Shira London, Elisa De Franco, Ghadir Elias-Assad, Marie Noufi Barhoum, Clari Felszer, Marina Paniakov, Scott A Weiner, Yardena Tenenbaum-Rakover
Background: Mutations in GLIS3 cause a rare syndrome characterized by neonatal diabetes mellitus (NDM), congenital hypothyroidism, congenital glaucoma and cystic kidneys. To date, 14 mutations in GLIS3 have been reported, inherited in an autosomal recessive manner. GLIS3 is a key transcription factor involved in β-cell development, insulin expression, and development of the thyroid, eyes, liver and kidneys. Cases: We describe non-identical twins born to consanguineous parents presenting with NDM, congenital hypothyroidism, congenital glaucoma, hepatic cholestasis, cystic kidney and delayed psychomotor development...
2021: Frontiers in Endocrinology
Tracey Jones-Hughes, Jo Campbell, Louise Crathorne
BACKGROUND: Progressive familial intrahepatic cholestasis is a rare, heterogeneous group of liver disorders of autosomal recessive inheritance, characterised by an early onset of cholestasis with pruritus and malabsorption, which rapidly progresses, eventually culminating in liver failure. For children and their parents, PFIC is an extremely distressing disease. Significant pruritus can lead to severe cutaneous mutilation and may affect many activities of daily living through loss of sleep, irritability, poor attention, and impaired school performance...
June 3, 2021: Orphanet Journal of Rare Diseases
Qinrui Fu, Jiamin Ye, Juejun Wang, Naishun Liao, Hongjuan Feng, Lichao Su, Xiaoguang Ge, Huanghao Yang, Jibin Song
Wilson's disease (WD) is a rare inherited disorder of copper metabolism with pathological copper hyperaccumulation in some vital organs. However, the clinical diagnosis technique of WD is complicated, aggressive, and time-consuming. In this work, a novel ratiometric photoacoustic (PA) imaging nanoprobe in the NIR-II window is developed to achieve noninvasive, rapid, and accurate Cu2+ quantitative detection in vitro and in vivo. The nanoprobe consists of Cu2+ -responsive IR970 dye and a nonresponsive palladium-coated gold nanorod (AuNR-Pd), achieving a concentration-dependent ratiometric PA970 /PA1260 signal change...
June 3, 2021: Small
Brian T Lee, Michele M Tana, Jeffrey A Kahn, Lily Dara
Autoimmune liver diseases are attributed to a complex interplay of biologic, acquired, and environmental factors. Increased prevalence, later stage of presentation, worse response to standard therapy, and transplant-related disparities have all been reported in racial and ethnic minorities such as Black and Latinx patients with autoimmune liver diseases. While biology and inherited genetic predispositions may partly explain these disparities, definitive and universal genetic variations underlying these differences in outcomes have not been defined...
May 31, 2021: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Jingsong Cao, Minjung Choi, Eleonora Guadagnin, Maud Soty, Marine Silva, Vincent Verzieux, Edward Weisser, Arianna Markel, Jenny Zhuo, Shi Liang, Ling Yin, Andrea Frassetto, Anne-Renee Graham, Kristine Burke, Tatiana Ketova, Cosmin Mihai, Zach Zalinger, Becca Levy, Gilles Besin, Meredith Wolfrom, Barbara Tran, Christopher Tunkey, Erik Owen, Joe Sarkis, Athanasios Dousis, Vladimir Presnyak, Christopher Pepin, Wei Zheng, Lei Ci, Marjie Hard, Edward Miracco, Lisa Rice, Vi Nguyen, Mike Zimmer, Uma Rajarajacholan, Patrick F Finn, Gilles Mithieux, Fabienne Rajas, Paolo G V Martini, Paloma H Giangrande
Glycogen Storage Disease 1a (GSD1a) is a rare, inherited metabolic disorder caused by deficiency of glucose 6-phosphatase (G6Pase-α). G6Pase-α is critical for maintaining interprandial euglycemia. GSD1a patients exhibit life-threatening hypoglycemia and long-term liver complications including hepatocellular adenomas (HCAs) and carcinomas (HCCs). There is no treatment for GSD1a and the current standard-of-care for managing hypoglycemia (Glycosade® /modified cornstarch) fails to prevent HCA/HCC risk. Therapeutic modalities such as enzyme replacement therapy and gene therapy are not ideal options for patients due to challenges in drug-delivery, efficacy, and safety...
May 25, 2021: Nature Communications
Jonathan A Fridell, Molly A Bozic, Benjamin J Ulrich, Andrew J Lutz, John A Powelson
Cystic fibrosis (CF) is an inherited autosomal recessive disorder. Despite optimized therapy, the majority of affected individuals ultimately die of respiratory failure. As patients with CF are living longer, extra-pulmonary manifestations may develop including pancreatic failure, which manifests as exocrine insufficiency, and CF related diabetes (CFRD). Both of these can be managed through pancreas transplantation. Pancreas transplantation is usually performed in combination with another organ, most often with a kidney transplant for end-stage diabetic nephropathy...
