Classification of GBA1 Variants: MDSGene Systematic Review

The major highlights for why there was a need for this review are as follows: 

1. Broad variant spectrum in GBA1: Different variants in the GBA1 gene can cause PD, act as genetic risk factors, or lead to GD. This necessitates a comprehensive review to understand these variant-specific implications across diverse populations.

2. Lack of Comprehensive Data: Despite existing studies, there were gaps in genotype-phenotype correlations for GBA1 variant carriers, particularly regarding PD. This review aimed to fill these gaps by summarizing findings from numerous patients. 

3. Ethnic and Demographic Differences: The review highlights the need for an understanding of how GBA1 variants manifest in different ethnic groups, given that the frequency and impact of these variants vary by ethnicity, which had not been sufficiently explored. 

4. Clinical Implications: There is a need to understand how specific variants influence disease progression, symptoms, and treatment responses, particularly dopaminergic therapy and deep brain stimulation in PD patients. This includes distinguishing between "severe" and "mild" variants based on the clinical severity of GD and their role in PD, which present different clinical features, such as motor complications and cognitive decline.  

5. Genetic testing, counseling, and trial design implications: Since the penetrance of GBA1 variants in PD is incomplete, as well as the ability to predict which GBA1 variant carriers will develop PD, a more comprehensive knowledge of the genotype-phenotype relations in GBA1-related disease is key for prognostic and trial design purposes 

The salient findings of the study include: 

1. The most frequent pathogenic or likely pathogenic variants were ‘N409S’ (aka ‘N370S;’ dominating among Jewish and whites), and ‘L483P’ (aka ‘L444P;’ dominating among Asians and Hispanics), whereas the most common coding risk variants were ‘E365K’ (E326K), and ‘T408M’ (T369M) (both common among whites).  

2. Half of the PD sample with available data was categorized as early-onset PD (EOPD), with onset before age 50, aligning with the well-established association of GBA1 variants with earlier disease onset in PD patients compared to those with idiopathic PD. The most common GBA1 variant in EOPD patients was ‘L483P,’ and most EOPD patients were predominantly of Asian ethnicity compared to LOPD patients, who were mainly of white ethnicity, revealing an intriguing new demographic distinction between the two groups. The effect of the variant type in the age of disease onset is reflected by the fact that PD patients with pathogenic or likely pathogenic variants, as well as those with ‘severe’ variants, had a disease onset approximately half a decade earlier than PD patients with ‘mild,’ or risk variants. 

3. There were no sex differences in the distribution of GBA1 variants based on clinical severity or between EOPD and LOPD, which suggests that the penetrance of PD-causing GBA1 variants is independent of sex. 

4. Motor cardinal features were similar between PD patients and other forms of parkinsonism, whereas motor complications and non-motor symptoms were more frequently reported in PD patients carrying ‘severe’ variants than in those with ‘risk’ or ‘mild’ variants.  

5. Cognitive decline was reported in most patients following surgical treatment, despite achieving beneficial motor function response.  

6. Most GD patients developing PD (GD-PD) harbored the ‘N409S’ variant, were of Ashkenazi Jewish ethnicity, and showed a positive response to chronic levodopa treatment. 

7. GBA1-LRRK2 co-occurrence was extremely rare (0.5% of the PD sample), and if present, most patients carried the ‘N409S’ GBA1 variant together with the ‘G2019S’ LRRK2 variant. This rarity may also be attributed to the limited investigation of LRRK2 variants, as most studies only tested for GBA1 variants. Larger population studies are warranted to study the GBA1-LRRK2 genotype-phenotype interaction. 

8. Dementia with Lewy bodies (DLB) was the most frequent atypical parkinsonian disorder among GBA1 variant carriers. The most common variant in DLB patients was the ‘E365K’ risk variant present in nearly half of the patients, followed by the ‘N409S,’ ‘T408M,’ and ‘L483P’ variants. In contrast to PD, GD, or GD-PD, in which the most common ethnicity was Jewish Ashkenazi, DLB patients were mostly white. The clinical course of DLB patients harboring GBA1 variants is typically aggressive, with severe motor and cognitive impairment and associated with visual hallucinations.