Effect And Predictive Value Of Routine Preoperative Laboratory Testing For Endoscopic Retrograde Cholangiopancreatography

Background and Aims: Several studies and guidelines are questioning routine preoperative laboratory tests in surgical and endoscopic procedures. Their effect in endoscopic retrograde cholangiopancreatography is not currently known. This study was carried out to evaluate the risk of adverse effects in endoscopic retrograde cholangiopancreatography and their association with preoperative lab tests. Materials and Methods: A single-center, prospective observational study on all 956 patients undergoing 1196 endoscopic retrograde cholangiopancreatographies in the Endoscopy Unit of Helsinki University Central Hospital from 1 March 2012 to 28 February 2013. Routine preoperative laboratory test results (basic blood count, creatinine, potassium, sodium, international normalized ratio/thromboplastin time, and amylase), health status, medication, and demographic information of all patients were analyzed in relation to adverse effects related to endoscopic retrograde cholangiopancreatography and procedural sedation. Results: Multivariate analysis showed post-endoscopic retrograde cholangiopancreatography pancreatitis (43 cases, 3.6%) to have no association with abnormal routine preoperative laboratory tests. Respiratory depression caused by sedation (128 cases, 11%) was not associated with abnormal routine preoperative laboratory tests, and anemia was found to be a slightly protecting factor. Cardiovascular depression caused by sedation was associated with thrombocytopenia (odds ratio = 1.87, p = 0.025) and, in male patients, hyponatremia (odds ratio = 3.66, p <0.001). Incidence of other adverse effects was too low for statistical analysis. Conclusion: Routine universal preoperative lab testing was not found to be successful in predicting adverse effects in endoscopic retrograde cholangiopancreatography procedures. Laboratory testing should be done focusing on each patient's individual needs.Peer reviewe

An Extended Targeted Copy Number Variation Detection Array Including 187 Genes for the Diagnostics of Neuromuscular Disorders

Background: Our previous array, the Comparative Genomic Hybridisation design (CGH-array) for nemaline myopathy (NM), named the NM-CGH array, revealed pathogenic copy number variation (CNV) in the genes for nebulin (NEB) and tropomyosin 3 (TPM3), as well as recurrent CNVs in the segmental duplication (SD), i.e. triplicate, region of NEB (TRI, exons 82-89, 90-97, 98-105). In the light of this knowledge, we have designed and validated an extended CGH array, which includes a selection of 187 genes known to cause neuromuscular disorders (NMDs). Objective: Our aim was to develop a reliable method for CNV detection in genes related to neuromuscular disorders for routine mutation detection and analysis, as a much-needed complement to sequencing methods. Methods: We have developed a novel custom-made 4×180 k CGH array for the diagnostics of NMDs. It includes the same tiled ultra-high density coverage of the 12 known or putative NM genes as our 8×60 k NM-CGH-array but also comprises a selection of 175 additional genes associated with NMDs, including titin (TTN), at a high to very high coverage. The genes were divided into three coverage groups according to known and potential pathogenicity in neuromuscular disorders. Results: The array detected known and putative CNVs in all three gene coverage groups, including the repetitive regions of NEB and TTN. Conclusions: The targeted neuromuscular disorder 4×180 k array-CGH (NMD-CGH-array v1.0) design allows CNV detection for a broader spectrum of neuromuscular disorders at a high resolution. © 2018 - IOS Press and the authors. All rights reserved.Peer reviewe

An unusual ryanodine receptor 1 (RYR1) phenotype: Mild calf-predominant myopathy

Objective To identify the genetic defect causing a distal calf myopathy with cores.Methods Families with a genetically undetermined calf-predominant myopathy underwent detailed clinical evaluation, including EMG/nerve conduction studies, muscle biopsy, laboratory investigations, and muscle MRI. Next-generation sequencing and targeted Sanger sequencing were used to identify the causative genetic defect in each family.Results A novel deletion-insertion mutation in ryanodine receptor 1 (RYR1) was found in the proband of the index family and segregated with the disease in 6 affected relatives. Subsequently, we found 2 more families with a similar calf-predominant myopathy segregating with unique RYR1-mutated alleles. All patients showed a very slowly progressive myopathy without episodes of malignant hyperthermia or rhabdomyolysis. Muscle biopsy showed cores or core-like changes in all families.Conclusions Our findings expand the spectrum of RYR1-related disorders to include a calf-predominant myopathy with core pathology and autosomal dominant inheritance. Two families had unique and previously unreported RYR1 mutations, while affected persons in the third family carried 2 previously known mutations in the same dominant allele.</div

Neuromyopathy with congenital cataracts and glaucoma: A distinct syndrome caused by POLG variants

