"Concordance" Revisited: A Multispecialty Appraisal of "Concordant" Preliminary Abdominopelvic CT Reports.

PURPOSE: To determine whether resident abdominopelvic CT reports considered prospectively concordant with the final interpretation are also considered concordant by other blinded specialists and abdominal radiologists. METHODS: In this institutional review board-approved retrospective cohort study, 119 randomly selected urgent abdominopelvic CT examinations with a resident preliminary report deemed prospectively "concordant" by the signing faculty were identified. Nine blinded specialists from Emergency Medicine, Internal Medicine, and Abdominal Radiology reviewed the preliminary and final reports and scored the preliminary report with respect to urgent findings as follows: 1.) concordant; 2.) discordant with minor differences; 3.) discordant with major differences that do not alter patient management; or 4.) discordant with major differences that do alter patient management. Predicted management resulting from scores of 4 was recorded. Consensus was defined as majority agreement within a specialty. Consensus major discrepancy rates (ie, scores 3 or 4) were compared to the original major discrepancy rate of 0% (0/119) using the McNemar test. RESULTS: Consensus scores of 4 were assigned in 18% (21/119, P < .001, Emergency Medicine), 5% (6/119, P = .03, Internal Medicine), and 13% (16/119, P < .001, Abdominal Radiology) of examinations. Consensus scores of 3 or 4 were assigned in 31% (37/119, P < .001, Emergency Medicine), 14% (17/119, P < .001, Internal Medicine), and 18% (22/119, P < .001, Abdominal Radiology). Predicted management alterations included hospital status (0-4%), medical therapy (1%-4%), imaging (1%-10%), subspecialty consultation (3%-13%), nonsurgical procedure (3%), operation (1%-3%), and other (0-3%). CONCLUSIONS: The historical low major discrepancy rate for urgent findings between resident and faculty radiologists is likely underreported.

The discovery of LRRK2 p.R1441S, a novel mutation for Parkinson's disease, adds to the complexity of a mutational hotspot.

Mutations in the LRRK2 gene result in autosomal dominant, late onset Parkinson's disease (PD). Three such mutations (p.R1441C, p.R1441G, and p.R1441H) are known to occur within codon 1441, and haplotype analyses indicate that each one has arisen independently on multiple occasions. We sequenced the entire coding region of 18 casual genes for PD or other parkinsonian neurodegenerative disorders in the proband of a family with autosomal dominant PD. We discovered a new missense mutation in the LRRK2 gene, c.4321C>A (p.R1441S). The mutation was predicted to be highly deleterious in silico (Combined Annotation Dependent Depletion score of 25.5) and segregated with disease in the pedigree. The clinical characteristics of affected family members were similar to those described in PD families with other mutations in LRRK2 codon 1441 and included resting tremor, rigidity, bradykinesia, unilateral onset, and a good response to levodopa. Age at onset ranged from 41 to 76. Two of the affected members of the pedigree underwent detailed, longitudinal neuropsychological testing, and both displayed evidence of mild cognitive deficits at or slightly preceding the onset of motor symptoms. LRRK2 p.R1441S represents the fourth pathogenic mutation observed within codon 1441 and its discovery adds to the remarkable complexity of a mutational hotspot within the ROC domain of the LRRK2 protein. © 2016 Wiley Periodicals, Inc.

LRRK2 mutations and risk variants in Japanese patients with Parkinson's disease.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic determinant of Parkinson's disease (PD) in European-derived populations, but far less is known about LRRK2 mutations and susceptibility alleles in Asians. To address this issue, we sequenced the LRRK2 coding region in 36 patients with familial PD, then genotyped variants of interest in an additional 595 PD cases and 1,641 controls who were all of Japanese ancestry. We also performed a meta-analysis of studies on G2385R, a polymorphism previously reported to associate with PD. One pathogenic (G2019S) and one putative pathogenic (R1067Q) mutation were each observed in two patients with sporadic PD. The overall mutation frequency among patients was 0.6%. G2385R was highly associated with PD under a dominant model in our dataset (adjusted OR, 1.83; 95% CI, 1.31-2.54; P = 3.3 x 10(-4)) and similar results were seen in the meta-analysis (summary OR assuming fixed effects, 2.55; 95% CI, 2.10-3.10). G2385R represents the first consistently replicated common PD susceptibility variant in a non-European population and its effect size is substantially greater than that reported for other well-validated genetic risk factors for the disease. However, LRRK2 mutations appear to be rare among Japanese patients with PD.

LRRK2 G2019S in families with Parkinson disease who originated from Europe and the Middle East: evidence of two distinct founding events beginning two millennia ago.

The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is the most common genetic determinant of Parkinson disease (PD) identified to date. It accounts for 1%-7% of PD in patients of European origin and 20%-40% in Ashkenazi Jews and North African Arabs with PD. Previous studies concluded that patients from these populations all shared a common Middle Eastern founder who lived in the 13th century. We tested this hypothesis by genotyping 25 microsatellite and single-nucleotide-polymorphism markers in 22 families with G2019S and observed two distinct haplotypes. Haplotype 1 was present in 19 families of Ashkenazi Jewish and European ancestry, whereas haplotype 2 occurred in three European American families. Using a maximum-likelihood method, we estimated that the families with haplotype 1 shared a common ancestor 2,250 (95% confidence interval 1,650-3,120) years ago, whereas those with haplotype 2 appeared to share a more recent founder. Our data suggest two separate founding events for G2019S in these populations, beginning at a time that coincides with the Jewish Diasporas.