Objective: To characterize a Parkinson’s disease (PD) family with high recurrence of the disease.

Background: Parkinson’s disease (PD) is a complex neurodegenerative disorder in which rare variants and common risk variants influence its etiology. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of late-onset familial and sporadic PD [1]. It has been proposed that LRRK2 and other genes with incomplete penetrance could act as facilitators of PD and that an additional burden is required to trigger the disease. Rare variants of the lysosome pathway such as β-Glucocerebrosidase (GBA) [2] or Phosphodiesterase 1 (SMPD1) [3] genes could be potential modifying factors of the effect of disease-causing LRRK2 variants.

Method: Clinical and neurological exams were made on the four patients and 4 relatives from a family segregating PD. The neuropathological study was performed in the index case. Genetic analysis was made using a next-generation sequencing targeted panel of 63 genes previously related to parkinsonisms and clinical exome. CNV screening was done using Multiplex Ligation-Dependent Probe Amplification.

Results: Four patients with Parkinson´s disease belonging to the same family were studied. Clinical examination showed that PD patients with earlier onset presented more motor complications. Neuropathology of the index case revealed a marked loss of substantia nigra neurons, absence of Lewy bodies, and Alzheimer’s disease-type pathology. Genetic analysis of 3 patients revealed they carry the new rare LRRK2 allele c.[c.356T> C;1463T> C] (p.[Leu.119Pro; Leu488Pro]) that is predicted to be pathogenic by affecting the armadillo domain. Besides, we found among the patients rare variants in GBA, SMPD1, and/or SPG11 genes linked to the lysosomal pathway. Patients with the more severe and early-onset disease were GBA carriers. Two unaffected relatives of the PD cases carry p.[Leu.119Pro; Leu488Pro] LRRK2 allele.

Conclusion: Our findings show a PD family carrying a new LRRK2 variant as the major gene, which is associated with a high genetic load of lysosomal genes, and neuropathology that is not typical of PD. p.[Leu.119Pro; Leu488Pro] is located in the armadillo interacting domain of LRRK2 suggesting there is a heterogeneity in the pathophysiology of LRRK2-related PD. This study can help to understand the variability of PD associated with LRRK2.

References: [1] J.H. Kluss, A. Mamais, M.R. Cookson, LRRK2 links genetic and sporadic Parkinson’s disease, Biochem Soc Trans 47(2) (2019) 651-661.
[2] E. Sidransky, M.A. Nalls, J.O. Aasly, J. Aharon-Peretz, G. Annesi, E.R. Barbosa, A. Bar-Shira, D. Berg, J. Bras, A. Brice, C.M. Chen, L.N. Clark, C. Condroyer, E.V. De Marco, A. Durr, M.J. Eblan, S. Fahn, M.J. Farrer, H.C. Fung, Z. Gan-Or, T. Gasser, R. Gershoni-Baruch, N. Giladi, A. Griffith, T. Gurevich, C. Januario, P. Kropp, A.E. Lang, G.J. Lee-Chen, S. Lesage, K. Marder, I.F. Mata, A. Mirelman, J. Mitsui, I. Mizuta, G. Nicoletti, C. Oliveira, R. Ottman, A. Orr-Urtreger, L.V. Pereira, A. Quattrone, E. Rogaeva, A. Rolfs, H. Rosenbaum, R. Rozenberg, A. Samii, T. Samaddar, C. Schulte, M. Sharma, A. Singleton, M. Spitz, E.K. Tan, N. Tayebi, T. Toda, A.R. Troiano, S. Tsuji, M. Wittstock, T.G. Wolfsberg, Y.R. Wu, C.P. Zabetian, Y. Zhao, S.G. Ziegler, Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease, N Engl J Med 361(17) (2009) 1651-61.
[3] Z. Gan-Or, L.J. Ozelius, A. Bar-Shira, R. Saunders-Pullman, A. Mirelman, R. Kornreich, M. Gana-Weisz, D. Raymond, L. Rozenkrantz, A. Deik, T. Gurevich, S.J. Gross, N. Schreiber-Agus, N. Giladi, S.B. Bressman, A. Orr-Urtreger, The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease, Neurology 80(17) (2013) 1606-10.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/association-of-a-new-pathogenic-variant-of-lrrk2-with-modifying-lysosomal-genes-in-a-family-with-parkinsons-disease/