MR imaging findings in Xp21.2 duplication syndrome

Xp21.2 duplication syndrome is a rare genetic disorder of undetermined prevalence and clinical relevance. As the use of chromosomal microarray has become first line for the work-up of childhood developmental delay, more gene deletions and duplications have been recognized. To the best of our knowledge, the imaging findings of Xp21.2 duplication syndrome have not been reported. We report a case of a 33 month-old male referred for developmental delay that was found to have an Xp21.2 duplication containing IL1RAPL1 and multiple midline brain malformations

Absence of JAK2V617F Mutated Endothelial Colony-Forming Cells in Patients With JAK2V617F Myeloproliferative Neoplasms and Splanchnic Vein Thrombosis

Philadelphia (Ph)-negative myeloproliferative neoplasms (MPN) are acquired hematologic diseases with increased production of mature blood cells. They include polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF). The most frequent molecular abnormality found in Ph negative MPN is JAK2V617F, an activating mutation of JAK2 which is responsible for constitutive signaling of various cytokine receptors. Arterial and venous thromboses are the main complications of these diseases and are responsible for high rates of morbidity and mortality. Of note there is a disproportionate incidence of thrombosis at unusual sites including splanchnic vein thrombosis.1 Splanchnic vein thromboses (SVT) involve one or more abdominal veins, the two most frequent are Portal Vein Thrombosis (PVT) and Budd Chiari Syndrome (BCS). Pathophysiology of thrombosis in MPN is complex and involves abnormalities in blood cells, plasma factors, and endothelial cells (ECs). Several groups, using different techniques, have shown JAK2V617F expression in endothelial cells (Supplemental Fig. 1, http://links.lww.com/HS/A79). Using laser capture microdissection, JAK2V617F was demonstrated in ECs from hepatic venules in 2 of 3 patients with PV and BCS.2JAK2V617F endothelial cells were demonstrated in microdissected splenic capillaries and in ECs cultured from splenic vein in patients with myelofibrosis but without SVT.3 Although these teams performed experiments to ensure that the DNA they obtained originated from ECs, it is difficult to completely rule out a possible contamination by blood cells. Analysis of endothelial progenitor cells, specifically endothelial colony forming cells (ECFCs), is an alternative way to look for JAK2V617F ECs. Indeed, ECFCs are reported to be the only “true” endothelial progenitor cells, as they are the only ones able to generate blood vessels in vivo: they display clonogenic potential, endothelial but not myeloid cell surface markers, and pronounced postnatal vascularisation ability in vivo.4,5 ECFCs are a unique tool to investigate endothelial molecular dysfunction in disease, as they give access to endothelial cells from patients in a non-invasive way and a promising tool for vascular regenerative approaches and gene therapy.6 Yoder et al studied 11 JAK2V617F MPN patients and reported 3 JAK2V617F ECFCs derived from only 1 of 11 patients. Of note, this patient presented with thrombosis and later developed PV.4 In another study, the JAK2V617F mutation was not detected in any of 75 ECFCs obtained from 57 patients with JAK2V617F MPN but no thrombosis.7 Teofili et al reported JAK2V617F ECFCs in 5 of 22 MPN patients, all with thrombotic complications including 1 with BCS and 1 with PVT.8 Lastly, 4 of 5 JAK2V617F-positive patients with BCS but without overt MPN had JAK2V617F ECFCs cultured from the bone marrow.9 Taken together, these results suggest that the presence of JAK2V617F ECFCs in patients is associated with thrombosis, even in the absence of overt MPN. Our groups have previously demonstrated (a) that the presence of JAK2V617F in ECs modifies their phenotype and makes them prothrombotic,10 highlighting the importance of looking for JAK2V617F ECs in patients; (b) the importance of using correctly characterized ECFCs in investigating this.6 Confirming that JAK2V617F positive ECFCs are associated with previous thrombosis in MPN patients would suggest that ECFCs culture and JAK2V617F genotyping may be used as a marker of thrombotic risk in MPN patients, before they develop thrombosis

