness a median of four years later than those with idiopathic Parkinson’s (at a median disease duration of 18 vs. 14 years). Carriers of the G2385R mutation were significantly less likely, by 38%, to experience this sleep problem over time.
Mortality rates generally were similar between the LRRK2-Parkinson’s and idiopathic Parkinson’s groups (13.1% vs. 14.2%). Statistical analyses that adjusted for potential influencing factors showed no significant group differences in survival.
Findings suggest that Parkinson’s patients carrying the G2385R mutation are more likely to experience a slower worsening of tremors and less likely to have daytime sleepiness. In turn, patients with the R1628P or A419V mutation manifest symptoms that more closely resemble those with the idiopathic form of the disease.
“To our knowledge, this is the first study to report the clinical profiles of patients with the LRRK2-A419V mutation,” the researchers wrote.
“These findings underscore the necessity for longitudinal studies of longer duration to further elucidate these observations,” the team concluded.
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