Inborn error of metabolism 1125625 223509147 2008-07-04T11:11:52Z DOI bot 6652755 Citation maintenance. Formatted: year. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. {{Infobox_Disease | Name = Inborn error of metabolism | Image = Metabolic pathways small.png| Caption = A few of the metabolic pathways in a cell. Metabolites are shown as dots and enzyme reactions as lines. | DiseasesDB = | ICD10 = {{ICD10|E|70||e|70}}-{{ICD10|E|90||e|70}} | ICD9 = {{ICD9|270}}-{{ICD9|279}} | ICDO = | OMIM = | MedlinePlus = 002438 | eMedicineSubj = emerg | eMedicineTopic = 768 | MeshID = D008661 | }} '''Inborn errors of metabolism''' comprise a large class of [[genetics|genetic]] [[disease]]s involving disorders of [[metabolism]]. The majority are due to defects of single [[gene]]s that code for [[enzyme]]s that facilitate conversion of various substances ([[substrate (biochemistry)|substrate]]s) into others ([[Product (chemistry)|product]]s). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are now often referred to as '''congenital metabolic diseases''' or '''inherited metabolic diseases''', and these terms are considered synonymous. The term ''inborn error of metabolism'' was coined by a British physician, [[Archibald Garrod]] (1857-1936), in the early 20th century (1908). He is known for the "one gene, one enzyme" hypothesis, which arose from his studies on the nature and inheritance of [[alkaptonuria]]. His seminal text, [http://www.esp.org/books/garrod/inborn-errors/facsimile/ Inborn Errors of Metabolism] was published in 1923. ==Major categories of inherited metabolic diseases== Traditionally the inherited metabolic diseases were categorized as disorders of [[carbohydrate]] metabolism, [[amino acid]] metabolism, [[organic acid]] metabolism, or [[lysosomal storage disease]]s. In recent decades, hundreds of new inherited disorders of metabolism have been discovered and the categories have proliferated. Following are some of the major classes of congenital metabolic diseases, with prominent examples of each class. Many others do not fall into these categories. [[ICD|ICD-10]] codes are provided where available. *Disorders of [[carbohydrate]] metabolism **E.g., [[glycogen storage disease]] (E74.0) *Disorders of [[List of amino acid metabolism disorders|amino acid]] metabolism **E.g., [[phenylketonuria]] (E70.0), [[maple syrup urine disease]] (E71.0), [[glutaric acidemia type 1]] *Disorders of [[organic acid]] metabolism ([[organic aciduria]]s) **E.g., [[alcaptonuria]] (E70.2) *Disorders of [[List of fatty acid metabolism disorders|fatty acid oxidation]] and [[mitochondrial]] metabolism **E.g., [[medium chain acyl dehydrogenase deficiency]] (glutaric acidemia type 2) *Disorders of [[porphyrin]] metabolism **E.g., [[acute intermittent porphyria]] (E80.2) *Disorders of [[purine]] or [[pyrimidine]] metabolism **E.g., [[Lesch-Nyhan syndrome]] (E79.1) *Disorders of [[steroid]] metabolism **E.g., [[congenital adrenal hyperplasia]] (E25.0) *Disorders of [[mitochondrial]] function **E.g., [[Kearns-Sayre syndrome]] (H49.8) *Disorders of [[peroxisomal]] function **E.g., [[Zellweger syndrome]] (Q87.8) *[[Lysosomal storage disorder]]s **E.g., [[Gaucher's disease]] (E75.22) ==Manifestations and presentations== Because of the enormous number of these diseases and wide range of systems affected, nearly every "presenting complaint" to a doctor may have a congenital metabolic disease as a possible cause, especially in childhood. The following are examples of potential manifestations affecting each of the major organ systems: *[[Growth failure]], [[failure