We identified three non-related patients manifesting a childhood-onset progressive neuromyopathy with congenital cataracts, delayed walking, distal weakness and wasting, glaucoma and swallowing difficulties. Electrophysiology and nerve biopsies showed a mixed axonal and demyelinating neuropathy, while muscle biopsy disclosed both neurogenic and myopathic changes with ragged red fibers, and muscle MRI showed consistent features across patients, with a peculiar concentric disto-proximal gradient of fatty replacement. We used targeted next generation sequencing and candidate gene approach to study these families. Compound biallelic heterozygous variants, p.[(Pro648Arg)]; [(His932Tyr)] and p.[(Thr251Ile),(Pro587Leu)]; [(Arg943Cys)], were found in the three patients causing this homogeneous phenotype. Our report on a subset of unrelated patients, that showed a distinct autosomal recessive childhood-onset neuromyopathy with congenital cataracts and glaucoma, expands the clinical spectrum of POLG-related disorders. It also confirms the association between cataracts and neuropathy with variants in POLG. Early onset cataract is otherwise rare in POLG-related disorders and so far reported only in a few patients with the clinical pattern of distal myopathy or neuromyopathy

Histopathological differences of myotonic dystrophy type 1 (DM1) and PROMM/DM2

Muscle biopsy findings in DM2 have been reported to be similar to those in DM1. The authors used myosin heavy chain immunohistochemistry and enzyme histochemistry for fiber type differentiation on muscle biopsies. Their results show that DM2 patients display a subpopulation of type 2 nuclear clump and other very small fibers and, hence, preferential type 2 fiber atrophy in contrast to type 1 fiber atrophy in DM1 patients

Role of LKB1 in lung cancer development

Three phenotypically related genetic syndromes and their lesions (LKB1, PTEN, and TSC1/2) are identified as frequently altered in lung cancer. LKB1, a kinase inactivated in 30% of lung cancers, is discussed in this review. Loss of LKB1 regulation often coincident with KRAS activation allows for unchecked growth and the metabolic capacity to accommodate the proliferation

Improved chromosome-level genome assembly of the Glanville fritillary butterfly (Melitaea cinxia) integrating Pacific Biosciences long reads and a high-density linkage map

Background The Glanville fritillary (Melitaea cinxia) butterfly is a model system for metapopulation dynamics research in fragmented landscapes. Here, we provide a chromosome-level assembly of the butterfly's genome produced from Pacific Biosciences sequencing of a pool of males, combined with a linkage map from population crosses. Results The final assembly size of 484 Mb is an increase of 94 Mb on the previously published genome. Estimation of the completeness of the genome with BUSCO indicates that the genome contains 92-94% of the BUSCO genes in complete and single copies. We predicted 14,810 genes using the MAKER pipeline and manually curated 1,232 of these gene models. Conclusions The genome and its annotated gene models are a valuable resource for future comparative genomics, molecular biology, transcriptome, and genetics studies on this species.Peer reviewe

High disease impact of myotonic dystrophy type 2 on physical and mental functioning

The aim of the study was to investigate health status in patients with myotonic dystrophy type 2 (DM2) and determine its relationship to pain and fatigue. Data on health status (SF-36), pain (MPQ) and fatigue (CIS-fatigue) were collected for the Dutch DM2 population (n = 32). Results were compared with those of sex- and age-matched adult-onset myotonic dystrophy type 1 (DM1) patients. In addition, we compared the obtained scores on health status of the DM2 group with normative data of the Dutch general population (n = 1742). Compared to DM1, the SF-36 score for bodily pain was significantly (p = 0.04) lower in DM2, indicating more body pain in DM2. DM2 did not differ from DM1 on any other SF-36 scales. In comparison to the Dutch population, DM2 patients reported lower scores (indicating worse clinical condition) on the physical functioning, role functioning-physical, bodily pain, general health, vitality, social functioning, and role functioning-emotional scales (p < 0.01 on all scales). The difference was most profound for the physical functioning scale. In the DM2 group the severity of pain was significantly correlated with SF-36 scores for bodily pain (p = 0.003). Fatigue was significantly correlated with the SF-36 scores for role functioning-physical (p = 0.001), general health (p = 0.02), and vitality (p = 0.02). The impact of DM2 on a patients’ physical, psychological and social functioning is significant and as high as in adult-onset DM1 patients. From the perspective of health-related quality of life, DM2 should not be considered a benign disease. Management of DM2 patients should include screening for pain and fatigue. Symptomatic treatment of pain and fatigue may decrease disease impact and help improve health status in DM2, even if the disease itself cannot be treated

Exome reanalysis and proteomic profiling identified TRIP4 as a novel cause of cerebellar hypoplasia and spinal muscular atrophy (PCH1)

TRIP4 is one of the subunits of the transcriptional coregulator ASC-1, a ribonucleoprotein complex that participates in transcriptional coactivation and RNA processing events. Recessive variants in the TRIP4 gene have been associated with spinal muscular atrophy with bone fractures as well as a severe form of congenital muscular dystrophy. Here we present the diagnostic journey of a patient with cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures. Initial exome sequencing analysis revealed no candidate variants. Reanalysis of the exome data by inclusion in the Solve-RD project resulted in the identification of a homozygous stop-gain variant in the TRIP4 gene, previously reported as disease-causing. This highlights the importance of analysis reiteration and improved and updated bioinformatic pipelines. Proteomic profile of the patient’s fibroblasts showed altered RNA-processing and impaired exosome activity supporting the pathogenicity of the detected variant. In addition, we identified a novel genetic form of PCH1, further strengthening the link of this characteristic phenotype with altered RNA metabolism