Objective: Here, we present a clinical case that mimicked the coincidence of idiopathic Parkinson’s disease (PD) and tauopathy.

Background: Mutation in leucine-rich-repeat-kinase 2 (LRRK2) gene is the most frequent cause of familial PD, and heterozygous variants of the glucocerebrosidase (GBA) gene are the most important genetic risk factor for PD. LRRK2 PD and dual LRRK2/GBA PD were described to be more benign than those of GBA PD and idiopathic PD [1] .

Method: Case History: A 54-year-old woman with Meige syndrome presented with a resting tremor typical for PD, which responded excellently to levodopa. Family history was negative. Seven years after the first symptoms, hypokinetic fluctuations, orofacial dyskinesia, and gait impairment were documented. Ten years after disease onset, symptoms worsened (Hoehn & Yahr Stage V) with severe on-off fluctuations and drug-induced hallucinosis without autonomic dysfunction supporting the diagnosis of PD. Ten years after the onset of parkinsonism, the patient developed a rapidly progressive aphasia phenotype. Neuropsychological and speech assessments revealed executive dysfunction and visuo-constructive deficits and a non-fluent, agrammatic aphasia, suitable for primary progressive aphasia (PPA). FDG-PET showed hypometabolism in the left > right frontal and temporal lobe, findings also compatible with PPA. Finally, the results were interpreted as a clinical tauopathy. The patient was genetically screened for LRRK2 and GBA variants. Postmortem histopathological examination was performed to detect alpha-synuclein- and/or tau pathology.

Results: The Genetic analysis discovered a Gaucher’s disease-associated heterozygous GBA variant (Asn409Ser) and a mutation in the LRRK2 gene (Gly2019Ser). After twelve years of disease duration, the patient deceased due to a pulmonary infection. Postmortem histopathology showed severe loss of dopaminergic neurons in the substantia nigra, and neither alpha-synuclein- nor tau aggregation.

Conclusion: The absence of alpha-synuclein aggregation in LRRK2 PD is compatible with other histopathological studies [2], but argues against a genuine pathogenic role of the GBA variant in this case. A gene-gene interaction, however, cannot be excluded. In contrast to other series in LRRK2 PD [1], this patient showed an aggressive disease course and red flags suggestive of a tauopathy conveying variability of phenotypes in hereditary PD.

References: 1 Ortega RA, Wang C, Raymond D et al. Association of Dual LRRK2 G2019S and GBA Variations With Parkinson Disease Progression. JAMA Netw Open. 2021.
2 Rivero-Ríos P, Romo-Lozano M, Fasiczka R et al. LRRK2-Related Parkinson’s Disease Due to Altered Endolysosomal Biology With Variable Lewy Body Pathology: A Hypothesis. Front Neurosci. 2020.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-case-with-clinical-features-of-alpha-synuclein-and-tauopathy-genetic-and-histopathological-workup/