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Inborn error

Patricie Burda, Terttu Suormala, Dorothea Heuberger, Alexandra Schäfer, Brian Fowler, D Sean Froese, Matthias R Baumgartner
5,10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the NADPH-dependent reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate using FAD as the cofactor. Severe MTHFR deficiency is the most common inborn error of folate metabolism, resulting in hyperhomocysteinemia and homocystinuria. Approximately 70 missense mutations have been described that cause severe MTHFR deficiency, however, in most cases their mechanism of dysfunction remains unclear. Few studies have investigated mutational specific defects; most of these assessing only activity levels from a handful of mutations using heterologous expression...
October 14, 2016: Journal of Inherited Metabolic Disease
Andrew Duncan, Calum Yacoubian, Robert Beetham, Anthony Catchpole, David Bullock
BACKGROUND: US and European guidelines suggest the use of calculated non-caeruloplasmin bound copper (free copper index) for the diagnosis and management of Wilson's Disease. However, there is concern that the required analytical measurements of caeruloplasmin and copper may not be sufficiently robust at the concentrations usually found. METHODS: Aliquots of six plasma specimens were sent to laboratories participating in the UK National External Quality Assessment Scheme for copper and caeruloplasmin...
October 13, 2016: Annals of Clinical Biochemistry
Ahmed Gaballa, Mikael Sundin, Arwen Stikvoort, Muhamed Abumaree, Mehmet Uzunel, Darius Sairafi, Michael Uhlin
Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established treatment modality for a variety of malignant diseases as well as for inborn errors of the metabolism or immune system. Regardless of disease origin, good clinical effects are dependent on proper immune reconstitution. T cells are responsible for both the beneficial graft-versus-leukemia (GVL) effect against malignant cells and protection against infections. The immune recovery of T cells relies initially on peripheral expansion of mature cells from the graft and later on the differentiation and maturation from donor-derived hematopoietic stem cells...
October 11, 2016: International Journal of Molecular Sciences
Isabelle Meyts, Barbara Bosch, Alexandre Bolze, Bertrand Boisson, Yuval Itan, Aziz Belkadi, Vincent Pedergnana, Leen Moens, Capucine Picard, Aurélie Cobat, Xavier Bossuyt, Laurent Abel, Jean-Laurent Casanova
The advent of next-generation sequencing (NGS) in 2010 has transformed medicine, particularly the growing field of inborn errors of immunity. NGS has facilitated the discovery of novel disease-causing genes and the genetic diagnosis of patients with monogenic inborn errors of immunity. Whole-exome sequencing (WES) is presently the most cost-effective approach for research and diagnostics, although whole-genome sequencing offers several advantages. The scientific or diagnostic challenge consists in selecting 1 or 2 candidate variants among thousands of NGS calls...
October 2016: Journal of Allergy and Clinical Immunology
Francyne Kubaski, Robert W Mason, Akiko Nakatomi, Haruo Shintaku, Li Xie, Naomi N van Vlies, Heather Church, Roberto Giugliani, Hironori Kobayashi, Seiji Yamaguchi, Yasuyuki Suzuki, Tadao Orii, Toshiyuki Fukao, Adriana M Montaño, Shunji Tomatsu
BACKGROUND: Mucopolysaccharidoses (MPS) are a group of inborn errors of metabolism that are progressive and usually result in irreversible skeletal, visceral, and/or brain damage, highlighting a need for early diagnosis. METHODS: This pilot study analyzed 2862 dried blood spots (DBS) from newborns and 14 DBS from newborn patients with MPS (MPS I, n = 7; MPS II, n = 2; MPS III, n = 5). Disaccharides were produced from polymer GAGs by digestion with chondroitinase B, heparitinase, and keratanase II...
