Article
Medicine, Legal
Lorenzo Gitto, Cristine E. Fuller, Vincent J. Calleo, Michel Tawil, Rasmey Thach, Carolyn Revercomb
Summary: Ornithine Transcarbamylase (OTC) deficiency is a rare genetic disorder characterized by hyperammonemia and central nervous system involvement, resulting in symptoms such as seizures, coma, and potential death. Early diagnosis and screening of family members for genetic mutations are crucial in preventing life-threatening complications associated with OTC deficiency.
JOURNAL OF FORENSIC SCIENCES
(2022)
Article
Gastroenterology & Hepatology
Koji Imoto, Masatake Tanaka, Takeshi Goya, Tomomi Aoyagi, Motoi Takahashi, Miho Kurokawa, Shigeki Tashiro, Masaki Kato, Motoyuki Kohjima, Yoshihiro Ogawa
Summary: This study investigated the mechanism of hyperammonemia induced by corticosteroid administration in a mouse model of OTCD. The results showed that corticosteroids induced hyperammonemia in OTCD mice by both muscle catabolism and suppression of gene expressions related to the urea cycle. Early intervention with renal replacement therapy should be considered in corticosteroid-induced UCD patients to prevent brain injuries or fatal outcomes.
BMC GASTROENTEROLOGY
(2022)
Article
Medicine, General & Internal
Xiao-Hui Fu, Yu-Hui Hu, Ian-Xiang Liao, Li Chen, Zhan-Qi Hu, Jia-Lun Wen, Shu-Li Chen
Summary: Liver transplantation can significantly improve neurological impairment caused by OTCD and eliminate the risk of hyperammonemia.
WORLD JOURNAL OF CLINICAL CASES
(2022)
Article
Medicine, General & Internal
Shin Enosawa, Huai-Che Hsu, Yusuke Yanagi, Hitomi Matsunari, Ayuko Uchikura, Hiroshi Nagashima
Summary: To develop novel medical technologies, a genetically engineered ornithine transcarbamylase-deficient (OTCD) pig strain was established and its characteristics and treatment responsiveness were reported. The OTCD pigs were obtained through mating an OTCD carrier female with a wild-type male, with the disease phenotype only appearing in males due to X-linked recessive inheritance. Treatment with nitrogen-scavenging agents based on a clinical protocol significantly extended the survival time of the OTCD pigs.
JOURNAL OF CLINICAL MEDICINE
(2021)
Review
Critical Care Medicine
S. Redant, A. Empain, A. Mugisha, P. Kamgang, R. Attou, P. M. Honore, D. De Bels
Summary: Hyperammonemia caused by urea cycle disorders is a rare metabolic encephalopathy that may be underdiagnosed. Treatment includes adapted nutrition, scavenging agents, and dialysis, but diagnosis and treatment in adults remain challenging, requiring timely intervention to prevent the risk of cerebral edema.
ANNALS OF INTENSIVE CARE
(2021)
Review
Behavioral Sciences
Xin Jin, Xinchen Zeng, Dong Zhao, Nan Jiang
Summary: Liver transplantation can fundamentally solve the problem of ammonia metabolism in the liver and avoid further damage to the central nervous system caused by hyperammonemia in OTCD patients with central nervous system injury. At the same time, if liver transplantation is performed as soon as possible, nerve repair is still possible, especially in children whose nervous systems are in the developmental stage.
BRAIN AND BEHAVIOR
(2022)
Article
Medicine, General & Internal
Shin Kadono, Dai Miyawaki, Ayako Goto, Kaoru Hirai, Shoko Sakamoto, Hiroki Hama, Sayaka Nishiura, Takashi Hamazaki, Koki Inoue
Summary: This study identified a rare congenital metabolic error called ornithine transcarbamylase (OTC) deficiency, which is associated with urea cycle disorders and hyperammonemia. The psychiatric symptoms of hyperammonemia can resemble those of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). While previous studies have reported misdiagnosis of OTC deficiency as ASD or ADHD, there have been no reports of comorbidity between OTC deficiency, ASD, and ADHD.
