TY - JOUR
T1 - First neuropathological description of a patient with Parkinson's disease and LRRK2 p.N1437H mutation
AU - Puschmann, Andreas
AU - Englund, Elisabet
AU - Ross, Owen A.
AU - Vilariño-Güell, Carles
AU - Lincoln, Sarah J.
AU - Kachergus, Jennifer M.
AU - Cobb, Stephanie A.
AU - Törnqvist, Anna Lena
AU - Rehncrona, Stig
AU - Widner, Håkan
AU - Wszolek, Zbigniew K.
AU - Farrer, Matthew J.
AU - Nilsson, Christer
N1 - Funding Information:
Andreas Puschmann, Håkan Widner, Jan Reimer, and Christer Nilsson received funding from The Swedish Parkinson Academy, Stiftelsen Olle Engkvist Byggmästare, AFA Insurance , The Swedish Parkinson Foundation, Apotekare Hedbergs Foundation, Elsa Schmitz Foundation , and Lund University Hospital Research Funds . Owen A. Ross, Carles Vilariño-Güell, Sarah J. Lincoln, Jennifer M. Kachergus, Stephanie A. Cobb, Zbigniew K. Wszolek, Matthew J. Farrer are supported by NIH/NINDS Morris K. Udall Center for Excellence in PD Research at Mayo Clinic (P50 NS072187) grant. Zbigniew K. Wszolek is partially supported by the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, Mayo Clinic Florida (MCF) Research Committee CR program (MCF #90052030), Dystonia Medical Research Foundation , and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch (MCF #90052031/PAU #90052).
PY - 2012/5
Y1 - 2012/5
N2 - The c.4309A. > C mutation in the LRRK2 gene (LRRK2 p.N1437H) has recently been reported as the seventh pathogenic LRRK2 mutation causing monogenic Parkinson's disease (PD). So far, only two families worldwide have been identified with this mutation. By screening DNA from seven brains of PD patients, we found one individual with seemingly sporadic PD and LRRK2 p.N1437H mutation. Clinically, the patient had levodopa-responsive PD with tremor, and developed severe motor fluctuations during a disease duration of 19 years. There was severe and painful ON-dystonia, and severe depression with suicidal thoughts during OFF. In the advanced stage, cognition was slow during motor OFF, but there was no noticeable cognitive decline. There were no signs of autonomic nervous system dysfunction. Bilateral deep brain stimulation of the subthalamic nucleus had unsatisfactory results on motor symptoms. The patient committed suicide. Neuropathological examination revealed marked cell loss and moderate alpha-synuclein positive Lewy body pathology in the brainstem. There was sparse Lewy pathology in the cortex. A striking finding was very pronounced ubiquitin-positive pathology in the brainstem, temporolimbic regions and neocortex. Ubiquitin positivity was most pronounced in the white matter, and was out of proportion to the comparatively weaker alpha-synuclein immunoreactivity. Immunostaining for tau was mildly positive, revealing non-specific changes, but staining for TDP-43 and FUS was entirely negative. The distribution and shape of ubiquitin-positive lesions in this patient differed from the few previously described patients with LRRK2 mutations and ubiquitin pathology, and the ubiquitinated protein substrate remains undefined.
AB - The c.4309A. > C mutation in the LRRK2 gene (LRRK2 p.N1437H) has recently been reported as the seventh pathogenic LRRK2 mutation causing monogenic Parkinson's disease (PD). So far, only two families worldwide have been identified with this mutation. By screening DNA from seven brains of PD patients, we found one individual with seemingly sporadic PD and LRRK2 p.N1437H mutation. Clinically, the patient had levodopa-responsive PD with tremor, and developed severe motor fluctuations during a disease duration of 19 years. There was severe and painful ON-dystonia, and severe depression with suicidal thoughts during OFF. In the advanced stage, cognition was slow during motor OFF, but there was no noticeable cognitive decline. There were no signs of autonomic nervous system dysfunction. Bilateral deep brain stimulation of the subthalamic nucleus had unsatisfactory results on motor symptoms. The patient committed suicide. Neuropathological examination revealed marked cell loss and moderate alpha-synuclein positive Lewy body pathology in the brainstem. There was sparse Lewy pathology in the cortex. A striking finding was very pronounced ubiquitin-positive pathology in the brainstem, temporolimbic regions and neocortex. Ubiquitin positivity was most pronounced in the white matter, and was out of proportion to the comparatively weaker alpha-synuclein immunoreactivity. Immunostaining for tau was mildly positive, revealing non-specific changes, but staining for TDP-43 and FUS was entirely negative. The distribution and shape of ubiquitin-positive lesions in this patient differed from the few previously described patients with LRRK2 mutations and ubiquitin pathology, and the ubiquitinated protein substrate remains undefined.
KW - Alpha-synuclein
KW - Autosomal dominant parkinsonism
KW - Deep brain stimulation
KW - LRRK2
KW - Suicide
KW - Ubiquitin
UR - http://www.scopus.com/inward/record.url?scp=84860380154&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84860380154&partnerID=8YFLogxK
U2 - 10.1016/j.parkreldis.2011.11.019
DO - 10.1016/j.parkreldis.2011.11.019
M3 - Article
C2 - 22154298
AN - SCOPUS:84860380154
SN - 1353-8020
VL - 18
SP - 332
EP - 338
JO - Parkinsonism and Related Disorders
JF - Parkinsonism and Related Disorders
IS - 4
ER -