Parkinsonism Associated with Glucocerebrosidase Mutation

Gaucher's disease (GD) is an autosomal recessive, lysosomal storage disease that causes abnormal accumulation of a glucocerebroside in multiple organs, as a result of mutations in the β-glucocerebrosidase gene (GBA), which is located at chromosome 1q21.1 Clinically, GD has a wide spectrum of clinical manifestations, and the spectrum of the disease tends to be correlated with residual enzyme activity. The most severe form of infantile-onset GD presents with widespread accumulation of glucosylceramide in a various cell types, leading rapidly to fatal neurodegenerative disease, whereas in the late-onset form, residual GBA enzyme activity results in highly variable clinical manifestations including hepatosplenomegaly, anemia, thrombocytopenia, and skeletal symptoms.1-3

There is increasing evidence that GBA mutations represent a genetic risk factor for the development of Parkinson's disease (PD); at autopsy, GD produces α-synuclein-immunoreactive Lewy bodies, and parkinsonism appears to be more prevalent in relatives of GD patients.3, 4 Furthermore, subsequent GBA genotyping studies on various PD cohorts have revealed that the frequency of GBA mutations is elevated in PD patients. Here we present Korean familial cases of PD with heterozygous mu-tations of GBA, which further supporting the association between these two disorders.

The neurological symptoms encountered in adult-type GD include seizures, psychosis, and dementia. However, many case reports have suggested indirect evidence of an association between GD and PD.2, 3 McKeran et al.5 reported a 55-year-old patient with GD who later developed parkinsonism. Neudorfer et al.6 described six patients in whom GD was accompanied by parkinsonism, and Machaczka et al.7 reported another patient with parkinsonism that preceded the clinical manifestations of GD by 12-years. Regarding the phenotypical analysis based on large case series, parkinsonism in GD shows classical symptoms of PD with a tendency toward the akinetic form, an early-onset form, and a relatively good response to levodopa.4, 8 Furthermore, dementia and visual hallucinations are frequently observed in parkinsonism with GD, which may be associated with pathological findings, with Lewy bodies being observed more frequently in parkinsonism with GD compared to PD on its own.8

Our patients had also exhibited classic parkinsonism with a young age at onset and an akinetic form, and had an excellent response to levodopa. Even though one patient (a younger sister) revealed laboratory abnormalities and pathological infiltrations of Gaucher cells, which may be attribute to the effects of the S271G/R359X double mutation, these two sisters had no overt clinically systemic manifestations of GD except for parkinsonism, as in the case series of heterozygote mutation reported previously.8 In addition, the enormous clinical variation between genotype and phenotype presentations in GD may explain the sole clinical manifestation of parkinsonism in our cases.9, 10

The association between parkinsonism and the S271G mutation in GBA has also been reported in both Greek and a Chinese cohort.11, 12 In addition, the R359X mutation in GBA found in this study was identified by Beutler and Gelbart in non-Jewish patients with GD type 2,13 and its prevalence is reported very low in among Spanish patients with GD.14 However, the R359X mutation in those reports did not accompany a parkinsonian phenotype. Although it is difficult to determine which mutation may have impacted the development of a parkinsonian phenotype in our patients, since the R359X mutation was found in both patients, the R359X mutation may act as a pathogen in the PD phenotype. To our knowledge, this is the first report demonstrating the association between parkinsonism and the R359X mutation in GBA. The different phenotype of the same R359X mutation in GBA may be ascribed to racial differences as well as environmental factors influencing expression of the risk gene. Nevertheless, the pathogenic or functional effects of the novel R359X mutation found in our PD patients needs to be further clarified. Nevertheless, the pathogenic or functional effects of the novel R359X mutation found in our PD patients needs to be further clarified.

The prevalence of GBA mutations being considered as susceptibility genes in PD differs with ethnicitys; the carrier frequency of GBA mutations is reportedly 10-31% in the Ashkenazi Jewish population and 2.9-12% among the non-Ashkenazi-Jewish.15 A recent study in a Japanese population found that GBA mutations were strikingly associated with PD, exhibiting a markedly high relative risk of 28.0 compared to controls.16 Currently, data regarding the association between GBA mutations and PD are not available for the Korean population, and future studies of Korean PD patients should compare the prevalence of GBA mutations among Asian PD populations.