GBA-associated parkinsonism and dementia: beyond α-synucleinopathies?

Area of Science:

• Neurogenetics
• Neurodegenerative Diseases
• Clinical Neurology

Background:

• The role of Glucocerebrosidase (GBA) gene mutations in neurodegenerative conditions beyond alpha-synucleinopathies remains largely undefined.
• Investigating GBA mutations is crucial for understanding the broader spectrum of parkinsonism-dementia disorders.

Purpose of the Study:

• To screen for GBA mutations in patients diagnosed with progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), primary progressive aphasia (PPA), and behavioral variant frontotemporal dementia (bvFTD).
• To clarify the contribution of GBA mutations to these non-alpha-synucleinopathy related neurodegenerative diseases.

Main Methods:

• Genomic screening for common GBA mutations was performed.
• A cohort of 303 patients (157 PSP, 39 CBS, 35 PPA, 72 bvFTD) and 587 healthy controls were analyzed.

Main Results:

• GBA mutations were identified in four patients: one with PSP, two with CBS, and one with PPA (also carrying a C9orf72 expansion).
• The overall prevalence of GBA mutations was low in these non-alpha-synucleinopathy conditions.
• A significantly higher prevalence of GBA mutations was observed in the corticobasal syndrome subgroup compared to controls.

Conclusions:

• The clinical spectrum associated with GBA mutations is broader than previously thought, encompassing phenotypes not typically linked to alpha-synucleinopathies.
• These findings highlight the potential relevance of GBA mutations for developing targeted therapeutic strategies for a wider range of neurodegenerative diseases.