GBA mutation severity

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Ziv Gan-Or, Avi Orr-Urtreger, Nir Giladi (Tel Aviv Sourasky Medical Center and Tel Aviv University), Susan Bressman (Beth Israel, New York) and colleagues in 2015; Roberto Cilia and colleagues at the Parkinson Institute, Milan, in 2016. Funders were not recorded here.

What happened

GBA mutations are labelled "mild" or "severe" by the form of Gaucher disease (the inherited enzyme-deficiency disorder) they cause when inherited from both parents. Gan-Or et al. (Neurology 2015) genotyped 1,000 Ashkenazi Jewish Parkinson's patients: odds ratios were 2.2 for mild and 10.3 for severe mutations. A meta-analysis of 11,453 patients and 14,565 controls gave odds ratios of 2.84 to 4.94 (mild) and 9.92 to 21.29 (severe); average onset was 53.1 years with severe and 58.1 with mild mutations. Cilia et al. (Annals of Neurology 2016) followed 2,764 Parkinson's patients, 123 of them GBA carriers (67 mild, 56 severe): carriers had higher dementia risk (hazard ratio 3.16) and death risk (1.85). Severe carriers had more dementia than mild ones (with similar mortality), and their scans were closer to dementia with Lewy bodies than to typical Parkinson's. A later Israeli cohort (Thaler et al., 2018) of 355 patients (152 non-carriers, 139 mild, 48 severe, 16 with Gaucher disease and Parkinson's) agreed: severe-mutation carriers had more non-motor symptoms, depression and loss of smell, and they and the Gaucher group had higher motor scores and more hallucinations and REM sleep behaviour disorder.

Why it moved us toward a cure

It turned the GBA finding (landmark 16) into a graded, dose-like story: the more the enzyme is impaired, the worse the disease, which supports the GCase-synuclein loop (landmark 35) as a real driver rather than a bystander. It also showed trial designers that carrier groups must be split by mutation.

Outcome

Advanced for the genetics. The GBA-targeted drugs tested so far have not slowed disease (landmark 69); ambroxol is in Phase 3 (landmark 321; background in landmark 40). Whether severity-specific treatment helps is unknown.

Sources

• Gan-Or et al., Neurology 2015;84:880–887, DOI 10.1212/WNL.0000000000001315
• Cilia et al., Ann Neurol 2016;80:662–673, DOI 10.1002/ana.24777
• Thaler et al., Parkinsonism Relat Disord 2018;55:45–49, DOI 10.1016/j.parkreldis.2018.05.009
• No correction or retraction found for the three papers (Crossref and Europe PMC, 20 Oct 2026); Gan-Or and Cilia each have only a linked comment.
• Not yet verified: whether mild-versus-severe classes hold in all ancestries; the funders.