1,114 results match your criteria pathways inborn

Identification of 2,2-Dimethylbutanoic Acid (HST5040), a Clinical Development Candidate for the Treatment of Propionic Acidemia and Methylmalonic Acidemia.

J Med Chem 2021 Apr 13. Epub 2021 Apr 13.

HemoShear Therapeutics Inc., 501 Locust Avenue, Charlottesville, Virginia 22902, United States.

Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare autosomal recessive disorders of propionyl-CoA (P-CoA) catabolism, caused by a deficiency in the enzymes P-CoA carboxylase and methylmalonyl-CoA (M-CoA) mutase, respectively. PA and MMA are classified as intoxication-type inborn errors of metabolism because the intramitochondrial accumulation of P-CoA, M-CoA, and other metabolites results in secondary inhibition of multiple pathways of intermediary metabolism, leading to organ dysfunction and failure. Herein, we describe the structure-activity relationships of a series of short-chain carboxylic acids which reduce disease-related metabolites in PA and MMA primary hepatocyte disease models. Read More

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The Adult Phenylketonuria (PKU) Gut Microbiome.

Microorganisms 2021 Mar 4;9(3). Epub 2021 Mar 4.

Department of Microbiology, Immunology, and Genetics, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.

Phenylketonuria (PKU) is an inborn error of phenylalanine metabolism primarily treated through a phenylalanine-restrictive diet that is frequently supplemented with an amino acid formula to maintain proper nutrition. Little is known of the effects of these dietary interventions on the gut microbiome of PKU patients, particularly in adults. In this study, we sequenced the V4 region of the 16S rRNA gene from stool samples collected from adults with PKU ( = 11) and non-PKU controls ( = 21). Read More

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Redox-Linked Coordination Chemistry Directs Vitamin B Trafficking.

Acc Chem Res 2021 Apr 2. Epub 2021 Apr 2.

Department of Biological Chemistry, Michigan Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.

ConspectusMetals are partners for an estimated one-third of the proteome and vary in complexity from mononuclear centers to organometallic cofactors. Vitamin B or cobalamin represents the epitome of this complexity and is the product of an assembly line comprising some 30 enzymes. Unable to biosynthesize cobalamin, mammals rely on dietary provision of this essential cofactor, which is needed by just two enzymes, one each in the cytoplasm (methionine synthase) and the mitochondrion (methylmalonyl-CoA mutase). Read More

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Cellular and molecular mechanisms breaking immune tolerance in inborn errors of immunity.

Cell Mol Immunol 2021 Apr 1. Epub 2021 Apr 1.

Department of Rheumatology and Immunology, Hannover Medical School, Hanover, Germany.

In addition to susceptibility to infections, conventional primary immunodeficiency disorders (PIDs) and inborn errors of immunity (IEI) can cause immune dysregulation, manifesting as lymphoproliferative and/or autoimmune disease. Autoimmunity can be the prominent phenotype of PIDs and commonly includes cytopenias and rheumatological diseases, such as arthritis, systemic lupus erythematosus (SLE), and Sjogren's syndrome (SjS). Recent advances in understanding the genetic basis of systemic autoimmune diseases and PIDs suggest an at least partially shared genetic background and therefore common pathogenic mechanisms. Read More

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Defective lysosomal storage in Fabry disease modifies mitochondrial structure, metabolism and turnover in renal epithelial cells.

J Inherit Metab Dis 2021 Mar 4. Epub 2021 Mar 4.

Department of General Paediatrics, Adolescent Medicine and Neonatology, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany.

Fabry disease (FD) is an X-linked lysosomal storage disorder. Deficiency of the lysosomal enzyme alpha-galactosidase (GLA) leads to accumulation of potentially toxic globotriaosylceramide (Gb3) on a multisystem level. Cardiac and cerebrovascular abnormalities as well as progressive renal failure are severe, life-threatening long-term complications. Read More

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Extreme phenotypes approach to investigate host genetics and COVID-19 outcomes.

Genet Mol Biol 2021 1;44(1 Suppl 1):e20200302. Epub 2021 Mar 1.