Article
Pediatrics
Hiroi Eguchi, Toshihiko Kakiuchi, Masanori Nishi, Kanako Kojima-Ishii, Kei Nishiyama, Yuhki Koga, Muneaki Matsuo
Summary: This case report describes a patient with juvenile myelomonocytic leukemia (JMML) who developed late-onset ornithine transcarbamylase deficiency (OTCD) after relapse. It highlights the importance of considering hyperammonemia as a differential diagnosis during the treatment of hematologic malignancies and emphasizes the need for prompt treatment.
FRONTIERS IN PEDIATRICS
(2022)
Review
Pediatrics
Majitha Seyed Ibrahim, Jessica I. Gold, Alison Woodall, Berna Seker Yilmaz, Paul Gissen, Karolina M. Stepien
Summary: Ornithine transcarbamylase deficiency (OTCD) is a common inherited disorder of the urea cycle, transmitted as an X-linked recessive trait. Defects in the OTC gene impair ureagenesis, leading to hyperammonemia, brain damage, and death. Symptoms of late-onset OTCD can vary in severity and can be worsened by metabolic stressors or increased demands on the urea cycle.
Review
Clinical Neurology
Kuntal Sen, Afrouz A. Anderson, Matthew T. Whitehead, Andrea L. Gropman
Summary: The urea cycle disorders (UCD) are rare genetic disorders resulting from deficiencies in enzymes or proteins that remove waste nitrogen from the body. This review focuses on neuroimaging studies in two types of UCD, highlighting the cognitive and neurobehavioral impacts, especially on executive function and working memory. Clinical management aims at neuroprotection from hyperammonemia and other metabolites, with a major challenge and research focus on preventing neurological injury. Neuroimaging modalities, particularly multimodal imaging platforms, provide valuable information for understanding neurocognitive function and biomarkers, improving clinical decision-making and therapeutic interventions.
FRONTIERS IN NEUROLOGY
(2021)
Article
Medicine, General & Internal
Rastislav Sysak, Katarina Brennerova, Romana Krlin, Peter Stencl, Igor Rusnak, Maria Vargova
Summary: Ornithine transcarbamylase deficiency can lead to hyperammonemia in pregnant women, particularly in the first week after delivery. This article emphasizes the importance of strict adherence to protein intake recommendations and multidisciplinary monitoring for pregnant patients with OTC deficiency. It also discusses a case of severe hepatic failure in an OTC deficient patient during pregnancy.
Article
Clinical Neurology
Svenja Scharre, Roland Posset, Sven F. Garbade, Florian Gleich, Marie J. Seidl, Ann-Catrin Druck, Juergen G. Okun, Andrea L. Gropman, Sandesh C. S. Nagamani, Georg F. Hoffmann, Stefan Koelker, Matthias Zielonka
Summary: This study developed a severity-adjusted classification system based on residual enzymatic OTC activity for predicting disease severity in male individuals with OTC-D. Residual enzymatic OTC activity was found to reliably predict disease severity and could serve as a tool for adjusting therapeutic strategies.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2022)
Article
Endocrinology & Metabolism
Stephanie Gobin-Limballe, Chris Ottolenghi, Fabien Reyal, Jean-Baptiste Arnoux, Maryse Magen, Marie Simon, Anais 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
Summary: This study on females in OTC deficient families found that 22% of heterozygous females were clinically affected, with a higher risk of severe disease in females with severe mutations. Variability in OTC activity and X inactivation profile within the liver was observed, with little correlation between the two in most cases.
JOURNAL OF INHERITED METABOLIC DISEASE
(2021)
Article
Hematology
Galina Tsykunova, Erle Kristensen, Asbjorg Stray-Pedersen, Oyvind Bruserud, Ida Wiig Sorensen, Oystein Bruserud, Tor Henrik Anderson Tvedt
Summary: Hyperammonemia is a rare and often fatal complication following stem cell transplantation, and its diagnosis can be delayed due to subtle symptoms. This case report describes a female patient who developed hyperammonemia after an autologous stem cell transplant, and it was determined to be caused by a urea cycle disorder through genetic investigations.
