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Low penetrance of Parkinson’s disease (PD) associated with GBApathogenic variants indicates the presence of modifiers genes. Clusters of PD cases in certain families with GBAvariants would serve as a strong evidence for the clinical relevance of such modifiers. We studied eight family trees of non-Parkinsonian, GBA-N370S homozygote, Gaucher probands, with multiple cases of PD. Differences in PD risk associated with different GBAvariants were balanced by variant homozygosity. In these families, all PD cases stemmed from only one of the proband’s parents. This observation provides a direct epidemiological evidence for genetic modifiers determining PD risk in GBAvariant carriers.

Background Compensatory mechanisms in Parkinson's disease (PD) are thought to explain the temporal delay between the beginning of the neurodegenerative process and the appearance of clinical signs. The enhanced structural integrity of the corticospinal tract was previously suggested as one of these mechanisms.Objective To understand the relations between corticospinal tract integrity and the anatomical, clinical, electrophysiological, and genetic PD characteristics.Methods We analyzed diffusion tensor imaging (DTI) fractional anisotropy (FA) data from 40 genotyped patients with PD (18 without known genetic cause, 11 with LRRK2-PD and 11 with GBA-PD) who were candidates for subthalamic deep brain stimulation (STN-DBS) and from 25 healthy, age-matched, controls.Results PD is associated with higher corticospinal FA values (p < 0.001) that are negatively correlated with the disease duration (p = 0.032), confirming previous results. Higher FA values are negatively correlated with cerebral grey matter volumes (p < 0.001) but not with the motor or cognitive PD characteristics, or with the subthalamic beta-oscillatory activity measured intra-operatively. Increased corticospinal FA values are strongly affected by the genetic etiology of PD, with higher values in the monogenic forms of the disease (p < 0.001). The compensatory index, calculated by dividing the corticostriatal FA value by the cerebral grey matter volume, is highest in GBA-PD (p < 0.001) at the time of evaluation for STN-DBS.Conclusions The genetic etiology of PD strongly shapes corticospinal tract changes along with disease-duration and cerebral grey matter atrophy. The changes may serve as compensatory mechanism.