Non-motor symptoms, such as cognitive impairments and depression, may be used as early predictors of parkinsonism in Gaucher disease patients on enzyme replacement therapy (ERT), according to a recent study.
The study, “Cognitive decline and depressive symptoms: early non-motor presentations of parkinsonism among Egyptian Gaucher patients,” was published in the journal Neurogenetics.
Gaucher disease is caused by a mutation in the GBA gene, which leads to abnormal production of beta-glucocerebrosidase, an enzyme necessary to break down a fatty substance called glucocerebroside.
Individuals carrying mutations in both copies of the GBA gene (one from each parent) develop Gaucher, while those carrying a mutation in a single copy of the gene, called carriers, typically do not. Yet, carriers have a higher risk of developing parkinsonism, a general term that comprises several disorders whose motor symptoms (e.g. tremor, slow movements, and muscle stiffness) resemble those of Parkinson’s disease.
Parkinsonism seems to manifest earlier in individuals carrying GBA mutations, and has been identified in patients with type 1 and type 3 Gaucher. However, not all GBA mutation carriers end up developing parkinsonism.
“Thus, there is an association between the GBA mutation and parkinsonism, but the exact pathophysiological [disease] mechanism behind GBA-associated parkinsonism remains unraveled,” investigators wrote.
Therefore, a team at the Ain Shams University conducted a study to examine the presence of typical manifestations of parkinsonism in Egyptian patients with Gaucher.
They also used statistical analyses to explore possible associations between parkinsonian features and several patient characteristics, including genetic background, disease severity (assessed by the severity scoring index, or SSI), symptoms of Gaucher, cognitive function, and signs of depression.
The study included data from 24 patients with Gaucher, ages 12–29, who were being followed at the Pediatric Hematology Clinic at the university, from October 2018 to September 2019.
All patients were being treated with ERT — most with Cerezyme (imiglucerase) since their diagnosis — at a dose of 60 units/kg every two weeks, and none had a family history of parkinsonism.
Results showed that 16 participants (66.6%) had parkinsonian features. Their mean age was 15.7, and all were on ERT. Among these, 13 (81.2%) were carriers of the L483P mutation (the most common mutation associated with type 3 Gaucher), and 12 (75%) had a set of symptoms that matched type 3 Gaucher.
The most common motor symptoms of parkinsonism in these patients included bradykinesia (slow movements) (75%), rigidity (16.6%), and resting tremors (12.5%).
Analyses showed that patients who had parkinsonian features tended to have higher SSI scores indicative of a more severe disease, as well as lower cognitive function. They also showed signs of depression.
Additional analyses revealed that cognitive function, Gaucher type, and the genetic background were all predictors of developing parkinsonism in patients with Gaucher.
“We speculate that the shorter lifespan and the more severe neurological and somatic [body] manifestations in those with type 3 GD [Gaucher disease] before the era of ERT hindered the appearance of the full-blown picture of parkinsonism in these patients,” the researchers wrote.
Non-motor symptoms of parkinsonism such as depression and cognitive impairment “can be used as early predictors for the development of parkinsonism in GD,” they added. “More research is needed to explore the mechanistic link between GBA mutations and parkinsonism and to address the unresolved long-term complications of GD patients on ERT.”