May 25, 2021: Clinical Transplantation
Cristiana Bianco, Elia Casirati, Francesco Malvestiti, Luca Valenti
Fatty liver disease can be triggered by a combination of excess alcohol, dysmetabolism and other environmental cues, which can lead to steatohepatitis and can evolve to acute/chronic liver failure and hepatocellular carcinoma, especially in the presence of shared inherited determinants. The recent identification of the genetic causes of steatohepatitis is revealing new avenues for more effective risk stratification. Discovery of the mechanisms underpinning the detrimental effect of causal mutations has led to some breakthroughs in the comprehension of the pathophysiology of steatohepatitis...
June 2021: JHEP reports: innovation in hepatology
Kris V Kowdley, Eric M Gochanour, Vinay Sundaram, Raj A Shah, Priya Handa
Hepcidin, a peptide hormone produced by hepatocytes, is the central regulator of systemic iron homeostasis through its interaction with ferroportin, the major cellular iron export protein. Hepcidin binding to ferroportin results in reduced iron export from macrophages and intestinal absorptive cells, leading to decreased serum iron levels. Hepcidin expression is influenced by several factors that include serum and liver iron stores, erythropoiesis, hypoxia, inflammation, and infection. Erythropoietic drive and hypoxia suppress hepcidin expression and promote red cell production...
May 2021: Hepatology Communications
Jingyi Guo, Lifan Duan, Xueying He, Shengbiao Li, Yi Wu, Ge Xiang, Feixiang Bao, Liang Yang, Hongyan Shi, Mi Gao, Lingjun Zheng, Huili Hu, Xingguo Liu
Mitochondrial DNA depletion syndrome (MDS) is a group of severe inherited disorders caused by mutations in genes, such as deoxyribonucleoside kinase (DGUOK). A great majority of DGUOK mutant MDS patients develop iron overload progressing to severe liver failure. However, the pathological mechanisms connecting iron overload and hepatic damage remains uncovered. Here, two patients' skin fibroblasts are reprogrammed to induced pluripotent stem cells (iPSCs) and then corrected by CRISPR/Cas9. Patient-specific iPSCs and corrected iPSCs-derived high purity hepatocyte organoids (iHep-Orgs) and hepatocyte-like cells (iHep) are generated as cellular models for studying hepatic pathology...
May 2021: Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
Rana Swed-Tobia, Imad Kassis, Karin Weiss, Galit Tal, Ron Shaoul, Tzipora C Falik-Zaccai, Hanna Mandel, Michal Meir
Inherited liver diseases may present in infancy as cholestatic jaundice progressing to severe hepatic dysfunction. Congenital cytomegalovirus (cCMV) infection may initially involve the liver, yet in otherwise healthy hosts rarely leads to long-term hepatic disease. We report a series of three patients, diagnosed with hereditary liver diseases: progressive familial intrahepatic cholestasis (PFIC) type IV, alpha 1 anti-trypsin deficiency (A1ATD) and Alagille syndrome (ALGS), who were also diagnosed with cCMV infection...
May 20, 2021: European Journal of Medical Genetics
Robert Hegarty, Philippa Gibson, Melissa Sambrotta, Sandra Strautnieks, Pierre Foskett, Sian Ellard, Julia Baptista, Suzanne Lillis, Sanjay Bansal, Roshni Vara, Anil Dhawan, Tassos Grammatikopoulos, Richard J Thompson
OBJECTIVE: To use next generation sequencing (NGS) technology to identify undiagnosed, monogenic diseases in a cohort of children who suffered from acute liver failure (ALF) without an identifiable etiology. STUDY DESIGN: We identified 148 under 10 years of age admitted to King's College Hospital, London, with ALF of indeterminate etiology between 2000 and 2018. A custom NGS panel of 64 candidate genes known to cause ALF and / or metabolic liver disease was constructed...
May 20, 2021: Journal of Pediatrics
Thomas A Forbes, Bob D Brown, Cheng Lai
RNA interference (RNAi) is a natural biological pathway that inhibits gene expression by targeted degradation or translational inhibition of cytoplasmic messenger RNA (mRNA) by the RNA induced silencing complex. RNAi has long been exploited in laboratory research to study the biological consequences of the reduced expression of a gene of interest. More recently RNAi has been demonstrated as a therapeutic avenue for rare metabolic diseases. This review presents an overview of the cellular RNAi machinery as well as therapeutic RNAi design and delivery...
May 22, 2021: British Journal of Clinical Pharmacology
Menachem Sadeh, Keren Yosovich, Ron Dabby
Glycogen storage disease type III is a rare inherited disease caused by decreased activity of glycogen debranching enzyme. It affects primarily the liver, cardiac muscle, and skeletal muscle. Pure involvement of the skeletal muscle with adult onset is extremely rare. We report on a patient with myopathy due to glycogen storage disease III, and describe the clinical features, and pathologic and genetic findings.
