Neurological effects of glucocerebrosidase gene mutations

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 ( GC ase), 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.