The frequency of GBA
mutations found in the British Parkinson's disease population is clearly a striking result as it represents the highest frequency of mutations of a single gene related to the development of the idiopathic disease in this population. Although former studies on the same series of British patients showed that other genes such as PTEN induced putative kinase 1 (PINK1
), leucine-rich repeat kinase 2 (LRRK2
) and DJ-1
may also play a role in the sporadic form of the disease (Abou-Sleiman et al
, 2006; Gilks et al
) mutations in GBA
have the highest prevalence with ~3.7% of all sporadic Parkinson's disease cases being affected (). Several studies have evaluated the frequency of GBA
mutations among Parkinson's disease patients and show similar results (Supplementary Table S4
). However, the majority of previous studies specifically screened the GBA
gene for previously reported common mutations and did not attempt sequencing analysis of the complete gene. Whilst we were unable to obtain a complete gene sequencing read for all 790 of our patients, our compiled data from all clear exon and intronic sequence reads represents the largest sequencing study of GBA
mutations in Parkinson's disease patients to date. However, one needs to take into consideration the fact that our data is based on a subset of patients who were referred to a specialized university clinic or who have donated their brains to our brain bank for research. We acknowledge the limitations of the retrospective nature of our data and the selection bias that is expected in this series. Nevertheless, the pathological evaluation of the GBA
mutant cases revealed that the observed morphological features were typical for sporadic Parkinson's disease, suggesting that a proportion of classical sporadic Parkinson's disease might indeed be caused by mutations in the GBA
Figure 1 Comparison of single gene mutations in a series of British sporadic Parkinson's disease. Prevalence of single gene mutations in a British series of sporadic Parkinson's disease. The data refers to former studies on the same series of sporadic Parkinson's (more ...)
The mutant GBA
gene frequency in the general population in the UK has been estimated at ~0.0016 in contrast to 0.034 in the Ashkenazi-Jewish population (Benson and Fensom, 1985
; Zimran et al
). Studies on control subjects from other non-Ashkenazi-Jewish populations have found very different frequencies ranging from 0.004 in a North American cohort (with a European ethnic background) to 0.017 in a Norwegian control sample (Toft et al
; Mata et al
). Thus, the observed frequency of 0.012 in our British control group is representative for a European population, and provides the best estimate for the British population to date. Regarding the clinical data on the Parkinson's disease patient group with GBA
mutations, it can be summarized that, in general, our findings confirm previously published results, stating that GBA
mutation carriers frequently have an earlier age of disease onset (AoO ≤ 50 years), show a good response to l
-Dopa treatment, and have an increased likelihood to present with symptoms of cognitive decline and dementia. In addition to that, we looked at the occurrence of other non-motor features such as visual hallucinations, which have been associated with Parkinson's disease.
Symptoms of cognitive decline are a common feature in parkinsonism. In a systematic review of prevalence studies which looked at dementia in the disease, a proportion of ~ 24–31% has been suggested (Aarsland et al
). In our Parkinson's disease patient group of GBA
mutation carriers, 48% had been given the diagnosis Parkinson's disease with dementia or showed clear symptoms of cognitive decline. Moreover, 40% of the patients with cognitive symptoms had an age of onset ≤ 50 years. Therefore, we hypothesize that mutations in GBA
might increase the risk of developing dementia or cognitive impairment in individuals with an early disease onset. This finding might be of importance given that patients rarely show symptoms of cognitive decline at an age younger than 55 years. Hence, in future research it will be interesting to determine whether GBA
mutations have an impact on the development of dementia in younger patients with an early disease onset.
The male-to-female ratio in our series was 3.5 : 1 which is comparable to the published range of 3:2 (Wooten et al
). In studies on Parkinson's disease patients which carry a GBA
mutation, the male-to-female ratio has been reported to be higher, ranging between 2 : 1 to 5 : 2 (Toft et al
; Gan-Or et al
; Mata et al
). In the present study, male GBA
mutation carriers were by far more frequently affected than women (26 male : 5 female; Pearson's chi-squared test: 5.12; P
= 0.024). Thus, the ratio observed in GBA
mutation carriers suggests that male individuals who have a mutated GBA
gene are more susceptible to develop Parkinson's disease than female mutation carriers.
Overall, the initial response to l
-Dopa treatment was good to very good. This finding is in accordance with results from previous research which described an excellent response to l
-Dopa therapy in Parkinson's disease probands heterozygous for GBA
mutations (Ziegler et al
; Mata et al
). However, one of the characteristics of Gaucher patients with parkinsonism is that their symptoms are mostly refractory to standard Parkinson therapy. Thus, it is possible that identical mutations in GBA
result in different phenotypic traits of Parkinson's disease (e.g
. good to no response to l
-Dopa treatment) and that other genetic modifiers play a role in the susceptibility to the disease.