June 1, 2021: Journal of Clinical Neuromuscular Disease
Yingqiang Chen, Ruoqing Li, Lin Zhang, Linlin Gan, Jianqiang Ding
OBJECTIVE: α-1 antitrypsin deficiency (AATD) is an inherited liver disease characterized by the "Z" mutations, which can cause pulmonary emphysema and liver fibrosis. Transplantation of the organ (i.e., the lung/liver) is the best treatment method, however, the scarcity of suitable donors limits its application. The cell transplantation technique poses an alternative way of combating liver failure. METHODS: Hepatic specific differentiation of the human induced pluripotent stem cells (iPSCs) was initiated with 100 ng/mL activin A, followed by 20 ng/mL of BMP-4 and 10 ng/mL of FGF-2...
2021: American Journal of Translational Research
Stephanie Gobin-Limballe, Chris Ottolenghi, Fabien Reyal, Jean-Baptiste Arnoux, Maryse Magen, Marie Simon, Anaïs Brassier, Fabienne Jabot-Hanin, Pascale De Lonlay, Clement Pontoizeau, Manel Guirat, Marlene Rio, Roselyne Gesny, Nadine Gigarel, Ghislaine Royer, Julie Steffann, Arnold Munnich, Jean-Paul Bonnefont
OTC deficiency, an inherited urea cycle disorder, is caused by mutations in the X-linked OTC gene. Phenotype-genotype correlations are well understood in males but still poorly known in females. Taking advantage of a cohort of 130 families (289 females), we assessed the relative contribution of OTC enzyme activity, X chromosome inactivation , and OTC gene sequencing to genetic counselling in heterozygous females. Twenty two percent of the heterozygous females were clinically affected, with episodic (11 %), chronic (7...
May 20, 2021: Journal of Inherited Metabolic Disease
Monica Zanconato Campitruz, Luis T Ortiz-Figueroa, Edgardo Santiago
BACKGROUND: Acute portal vein thrombosis is a rare medical event usually seen in liver disease, but it can also occur due to any inherited or acquired procoagulable state that triggers venous occlusion. Hormonal therapies have been associated with an increased risk of prothrombotic states. This case report documents a portomesenteric venous thrombosis in a postmenopausal woman with testosterone implant for the treatment of hypoactive sexual desire and discusses the importance of identifying hypercoagulable risk factors before initiating hormone replacement therapy...
May 19, 2021: Journal of Medical Case Reports
Jie Bai, Lu Li, Hui Liu, Shuang Liu, Li Bai, Wenyan Song, Yu Chen, Sujun Zheng, Zhongping Duan
Background and Aims: Bilirubin encephalopathy/kernicterus is very rare in adults. This study is aimed to investigate the clinical manifestations and genetic features of two patients with UGT1A1 -related kernicterus. Methods: Sanger sequencing analysis was performed to identify UGT1A1 gene mutations in the patients and their families. Bioinformatics analysis was used to predict the potential functional effects of novel missense mutations. Clinical manifestations and biochemical parameters were collected and analyzed...
April 28, 2021: Journal of Clinical and Translational Hepatology
Lucas T Jennelle, Christopher H Dampier, Stephanie Tring, Steven Powell, Graham Casey
INTRODUCTION: Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer (CRC) syndrome characterized by accelerated adenoma development due to inherited (or de novo) mutations in the APC regulator of WNT signaling pathway (APC) gene. The mechanism underlying this accelerated polyp development in subjects with FAP has not been defined. Given that LGR5+ stem cells drive crypt cell proliferation, we hypothesized that FAP crypts would demonstrate aberrant leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) staining patterns...
May 17, 2021: Clinical and Translational Gastroenterology
Stefania Bruno, Maria Beatriz Herrera Sanchez, Giulia Chiabotto, Valentina Fonsato, Victor Navarro-Tableros, Chiara Pasquino, Marta Tapparo, Giovanni Camussi
Human liver stem cells (HLSCs) were described for the first time in 2006 as a new stem cell population derived from healthy human livers. Like mesenchymal stromal cells, HLSCs exhibit multipotent and immunomodulatory properties. HLSCs can differentiate into several lineages under defined in vitro conditions, such as mature hepatocytes, osteocytes, endothelial cells, and islet-like cell organoids. Over the years, HLSCs have been shown to contribute to tissue repair and regeneration in different in vivo models, leading to more than five granted patents and over 15 peer reviewed scientific articles elucidating their potential therapeutic role in various experimental pathologies...
2021: Frontiers in Cell and Developmental Biology
Dipti Kapoor, Divyani Garg, Suvasini Sharma, Vinay Goyal
Although acquired manganese neurotoxicity has been widely reported since its first description in 1837 and is popularly referred to as "manganism," inherited disorders of manganese homeostasis have received the first genetic signature as recently as 2012. These disorders, predominantly described in children and adolescents, involve mutations in three manganese transporter genes, i.e., SLC30A10 and SLC39A14 which lead to manganese overload, and SLC39A8 , which leads to manganese deficiency. Both disorders of inherited hypermanganesemia typically exhibit dystonia and parkinsonism with relatively preserved cognition and are differentiated by the occurrence of polycythemia and liver involvement in the SLC30A10 -associated condition...
January 2021: Annals of Indian Academy of Neurology
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