Abstract
The association between Gaucher disease (GD) and Parkinson disease (PD) has been described for almost two decades. In the biallelic state (homozygous or compound heterozygous) mutations in the glucocerebrosidase gene (GBA) may cause GD, in which glucosylceramide, the sphingolipid substrate of the glucocerebrosidase enzyme (GCase), accumulates in visceral organs leading to a number of clinical phenotypes. In the biallelic or heterozygous state, GBA mutations increase the risk for PD. Mutations of the GBA allele are the most significant genetic risk factor for idiopathic PD, found in 5%–20% of idiopathic PD cases depending on ethnicity. The neurological consequences of GBA mutations are reviewed and the proposition that GBA mutations result in a disparate but connected range of clinically and pathologically related neurological features is discussed. The literature relating to the clinical, biochemical and genetic basis of GBA PD, type 1 GD and neuronopathic GD is considered highlighting commonalities and distinctions between them. The evidence for a unifying disease mechanism is considered.
Highlights
Gaucher disease (GD) is an autosomal recessive disorder caused by mutations of the glucocerebrosidase gene (GBA)
The discovery that GD1 patients have a lifetime risk of developing Parkinson disease (PD) of approximately 10%–30% compared to approximately 1%–2% in the general population indicates that central nervous system (CNS) dysfunction as a consequence of a GBA mutation can be lifelong
For instance severe GBA mutations, which by definition are associated with neuronopathic Gaucher disease (nGD) [76], increase the risk of PD by around four times compared to mild ones [26]
Summary
Gaucher disease (GD) is an autosomal recessive disorder caused by mutations of the glucocerebrosidase gene (GBA). Mutations cause a reduction or complete loss of GCase activity which (in the case of some biallelic subjects) leads to the accumulation of glucosylceramide (and its deacylated derivative glucosylsphingosine) in visceral organs, causing a variety of clinical phenotypes. The discovery that GD1 patients have a lifetime risk of developing Parkinson disease (PD) of approximately 10%–30% compared to approximately 1%–2% in the general population indicates that CNS dysfunction as a consequence of a GBA mutation can be lifelong.
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