Article
Genetics & Heredity
Kathryn Clarkston, Joy Lee, Sarah Donoghue, Heidi Peters, Hernan Eiroa, Amit A. Shah, Kathleen Loomes, Jessica Wen, Mark Oliver, Winita Hardikar, Carlos E. Prada, Akihiro Asai
Summary: This study describes 10 females with ornithine transcarbamylase (OTC) deficiency and liver dysfunction, showing a unique pattern of hepatocyte injury where initial hyperammonemia and coagulopathy is followed by a delayed peak in aminotransferase levels. Five patients eventually underwent liver transplant for recurrent metabolic crises. Further investigations into the pathophysiology of liver dysfunction in OTC-deficient patients are needed to develop therapies and prevent the need for liver transplant.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2021)
Article
Biochemistry & Molecular Biology
David Castillo-Azofeifa, Elena N. Fazio, Roy Nattiv, Hayley J. Good, Tomas Wald, Michael A. Pest, Frederic J. de Sauvage, Ophir D. Klein, Samuel Asfaha
Review
Developmental Biology
Tingsheng Yu, Ophir D. Klein
Article
Genetics & Heredity
Estelle Wall, Jonathan Scoles, Adriane Joo, Ophir Klein, Carlo Quinonez, Jeffrey O. Bush, Gail R. Martin, Diana J. Laird
G3-GENES GENOMES GENETICS
(2020)
Article
Cell & Tissue Engineering
Naren P. Tallapragada, Hailey M. Cambra, Tomas Wald, Samantha Keough Jalbert, Diana M. Abraham, Ophir D. Klein, Allon M. Klein
Summary: This study explores how intestinal organoids self-organize and generate stem cell zones (SCZs) of typical size. The size of SCZs is influenced by ion channel-mediated inflation and mechanosensitive Piezo-family channels, leading to fission through dynamic behavior. Inflation drives stem cell differentiation and induces a stretch-responsive cell state with large transcriptional changes, including upregulation of Piezo1.
Article
Developmental Biology
Rebecca Kim, Tingsheng Yu, Jingjing Li, Jan Prochazka, Amnon Sharir, Jeremy B. A. Green, Ophir D. Klein
Summary: This study demonstrates the crucial role of Wnt/beta-catenin signaling in the earliest stages of tooth formation, with the relative timing of epithelial and mesenchymal cell convergence regulated by canonical Wnt signaling determining invagination versus evagination morphogenesis. These findings reveal new insights into Wnt/beta-catenin signaling in tooth formation and epithelial morphogenesis.
Article
Cell Biology
Brisa Palikuqi, Jeremie Rispal, Ophir Klein
Summary: The intestinal epithelium undergoes continuous cellular turnover, and intestinal stem cells (ISCs) can both self-renew and differentiate. Under stress conditions, intestinal epithelial cells are quite plastic, allowing for dedifferentiation and reversal of cell fate. The ISC niche, made up of various cell types, plays a central role in intestinal function.
COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY
(2022)
Article
Cell & Tissue Engineering
Brisa Palikuqi, Jeremie Rispal, Efren A. Reyes, Dedeepya Vaka, Dario Boffelli, Ophir Klein
Summary: The intestinal epithelium can continuously renew and regenerate, and the proliferation and maintenance of intestinal stem cells (ISCs) are regulated by their surrounding niche cells. In this study, lymphatic endothelial cells (LECs) were found to play an essential role in supporting epithelial renewal and repair by secreting molecules in close proximity to crypt epithelial cells. LECs were identified as a crucial source of Wnt signaling in the small intestine, and their loss hindered recovery after cytotoxic injury.