Universidade de São Paulo, Instituto de Biociências, Departamento de Genética e Biologia Evolutiva, Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, São Paulo, SP, Brazil.

COVID-19 comprises clinical outcomes of SARS-CoV-2 infection and is highly heterogeneous, ranging from asymptomatic individuals to deceased young adults without comorbidities. There is growing evidence that host genetics play an important role in COVID-19 severity, including inborn errors of immunity, age-related inflammation and immunosenescence. Here we present a brief review on the known order of events from infection to severe system-wide disturbance due to COVID-19 and summarize potential candidate genes and pathways. Read More

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Ethylmalonic encephalopathy ETHE1 p. D165H mutation alters the mitochondrial function in human skeletal muscle proteome.

Mitochondrion 2021 Feb 24;58:64-71. Epub 2021 Feb 24.

Institute of Bioinformatics, International Tech Park, Bangalore, India; Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India; Manipal Academy of Higher Education, Manipal, India. Electronic address:

Ethylmalonic encephalopathy (EE) is a rare autosomal recessive inborn error of metabolism. To study the molecular effects of ETHE1 p. D165H mutation, we employed mass spectrometry-based mitochondrial proteome and phosphoproteome profiling in the human skeletal muscle. Read More

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February 2021

[Clinical and molecular inflammatory alterations in chronic granulomatous disease].

Rev Alerg Mex 2020 Oct-Dec;67(4):370-380

Secretaría de Salud, Instituto Nacional de Pediatría, Unidad de Investigación en Inmunodeficiencias, Ciudad de México, México.

Chronic granulomatous disease (CGD) is an inborn error of immunity. CGD is characterized by a deficiency in the function of the NADPH oxidase complex. CGD has been an opportunity to study the function of reactive oxygen species (ROS) in the innate immune system. Read More

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February 2021

Inherited disorders of complex lipid metabolism: A clinical review.

J Inherit Metab Dis 2021 Feb 16. Epub 2021 Feb 16.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Over 80 human diseases have been attributed to defects in complex lipid metabolism. A majority of them have been reported recently in the setting of rapid advances in genomic technology and their increased use in clinical settings. Lipids are ubiquitous in human biology and play roles in many cellular and intercellular processes. Read More

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February 2021

Physiological Perspectives on the Use of Triheptanoin as Anaplerotic Therapy for Long Chain Fatty Acid Oxidation Disorders.

Front Genet 2020 15;11:598760. Epub 2021 Jan 15.

Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.

Inborn errors of mitochondrial fatty acid oxidation (FAO) comprise the most common group of disorders identified through expanded newborn screening mandated in all 50 states in the United States, affecting 1:10,000 newborns. While some of the morbidity in FAO disorders (FAODs) can be reduced if identified through screening, a significant gap remains between the ability to diagnose these disorders and the ability to treat them. At least 25 enzymes and specific transport proteins are responsible for carrying out the steps of mitochondrial fatty acid metabolism, with at least 22 associated genetic disorders. Read More

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January 2021

From Congenital Disorders of Fat Malabsorption to Understanding Intra-Enterocyte Mechanisms Behind Chylomicron Assembly and Secretion.

Front Physiol 2021 27;12:629222. Epub 2021 Jan 27.

Research Centre, CHU Ste-Justine, Université de Montréal, Montreal, QC, Canada.

During the last two decades, a large body of information on the events responsible for intestinal fat digestion and absorption has been accumulated. In particular, many groups have extensively focused on the absorptive phase in order to highlight the critical "players" and the main mechanisms orchestrating the assembly and secretion of chylomicrons (CM) as essential vehicles of alimentary lipids. The major aim of this article is to review understanding derived from basic science and clinical conditions associated with impaired packaging and export of CM. Read More

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January 2021

Oxidative stress in phenylketonuria-evidence from human studies and animal models, and possible implications for redox signaling.

Metab Brain Dis 2021 04 13;36(4):523-543. Epub 2021 Feb 13.

Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600-Anexo, Porto Alegre, RS, CEP 90.035-003, Brazil.