In our subset of Parkinson's disease patients with GBA
mutations, non-treatment associated visual hallucinations were present in almost half of the cases. Visual hallucinations are a common feature in Parkinson's disease and have been estimated to occur in up to 50% of patients (Williams and Lees, 2005
). As in idiopathic Parkinson's disease, the occurrence of visual hallucinations in patients with GBA
mutations is likely to be the consequence of the extension of the Lewy body pathology in the temporal lobe (Harding et al
These data implicating GBA mutants in Parkinson's disease pathogenesis strongly motivates an evaluation of potential pathways. There are two broad possibilities. First haploinsufficiency of GBA leads directly to an accumulation of glucosylceramide and a concomitant impairment of ceramide metabolism and thereby increases the risk of developing the disease. The second possibility is that a novel property of the mutant enzyme is contributing to the risk of developing parkinsonism.
If one considers the neuronopathic form of Gaucher's disease it seems unlikely that the association between mutant GBA alleles and parkinsonism relates solely to the catalytic activity of the mutant enzyme although it is possible that there will be a subtle dysregulation in ceramide metabolism. In heterozygote mutant carriers, the unaffected allele would likely provide adequate GBA activity to degrade most of the glucosylceramide entering the lysosome.
If there is a novel toxic function playing a role it is of note that most of the mutations described here are missense alleles which would be predicted to produce a protein product. A precise toxic function is unclear but for a number of these alleles, it has been demonstrated that the mutant enzyme produced is unstable and, instead of being targeted to the lysosome, is diverted by the quality control mechanisms of the cell to proteosomal degradation (Schmitz et al
). Lewy bodies are seen in the brains of Gaucher patients who develop Parkinson's disease and a particularly severe involvement of neuronal populations of the CA2-CA4 hippocampal subregions has been documented. Immunohistochemical studies have demonstrated that constitutive levels of GBA expression are high in these hippocampal subregions (Wong et al
). Therefore it seems likely that the expression of high levels of the unstable mutant enzyme may play a role in the formation of Lewy bodies in Gaucher patients with parkinsonism.
In the cases presented in this study, neuropathological analysis (including Braak staging and grading using consensus criteria) demonstrated extensive Lewy body pathology in a pattern identical to that seen in sporadic Parkinson's disease controls matched for age at disease onset, disease duration and gender. Furthermore a larger proportion of the cases with GBA
mutations tended to have neocortical Lewy body pathology than the sporadic cases, although investigation of larger cohorts is required to confirm this. The autophagy-lysosome pathway, including chaperone-mediated autophagy and macroautophagy is an important mechanism for the degradation of cellular α-synuclein (Vogiatzi et al
). The findings of this study supports the hypothesis that mutant glucocerebrosidase may interfere with cellular pathways related to lysosomal degradation of cellular α-synuclein and that these mechanisms might also be fundamental in Lewy body formation in the sporadic form of the disease. Further research will be essential to establish whether neuronal cell death might be a consequence of a misfolded GBA enzyme or how alteration of the glucosylceramide/ceramide metabolism could contribute to the development of Parkinson's disease.
The results from this study and those from other reports in Parkinson's disease patients clearly establish that GBA mutations account for a significant minority of cases. The clinical and pathological data reported here emphasise that these cases are indistinguishable from what is normally considered as idiopathic Parkinson's disease. This has important implications for genetic counselling of such patients and indeed relatives of patients with Gaucher's disease. The classical scenario of autosomal recessive disease is that carriers are both unaffected and the recurrence risk to their offspring is incredibly low in the absence of a consanguineous relationship. These data and findings emerging from studies of proven autosomal recessive Parkinson's disease genes (e.g. parkin, DJ-1 and PINK1) in which there is some, but controversial, evidence to support a role of heterozygous mutations have changed the terrain and suggest that carrying a single heterozygous mutation is associated with increased risk. To provide accurate information to patients and their families one really requires a reliable and accurate estimate of prevalence to be made. This will be difficult but will probably require international collaboration to achieve sufficient numbers of cases. Even then given the allelic variability which may in part influence penetrance means that accurate predictive risk counseling will be fraught. However it is obligatory for the clinicians who are making these genetic diagnoses that a discussion of these difficulties is conducted with the patients and their families. Our data reinforce the proposed association between GBA mutations and Parkinson's disease. While this link has been investigated in a number of genetic association studies in the last few years, the functional aspects of how GBA mutations might impact on neuronal cell death in Parkinson's disease remains to be elucidated.