Post-infectious irritable bowel syndrome: renaissance time?

Postinfectious irritable bowel syndrome (PI–IBS) is a distinct phenotype of the disease. The occurrence of gastrointestinal symptoms in PI–IBS is in direct chronological connection with an episode of acute intestinal infection. Previously the problem was considered as the outcome of parasitic, protozoal or bacterial infection. The global spread of a novel coronavirus infection (COVID-19) and increase in the number of new cases of IBS in the population suggests a renaissance of PI–IBS and makes us look at this problem again. This article summarizes and presents modern information on the possible mechanisms of development of PI–IBS, including in persons who have undergone COVID-19.

Hsp90 Inhibition: A Promising Therapeutic Approach for ARSACS

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease caused by mutations in the SACS gene, encoding the 520 kDa modular protein sacsin, which comprises multiple functional sequence domains that suggest a role either as a scaffold in protein folding or in proteostasis. Cells from patients with ARSACS display a distinct phenotype including altered organisation of the intermediate filament cytoskeleton and a hyperfused mitochondrial network where mitochondrial respiration is compromised. Here, we used vimentin bundling as a biomarker of sacsin function to test the therapeutic potential of Hsp90 inhibition with the C-terminal-domain-targeted compound KU-32, which has demonstrated mitochondrial activity. This study shows that ARSACS patient cells have significantly increased vimentin bundling compared to control, and this was also present in ARSACS carriers despite them being asymptomatic. We found that KU-32 treatment significantly reduced vimentin bundling in carrier and patient cells. We also found that cells from patients with ARSACS were unable to maintain mitochondrial membrane potential upon challenge with mitotoxins, and that the electron transport chain function was restored upon KU-32 treatment. Our preliminary findings presented here suggest that targeting the heat-shock response by Hsp90 inhibition alleviates vimentin bundling and may represent a promising area for the development of therapeutics for ARSACS.

Hemochromatosis classification: update and recommendations by the BIOIRON Society

Hemochromatosis (HC) is a genetically heterogeneous disorder in which uncontrolled intestinal iron absorption may lead to progressive iron overload responsible for disabling and life-threatening complications such as arthritis, diabetes, heart failure, hepatic cirrhosis, and hepatocellular carcinoma. The recent advances in the knowledge of pathophysiology and molecular basis of iron metabolism have highlighted that HC is caused by mutations in at least five genes, resulting in insufficient hepcidin production or, rarely, resistance to hepcidin action. This has led to an HC classification based on different molecular subtypes, mainly reflecting successive gene discovery. This scheme was difficult to adopt in clinical practice and therefore needs revision. Here we present recommendations for unambiguous HC classification developed by a working group of the International Society for the Study of Iron in Biology and Medicine (BIOIRON Society) including both clinicians and basic scientists during a meeting in Heidelberg, Germany. We propose to deemphasize the use of the molecular subtype criteria in favor of a classification addressing both clinical issues and molecular complexity. Ferroportin Disease (former type 4a) has been excluded because of its distinct phenotype. The novel classification aims to be of practical help whenever a detailed molecular characterization of HC is not readily available.

Analyse von Zellfunktionen mit Hochdurchsatz-Mikroskopie und KI

Genes that share a distinct phenotype often share biological functions. A principle that is used in genetic screens and that provides the basis for our understanding of key biological processes. Traditionally, individual phenotypes were used to group mutant alleles into cellular pathways. Today, high-throughput technologies allow the screening of thousands of perturbations. Using computational methods and machine learning, millions of images are profiled to assign biological effects to genes and drugs.

Exertional intolerance and dyspnea with preserved lung function: an emerging long COVID phenotype?

The COVID-19 pandemic has resulted in significant acute morbidity and mortality worldwide. There is now a growing recognition of the longer-term sequelae of this infection, termed “long COVID”. However, little is known about this condition. Here, we describe a distinct phenotype seen in a subset of patients with long COVID who have reduced exercise tolerance as measured by the 6 min walk test. They are associated with significant exertional dyspnea, reduced health-related quality of life and poor functional status. However, surprisingly, they do not appear to have any major pulmonary function abnormalities or increased burden of neurologic, musculoskeletal or fatigue symptoms.

Extent of eosinophilic esophagitis predicts response to treatment

Background and study aim The clinical impact of eosinophilic esophagitis (EoE) limited to the distal esophagus (Lim-EE) vs. diffuse involvement (Dif-EE) is unknown. This study compared clinical characteristics and outcomes of Lim-EE vs. Dif-EE. Patients and methods This retrospective, single-center study of patients with EoE between December 2011 and December 2019 evaluated treatment response based on repeated pathology and/or clinical improvement using comparative statistics. Results 479 patients were identified (126 Lim-EE, 353 Dif-EE). Lim-EE patients had a higher incidence of endoscopically identified esophagitis (23.0 % vs. 14.7 %; P = 0.04), were older (50.8 [SD 16.2] vs. 46.4 [SD 15.3] years; P = 0.007), and were more likely to present with iron deficiency anemia (5.6 % vs. 1.7 %; P = 0.05), dyspepsia (15.1 % vs. 8.8 %; P = 0.06) or for Barrett’s surveillance (10.3 % vs. 3.7 %; P = 0.02). Patients with Dif-EE presented more frequently with dysphagia (57.2 % vs. 45.2 %; P = 0.02). Both groups had similar proton pump inhibitor (87.2 % vs. 83.3 %; P = 0.37) and steroid (12.8 % vs. 21.4 %; P = 0.14) use. Patients with Lim-EE had a better clinicopathologic response (61.5 % vs. 44.8 %; P = 0.009). On multivariate analysis, EoE extent predicted treatment response with an odds ratio of 1.89 (95 % confidence interval 1.13–3.20; P = 0.02). However, treatment response based only on repeat biopsy results showed no statistical difference between Lim-EE (52.5 %) and Dif-EE (39.7 %; P = 0.15). Conclusions Lim-EE may represent a distinct phenotype separate from Dif-EE, with more overlap with gastroesophageal reflux disease and better treatment response.

