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Glucocerebrosidase (GBA1) variants constitute numerically the most common known genetic risk factor for Parkinson's disease (PD) and are distributed worldwide. Access to GBA1 genotyping varies across the world and even regionally within countries. Guidelines for GBA1 variant counseling are evolving. We review the current knowledge of the link between GBA1 and PD, and discuss the practicalities of GBA1 testing. Lastly, we provide a consensus for an approach to counseling people with GBA1 variants, notably the communication of PD risk. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

RESUMEN

The discovery of glucocerebrosidase (GBA1) mutations as the greatest numerical genetic risk factor for the development of Parkinson disease (PD) resulted in a paradigm shift within the research landscape. Efforts to elucidate the mechanisms behind GBA1-associated PD have highlighted shared pathways in idiopathic PD including the loss and gain-of-function hypotheses, endoplasmic reticulum stress, lipid metabolism, neuroinflammation, mitochondrial dysfunction and altered autophagy-lysosomal pathway responsible for degradation of aggregated and misfolded a-synuclein. GBA1-associated PD exhibits subtle differences in phenotype and disease progression compared to idiopathic counterparts notably an earlier age of onset, faster motor decline and greater frequency of non-motor symptoms (which also constitute a significant aspect of the prodromal phase of the disease). GBA1-targeted therapies have been developed and are being investigated in clinical trials. The most notable are Ambroxol, a small molecule chaperone, and Venglustat, a blood-brain-barrier-penetrant substrate reduction therapy agent. It is imperative that further studies clarify the aetiology of GBA1-associated PD, enabling the development of a greater abundance of targeted therapies in this new era of precision medicine.

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RESUMEN

Biallelic (homozygous or compound heterozygous) glucocerebrosidase gene (GBA) mutations cause Gaucher disease, whereas heterozygous mutations are numerically the most important genetic risk factor for Parkinson disease (PD) and are associated with the development of other synucleinopathies, notably Dementia with Lewy Bodies. This phenomenon is not limited to GBA, with converging evidence highlighting further examples of autosomal recessive disease genes increasing neurodegeneration risk in heterozygous mutation carriers. Nevertheless, despite extensive research, the cellular mechanisms by which mutations in GBA, encoding lysosomal enzyme ß-glucocerebrosidase (GCase), predispose to neurodegeneration remain incompletely understood. Alpha-synuclein (A-SYN) accumulation, autophagic lysosomal dysfunction, mitochondrial abnormalities, ER stress and neuroinflammation have been proposed as candidate pathogenic pathways in GBA-linked PD. The observation of GCase and A-SYN interactions in PD initiated the development and evaluation of GCase-targeted therapeutics in PD clinical trials.

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Genetics has driven significant discoveries in the field of neurodegenerative diseases (NDDs). An emerging theme in neurodegeneration warrants an urgent and comprehensive update: that carrier status of early-onset autosomal recessive (AR) disease, typically considered benign, is associated with an increased risk of a spectrum of late-onset NDDs. Glucosylceramidase beta (GBA1) gene mutations, responsible for the AR lysosomal storage disorder Gaucher disease, are a prominent example of this principle, having been identified as an important genetic risk factor for Parkinson disease. Genetic analyses have revealed further examples, notably GRN, TREM2, EIF2AK3, and several other LSD and mitochondria function genes. In this Review, we discuss the evidence supporting the strikingly distinct allele-dependent clinical phenotypes observed in carriers of such gene mutations and its impact on the wider field of neurodegeneration.

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