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The effect of cofactors and vitamins on homocysteine and methylmalonic acid metabolism in helath and disease

English title The effect of cofactors and vitamins on homocysteine and methylmalonic acid metabolism in helath and disease
Applicant Baumgartner Matthias
Number 138521
Funding scheme Project funding
Research institution Universitäts-Kinderspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Metabolic Disorders
Start/End 01.01.2012 - 31.12.2014
Approved amount 273'000.00
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All Disciplines (4)

Discipline
Metabolic Disorders
Molecular Biology
Paediatrics
Biochemistry

Keywords (10)

vitamin B12; cobalamin; homocysteine; methylmalonic acid; 5-methyl-tetrahydrofolate; S-adenosylmethionine; methionine synthase deficiency; methylmalonyl-CoA mutase deficiency; organic acidurias; cobalamin complementation

Lay Summary (English)

Lead
Lay summary

Large elevations of homocysteine, an amino acid derived from the protein amino acid methionine, and methylmalonic acid (MMA), an intermediary metabolite in the breakdown of several substances, are found in rare inborn errors of intracellular vitamin B12 (cobalamin) metabolism and in vitamin B12 deficiency. These elevations can lead to severe neurological damage. A milder increase of homocysteine is linked as risk factor or marker to premature arteriosclerosis. An important player in homocysteine regulation is cobalamin. Understanding the role of severe and mild disturbances of homocysteine and cobalamin metabolism requires knowledge of the basic metabolic steps involved. After cobalamin enters the cell it has to be converted to two active coenzymes, one is adenosylcobalamin, and the other methylcobalamin. This takes place in two different compartments in the cell, the cytosol and mitochondria and the conversion requires a number of steps that are defined biochemically and by genetic complementation as cblA-G. We have shown that the cblD defect affects both mitochondrial and cytosolic cobalamin metabolism indicating that the cblD protein plays a key role in channelling of cobalamin within the cell. Using the microcell mediated chromosome transfer technique we have identified the gene (MMADHC) responsible for the CblD defect. The cblC gene (MMACHC) is thought to encode a cobalamin transporter. We collaborated in the discovery of the the cblF gene (LMBRD1) that encodes a lysosomal membrane protein. We have recently discovered a further step in the pathway, cblJ which is closely related to cblF. The discovery of these genes and mutations responsible for the cblC, cblD, cblF and cblJ are important advances in understanding these processes. Although many open questions remain the knowledge we have gained underpins the concept of special molecule channeling systems which protect essential substances present in very low concentrations in the cell, in this case cobalamin and which direct them to their targets. Further, our studies will provide insight into how the different components of the channelling system interact and especially how the intriguing cblD protein acts as a molecular switch in trafficking of this micronutrient in different cellular compartments.

