Abstract
Leucine-rich repeat kinase 2 (LRRK2) mutation is the most common cause of genetic-related parkinsonism and is usually associated with Lewy body pathology; however, tau, α-synuclein, and ubiquitin pathologies have also been reported. We report the case of a patient carrying the LRRK2 G2019S mutation and a novel heterozygous variant c.370C>G, p.Q124E in exon 4 of the microtubule-associated protein tau (MAPT). The patient developed parkinsonism with good levodopa response in her 70s. Neuropathological analysis revealed nigral degeneration and Alzheimer-type tau pathology without Lewy bodies. Immunohistochemical staining using phospho-TDP-43 antibodies identified occasional TDP-43 pathology in the hippocampus, temporal neocortex, striatum, and substantia nigra. However, TDP-43 pathology was not identified in another 4 archival LRRK2 G2019S cases with Lewy body pathology available in the Queen Square Brain Bank. Among other published cases of patients carrying LRRK2 G2019S mutation, only 3 were reportedly evaluated for TDP-43 pathology, and the results were negative. The role of the MAPT variant in the clinical and pathological manifestation in LRRK2 cases remains to be determined.
Highlights
Among the 5 identified pathogenic leucine-rich repeat kinase 2 (LRRK2) mutations, G2019S is the most common, and accounts for 1% of sporadic Parkinson’s disease and 4% of hereditary parkinsonism worldwide (Healy et al, 2008)
The microtubule-associated protein tau (MAPT) p.Q124E variant is absent in all control subjects in the public databases (N 1⁄4 6568, of which 3913 are caucasians), which include, Ensemble and Exome Variant Server (Exome Variant Server, NHLBI GO Exome Sequencing Project (ESP), Seattle, WA (URL: http://evs.gs.washington.edu/EVS/) [(1,2013) accessed]); this variant is absent in the 4 LRRK2 cases with Lewy body pathology
Rajput et al reported a case with slow, progressive, nonelevodopa-responsive parkinsonism and tau-positive neurofibrillary tangles (NFTs) resembling the neuropathology of progressive supranuclear palsy (PSP) (Rajput et al, 2006), Giasson et al and Gaig et al each reported a case with classical tremor-dominant parkinsonism and pure nigral degeneration (Gaig et al, 2008; Giasson et al, 2006), and, Dachsel et al reported a case with dementia and tremor and pathology consisted of FTLD with ubiquitinated neuronal inclusions (FTLD-U) (Dachsel et al, 2007)
Summary
Among the 5 identified pathogenic leucine-rich repeat kinase 2 (LRRK2) mutations, G2019S is the most common, and accounts for 1% of sporadic Parkinson’s disease and 4% of hereditary parkinsonism worldwide (Healy et al, 2008). Clinical presentation of LRRK2 mutation resembles idiopathic Parkinson’s disease but may be associated with a more benign disease course (Healy et al, 2008). Most patients with LRRK2 mutation exhibit neuropathological features consistent with typical Lewy body Parkinson’s disease (Gilks et al, 2005; Khan et al, 2005; Zimprich et al, 2004); ,. TDP-43erelated pathology was reported in 3 patients carrying LRRK2 mutations (p.R1441C, p.R793M and L1165P) (Covy et al, 2009; Wider et al, 2010). We report a patient with a clinical diagnosis of Parkinson’s disease, who in post-mortem was found to have nigral degeneration without Lewy body pathology, and was shown to carry the LRRK2 G2019S mutation and a novel heterozygous variant c.370C>G, p.Q124E in exon 4 of the microtubule-associated protein tau (MAPT)
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