Phenylketonuria (PKU) is one of the commonest inborn error of amino acid metabolism. Before mass neonatal screening was possible, and the success of introducing diet therapy right after birth, the typical clinical finds in patients ranged from intellectual disability, epilepsy, motor deficits to behavioral disturbances and other neurological and psychiatric symptoms. Since early diagnosis and treatment became widespread, usually only those patients who do not strictly follow the diet present psychiatric, less severe symptoms such as anxiety, depression, sleep pattern disturbance, and concentration and memory problems. Read More

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Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism.

Nat Commun 2021 02 11;12(1):964. Epub 2021 Feb 11.

Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.

Metabolite levels in urine may provide insights into genetic mechanisms shaping their related pathways. We therefore investigate the cumulative contribution of rare, exonic genetic variants on urine levels of 1487 metabolites and 53,714 metabolite ratios among 4864 GCKD study participants. Here we report the detection of 128 significant associations involving 30 unique genes, 16 of which are known to underlie inborn errors of metabolism. Read More

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February 2021

Lifelong Immune Modulation Versus Hematopoietic Cell Therapy for Inborn Errors of Immunity.

J Allergy Clin Immunol Pract 2021 Feb;9(2):628-639

Department of Blood and Marrow Transplant, Royal Manchester Children's Hospital, Manchester, United Kingdom. Electronic address:

Advances in diagnosis of inborn errors of immunity (IEI) and an understanding of the molecular and immunologic mechanisms of these disorders have led to both the development of new therapies and improved approaches to hematopoietic cell transplantation (HCT). For example, monoclonal antibodies (mAbs) and small molecules, such as Janus tyrosine kinase inhibitors, that can modulate immunologic pathways have been designed for or repurposed for management of IEI. A better understanding of molecular mechanisms of IEI has led to use of drugs typically considered "immunosuppressive" to modulate the immune response, such as mammalian target of rapamycin inhibitors in disorders of phosphoinositide 3-kinase gain of function. Read More

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February 2021

Urine proteomics analysis of patients with neuronal ceroid lipofuscinoses.

iScience 2021 Feb 31;24(2):102020. Epub 2020 Dec 31.

Inborn Errors of Metabolism Section, Genetics & Genomic Medicine Unit, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.

The neuronal ceroid lipofuscinoses (NCL) are a group of 13 rare neurodegenerative disorders characterized by accumulation of cellular storage bodies. There are few therapeutic options, and existing tests do not monitor disease progression and treatment response. However, urine biomarkers could address this need. Read More

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February 2021

Minor Clinical Impact of COVID-19 Pandemic on Patients With Primary Immunodeficiency in Israel.

Front Immunol 2020;11:614086. Epub 2021 Jan 14.

The Jeffrey Modell Foundation Israeli Network for Primary Immunodeficiency, New York, NY, United States.

In the last few months the world has witnessed a global pandemic due to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection causing coronavirus disease 2019 (COVID-19). Obviously, this pandemic affected individuals differently, with a significant impact on populations considered to be at high-risk. One such population, was assumed to be patients with primary genetic defect involving components or pathways of the immune system. Read More

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February 2021

Cholesterol metabolism pathways - are the intermediates more important than the products?

FEBS J 2021 Jan 28. Epub 2021 Jan 28.

Swansea University Medical School, UK.

Every cell in vertebrates possesses the machinery to synthesise cholesterol and to metabolise it. The major route of cholesterol metabolism is conversion to bile acids. Bile acids themselves are interesting molecules being ligands to nuclear and G protein-coupled receptors, but perhaps the intermediates in the bile acid biosynthesis pathways are even more interesting and equally important. Read More

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January 2021

Molecular and biochemical investigations of inborn errors of metabolism-altered redox homeostasis in branched-chain amino acid disorders, organic acidurias, and homocystinuria.

Free Radic Res 2021 Jan 27:1-14. Epub 2021 Jan 27.

Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India.

India, resembling other developing nations, is confronting a hastening demographic switch to non-communicable diseases. Inborn errors of metabolism (IEM) constitute a varied heterogeneous group of disorders with variable clinical appearance, primarily in the pediatric populace. Congenital deformities and genetic disorders are significant for mortality throughout the world, and the Indian scenario is not very different. Read More

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January 2021

Cytopenia in autosomal dominant polycystic kidney disease (ADPKD): merely an association or a disease-related feature with prognostic implications?