Identification of genes will provide the basis for the discovery of common polymorphisms which may lead to mild disturbances of homocysteine metabolism in common disease such as loss of cognitive function as well as macular degeneration in the elderly, and sub clinical cobalamin deficiency in childhood. Knowledge gained may lead to improved treatment of patients with inherited defects of cobalamin and folate metabolism as well as of patients with milder abnormalities of homocysteine and methylmalonic acid metabolism.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Characterization of functional domains of the cblD (MMADHC) gene product
Jusufi Jehona, Suormala Terttu, Burda Patricie, Fowler Brian, Froese D. Sean, Baumgartner Matthias R. (2014), Characterization of functional domains of the cblD (MMADHC) gene product, in JOURNAL OF INHERITED METABOLIC DISEASE, 37(5), 841-849.
Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data
Huemer Martina, Bürer Céline, Ješina Pavel, Kožich V., Landolt M. A., Suormala Terttu M., Fowler Brian, Augoustides- Savvopoulou Persephone, Blair E., Brennerova Katarina, Broomfield Alexander A., De Meirleir Linda J., Gökçay Gülden Huner, Hennermann Julia B., Jardine P., Koch Johannes, Lorenzl Stefan, Lotz-Havla Amelie Sophia, Noss J., Parini Rossella, Peters Heidi L., Plecko Barbara R., Ramos F. J., Schlune Andrea, Tsiakas Konstantinos (2014), Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data, in Journal of Inherited Metabolic Disease.
Clinical presentation and outcome in 88 patients with the cblC defect
Fischer Sabine (2014), Clinical presentation and outcome in 88 patients with the cblC defect, in J. Inherit. Metab. Dis., 37, 831-840.
Functional characterization and categorization of missense mutations that cause methylmalonyl-coA mutase (MUT) deficiency
Forny Patrick, Froese Doug Sean, Suormala Terttu M., Yue Wyatt W., Baumgartner Matthias R. (2014), Functional characterization and categorization of missense mutations that cause methylmalonyl-coA mutase (MUT) deficiency, in Human Mutation, 35(12), 1449-1458.
Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia.
Baumgartner Matthias R, Hörster Friederike, Dionisi-Vici Carlo, Haliloglu Goknur, Karall Daniela, Chapman Kimberly A, Huemer Martina, Hochuli Michel, Assoun Murielle, Ballhausen Diana, Burlina Alberto, Fowler Brian, Grünert Sarah C, Grünewald Stephanie, Honzik Tomas, Merinero Begoña, Pérez-Cerdá Celia, Scholl-Bürgi Sabine, Skovby Flemming, Wijburg Frits, MacDonald Anita, Martinelli Diego, Sass Jörn Oliver, Valayannopoulos Vassili, Chakrapani Anupam (2014), Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia., in Orphanet journal of rare diseases, 9, 130-130.
Quality of life, psychological adjustment, and adaptive functioning of patients with intoxication-type inborn errors of metabolism ¿ a systematic review.
Zeltner Nina A, Huemer Martina, Baumgartner Matthias R, Landolt Markus A (2014), Quality of life, psychological adjustment, and adaptive functioning of patients with intoxication-type inborn errors of metabolism ¿ a systematic review., in Orphanet journal of rare diseases, 9(1), 159-159.
Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy.
Huemer Martina, Scholl-Bürgi Sabine, Hadaya Karine, Kern Ilse, Beer Ronny, Seppi Klaus, Fowler Brian, Baumgartner Matthias R, Karall Daniela (2014), Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy., in Orphanet journal of rare diseases, 9(1), 161-161.
An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1
Yu Hungchun, Sloan Jennifer L., Scharer Gunter H., Brebner Alison, Quintana Anita M., Achilly Nathan P., Manoli Irini, Coughlin Curtis R., Geiger Elizabeth A., Schneck Una, Watkins David L., Suormala Terttu M., Van Hove Johan L K, Fowler Brian, Baumgartner Matthias R., Rosenblatt David S., Venditti Charles P., Shaikh Tamim H. (2013), An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1, in American Journal of Human Genetics, 93(3), 506-514.
cblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period
Palanca D, Garcia-Cazorla A, Ortiz J, Jou C, Cusi V, Sunol M, Toll T, Perez B, Ormazabal A, Fowler B, Artuch R (2013), cblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period, in JIMD Rep, 57.
Interaction between methionine synthase isoforms and MMACHC: characterization in cblG-variant, cblG and cblC inherited causes of megaloblastic anaemia
Fofou-Caillierez Ma'atem, Mrabet Nadir T., Chery Celine, Dreumont Natacha, Flayac Justine, Pupavac Mihaela, Paoli Justine, Alberto Jean-Marc, Coelho David, Camadro Jean-Michel, Feillet Francois, Watkins David, Fowler Brian, Rosenblatt David S., Gueant Jean-Louis (2013), Interaction between methionine synthase isoforms and MMACHC: characterization in cblG-variant, cblG and cblC inherited causes of megaloblastic anaemia, in HUMAN MOLECULAR GENETICS, 22(22), 4591-4601.
Novel Deletion Mutation Identified in a Patient with Late-Onset Combined Methylmalonic Acidemia and Homocystinuria, cblC Type.
Backe PH, Ytre-Arne M, Rohr AK, Brodtkorb E, Fowler B, Rootwelt H, Bjoras M, Morkrid L (2013), Novel Deletion Mutation Identified in a Patient with Late-Onset Combined Methylmalonic Acidemia and Homocystinuria, cblC Type., in JIMD rep, 79.
Renal involvement in a patient with cobalamin A type (cblA) methylmalonic aciduria: A 42-year follow-up
Haarmann Anke, Mayr Michael, Kölker Stefan, Baumgartner E. Regula, Schnierda J., Hopfer Helmut, Devuyst Olivier, Baumgartner Matthias R. (2013), Renal involvement in a patient with cobalamin A type (cblA) methylmalonic aciduria: A 42-year follow-up, in Molecular Genetics and Metabolism, 472.
3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals.
Grünert Sarah C, Stucki Martin, Morscher Raphael J, Suormala Terttu, Bürer Celine, Burda Patricie, Christensen Ernst, Ficicioglu Can, Herwig Jürgen, Kölker Stefan, Möslinger Dorothea, Pasquini Elisabetta, Santer René, Schwab K Otfried, Wilcken Bridget, Fowler Brian, Yue Wyatt W, Baumgartner Matthias R (2012), 3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals., in Orphanet journal of rare diseases, 7, 31-31.
A single mutation in MCCC1 or MCCC2 as a potential cause of positive screening for 3-methylcrotonyl-CoA carboxylase deficiency.
Morscher Raphael J, Grünert Sarah Catharina, Bürer Céline, Burda Patricie, Suormala Terttu, Fowler Brian, Baumgartner Matthias R (2012), A single mutation in MCCC1 or MCCC2 as a potential cause of positive screening for 3-methylcrotonyl-CoA carboxylase deficiency., in Molecular genetics and metabolism, 105(4), 602-6.
Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism.
Stucki Martin, Coelho David, Suormala Terttu, Burda Patricie, Fowler Brian, Baumgartner Matthias R (2012), Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism., in Human molecular genetics, 21(6), 1410-8.
Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism.
Coelho David, Kim Jaeseung C, Miousse Isabelle R, Fung Stephen, du Moulin Marcel, Buers Insa, Suormala Terttu, Burda Patricie, Frapolli Michele, Stucki Martin, Nürnberg Peter, Thiele Holger, Robenek Horst, Höhne Wolfgang, Longo Nicola, Pasquali Marzia, Mengel Eugen, Watkins David, Shoubridge Eric A, Majewski Jacek, Rosenblatt David S, Fowler Brian, Rutsch Frank, Baumgartner Matthias R (2012), Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism., in Nature genetics, 44(10), 1152-5.
Recessive spastic paraparesis associated with complex I deficiency due to MTHFR mutations.
Bathgate Deborah, Yu-Wai-Man Patrick, Webb Brian, Taylor Robert W, Fowler Brian, Chinnery Patrick F (2012), Recessive spastic paraparesis associated with complex I deficiency due to MTHFR mutations., in Journal of neurology, neurosurgery, and psychiatry, 83(1), 115-115.

