title: Clinical and pathological characteristics of patients with leucine-rich repeat kinase-2 mutations.
abstract: Mutations in LRRK2 are the single most common known cause of Parkinson's disease (PD). Two new PD patients with LRRK2 mutation were identified from a cohort with extensive postmortem assessment. One of these patients harbors the R793M mutation and presented with the typical clinical and pathological features of PD. A novel L1165P mutation was identified in a second patient. This patient had the classical and pathological features of PD, but additionally developed severe neuropsychological symptoms and dementia associated with abundant neurofibrillary tangles in the hippocampal formation; features consistent with a secondary diagnosis of tangle-predominant dementia. alpha-Synuclein-containing pathological inclusions in these patients also were highly phosphorylated at Ser-129, similar to other patients with idiopathic PD. These two PD patients also were characterized by the presence of occasional cytoplasmic TDP-43 inclusions in the temporal cortex, a finding that was not observed in three other patients with the G2019S mutation in LRRK2. These findings extend the clinical and pathological features that may be associated with LRRK2 mutations.
authors.affiliation: Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6084, USA.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Covy
authors.forename: Wuxing
authors.initials: W
authors.lastname: Yuan
authors.forename: Elisa A
authors.initials: EA
authors.lastname: Waxman
authors.forename: Howard I
authors.initials: HI
authors.lastname: Hurtig
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: Benoit I
authors.initials: BI
authors.lastname: Giasson
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005799:Genes, Dominant; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D016874:Neurofibrillary Tangles; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology / Q000523:psychology; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000473:pathology / Q000523:psychology; D010766:Phosphorylation; D010768:Phosphoserine / Q000032:analysis; D017354:Point Mutation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013702:Temporal Lobe / Q000473:pathology; D051844:alpha-Synuclein / Q000032:analysis
chemical_list: D051844:alpha-Synuclein; D010768:Phosphoserine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases