Objective: To describe the clinical features, genetic analysis and brain pathology of some members of a family affected by Parkinson´s disease.

Background: Mutations of the Leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkinson´s disease (PD) with autosomal dominant inheritance. G2019S LRRK2 mutation located within the kinase domain is the most frequent, nevertheless mutations affecting other domains have been described. Brains with LRRK2 mutations display dopaminergic neuronal loss in the substantia nigra, half of the brains have Lewy bodies (LB) and the same proportion has tau pathology.

Methods: After 25 years of follow-up, a molecular analysis using a genetic panel with candidate genes for parkinsonisms and pathological examination of the brain were performed in a woman with PD. Her father, two brothers and a nephew were also diagnosed of PD. Genetic analysis was carried out in her nephew too.

Results: This 84 year old patient had a 25 year history of PD. Symptoms started with right leg tremor. A good response to levodopa with the development of motor fluctuations and dyskinesias dominated the clinical picture. She did not have cognitive impairment neither psychotic symptoms. She died from a septic shock and her brain was donated. Autopsy showed severe neuronal loss in the substantia nigra and mild in locus coeruleus but no α-synuclein-positive structures or LB were present. There were tau inclusions in the cortex, striatum and in other nucleus of midbrain. No TDP-43-positive inclusions were found. Her nephew´s PD started at the same age and he also had a very good response to levodopa. He developed dyskinesias and motor fluctuations but he had a psychotic episode. The molecular analysis showed the proband is carrier of two rare variants in LRRK2 gene. The variants were p.Leu119Pro (c.356T>C; rs33995463, HGMD: CM150168 and ClinVar: 39167) previously reported as a variant of uncertain significance (VUS), and p.Leu488Pro (c.1463T>C) that is novel. The molecular study of her nephew also showed these two LRRK2 rare variants thus indicating they are in Cys. Molecular analysis of her brother is pending.

Conclusions: We propose that the LRRK2 allele containing both the p.Leu119Pro and p.Leu488Pro variants is the cause of PD in this Spanish family. The study of other affected members of this family will show whether this LRRK2 mutant allele are not associated with LB pathology.

« Back to 2018 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/lrrk2-p-leu119pro-and-p-leu488pro-in-a-family-with-neuropathologycally-confirmed-parkinsons-disease-without-lewy-bodies/