AUTHOR=Wise Adina , Ortega Roberto A. , Raymond Deborah , Cervera Alessandra , Thorn Emma , Leaver Katherine , Russell David S. , Bressman Susan B. , Crary John F. , Saunders-Pullman Rachel 

TITLE=Multiple sclerosis in LRRK2 G2019S Parkinson’s disease and isolated nigral degeneration in a homozygous variant carrier

JOURNAL=Frontiers in Neurology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1450654

DOI=10.3389/fneur.2024.1450654

ISSN=1664-2295

ABSTRACT=<sec id="sec1"><title>Background</title><p><italic>LRRK2</italic> variants have been associated with immune dysregulation as well as immune-related disorders such as IBD. A possible relationship between multiple sclerosis (MS) and <italic>LRRK2</italic> PD has also been suggested. Further, neuropathologic studies of homozygous <italic>LRRK2</italic> G2019S carriers with Parkinson’s disease (PD) are rare, and there are no systematic reports of clinical features in those cases.</p></sec><sec id="sec2"><title>Methods</title><p>We investigated the co-occurrence of PD and MS in our research cohort and report on two cases of MS in <italic>LRRK2</italic> PD as well as neuropathological findings for one.</p></sec><sec id="sec3"><title>Results</title><p>MS preceded PD in 1.4% (2/138) of participants with <italic>LRRK2</italic> G2019S variants, and in none (0/638) with idiopathic PD (<italic>p</italic> = 0.03). One case with MS and PD was a <italic>LRRK2</italic> G2019S homozygous carrier, and neuropathology showed evidence of substantia nigra pars compacta degeneration and pallor without Lewy deposition, as well as multiple white matter lesions consistent with MS-related demyelination.</p></sec><sec id="sec4"><title>Discussion</title><p>The increased prevalence of MS in <italic>LRRK2</italic> PD further supports an important role for immune function for <italic>LRRK2</italic> PD. This co-occurrence, while rare, suggests that MS may be an expression of the <italic>LRRK2</italic> G2019S variant that includes both MS and PD, with MS predating features diagnostic of PD. The neuropathology suggests that the MS-related effects occurred independent of synuclein deposition. Importantly, and in addition, the neuropathological results not only support the MS diagnosis, but provide further evidence that Lewy body pathology may be absent even in homozygote <italic>LRRK2</italic> carriers.</p></sec>