Collaboration

Group / person Country
Types of collaboration
Prof. Victor Kozich, Institute of Inherited Metabolic Disorders, Charles University, Prague Czech Republic (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
Several European wide national centres for Inherited metabolic disorders Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Bruno Gasnier, CNRS Paris France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Wyatt Hue, Structural Genomics Consortium, Oxford (Head Prof. Udo Oppermann) Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
E-HOD, coordinator Prof. Henk Blom, Universitätsklinikum Freiburg im Breisgau Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. David Rosenblatt, McGill University, Montreal Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
E-IMD, coordinator Prof. Dr. Stefan Kölker, UniversitätsKlinikum Heidelberg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. David Valle, Johns Hopkins University, Baltimore United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Dr. Frank Rutsch, Universitätsklinikum Münster Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
SSIEM Annual Symposium Poster Adenosylcobalamin deficiency (MMAB) diagnosed by slightly abnormal routine newborn screening 02.09.2014 Innsbruck, Austria Fowler Brian; Baumgartner Matthias;
SSIEM Annual Symposium Talk given at a conference Health-realted quality of life in children and adolescents with intoxication-type inborn errors of metabolism - patients' and caregivers' perspectives 02.09.2014 Innsbruck, Austria Baumgartner Matthias;
SSIEM Annual Symposium Poster Disodres of methylation CblE and G type: Clinical signs and symptoms at presentation and during the course in 24 patients 02.09.2014 Innsbruck, Austria Baumgartner Matthias; Fowler Brian;
SSIEM Annual Symposium Talk given at a conference A novel mouse model of methlymalonic acidemia circumvents neonatal lethality 02.09.2014 Innsbruck, Austria Baumgartner Matthias;
SSIEM Annual Symposium Poster Recommended guidelines for newborn screening of the homocystinurias 02.09.2014 Innsbruck, Austria Baumgartner Matthias;
SSIEM Annual Symposium Talk given at a conference Studies of methlenetetrahydrofolate reductase (MTHFR) deficiency 02.09.2014 Innsbruck, Austria Baumgartner Matthias; Fowler Brian; Froese Sean;
SSIEM Annual Symposium Talk given at a conference Characterization of functional domains of the cblD (MMADHC) gene product 02.09.2014 Innsbruck, Austria Fowler Brian; Baumgartner Matthias; Froese Sean;
SIMD annual meeting Talk given at a conference Functional charcterization and categorization of missense mutations that cause methlymalonyl-CoA mutase deficiency 09.03.2014 Asilomar, United States of America Froese Sean; Baumgartner Matthias;
SIMD annual meeting Poster Runs of homozygosity associated with phenotypic expression in cases of 3-MCC deficiency 09.03.2014 Asilomar, United States of America Baumgartner Matthias;
IX Latin American Congress Inborn Errors of Metabolism and Neonatal Screening Talk given at a conference IEMs associated with defects in the metabolic pathways of cobalamin and other B vitamins 01.12.2013 Medellin, Colombia Fowler Brian;
Journée de la SFIEM Talk given at a conference Metabolic fates of methionine, B12 and folates and their implications in pathology 18.11.2013 Paris, France Fowler Brian;
Seminar at Sigma-Aldrich Chemie GmbH (Dr. Roland Wohlgemuth) Individual talk Metabolic Networks and Inborn Errors of Metabolism: Garrod Metabolomics, Basic research  diagnosis e.g. 15.11.2013 Buchs, Switzerland Fowler Brian;
ICMR Sponsored Workshop / CME on Laboratory Diagnostic Techniques in Inborn Errors of Metabolism Talk given at a conference Inborn errors of Metabolism: from basic research to diagnosis. Homocysteine & Cobalamin Defects 30.09.2013 Manipal, India Fowler Brian;
9th International Conference on Homocysteine and One-Carbon Metabolism Talk given at a conference Inborn errors of homocysteine and one-carbon metabolism 08.09.2013 Dublin, Ireland Fowler Brian;
12th International congress of inborn errors of metabolism Poster Methylmalonyl-CoA epimerase (MCE) deficiency: nine new cases 03.09.2013 Barcelona, Spain Fowler Brian; Froese Sean; Baumgartner Matthias;
12th International congress of inborn errors of metabolism Poster Functional characterization of 23 methylmalonyl-CoA mutase mutant alleles in a mammalian expression system 03.09.2013 Barcelona, Spain Fowler Brian; Froese Sean; Baumgartner Matthias;
12th International congress of inborn errors of metabolism Poster First case of macular degeneration in cobalamin d deficiency 03.09.2013 Barcelona, Spain Baumgartner Matthias;
12th International congress of inborn errors of metabolism Talk given at a conference Guidelines for MMA/PA – development process and perspective 03.09.2013 Barcelona, Spain Baumgartner Matthias;
12th International congress of inborn errors of metabolism Poster A second patient with a defect of the trifunctional methylene-thf-dehydrogenase (MTHFD1) protein 03.09.2013 Barceloa, Spain Coelho David; Fowler Brian; Baumgartner Matthias;
12th International congress of inborn errors of metabolism Poster European network and registry for homocystinurias and methylation defects (E-HOD) 03.09.2013 Barcelona, Spain Baumgartner Matthias;
12th International congress of inborn errors of metabolism Poster Characterization of functional domains of MMADHC, a protein responsible for intracellular cobalamin processing 03.09.2013 Barcelona, Spain Baumgartner Matthias; Fowler Brian; Coelho David; Froese Sean;
CPD workshop on Biochemical Genetic Disorders, Mater Dei Hospital, Malta Talk given at a conference Inborn errors of Metabolism: from basic research to diagnosis. Homocysteine & Cobalamin Defects 26.05.2013 Malta, Malta Fowler Brian;
12th day of Clinical Research, University Hospital Zurich Talk given at a conference Biochemistry and novel gene defects of intracellular vitamin B12 metabolism 04.04.2013 Zürich, Switzerland Baumgartner Matthias;
Oxford Rare Disease Symposium Talk given at a conference Biochemistry and novel gene defects of intracellular vitamin B12 metabolism 01.02.2013 St. Catherine's College, University of Oxford, Oxford, Great Britain and Northern Ireland Baumgartner Matthias;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Blockade in den Zellen: Neue Ursache des Vitamin-B12-Mangels entdeckt NZZ Forschung und Technik German-speaking Switzerland 2012
Media relations: print media, online media Vitamin-B12-Mangel: den Ursachen auf der Spur UZH-Kommunikation Pressemitteilung German-speaking Switzerland 2012

Awards

Title Year
Best oral presentation, 3rd retreat Children's Research Center, University Hospital Zurich 2013

Associated projects

Number Title Start Funding scheme
156907 The effect of cofactors and vitamins on homocysteine and methylmalonic acid metabolism in helath and disease 01.01.2015 Project funding
122568 The effect of cofactors and vitamins on homocysteine and methylmalonic acid metabolism in health and disease 01.01.2009 Project funding
122568 The effect of cofactors and vitamins on homocysteine and methylmalonic acid metabolism in health and disease 01.01.2009 Project funding
175779 The effect of cofactors and vitamins on homocysteine and methylmalonic acid metabolism in health and disease 01.01.2018 Project funding

