LRRK2 G2019S mutation in Parkinson’s disease: A neuropsychological and neuropsychiatric study in a large Algerian cohort

Abstract

A series of 106 patients with isolated or familial Parkinsonism underwent clinical evaluation and genetic testing for the LRRK2 G2019S mutation which was identified in 34/106 patients (32%). Seventy one of them accepted to be evaluated for neuropsychological and neuropsychiatric studies with the aim to compare mutation carriers with non-carriers. For neuropsychological testing, comparisons between LRRK2 G2019S carriers and non-carriers were made after stratification according to the level of education: median and high school versus low level. Memory was investigated with the five words test, 2 novel tests with verbalized visual material dedicated to illiterate patients, the TNI-93 (nine pictures test), The TMA-93 (associative memory test), and digit spans (forward/backward). Cognitive analyse did not show major differences between the two groups of patients. Nevertheless, behavioral abnormalities, mostly depression and hallucinations, were more frequent in the LRRK2 G2019S carriers, suggesting the presence of a greater involvement of the limbic system in these patients. Sleep disorders which were also more common amongst mutation carriers than non-carriers might be related to depression.

Introduction

Idiopathic Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder in the elderly and the most common movement disorder. Although the cause of PD remains unclear, its etiology is most likely a combination of complex genetic and environmental factors [1]. Approximately 85% of cases were sporadic, with familial clustering seen in 10–15% and monogenic inheritance in less than 10% [2]. There are at least 13 known loci, with 9 causative genes identified to date [3]. The recent discovery of the LRRK2 (Leucine-rich repeat kinase 2) gene that encodes dardarin, revolutionized the genetics of Parkinson’s disease, since a single G2019S mutation causes a significant proportion of autosomal dominant forms of PD. Thus, it represents the most common mutation identified in PD so far. Subsequent studies have shown that the frequency of LRRK2 G2019S mutation varies greatly according to geographical or ethnic origin. The highest frequency was found in North African Arabs where this mutation accounts for 41% of isolated and 37% of familial PD [4], versus 1–2% and 5–6% in Europe [5]. Furthermore, the G2019S mutation was found in approximately 30% of Ashkenazi Jews with familial forms of PD, and 13% of cases with no family history of PD [6]. Recently, we reported a clinical and genetic study of a series of 136 PD patients from North Africa and confirmed the high proportion of LRRK2 G2019S mutation among these patients [7]. In this study, a comparison of the clinical features of PD between G2019S mutation carriers and non-carriers revealed that they were similar except for l-Dopa induced dyskinesias which were significantly more frequent in the group with G2019S mutation (53%) than without (16%). Non-motor symptoms were not studied in this subset of PD patients. In order to achieve a full clinical characterization of PD patients harboring this mutation and to compare them with non-carriers, we decided to undertake detailed neurological but especially a neuropsychological and psychiatric evaluation of 106 patients from this series.