to thrive]], weight loss *[[intersex|Ambiguous genitalia]], [[delayed puberty]], [[precocious puberty]] *[[Developmental delay]], [[seizure]]s, [[dementia]], [[encephalopathy]], [[stroke]] *[[Deafness]], [[blindness]], [[pain agnosia]] *Skin [[rash]], abnormal [[pigmentation]], lack of pigmentation, [[hirsutism|excessive hair growth]], lumps and bumps *Dental abnormalities *[[Immunodeficiency]], [[thrombocytopenia]], [[anemia]], enlarged [[spleen]], enlarged [[lymph node]]s *Many forms of [[cancer]] *Recurrent [[vomiting]], [[diarrhea]], [[abdominal pain]] *Excessive [[urination]], [[renal failure]], [[dehydration]], [[edema]] *[[Hypotension]], [[heart failure]], enlarged heart, [[hypertension]], [[myocardial infarction]] *[[Hepatomegaly]], [[jaundice]], [[liver failure]] *Unusual facial features, [[congenital malformation]]s *Excessive breathing ([[hyperventilation]]), [[respiratory failure]] *Abnormal behavior, [[clinical depression|depression]], [[psychosis]] *Joint pain, [[muscle]] weakness, cramps *[[Hypothyroidism]], [[adrenal insufficiency]], [[hypogonadism]], [[diabetes mellitus]] ==Diagnostic techniques== Because of the multiplicity of conditions, many different [[diagnostic test]]s are used for screening. An abnormal result is often followed by a subsequent "definitive test" to confirm the suspected diagnosis. Common screening tests used in the last sixty years: *[[Ferric chloride test]] (turned colors in reaction to various abnormal metabolites in urine) *[[Ninhydrin]] [[paper chromatography]] (detected abnormal [[amino acid]] patterns) *[[Guthrie test|Guthrie bacterial inhibition assay]] (detected a few amino acids in excessive amounts in blood) The dried blood spot can be used for multianalyte testing using Tandem Mass Spectroscopy (MS/MS). *Quantitative [[plasma amino acids]], quantitative [[urine amino acids]] *Urine [[organic acid]]s by [[mass spectrometry]] Specific diagnostic tests (or focused screening for a small set of disorders): *Tissue [[biopsy]] or [[necropsy]]: [[liver]], [[muscle]], [[brain]], [[bone marrow]] *Skin biopsy and fibroblast cultivation for specific enzyme testing *Specific [[DNA testing]] ==Newborn screening== Dozens of congenital metabolic diseases are now detectable by [[newborn screening]] tests, especially the expanded testing using mass spectrometry. This is an increasingly common way for the diagnosis to be made and sometimes results in earlier treatment and a better outcome. ==Management== :{{Expand-section|date=June 2008}} In the middle of the 20th century the principal treatment for some of the [[amino acid disorder]]s was restriction of dietary protein and all other care was simply management of complications. In the last two decades, enzyme replacement, gene transfer, and organ transplantation have become available and beneficial for many previously untreatable disorders. Some of the more common or promising are listed. *Dietary restriction **E.g., reduction of dietary protein remains a mainstay of treatment for [[phenylketonuria]] and other [[amino acid disorder]]s. *Dietary supplementation or replacement **E.g., cornstarch several times a day helps prevent people with [[glycogen storage disease]] from becoming [[hypoglycemia|hypoglycemic]] as quickly. *Vitamins **E.g., [[thiamine]] supplementation benefits several types of [[lactic acidosis]]. *Intermediary metabolites, compounds, or drugs that facilitate or retard specific metabolic pathways **E.g., *Dialysis **E.g., *Enzyme replacement **E.g., *Gene transfer **E.g., *Bone marrow or organ transplantation **E.g., *Treatment