Abstract

Background: Inborn errors of methionine metabolism which result in a large elevation of homocysteine are associated with severe vascular abnormalities. Milder increases of plasma homocysteine are associated with cardiovascular events. In man homocysteine is formed from methionine, then either catabolised via transsulphuration, involving vitamin B6, or remethylated to methionine involving several co-factors including vitamin B12 (cobalamin) and 5-methyltetrahydrofolate. Key players in homocysteine regulation are cobalamin, 5- methyltetrahydrofolate and adenosylmethionine. Understanding the role of severe and mild disturbances of metabolism of these compounds in causing disease requires knowledge of the basic metabolic steps involved.Many abnormalities of metabolism of methylmalonic acid are known resulting in disease of widely varying severity. In man only 2 reactions are known that require a cobalamin (Cbl) coenzyme for activity: adenosylcobalamin is the coenzyme for the mutase which catalyses the conversion of methylmalonyl-CoA to succinyl-CoA; methionine synthase which remethylates homocysteine to methionine requires methylcobalamin as well as 5-methyltetrahydrofolate which is formed by methylenetetrahydrofolate reductase (MTHFR). Polymorphisms of this reductase have been implicated as a risk factor in common diseases such as cardiovascular disease, cancer and neural tube defects. The intracellular conversion of OHCbl to the active coenzymes adenosylcobalamin in the mitochondrion and methylcobalamin in the cytosol requires a number of molecular steps associated with mutant classes that are defined biochemically and by genetic complementation as cblA-G. We have shown that the cblD defect affects both cytosolic and mitochondrial pathways indicating that the cblD protein must play a key role in channelling of Cbl within the cell. Our recent discovery of the gene and mutations responsible for the cblD, cblF and the novel cblX defects are important steps in understanding these processes but many open questions remain. The goals of this project are to elucidate the molecular mechanisms and interactions of the intriguing cblD protein and investigate its role in cobalamin trafficking. Also the function of the novel cblX protein including detailed studies of the expression of normal and mutant genes will be investigated. Furthermore, we will attempt to answer open questions regarding clinical and pathophysiological aspects of methylmalonic aciduria and the cblC disorder and also study novel therapeutic approaches. Finally, we will continue our studies of functional consequences of mutant alleles in patients with MTHFR deficiency.Working Hypothesis: The overall goals of this project are to understand intracellular metabolism of cobalamin and folate as determinants of homocysteine and methylmalonic acid in health and disease. Elucidation of the cblD and cblX defects in human mutants and the function of the cblD protein will increase understanding of cobalamin trafficking within the cell. Specific Aims and Experimental Design: 1. Detailed classification of cell lines from patients with disorders of homocysteine (Hcy) and methylmalonic acid (MMA) metabolism.2. Elucidation of molecular mechanisms and interactions of the cblD gene product and its role in intracellular cobalamin trafficking by:a.testing of functional significance of mutant MMADHC alleles detected in patients with the cblD defectb.characterization of functional domains of the cblD proteinc.investigation of the intracellular localisation of the cblD proteind.identification of potential cblD binding partners e.purification and crystallography of the cblD protein in collaboration with another group3. Elucidation of molecular mechanisms of the cblX gene product and its role in intracellular cobalamin trafficking by:a.testing of functional significance of mutant ABCD4 alleles detected in patients with the cblX defectb.investigation of the intracellular localisation of the cblX proteinc.studies of the function of ABCD4 and identification of potential binding partners4. Studies of the rare severe inherited disorders of Hcy and MMA metabolism:a.investigations of patients with variant severe forms of MTHFR deficiencyb.search for a specific enzyme deficiency among patients with unexplained hyperhomocysteinaemia and unexplained methylmalonic aciduriac.Study of the effect of PTC124 (Ataluren) on read-through of nonsense mutations in patients with isolated MMAuria 5. Prospective study on diagnostic, clinical and therapeutic aspects and long-tem outcome in patients with isolated MMAurias and the cblC defect as part of the European registry and network for Intoxication type Metabolic Disorders (E-IMD) Expected value of the proposed project: Knowledge gained in the proposed studies will provide insight into the so far incompletely understood cellular and molecular biology of intracellular cobalamin processing, especially the role of the novel cblX protein and the intriguing cblD protein with its ability to act as a molecular switch in trafficking of this micronutrient in different cellular compartments. Characterization of the genes may lead to discovery of common polymorphisms which cause mild disturbances of Hcy metabolism in common disease such as loss of cognitive function as well as macular degeneration in the elderly, and sub clinical Cbl deficiency in childhood. Knowledge gained may lead to improved treatment of patients with inherited defects of Cbl and folate metabolism as well as to a better understanding of milder abnormalities of Hcy and MMA metabolism.
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