Objective: To report a novel case of young-onset Parksinon’s disease (YOPD) associated with a pathogenic deletion of the proline-rich transmembrane protein 2 gene (PRRT2).

Background: PRRT2 encodes the protein proline-rich transmembrane protein 2 (PRRT2), which is involved in neurotransmitter release and synaptic signaling. PRRT2 contains four exons and codes 340 amino acids that are highly expressed in the cerebral cortex, basal ganglia, and cerebellum. Historically, pathogenic variants in PRRT2 have been associated with paroxysmal kinesigenic dyskinesia (PKD), which is characterized by dystonia, choreoathetosis, and ballismus. It has also been linked to benign familial infantile epilepsy and hemiplegic migraine. However, mutations in PRRT2 have not yet been reported to be associated with YOPD.

Method: Case report.

Results: A 37-year-old woman with hypertension and a family history of idiopathic Parkinson’s disease (PD) presented for evaluation of bradykinesia. Her initial symptoms involved generalized slowing of movement, shuffling gait, and tremors primarily at rest. Examination revealed increased tone in all extremities, resting tremors in the upper extremities, stooped posture, shuffling gait, and bradykinesia. Dopamine transporter scan demonstrated loss of dopaminergic neuronal function in the bilateral striata. Genetic testing for 61 genes with known links to parkinsonism and/or dystonia was pursued given the young age of symptom onset, which revealed a pathogenic deletion of the full coding sequence of PRRT2. No additional mutations were detected on her genetic panel. She denied symptoms of PKD, hemiplegic migraine, or infantile seizures. She was treated with carbidopa-levodopa with improvement in her symptoms and has maintained good response for over two years without any emergence of a neurological disorder other than YOPD.

Conclusion: Our patient was evaluated for bradykinesia, shuffling gait, and resting tremors and was diagnosed with YOPD, likely due to pathogenic deletion of PRRT2. While a mutation in PRRT2 has not yet been linked to PD, its resultant PRRT2 protein is known to be highly expressed in the basal ganglia, which may explain its potential to be causative for parkinsonism. This patient is the first reported case of YOPD associated with a mutation in PRRT2 and may further highlight the broad spectrum of neurological disorders that may be linked to pathogenic variants of this gene.

References: 1. Landolfi A, Barone P, Erro R. The Spectrum of PRRT2-Associated Disorders: Update on Clinical Features and Pathophysiology. Front Neurol. 2021 Mar 4;12:629747. doi: 10.3389/fneur.2021.629747. PMID: 33746883; PMCID: PMC7969989.
2. Yang L, You C, Qiu S, Yang X, Li Y, Liu F, Zhang D, Niu Y, Xu L, Xu N, Li X, Luo F, Yang J, Li B. Novel and de novo point and large microdeletion mutation in PRRT2-related epilepsy. Brain Behav. 2020 May;10(5):e01597. doi: 10.1002/brb3.1597. Epub 2020 Mar 31. PMID: 32237035; PMCID: PMC7218244.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/young-onset-parkinsons-disease-in-a-female-with-pathogenic-deletion-of-the-prrt2-gene/