of symptoms and complications **E.g., *Prenatal diagnosis and avoidance of pregnancy or abortion of an affected fetus **E.g., ==Resources== For clinicians and scientists in the field of inborn errors of metabolism, good resources include books by Scriver <ref> [[Charles Scriver]], Beaudet, A.L., Valle, D., Sly, W.S., Vogelstein, B., Childs, B., Kinzler, K.W. (accessed 2007). [http://www.ommbid.com The Online Metabolic and Molecular Bases of Inherited Disease]. New York: McGraw-Hill. - Summaries of 255 chapters, full text through many universities. There is also the [http://books.mcgraw-hill.com/medical/ommbid/blog/ OMMBID blog]. </ref>. Fernandes <ref> {{cite book | last = Fernandes | first = J. | authorlink = | coauthors = Saudubray, J.M.; van den Berghe, G.; Walter, J.H. | title = Inborn Metabolic Diseases : Diagnosis and Treatment | publisher = Springer |edition= 4th | date = 2006 | location = | pages = 561 p | url = http://www.springer.com/dal/home/medicine/pediatrics?SGWID=1-10079-22-97001537-0 | doi = | isbn = }} </ref>, Clarke <ref> {{cite book | last = Clarke | first = J.T.R. | authorlink = | coauthors = | title = A Clinical Guide to Inherited Metabolic Diseases | publisher = Cambridge University Press |edition= 3rd | date = 2005 | location = Cambridge | pages = 358 p | url = http://www.cambridge.org/uk/catalogue/catalogue.asp?isbn=9780521614993 | doi = 10.2277/0521614996 | isbn = 978-0521614993 }} </ref>, Blau (diagnosis) <ref> {{cite book | last = Blau | first = N. | authorlink = | coauthors = Duran, M.; Blaskovics, M.E.; Gibson, K.M. | title = Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases | publisher = Springer |edition= 2nd | date = 2002 | location = | pages = 716 p | url = http://www.springer.com/dal/home?SGWID=1-102-22-2083693-0&changeHeader=true | doi = | isbn = 978-3-540-42542-7 }} </ref>, Blau (treatment) <ref> {{cite book | last = Blau | first = N | authorlink = | coauthors = Hoffmann, G.F.; Leonard, J.; Clarke, J.T.R. | title = Physician's Guide to the Treatment And Follow-up of Metabolic Diseases | publisher = Springer |edition= 1st | date = 2006 | location = | pages = 416 p | url = http://www.springer.com/dal/home?SGWID=1-102-22-34377103-0&changeHeader=true | doi = | isbn = 3-540-22954-X }} </ref>, Lyon <ref> {{cite book | last = Lyon | first = G. | authorlink = | coauthors = Kolodny, E.H.; Pastores, G. | title = Neurology of Hereditary Molecular & Metabolic Disease of Children | publisher = McGraw-Hill Professional |edition= 3rd | date = 2006 | location = | pages = 500p | url = http://www.mhprofessional.com/product.php?cat=116&isbn=0071445080 | doi = | id = }} </ref>, Nyhan <ref> {{cite book | last = Nyhan | first = W.L. | authorlink = | coauthors = Barshop, B.; Ozand, P.T. | title = Atlas of Metabolic Diseases | publisher = Oxford University Press |edition= 2nd | date = 2005 | location = | pages = 800 p | url = http://www.oup.com/us/catalog/general/subject/Medicine/Genetics/~~/dmlldz11c2EmY2k9OTc4MDM0MDgwOTcwOQ== | doi = | id = }} </ref>, Hoffmann <ref> {{cite book | last = Hoffmann | first = G.F | authorlink = | coauthors = Nyhan, W.L.; Zschocke, J.; Kahler, S.G; Mayatepek, E. | title = Inherited Metabolic diseases | publisher = Lippincott Williams & Wilkins |edition= | date = 2001 | location = | pages = 448 p | url = http://www.lww.com/product/?978-0-7817-2900-0 | doi = | id = }} </ref> and Zschocke <ref> {{cite book | last = Zschocke | first = J | authorlink = | coauthors = Hoffmann, G.F. | title = Vademecum Metabolicum | publisher = Schattauer GmbH |edition= 2nd | date = 2004 | location = | pages = 176 p | url = http://82.139.217.185/schatt/gv/titles/schat2385.asp | doi = | id = }} </ref>. Other ressources include [http://www.genereviews.org/ genetests], [http://www.orpha.net/ orphanet], [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM OMIM], [[Metab-L]],societies such as the [http://www.ssiem.org/ SSIEM], the [http://www.simd.org/ SIMD] and links therein. For medical students and clinicians looking for overviews of the field, such reviews can be found on [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?DB=pubmed pubmed] and in good pediatric textbooks (e.g. articles by Saudubray<ref>{{cite journal |author=Saudubray J, Sedel F, Walter J |title=Clinical approach to treatable inborn metabolic diseases: an introduction |journal=J Inherit Metab Dis |volume=29 |issue=2-3 |pages=261–74 |year= 2006|pmid=16763886 |doi=10.1007/s10545-006-0358-0}}</ref>, Ellaway<ref>{{cite journal |author=Ellaway C, Wilcken B, Christodoulou J |title=Clinical approach to inborn errors of metabolism presenting in the newborn period |journal=J Paediatr Child Health |volume=38 |issue=5 |pages=511–7 |year=2002 |pmid=12354271 |doi=10.1046/j.1440-1754.2002.00047.x}}</ref>, Raghuveer<ref>{{cite journal |author=Raghuveer T, Garg U, Graf W |title=Inborn errors of metabolism in infancy and early childhood: an update |journal=Am Fam Physician |volume=73 |issue=11 |pages=1981–90 |year=2006 |pmid=16770930}}</ref> or Burton<ref>{{cite journal |author=Burton B |title=Inborn errors of metabolism in infancy: a guide to diagnosis |journal=Pediatrics |volume=102 |issue=6 |pages=E69 |year=1998 |pmid=9832597 |doi=10.1542/peds.102.6.e69}}</ref> and textbooks by Hay<ref> {{cite book | last = Hay | first = W.H., Jr. | authorlink = | coauthors = Levin, M.J.; Sondheimer, J.M.; Deterding, R.R. | title = Current Pediatric Diagnosis and Treatment | publisher = McGraw-Hill |edition= 18th ed. | date = 2006 | location = | pages = 1306 p | url = http://www.accessmedicine.com/resourceTOC.aspx?resourceID=14 | doi = | id = }} </ref> or Behrman<ref> {{cite book | last = Behrman | first = R.E. | authorlink = | coauthors = Kliegman, R.M.; Jenson, H.B. | title = Nelson Textbook of Pediatrics | publisher = Elsevier |edition= 17th ed. | date = 2004 | location = | pages = 2672 p | url = http://www.nelsonpediatrics.com/ | doi = | id = }} </ref>). For patients, their families or other individuals seeking good information and support groups, the [[National Institutes of Health]] offers the [http://rarediseases.info.nih.gov/ office of rare diseases], [http://ghr.nlm.nih.gov/ genetics home reference], [http://www.nlm.nih.gov/medlineplus/ medlineplus] and [http://health.nih.gov/ health information]. The National Human Genome Research Institute hosts an [http://www.genome.gov/10000409 information center], a section for [http://www.genome.gov/19016903 patients and the public] and additional [http://www.genome.gov/Education/ educational resources]. Support groups can be found at [http://www.rarediseases.org/ NORD], [http://www.geneticalliance.org/ Genetic Alliance] and [http://www.orpha.net/ Orphanet]. The [http://www.kumc.edu/gec/about.html genetic education center] at the KUMC has many more useful links. ==References== {{reflist|2}} {{Carbohydrate metabolic pathology}} {{Other metabolic pathology}} [[Category:Pediatrics]] [[Category:Inborn errors of metabolism| ]] [[Category:Metabolism]] [[es:Error congénito del metabolismo]] [[fr:Maladie métabolique congénitale]] [[lt:Paveldimos metabolinės ligos]] [[pt:Erros Metabólicos Hereditários]] [[tr:Doğuştan metabolizma bozuklukları]]