A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies

Leukodystrophies (LD) and genetic leukoencephalopathies (gLE) are disorders that result in white matter abnormalities in the central nervous system (CNS). Magnetic resonance (MR) imaging (MRI) has dramatically improved and systematized the diagnosis of LDs and gLEs, and in combination with specific clinical features, such as Addison’s disease in Adrenoleukodystrophy or hypodontia in Pol-III related or 4H leukodystrophy, can often resolve a case with a minimum of testing. The diagnostic odyssey for the majority LD and gLE patients, however, remains extensive – many patients will wait nearly a decade for a definitive diagnosis and at least half will remain unresolved. The combination of MRI, careful clinical evaluation and next generation genetic sequencing holds promise for both expediting the diagnostic process and dramatically reducing the number of unresolved cases. Here we present a workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis, including salient clinical features suggesting a specific diagnosis, neuroimaging features and molecular genetic testing. We also discuss recommendations on the use of broad-spectrum next-generation sequencing in instances of ambiguous MRI or clinical findings. We conclude with a proposal for systematic trials of genome-wide agnostic testing as a first line diagnostic in LDs and gLEs given the increasing number of genes associated with these disorders

Approach for Predicting Production Scenarios Focused on Cross Impact Analysis

AbstractOne of the most consistent challenges in business is anticipating what the future holds and what impact it may have on current production systems. The scenario technique is a well-established method for developing and forecasting multiple future development paths for companies. However, this method is mostly employed to develop and to support strategic long-term decisions. The core idea of the approach introduced in this paper is to convey the future impact of today's decisions on production systems to employees involved in production planning processes. With the help of immersive visualization, performed in virtual reality (VR) systems, planning participants can perceive how the factory must adapt to fit future demands.In this paper, the focus is on the fourth phase of the scenario technique – so called scenario development – and, in particular, the cross impact analysis. With this methodology, the interrelations, or cross impacts of the different basic elements are determined. The cross impact analysis results serve as a basis for the development of a standardized tool that can be used to create probable production scenarios out of given production systems. This standardized tool will facilitate the usage of the scenario technique for factory planning projects, as it focuses the immense diversity of future uncertainties companies are faced with on the factory level

TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease

Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms

Evaluating triple oxygen isotope estimates of gross primary production at the Hawaii Ocean Time-series and Bermuda Atlantic Time-series Study sites

Author Posting. © American Geophysical Union, 2012. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 117 (2012): C05012, doi:10.1029/2010JC006856.The triple oxygen isotopic composition of dissolved oxygen (17Δ) is a promising tracer of gross oxygen productivity (P) in the ocean. Recent studies have inferred a high and variable ratio of P to 14C net primary productivity (12–24 h incubations) (e.g., P:NPP(14C) of 5–10) using the 17Δ tracer method, which implies a very low efficiency of phytoplankton growth rates relative to gross photosynthetic rates. We added oxygen isotopes to a one-dimensional mixed layer model to assess the role of physical dynamics in potentially biasing estimates of P using the 17Δ tracer method at the Bermuda Atlantic Time-series Study (BATS) and Hawaii Ocean Time-series (HOT). Model results were compared to multiyear observations at each site. Entrainment of high 17Δ thermocline water into the mixed layer was the largest source of error in estimating P from mixed layer 17Δ. At both BATS and HOT, entrainment bias was significant throughout the year and resulted in an annually averaged overestimate of mixed layer P of 60 to 80%. When the entrainment bias is corrected for, P calculated from observed 17Δ and 14C productivity incubations results in a gross:net productivity ratio of 2.6 (+0.9 −0.8) at BATS. At HOT a gross:net ratio decreasing linearly from 3.0 (+1.0 −0.8) at the surface to 1.4 (+0.6 −0.6) at depth best reproduced observations. In the seasonal thermocline at BATS, however, a significantly higher gross:net ratio or large lateral fluxes of 17Δ must be invoked to explain 17Δ field observations.We acknowledge support from Center for Microbial Oceanography Research and Education (CMORE) (NSF EF-0424599) and NOAA Global Carbon Program (NA 100AR4310093). BL thanks the USA-Israel Binational Science Foundation for supporting his project at BATS.2012-11-0

RMND1-related leukoencephalopathy with temporal lobe cysts and hearing loss—another mendelian mimicker of congenital cytomegalovirus infection