388 Familial natural short sleepers have greater resilience than unaffected family members

Introduction Resilience, a life-long trait, corresponds to the ability to bounce back from adversity. What factors influence resilience is unclear. Here we describe a cohort of individuals with familial natural short sleep (FNSS). Four genes in five families have been identified that confer this trait, DEC2, NPSR1, GRM1 and ADRB1. Individuals in this cohort share a resilience phenotype alongside this decreased sleep need. Methods Those reporting less than 6.5 hours of sleep when allowed to sleep ad libitum without any complaints regarding overnight sleep or daytime sleepiness were then interviewed to determine FNSS affected status from 2009 to 2020. Data on mood, depression, sleepiness and resilience were collected from participants and family members enrolled in the FNSS study. Results 163 individuals meeting criteria for FNSS were enrolled. Compared to 47 unaffected family members, they had significantly shorter sleep duration as measured by self report and actigraphy, significantly more resilience as measured by the Connor-Davidson Resilience Scale, significantly less sleepiness as measured by the Epworth Sleepiness Scale, and significantly fewer symptoms of depression as measured by the Beck Depression Inventory. Conclusion FNSS individuals appear to have a distinct phenotype including shorter sleep duration, greater resilience, less subjective sleepiness, and fewer symptoms of depression. Better understanding the genetics and characteristics of those with familial natural short sleep may provide insight into mechanisms of both restorative sleep and resilience. Support (if any) This work was supported by NIH grants NS099333, NS072360 and NS104782 to L.J.P. and Y-H.F., and by the William Bowes Neurogenetics Fund to L.J.P. and Y.H.F.

CTNNB1-Mutant Aldosterone-Producing Adenomas With Somatic Mutations of GNA11/GNAQ Have Distinct Phenotype and Genotype

Background: We report (this meeting) somatic mutation of GNA11/Q in CTNNB1-mutant APAs. The recurrent co-driver mutation causes reversible hypertension in puberty, pregnancy, or menopause. We have investigated the molecular mechanism of this association. Methods: Gene expression profiles in 3 double mutant APAs were studied by unsupervised hierarchical clustering analysis and enrichment analysis of 362 differentially expressed genes and validated by qPCR, IFC and IHC in 10 double mutant APAs or transfected primary adrenal cells. Multiple region biopsies were performed in 7 adrenals adjacent to double-mutant APAs and 4 APAs with KCNJ5 or CACNA1D mutations. The findings of APA mutations in adjacent adrenals were replicated in each case by ddPCR ± NGS. Results: Unsupervised hierarchical clustering analysis showed clustering of the double-mutant APAs, and a high proportion of genes were many-fold upregulated compared to other APAs. LHCGR, TMEM132E, DKK1, C9orf84, FAP, GNRHR and MPP3 are among the genes with high expression. A small number of genes are down-regulated in the double-mutant APAs, including CYP11B1. qPCR confirmed an average of ~10 to 1000-fold higher expression of the hallmark genes in double-mutants. Enrichment analysis showed significant enrichment of features or terms concerned with cell junction and cell adhesion (P<10–8). IFC confirmed LHCGR intensity was 31–144 fold higher in primary adrenal cells with GNA11-p.Gln209Pro transfection and high CTNNB1 intensity. LHCGR intensity was qualitatively and quantitatively associated with immunofluorescence for CTNNB1. IHC of double-mutant APAs showed absent CYP11B1 but strong staining of CYP11B2. qPCR confirmed a lower CYP11B1/CYP11B2 ratio and a higher LHCGR expression (P<10–3, both). IHC confirmed LHCGR positivity in double-mutant APAs but distribution varied both within and between cells. Adjacent ZG was hyperplastic, with absence of both CYP11B1 and CYP11B2 staining, but weak/moderate staining for LHCGR. The same GNA11 ± CTNNB1 somatic mutations were detected in multiple regions of the adjacent adrenals to 3 double mutant APAs. qPCR of hallmark APA genes differed from the APAs. High concordance between ddPCR, NGS and Sanger sequencing of the findings of APA mutations in adjacent adrenals when analysed in the same sample. No mutations were found in 4 adrenals adjacent to APAs with KCNJ5 or CACNA1D mutations, nor in other 4 adrenals adjacent to double-mutant APAs. Conclusions: Patients harboring APAs with somatic mutations in both GNA11/GNAQ Q209 and CTNNB1 have distinct phenotype in both the APAs and their adjacent adrenals. Same GNA11 ± CTNNB1 somatic mutations were found in the adjacent adrenals to double mutant APAs. We infer that a double-hit within related pathways is more likely than a single-hit to cause large increases in expression of LHCGR, and of other genes which may influence clinical presentation.