October 7, 2016: Journal of Inherited Metabolic Disease
Mayara Sandrielly Pereira Soares, Pathise Souto Oliveira, Gabriela Nogueira Debom, Bruna da Silveira Mattos, Carla Roberta Polachini, Jucimara Baldissarelli, Vera Maria Morsch, Maria Rosa Chitolina Schetinger, Rejane Giacomelli Tavares, Francieli Moro Stefanello, Roselia Maria Spanevello
High levels of methionine (Met) and methionine sulfoxide (MetO) are found in several genetic abnormalities. Oxidative stress is involved in the pathophysiology of many inborn errors of metabolism. However, little is known about the role of oxidative damage in hepatic and renal changes in hypermethioninemia. We investigated the effect of chronic treatment with Met and/or MetO on oxidative stress parameters in liver and kidney, as lipid peroxidation (TBARS), total sulfhydryl content (SH), reactive oxygen species (ROS) and enzymes activities superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and delta aminolevulinic dehydratase (ALA-D)...
October 7, 2016: Amino Acids
Leniza G De Castro-Hamoy, Mary Anne D Chiong, Sylvia C Estrada, Cynthia P Cordero
Maple syrup urine disease (MSUD) is a rare inborn error of metabolism resulting from a deficiency in the branched-chain alpha-ketoacid dehydrogenase complex. MSUD has been reported to be the most common inborn error of metabolism in the Philippines. We described all patients with maple syrup urine disease patients diagnosed through newborn screening during its first 2 years of implementation and the challenges encountered during their medical management. There were 24 patients diagnosed with maple syrup urine disease for the 2-year period...
October 6, 2016: Journal of Community Genetics
Clara D M van Karnebeek, Kristin Bowden, Elizabeth Berry-Kravis
BACKGROUND: Neurogenetic developmental conditions represent a heterogeneous group of rare inherited disorders with neurological manifestation during development. Treatments for these conditions have largely been supportive; however, a number of treatments are emerging which target the underlying physiology and offer great potential. Our aim was to present a state-of-the-art overview of the current and potential causal treatments available or under development for neurogenetic developmental conditions...
July 26, 2016: Pediatric Neurology
A Simons, F Eyskens, I Glazemakers, D van West
Many patients who visit a centre for hereditary metabolic diseases remarkably also suffer from a child psychiatric disorder. Those child psychiatric disorders may be the first sign or manifestation of an underlying metabolic disorder. Lack of knowledge of metabolic disorders in child psychiatry may lead to diagnoses being missed. Patients therefore are also at risk for not accessing efficacious treatment and proper counselling. To search the literature for the co-occurrence of child psychiatric disorders, such as ADHD, autism, psychosis, learning disorders and eating disorders and metabolic disorders...
September 30, 2016: European Child & Adolescent Psychiatry
Maryam Abiri, Saeed Talebi, Jouni Uitto, Leila Youssefian, Hassan Vahidnezhad, Tina Shirzad, Shadab Salehpour, Sirous Zeinali
Most inborn errors of metabolism (IEMs) are inherited in an autosomal recessive manner. IEMs are one of the major concerns in Iran due to its extensive consanguineous marriages. Herein, we report two patients with two co-existent IEMs: a girl affected by classic phenylketonuria (PKU) and maple syrup urine disease (MSUD) and a male patient affected with Sandhoff disease and PKU, where Sandhoff disease was suspected due to the presence of a cherry-red spot in the eyes at 6 months which is unrelated to PKU. Sequencing of candidate genes in the first patient revealed one novel and three recurrent compound heterozygous mutations of p...
October 1, 2016: Journal of Pediatric Endocrinology & Metabolism: JPEM
Songul Gokay, Pembe Soylu Ustkoyuncu, Fatih Kardas, Mustafa Kendirci
BACKGROUND: Hereditary tyrosinemia type 1 (HT1) is a rare, inborn error of tyrosine metabolism. It is a fatal disorder without treatment. Early treatment may prevent acute liver failure, renal dysfunction, liver cirrhosis, hepatocellular carcinoma (HCC) and improves survival. The aim of the present study is to describe the clinical, biochemical, imaging and follow-up of seven patients with HT1 and to define the consequences of the late and interrupted treatment. METHODS: A retrospective study was carried out with seven HT1 patients...