Article
Multidisciplinary Sciences
Adam J. Stevens, Andrew R. Harris, Josiah Gerdts, Ki H. Kim, Coralie Trentesaux, Jonathan T. Ramirez, Wesley L. McKeithan, Faranak Fattahi, Ophir D. Klein, Daniel A. Fletcher, Wendell A. Lim
Summary: Cell adhesion molecules play a crucial role in various cellular processes, and their synthetic counterparts can be generated by combining extracellular interactions with intracellular domains. These synthetic molecules allow for customized cell-cell interactions with properties similar to native interactions. The intracellular domains determine the interface morphology and mechanics, while the extracellular interaction domains specify the connectivity between cells. This toolkit of synthetic cell adhesion molecules enables the assembly of multicellular architectures and the systematic remodeling of native tissues, providing insights into the evolution of different classes of cell-cell interfaces. Overall, these tools have significant implications for cell and tissue engineering and the study of multicellular organization.
Article
Biochemistry & Molecular Biology
Jordan J. Bannister, Matthias Wilms, J. David Aponte, David C. Katz, Ophir D. Klein, Francois P. Bernier, Richard A. Spritz, Benedikt Hallgrimsson, Nils D. Forkert
Summary: Human genetic syndromes are difficult to diagnose clinically, and facial phenotype plays a crucial role in diagnosis. Computer-assisted facial phenotyping has shown promise in aiding diagnosis. This study compares the performance of 2D and 3D image-based approaches to syndrome diagnosis and finds that 3D surface-based classification models outperform 2D image-based models. These findings suggest that the adoption of 3D facial scanning technology and collection of syndromic 3D facial scan data can greatly improve face-based syndrome diagnosis.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Genetics & Heredity
Sahin Naqvi, Seungsoo Kim, Hanne Hoskens, Harold S. S. Matthews, Richard A. A. Spritz, Ophir D. D. Klein, Benedikt Hallgrimsson, Tomek Swigut, Peter Claes, Jonathan K. K. Pritchard, Joanna Wysocka
Summary: Transcriptional regulation is robust but sensitive to transcription factor (TF) dosage, especially in craniofacial morphology. By modulating TF levels in human facial progenitor cells, researchers found that most SOX9-dependent regulatory elements (REs) are buffered against small decreases in SOX9 dosage, while REs directly regulated by SOX9 are more sensitive and affect chondrogenesis and craniofacial shape variation associated with PRS.
Article
Multidisciplinary Sciences
Mona M. Christensen, Outi Hallikas, Rishi Das Roy, Vilma Vaananen, Otto E. Stenberg, Teemu J. Hakkinen, Jean-Christophe Francois, Robert J. Asher, Ophir D. Klein, Martin Holzenberger, Jukka Jernvall
Summary: When it comes to differences in body size due to evolution, organs tend to scale proportionally. This study focuses on the scaling of mammalian molar teeth, specifically looking at the development process in mice and rats. While the shapes of their molars are similar, the rat molars are twice the size of the mouse molars. The study reveals that insulin-like growth factor 1 (Igf1), a known regulator of body size, is more highly expressed in rat molars compared to mouse molars, and its modulation can reproduce the observed scaling process.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Yi Liu, Efren Reyes, David Castillo-Azofeifa, Ophir D. Klein, Todd Nystul, Diane L. Barber
Summary: Liu et al. find that intracellular pH dynamics regulate the secretory cell fate decision of intestinal stem cells. They observe an intracellular pH gradient in mouse small intestinal crypts, with the lowest pH in crypt stem cells and increasing along the crypt column. Disrupting this gradient inhibits crypt budding and Paneth cell differentiation, which can be rescued by exogenous WNT. They demonstrate that intracellular pH dynamics acts downstream of ATOH1, with increased pH promoting differentiation toward the secretory lineage. These findings establish a role for intracellular pH dynamics in cell fate decisions within an adult stem cell lineage.
NATURE COMMUNICATIONS
(2023)
Editorial Material
Dentistry, Oral Surgery & Medicine
O. D. Klein
JOURNAL OF DENTAL RESEARCH
(2023)
Article
Multidisciplinary Sciences
Satoshi Toda, Wesley L. McKeithan, Teemu J. Hakkinen, Pilar Lopez, Ophir D. Klein, Wendell A. Lim
Article
Endocrinology & Metabolism
Pauline Marangoni, Cyril Charles, Youngwook Ahn, Kerstin Seidel, Andrew Jheon, Bernhard Ganss, Robb Krumlauf, Laurent Viriot, Ophir D. Klein