Objective: To characterize an early-onset Parkinson’s disease (EOPD) patient with atypical clinical phenotype.

Background: Genome sequencing is allowing new Parkinsonian Syndromes (PS)-associated genes identification. However, genetic diagnosis yield in PD and PS are still very low and it is urgent the detection and characterization of new genes. PS genetics architecture includes Mendelian genes and risk factors with incomplete penetrance that could act as facilitators of PD expression as rare variants of the lysosome pathway. Here we show the multidisciplinary study of the patient.

Method: Precision phenotyping including video recordings, and rating scales for the diagnosis of PD were used (UK Brain Bank Criteria). In addition, biochemical and neuroimaging analyses were performed.
The patient and its parents were analyzed by trio-WES. A custom bioinformatic pipeline was used for variants filtering and prioritization.

Results: The patient is a 43-year-old man with early-onset, levodopa-responsive progressive parkinsonism with motor fluctuations and off-dystonic states. MRI showed multiple demyelinating lesions, and dopamine transporter (DAT) single-photon emission computed tomography demonstrated the loss of striatal DAT.
Trio-WES revealed the patient carries the variant c.937G>T/p.Asp313Tyr inherited from his mother in the X-linked GLA gene (α-galactosidase A, GALA) typically associated with Fabry disease (FD). p.Asp313Tyr has been found in classical PD in females, however its pathogenicity is controversial [1-3]. In addition, we found the patient is heterozygous for the pathogenic variant c.1448T>C/p.Leu483Pro in the GBA gene (glucocerebrosidase), a risk factor for PD [4]. Biochemical analyses showed normal GALA activity together with GBA activity increment in leukocytes.

Conclusion: These results highlight the genetic diversity linked to EOPD and the need to discover new genotype/phenotype correlations underlying this extremely heterogeneous group of disorders. The patient has an MRI with multiple demyelinating lesions but a clinical phenotype of PD, which may constitute a new phenotype. The additive effect of GLA and GBA variants of the lysosomal pathway may be responsible for the EOPD and atypical features of the patient, with non-penetrance in the mother. Currently, we are performing biochemical and cellular approaches to know the impact of found variants in the patient’s fibroblasts.

References: [1] Yasuda, M., Shabbeer, J., Benson, S. D., Maire, I., Burnett, R. M., & Desnick, R. J. (2003). Fabry disease: characterization of alpha-galactosidase A double mutations and the D313Y plasma enzyme pseudodeficiency allele. Human mutation, 22(6), 486–492. https://doi.org/10.1002/humu.10275
[2] Lenders, M., Duning, T., Schelleckes, M., Schmitz, B., Stander, S., Rolfs, A., Brand, S. M., & Brand, E. (2013). Multifocal white matter lesions associated with the D313Y mutation of the α-galactosidase A gene. PloS one, 8(2), e55565. https://doi.org/10.1371/journal.pone.0055565
[3] Lackova, A., Beetz, C., Oppermann, S., Bauer, P., Pavelekova, P., Lorincova, T., Ostrozovicova, M., Kulcsarova, K., Cobejova, J., Cobej, M., Levicka, P., Liesenerova, S., Sendekova, D., Sukovska, V., Gdovinova, Z., Han, V., Rizig, M., Houlden, H., & Skorvanek, M. (2022). Prevalence of Fabry Disease among Patients with Parkinson’s Disease. Parkinson’s disease, 2022, 1014950. https://doi.org/10.1155/2022/1014950
[4] Anheim, M., Elbaz, A., Lesage, S., Durr, A., Condroyer, C., Viallet, F., Pollak, P., Bonaïti, B., Bonaïti-Pellié, C., Brice, A., & French Parkinson Disease Genetic Group (2012). Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers. Neurology, 78(6), 417–420. https://doi.org/10.1212/WNL.0b013e318245f476

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gla-associated-early-onset-parkinsons-disease-the-mimicry-between-fabry-disease-and-parkinsonisms/