October 1, 2016: Journal of Pediatric Endocrinology & Metabolism: JPEM
Jason D Arroyo, Alexis A Jourdain, Sarah E Calvo, Carmine A Ballarano, John G Doench, David E Root, Vamsi K Mootha
Oxidative phosphorylation (OXPHOS) is the major pathway for ATP production in humans. Deficiencies in OXPHOS can arise from mutations in either mitochondrial or nuclear genomes and comprise the largest collection of inborn errors of metabolism. At present we lack a complete catalog of human genes and pathways essential for OXPHOS. Here we introduce a genome-wide CRISPR "death screen" that actively selects dying cells to reveal human genes required for OXPHOS, inspired by the classic observation that human cells deficient in OXPHOS survive in glucose but die in galactose...
September 9, 2016: Cell Metabolism
Robert Chiesa, Robert F Wynn, Paul Veys
PURPOSE OF REVIEW: This review summarizes the main results of haematopoietic stem cell transplantation (HSCT) in selected inborn errors of metabolism (IEMs). RECENT FINDINGS: Early diagnosis and immediate referral to an IEM specialist is of paramount importance to improve clinical outcome: patients who are transplanted early or in their presymptomatic phase generally achieve better correction of their somatic symptoms and neurocognitive development. Long-term outcome in children with Hurler syndrome is influenced by age at HSCT, baseline clinical status and post-HSCT enzyme levels...
November 2016: Current Opinion in Hematology
Ni-Chung Lee, Yu-May Lee, Pin-Wen Chen, Barry J Byrne, Wuh-Liang Hwu
Aromatic L-amino acid decarboxylase (AADC) deficiency is an inborn error of monoamine neurotransmitter synthesis, which results in dopamine, serotonin, epinephrine, and norepinephrine deficiencies. The DDC gene founder mutation IVS6+4A>T is highly prevalent in Chinese patients with AADC deficiency. In this study, we designed several U1 snRNA vectors to adapt U1 snRNA binding sequences of the mutated DDC gene. We found that only the modified U1 snRNA (IVS-AAA) that completely matched both the intronic and exonic U1 binding sequences of the mutated DDC gene could correct splicing errors of either the mutated human DDC minigene or the mouse artificial splicing construct in vitro We further injected an adeno-associated viral (AAV) vector to express IVS-AAA in the brain of a knock-in mouse model...
September 21, 2016: Human Molecular Genetics
Carsten Speckmann, Sam Doerken, Alessandro Aiuti, Michael H Albert, Waleed Al-Herz, Luis M Allende, Allessia Scarselli, Tadej Avcin, Ruy Perez-Becker, Caterina Cancrini, Andrew Cant, Silvia Di Cesare, Andrea Finocchi, Alain Fischer, H Bobby Gaspar, Sujal Ghosh, Andrew Gennery, Kimberly Gilmour, Luis I González-Granado, Monica Martinez-Gallo, Sophie Hambleton, Fabian Hauck, Manfred Hoenig, Despina Moshous, Benedicte Neven, Tim Niehues, Luigi Notarangelo, Capucine Picard, Nikolaus Rieber, Ansgar Schulz, Klaus Schwarz, Markus G Seidel, Pere Soler-Palacin, Polina Stepensky, Brigitte Strahm, Thomas Vraetz, Klaus Warnatz, Christine Winterhalter, Austen Worth, Sebastian Fuchs, Annette Uhlmann, Stephan Ehl
BACKGROUND: Absent T cell immunity resulting in life-threatening infections provides a clear rationale for hematopoetic stem cell transplantation (HSCT) in patients with severe combined immunodeficiency (SCID). Combined immunodeficiencies (CID) and "atypical" SCID show reduced, not absent T-cell immunity. If associated with infections or autoimmunity, they represent profound CID (P-CID), for which outcome data are insufficient for unambiguous early transplant decisions. OBJECTIVES: We recruit non-transplanted P-CID patients aged 1-16 years to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunological and/or clinical parameters may be predictive for outcome...