Pediatr Nephrol 2021 Jan 27. Epub 2021 Jan 27.

Department of Development and Regeneration, GPURE, PKD Research Group, Laboratory of Pediatrics, KU Leuven, Leuven, Belgium.

Autosomal dominant polycystic kidney disease (ADPKD) is associated with distinct cytopenias in observational studies; the most consistent and strongest association is seen with alternations in the lymphocytic lineages. Although the underlying mechanism of these associations is unclear, it has been hypothesized to be secondary to sequestration of white blood cells in cystic organs, or related to the uremic environment in chronic kidney disease (CKD). However, since mutations in PKD1 or -2 affect several immunomodulating pathways, cytopenia may well be an unrecognized extrarenal manifestation of ADPKD. Read More

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January 2021

Primary Immune Regulatory Disorders and Targeted Therapies

Turk J Haematol 2021 02 14;38(1):1-14. Epub 2021 Jan 14.

Marmara University Faculty of Medicine, Division of Pediatric Allergy and Immunology, İstanbul, Turkey

Primary immune regulatory disorders (PIRDs) are a group of diseases belonging to inborn errors of immunity. They usually exhibit lymphoproliferation, autoimmunities, and malignancies, with less susceptibility to recurrent infections. Unlike classical primary immune deficiencies, in autoimmune manifestations, such as cytopenias, enteropathy can be the first symptom of diseases, and they are typically resistant to treatment. Read More

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February 2021

Proteomic Profiling of the First Human Dental Pulp Mesenchymal Stem/Stromal Cells from Carbonic Anhydrase II Deficiency Osteopetrosis Patients.

Int J Mol Sci 2020 Dec 31;22(1). Epub 2020 Dec 31.

Therapeutics & Biomarker Discovery for Clinical Applications, Stem Cell & Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia.

Osteopetrosis is a hereditary disorder characterized by sclerotic, thick, weak, and brittle bone. The biological behavior of mesenchymal cells obtained from osteopetrosis patients has not been well-studied. Isolated mesenchymal stem/stromal cells from dental pulp (DP-MSSCs) of recently extracted deciduous teeth from osteopetrosis (OP) patients and healthy controls (HCs) were compared. Read More

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December 2020

Occurrence of Inborn Errors of Metabolism in newborns, diagnosis and prophylaxis.

Endocr Metab Immune Disord Drug Targets 2020 Dec 22. Epub 2020 Dec 22.

Department of Biotechnology, GLA University, Mathura, Uttar Pradesh. India.

Inborn errors of metabolism (IEM) are heterogeneous group of rare genetic disorders which are generally transmitted as autosomal or X-linked recessive ones. These defects arise due to mutations associated with specific gene(s) especially the ones associated with key metabolic enzymes. These enzymes or their product(s) are involved in various metabolic pathways- leading to accumulation of intermediary metabolite(s), which reflects their toxic effects upon mutations. Read More

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December 2020

Combined immunodeficiencies.

J Pediatr (Rio J) 2021 Mar-Apr;97 Suppl 1:S39-S48. Epub 2020 Dec 17.

Universidade Federal de São Paulo, Departamento de Pediatria, São Paulo, SP, Brazil.

Objectives: Inborn Errors of Immunity (IEI), also known as primary immunodeficiencies, correspond to a heterogeneous group of congenital diseases that primarily affect immune response components. The main clinical manifestations comprise increased susceptibility to infections, autoimmunity, inflammation, allergies and malignancies. The aim of this article is to review the literature on combined immunodeficiencies (CIDs) focusing on the diagnosis and treatment and the particularities of the clinical management of these patients. Read More

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December 2020

Essential gene prediction using limited gene essentiality information-An integrative semi-supervised machine learning strategy.

PLoS One 2020 30;15(11):e0242943. Epub 2020 Nov 30.

Chemical Engineering and Process Development, CSIR-National Chemical Laboratory, Pune, Maharashtra, India.

