Citations

ABSTRACTBackgroundMutations in the leucine‐rich repeat kinase 2 gene (LRRK2) are the most common genetic cause of Parkinson's disease (PD). Unexpectedly, tau pathology has been reported in a subset of LRRK2 mutation carriers.MethodsTo estimate the frequency of pathogenic LRRK2 mutations and to evaluate the association of common LRRK2 variants with risk of primary tauopathies, we studied 1039 progressive supranuclear palsy (PSP) and 145 corticobasal degeneration patients from the Mayo Clinic Florida brain bank and 1790 controls ascertained at Mayo Clinic. Sanger sequencing of LRRK2 exons 30, 31, 35, and 41 was performed in all patients, and genotyping of all 17 known exonic variants with minor allele frequency >0.5% was performed in patients and controls.ResultsLRRK2 mutational screening identified 2 known pathogenic mutations (p.G2019S and p.R1441C), each in 1 PSP patient, the novel p.A1413T mutation in a PSP patient and the rare p.R1707K mutation in a corticobasal degeneration patient. Both p.A1413T and p.R1707K mutations were predicted damaging by at least 2 of 3 prediction programs and affect evolutionary conserved sites of LRRK2. Association analysis using common LRRK2 variants only showed nominal association of the p.L153L variant with PSP.ConclusionsOur study confirms the presence of pathogenic and potentially pathogenic LRRK2 mutations in pathologically confirmed primary tauopathies, albeit with low frequency. In contrast to PD, common LRRK2 variants do not appear to play a major role in determining PSP and corticobasal degeneration risk. © 2016 International Parkinson and Movement Disorder Society.

ABSTRACT Background Linkage analyses of families with primary familial brain calcification (formerly idiopathic basal ganglia calcification [IBGC]) identified 3 candidate loci (IBGC1‐3). Recently, SLC20A2 mutations were found in the IBGC1 and IBGC3 families, merging these 2 loci. We here elucidate the genetic cause of primary familial brain calcification in the ‘IBGC2’ kindred. Methods We sequenced known primary familial brain calcification genes and quantified SLC20A2 and PDGFB . Moreover, CT scans of affected and unaffected family members were evaluated by 2 blinded neuroradiologists for distribution of brain calcification. Results A heterozygous multiexonic SLC20A2 deletion was detected in several affected family members. A reevaluation of neuroimaging data revealed a subset of mutation‐negative individuals with only mild and/or unilateral calcification. Conclusions The identified SLC20A2 mutation resolves the genetic cause of primary familial brain calcification in the ‘IBGC2’ kindred, collapsing ‘IBGC2’ into IBGC1. We suggest an algorithm for predicting the chances of finding genetic mutations that has to be validated in further studies. Our study enhances criteria for the evaluation of neuroimaging data, contributing further to the much needed harmonization of diagnostic and research data collection in primary familial brain calcification. © 2016 International Parkinson and Movement Disorder Society.

AbstractMutations in microtubule‐associated protein tau gene (MAPT) cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP‐17). Here, we describe a patient with FTDP‐17 and a novel missense mutation in exon 13 of MAPT, p.E372G. We compare clinicopathologic features of this patient to two previously unreported patients with another exon 13 mutation, p.G389R. The patient with the p.E372G mutation was a 40‐year‐old man with behavioral variant frontotemporal dementia (bvFTD), who subsequently developed agrammatic speech and parkinsonism. One of the FTDP‐17 patients with p.G389R mutation presented at age 24 with agrammatic variant of primary progressive aphasia, and subsequently behavioral dysfunction. The other presented at age 53 with bvFTD, followed by agrammatic speech and corticobasal syndrome. Neuropathologic features of FTDP‐17 due to p.E372G were similar to those of p.G389R, including tau‐immunoreactive Pick body‐like neuronal inclusions and swollen, tapering thread‐like processes in white matter immunoreactive for 3‐repeat and 4‐repeat tau. Biochemical analysis of insoluble tau showed similar isoform compositions in p.E372G and p.G389R. Functional studies of the p.E372G mutation showed marked increase in tau filament formation and its reduced ability to promote microtubule assembly. Together these findings indicate that p.E372G is a pathogenic MAPT mutation that causes FTDP‐17 similar to p.G389R.