September 19, 2016: Journal of Allergy and Clinical Immunology
Mareike Sandvoß, Arne Björn Potthast, Frauke von Versen-Höynck, Anibh Martin Das
The hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome is frequently observed in mothers whose offspring have long-chain fatty acid oxidation defects. We previously found that fatty acid oxidation is compromised not only in these inborn errors of metabolism but also in human umbilical vein endothelial cells (HUVECs) from all pregnancies complicated by the HELLP syndrome. Sirtuins are oxidized nicotinamide adenine dinucleotide (NAD(+))dependent deacetylases linked to the metabolic status of the cell...
September 20, 2016: Reproductive Sciences
Abdellah Tebani, Carlos Afonso, Stéphane Marret, Soumeya Bekri
The rise of technologies that simultaneously measure thousands of data points represents the heart of systems biology. These technologies have had a huge impact on the discovery of next-generation diagnostics, biomarkers, and drugs in the precision medicine era. Systems biology aims to achieve systemic exploration of complex interactions in biological systems. Driven by high-throughput omics technologies and the computational surge, it enables multi-scale and insightful overviews of cells, organisms, and populations...
2016: International Journal of Molecular Sciences
Sílvia Vilarinho, Sinan Sari, Francesca Mazzacuva, Kaya Bilgüvar, Güldal Esendagli-Yilmaz, Dhanpat Jain, Gülen Akyol, Buket Dalgiç, Murat Günel, Peter T Clayton, Richard P Lifton
Acyl CoA Oxidase 2 (ACOX2) encodes branched-chain acyl-CoA oxidase, a peroxisomal enzyme believed to be involved in the metabolism of branched-chain fatty acids and bile acid intermediates. Deficiency of this enzyme has not been described previously. We report an 8-y-old male with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Exome sequencing revealed a previously unidentified homozygous premature termination mutation (p.Y69*) in ACOX2 Immunohistochemistry confirmed the absence of ACOX2 expression in the patient's liver, and biochemical analysis showed marked elevation of intermediate bile acids upstream of ACOX2...
October 4, 2016: Proceedings of the National Academy of Sciences of the United States of America
Yi Wang, Cindy S Ma, Yun Ling, Aziz Bousfiha, Yildiz Camcioglu, Serge Jacquot, Kathryn Payne, Elena Crestani, Romain Roncagalli, Aziz Belkadi, Gaspard Kerner, Lazaro Lorenzo, Caroline Deswarte, Maya Chrabieh, Etienne Patin, Quentin B Vincent, Ingrid Müller-Fleckenstein, Bernhard Fleckenstein, Fatima Ailal, Lluis Quintana-Murci, Sylvie Fraitag, Marie-Alexandra Alyanakian, Marianne Leruez-Ville, Capucine Picard, Anne Puel, Jacinta Bustamante, Stéphanie Boisson-Dupuis, Marie Malissen, Bernard Malissen, Laurent Abel, Alain Hovnanian, Luigi D Notarangelo, Emmanuelle Jouanguy, Stuart G Tangye, Vivien Béziat, Jean-Laurent Casanova
Combined immunodeficiency (CID) refers to inborn errors of human T cells that also affect B cells because of the T cell deficit or an additional B cell-intrinsic deficit. In this study, we report six patients from three unrelated families with biallelic loss-of-function mutations in RLTPR, the mouse orthologue of which is essential for CD28 signaling. The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis...
September 19, 2016: Journal of Experimental Medicine
Richard D Beger, Warwick Dunn, Michael A Schmidt, Steven S Gross, Jennifer A Kirwan, Marta Cascante, Lorraine Brennan, David S Wishart, Matej Oresic, Thomas Hankemeier, David I Broadhurst, Andrew N Lane, Karsten Suhre, Gabi Kastenmüller, Susan J Sumner, Ines Thiele, Oliver Fiehn, Rima Kaddurah-Daouk
INTRODUCTION BACKGROUND TO METABOLOMICS: Metabolomics is the comprehensive study of the metabolome, the repertoire of biochemicals (or small molecules) present in cells, tissues, and body fluids. The study of metabolism at the global or "-omics" level is a rapidly growing field that has the potential to have a profound impact upon medical practice. At the center of metabolomics, is the concept that a person's metabolic state provides a close representation of that individual's overall health status...
2016: Metabolomics: Official Journal of the Metabolomic Society
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