Background Leukoencephalopathy with temporal lobe cysts may be associated with monogenetic conditions such as Aicardi–Goutières syndrome or RNASET2 mutations and with congenital infections such as cytomegalovirus. In view of the fact that congenital cytomegalovirus is difficult to confirm outside the neonatal period, excluding a Mendelian disorder is extremely relevant, changing family planning and medical management in affected families. We performed diagnostic testing in individuals with leukoencephalopathy with temporal lobe cysts without a definitive diagnosis of congenital cytomegalovirus infection. Methods We reviewed a large-scale biorepository of patients with unsolved leukodystrophies and identified two individuals with required for meiotic nuclear division 1 (RMND1) mutations and similar magnetic resonance imaging (MRI) features, including temporal lobe cysts. Ten additional subjects with confirmed RMND1 mutations were identified as part of a separate disease specific cohort. Brain MRIs from all 12 individuals were reviewed for common neuroradiological features. Results MRI features in RMND1 mutations included temporal lobe swelling, with rarefaction and cystic evolution, enlarged tips of the temporal lobes, and multifocal subcortical white matter changes with confluent periatrial T2 signal hyperintensity. A combination of these features was present in ten of the 12 individuals reviewed. Conclusions Despite the small number of reported individuals with RMND1 mutations, a clinically recognizable phenotype of leukoencephalopathy with temporal lobe swelling, rarefaction, and cystic changes has emerged in a subset of individuals. Careful clinical phenotyping, including for lactic acidosis, deafness, and severe muscle involvement seen in RMND1 mutation positive individuals, and MRI pattern recognition will be important in differentiating these patients from children with congenital infections like cytomegalovirus

L1 Mosaicism in Mammals:Extent, Effects, and Evolution

The retrotransposon LINE-1 (long interspersed element 1, L1) is a transposable element that has extensively colonized the mammalian germline. L1 retrotransposition can also occur in somatic cells, causing genomic mosaicism, as well as in cancer. However, the extent of L1-driven mosaicism arising during ontogenesis is unclear. We discuss here recent experimental data which, at a minimum, fully substantiate L1 mosaicism in early embryonic development and neural cells, including post-mitotic neurons. We also consider the possible biological impact of somatic L1 insertions in neurons, the existence of donor L1s that are highly active (‘hot’) in specific spatiotemporal niches, and the evolutionary selection of donor L1s driving neuronal mosaicism

Correction to: Magnetic resonance imaging spectrum of succinate dehydrogenase-related infantile leukoencephalopathy: MRI in Leukoencephalopathy (Annals of Neurology, (2016), 79, 3, (379-386), 10.1002/ana.24572)

In our article published in March 2016, we described a series of 19 individuals with succinate dehydrogenase (SDH) deficiency-related leukoencephalopathy. Subsequent analysis of genomic data from one of the reported individuals revealed that one is a compound heterozygote for two likely pathogenic variants in DARS2. As reported in our article, individual 12 carries compound heterozygous variants in SDHB, c.541-2A>G that alters a canonical splice site and c.423+20T>A explicitly classified as a “variant of unknown significance.” Routine reanalysis of the genomic data of this patient has now revealed biallelic DARS2 variants that we have classified as “likely pathogenic” following ACMG guidelines: c.228-21_-20delinsCC and c.294G>T; p.(Glu98Asp). The intronic variant, c.228-21_-20delinsCC, has previously been reported and is in a known mutational hotspot that results in the skipping of exon 3 in the DARS2 mRNA. Mutations in DARS2 result in leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL), which has a similar presentation to SDH deficiency-related leukoencephalopathy and overlapping clinical features. At this time, it is assumed that the individual is affected by LBSL and the contributions of the SDHB variants are unknown. Our article discusses the similar clinical course and neuroimaging features of individuals with SDH deficiency-related leukoencephalopathy and LBSL. This new finding does not change the diagnostic pattern observed on magnetic resonance imaging we reported for individuals with SDH deficiency-related leukoencephalopathy. Potential Conflicts of Interest AV receives support from Shire, Gilead, Eli Lilly and Illumina for research activities