Targeting three defects with one strategy The neurodegenerative diseases amyotrophic lateral sclerosis and frontotemporal dementia are most commonly caused by a mutation in the C9orf72 gene. The mutation is an expanded hexanucleotide repeat in a noncoding region. The expanded repeat produces sense and antisense RNA transcripts, which accumulate in patient cells and appear to sequester RNA-binding proteins. The sense and antisense transcripts are also translated into dipeptide repeat proteins, which are aggregation-prone and accumulate in the brain and spinal cord. Last, loss of function from reduced expression of C9orf72 in neurons and glia could contribute to the disease. Kramer et al. targeted both sense and antisense repeats by blocking a single gene called SPT4 , which mitigated degeneration in human cells by reducing all three types of pathologies. Science , this issue p. 708

Although studies on simulation of rare complications have become more common in the trauma and obstetric literature, there is a paucity of studies on simulation of rare laparoscopic emergencies. High-fidelity models, virtual reality systems, and porcine labs are available; however, their cost limits wider use and repetition of skills. A low-cost, laparoscopic entry and emergency model was created using on-hand base parts. A convenience sample of obstetrics/gynecology and general surgery residents and attending surgeons completed a laparoscopic entry and emergency scenario using an innovative model in the multidisciplinary simulation center. A total of 29 gynecology, urology, and general surgery residents, fellows, and attending surgeons participated in the laparoscopic emergency simulation drill. Of the 29 participants of the laparoscopic emergency simulation drill using the model, 27 (93.1%) agreed or strongly agreed that the simulated drill approximates the stress of a vascular injury during laparoscopy and 27 (93.1%) agreed or strongly agreed that the model set up appears appropriate for approximating a retroperitoneal hematoma. The reusable, laparoscopic simulation model and emergency drill were rated favorably by participants. The model and drill have the potential to be used for multidisciplinary drills that include anesthesiologists, surgical nurses, surgical technologists, and surgeons.

Abstract Frontotemporal lobar degeneration ( FTLD ) comprises a highly heterogeneous group of disorders clinically associated with behavioral and personality changes, language impairment, and deficits in executive functioning, and pathologically associated with degeneration of frontal and temporal lobes. Some patients present with motor symptoms including amyotrophic lateral sclerosis. Genetic research over the past two decades in FTLD families led to the identification of three common FTLD genes (microtubule‐associated protein tau, progranulin, and chromosome 9 open reading frame 72) and a small number of rare FTLD genes, explaining the disease in almost all autosomal dominant FTLD families but only a minority of apparently sporadic patients or patients in whom the family history is less clear. Identification of additional FTLD (risk) genes is therefore highly anticipated, especially with the emerging use of next‐generation sequencing. Common variants in the transmembrane protein 106 B were identified as a genetic risk factor of FTLD and disease modifier in patients with known mutations. This review summarizes for each FTLD gene what we know about the type and frequency of mutations, their associated clinical and pathological features, and potential disease mechanisms. We also provide an overview of emerging disease pathways encompassing multiple FTLD genes. We further discuss how FTLD specific issues, such as disease heterogeneity, the presence of an unclear family history and the possible role of an oligogenic basis of FTLD , can pose challenges for future FTLD gene identification and risk assessment of specific variants. Finally, we highlight emerging clinical, genetic, and translational research opportunities that lie ahead. image Genetic research led to the identification of three common FTLD genes with rare variants ( MAPT , GRN , and C9orf72 ) and a small number of rare genes. Efforts are now ongoing, which aimed at the identification of rare variants with high risk and/or low frequency variants with intermediate effect. Common risk variants have also been identified, such as TMEM106B . This review discusses the current knowledge on FTLD genes and the emerging disease pathways encompassing multiple FTLD genes. This article is part of the Frontotemporal Dementia special issue .