Objective: Description of the phenotype of a Parkinson’s disease (PD) patient carrying mutations in both GBA and LRRK2 genes.

Background: Monogenic PD due to LRRK2 gene mutations (LRRK2-PD) is associated with a relatively similar phenotype when comparing to idiopathic PD. PD in patients carrying GBA gene mutations (GBA-PD) has an earlier mean age of onset, in association with cognitive impairment and more pronounced motor progression. Cases of co-occurring mutations in PD have rarely been described.

Method: Description of a clinical case of GBA-LRRK2-PD, studying the patient’s clinical course.

Results: Woman, 57 years-old, with a predominantly akinetic-rigid syndrome since 44 years of age, associated with RBD. She progressively developed motor fluctuations and choreic dyskinesias. Neuropsychological evaluation disclosed a mild cognitive impairment after 11 years of disease. At 13 years of disease, she presented with a MoCA of 20/30, slow eye movements (mainly vertical ones) with no ophthalmoparesis, smooth pursuit eye movement impairment, facial dystonia and anterocolis, asymmetric akinetic-rigid parkinsonism, postural instability, MDS-UPDRS III (on) 45, HY 2. Brain MRI documented an asymmetric reduction of substantia nigra and locus coeruleus’ neuromelanin signal, with no change of the parkinsonism index, nor any other abnormalities. She had a family history of a paternal aunt with parkinsonism and dementia, no known consanguinity. Dominant (PARK 1, SCA2) and recessive (PARK9, PARK15, NPC) parkinsonism genetic testing was negative. A heterozygous c.1226A>G p.Asn409Ser mutation in the GBA gene and a heterozygous c.6055A>G p.Gly2019Ser mutation in the LRRK2 gene were identified.

Conclusion: There are few cases described of GBA-LRRK2-PD, and their clinical phenotype is not yet totally established. There is evidence of a possible modulation of individual phenotypes associated with each mutation by the presence of a second mutation on a different gene, but the literature on this matter is thus far scarce. The case of our patient with a G2019S mutation on the LRRK2 gene and a concomitant mutation on the GBA gene illustrates the clinical worsening of the classical LRRK2 phenotype with the presence of a GBA mutation.

References: 1) Yahalom G, Greenbaum L, Israeli-Korn S, et al. Carriers of both GBA and LRRK2 mutations, compared to carriers of either, in Parkinson’s disease: Risk estimates and genotype-phenotype correlations. Parkinsonism Relat Disord 2018, doi: 10.1016/j.parkreldis.2018.12.014. 2) Malek N, Weil RS, Bresner C, et al. Features of GBA-associated Parkinson’s disease at presentation in the UK Tracking Parkinson’s study. J Neurol Neurosurg Psychiatry 2018; 89: 702–709. 3) O’Regan G, deSouza R-M, Balestrino R, Schapira AH. Glucocerebrosidase Mutations in Parkinson Disease. Journal of Parkinson’s Disease 2017; 7: 411–422. 4) Pal G, Robertson E, O’Keefe J, Hall Deborah. The Neuropsychiatric and Motor Profile of GBA-Associated Parkinson’s Disease: A Review. Mov Disord Clin Pract. 2015; 16; 3(1):4-8. 5) Jesús S, Huertas I, Bernal-Bernal I, et al. GBA Variants Influence Motor and Non-Motor Features of Parkinson’s Disease. PLoS ONE 2016; 11(12): e0167749. 6) Asselta R, Rimoldi V, Siri C, et al. Glucocerebrosidase mutations in primary parkinsonism. Parkinsonism and Related Disorders 2014; 20: 1215-1220. 7) Sidransky E, Lopez G. The link between the GBA gene and parkinsonism. Lancet Neurol. 2012; 11(11): 986–998. 8) Gan-Or Z, Bar-Shira A, Mirelman A, et al. LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson disease. Neurogenetics 2010; 11:121–125. 9) Da Silva C, Abreu GM, Acero PHC, et al. Clinical profiles associated with LRRK2 and GBA mutations in Brazilians with Parkinson’s disease. Journal of the Neurological Sciences 2017; 381: 160–164.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gba-lrrk2-parkinsons-disease-a-clinical-case/