Saunders-Pullman R, Mirelman A, Alcalay RN, Wang C, Ortega RA, Raymond D, Mejia-Santana H, Orbe-Reilly M, Johannes BA, Thaler A, Ozelius L, Orr-Urtreger A, Marder KS, Giladi N, Bressman SB, LRRK2 Ashkenazi Jewish Consortium. Progression in the LRRK2-Asssociated Parkinson Disease Population. JAMA Neurol. 2018 Mar 1;75(3):312-319. PubMed.

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  1. This study by Saunders-Pullman et al. and the LRRK2 Ashkenazi Jewish Consortium further confirms previous cross-sectional/retrospective findings that LRRK2 mutation carriers have a milder motor course (Fernandez-Santiago et al., 2016; Kestenbaum and Alcalay, 2017; Nishioka et al., 2010; Saunders-Pullman et al., 2015; Trinh et al., 2014), and it provides valuable information and resources for future clinical trials. As more and more disease-modifying therapies and genetic modifiers for LRRK2 are found, it would be important to characterize their effect in this homogeneous PD group. It would also be important to not only characterize the motor progression but also the non-motor symptoms such as autonomic dysfunction, sleep patterns, and olfactory dysfunction, as these symptoms also progress during the course of PD. The phenomena can be specific to the p.G2019S mutation because different LRRK2 mutations (e.g. p.G2385R, p.R1441G) have more progressive clinical courses, which may depend on different biological effects of the mutation, on the ethnic background, and on the environment. Lastly, unlike idiopathic PD, the authors find that postural instability and gait disorder does not correlate with a more rapid progression in LRRK2 mutation carriers. This also confirms previous findings that show PIGD and tremor do not predict the clinical course of LRRK2 PD as it does for idiopathic PD (Trinh et al., 2014). 

    LRRK2 mutation carriers are known for their pleomorphic pathology (Lewy body inclusions, TDP43 proteinopathies) and even the absence of Lewy bodies (Kalia et al., 2015). As Lewy body pathology correlates with non-motor features (olfactory dysfunction, gastrointestinal dysfunction, REM sleep behavior disorder) and these are also less frequently seen in LRRK2, as shown from previous cross-sectional studies, perhaps the pathology spread and disease vulnerability patterns are different from idiopathic PD. Idiopathic PD may arise from exogenous exposures through the enteric nervous system and proceeding through the vagus and medulla, which correlates with the “spread of LB pathology” while LRRK2 PD pathophysiology could be more driven by endogenous factors allowing for selective vulnerability patterns that differ from idiopathic PD.

    References:

    Fernández-Santiago R, Iranzo A, Gaig C, Serradell M, Fernández M, Tolosa E, Santamaría J, Ezquerra M. Absence of LRRK2 mutations in a cohort of patients with idiopathic REM sleep behavior disorder. Neurology. 2016 Mar 15;86(11):1072-3. Epub 2016 Jan 8 PubMed.

    Kestenbaum M, Alcalay RN. Clinical Features of LRRK2 Carriers with Parkinson's Disease. Adv Neurobiol. 2017;14:31-48. PubMed.

    Nishioka K, Kefi M, Jasinska-Myga B, Wider C, Vilariño-Güell C, Ross OA, Heckman MG, Middleton LT, Ishihara-Paul L, Gibson RA, Amouri R, Ben Yahmed S, Ben Sassi S, Zouari M, El Euch G, Farrer MJ, Hentati F. A comparative study of LRRK2, PINK1 and genetically undefined familial Parkinson's disease. J Neurol Neurosurg Psychiatry. 2010 Apr;81(4):391-5. PubMed.

    Saunders-Pullman R, Alcalay RN, Mirelman A, Wang C, Luciano MS, Ortega RA, Glickman A, Raymond D, Mejia-Santana H, Doan N, Johannes B, Yasinovsky K, Ozelius L, Clark L, Orr-Utreger A, Marder K, Giladi N, Bressman SB, AJ LRRK2 Consortium. REM sleep behavior disorder, as assessed by questionnaire, in G2019S LRRK2 mutation PD and carriers. Mov Disord. 2015 Nov;30(13):1834-9. Epub 2015 Sep 14 PubMed.

    Trinh J, Amouri R, Duda JE, Morley JF, Read M, Donald A, Vilariño-Güell C, Thompson C, Szu Tu C, Gustavsson EK, Ben Sassi S, Hentati E, Zouari M, Farhat E, Nabli F, Hentati F, Farrer MJ. Comparative study of Parkinson's disease and leucine-rich repeat kinase 2 p.G2019S parkinsonism. Neurobiol Aging. 2014 May;35(5):1125-31. Epub 2013 Nov 22 PubMed.

    Kalia LV, Lang AE, Hazrati LN, Fujioka S, Wszolek ZK, Dickson DW, Ross OA, Van Deerlin VM, Trojanowski JQ, Hurtig HI, Alcalay RN, Marder KS, Clark LN, Gaig C, Tolosa E, Ruiz-Martínez J, Marti-Masso JF, Ferrer I, López de Munain A, Goldman SM, Schüle B, Langston JW, Aasly JO, Giordana MT, Bonifati V, Puschmann A, Canesi M, Pezzoli G, Maues De Paula A, Hasegawa K, Duyckaerts C, Brice A, Stoessl AJ, Marras C. Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol. 2015 Jan;72(1):100-5. PubMed.

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