Essential gene prediction helps to find minimal genes indispensable for the survival of any organism. Machine learning (ML) algorithms have been useful for the prediction of gene essentiality. However, currently available ML pipelines perform poorly for organisms with limited experimental data. Read More

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January 2021

[Remethylation disorders: about two cases].

Ann Biol Clin (Paris) 2020 Dec;78(6):647-654

Service de biochimie et génétique moléculaire, CHU Clermont-Ferrand, Clermont-Ferrand, France, Service de biochimie, Faculté de médecine et des professions paramédicales, Université Clermont Auvergne, CNRS UMR 6293, Inserm U1103, Clermont-Ferrand, France.

In order to propose a course of action to be taken in the face of any hyperhomocysteinemia, we have reported for the first time in a French journal the recommendations made within the framework of the European E-HOD project for the diagnosis and treatment of remethylation disorders. The remethylation route ensures homocysteine-methionine conversion. It is linked to the folate cycle and the intracellular metabolism of cobalamins. Read More

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December 2020

Standardizing and increasing the utility of lipidomics: a look to the next decade.

Expert Rev Proteomics 2020 10 3;17(10):699-717. Epub 2020 Dec 3.

Swansea University Medical School , Swansea, Wales, UK.

We present our views on the current application of mass spectrometry (MS) based lipidomics and how lipidomics can develop in the next decade to be most practical use to society. That is not to say that lipidomics has not already been of value. In-fact, in its earlier guise as metabolite profiling most of the pathways of steroid biosynthesis were uncovered and via focused lipidomics many inborn errors of metabolism are routinely clinically identified. Read More

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October 2020

Treatment of patients with immunodeficiency: Medication, gene therapy, and transplantation.

J Pediatr (Rio J) 2021 Mar-Apr;97 Suppl 1:S17-S23. Epub 2020 Nov 9.

Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Imunologia, São Paulo, SP, Brazil.

Objectives: To provide an overview of drug treatment, transplantation, and gene therapy for patients with primary immunodeficiencies.

Source Of Data: Non-systematic review of the literature in the English language carried out at PubMed.

Synthesis Of Data: The treatment of patients with primary immunodeficiencies aims to control their disease, especially the treatment and prevention of infections through antibiotic prophylaxis and/or immunoglobulin replacement therapy. Read More

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November 2020

When to measure plasma homocysteine and how to place it in context: The homocystinurias.

Martina Huemer

J Mother Child 2020 Oct 2;24(2):39-46. Epub 2020 Oct 2.

Division of Metabolism, Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland.

This review presents clinical patterns that should trigger homocysteine measurement in blood, as well as the further diagnostic work-up focused on inborn errors of metabolism and disorders of vitamin B12 (cobalamin) absorption and supply. The numerous conditions (e.g. Read More

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October 2020

Chronic Mucocutaneous Candidiasis in Early Life: Insights Into Immune Mechanisms and Novel Targeted Therapies.

Front Immunol 2020 16;11:593289. Epub 2020 Oct 16.

Pediatrics Department A, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.

Children with chronic mucocutaneous candidiasis (CMC) experience recurrent infections with . Moreover, immune dysregulation in the early life of these patients induces various autoimmune diseases and affects normal growth and development. The adaptive and innate immune system components play a significant role in anti-fungal response. Read More

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October 2020

Epithelial cell-adhesion protein cadherin 26 is dysregulated in congenital diaphragmatic hernia and congenital pulmonary airway malformation.

Pediatr Surg Int 2021 Jan 8;37(1):49-57. Epub 2020 Nov 8.

Departments of Surgery, Division of Pediatric Surgery, Pediatrics and Child Health and Physiology and Pathophysiology (Adjunct), University of Manitoba and Children's Hospital Research Institute of Manitoba, Biology of Breathing Theme, AE402-840 Sherbrook Street Winnipeg, Manitoba, R3A 1R9, Canada.

Background: Congenital diaphragmatic hernia (CDH) and congenital pulmonary airway malformation (CPAM) are two inborn pathologies of the lung of unknown origin. Alterations of gene expression in airway epithelial cells are involved in the pathobiology of both diseases. We previously found decreased expression of the epithelial cell adhesion protein cadherin 26 (CDH26) in hypoplastic mice lungs. Read More

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January 2021