Inborn error of metabolism
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| Inborn error of metabolism Classification and external resources | |
| ICD-10 | E70.-E90. |
|---|---|
| ICD-9 | 270-279 |
| eMedicine | emerg/768 |
| MeSH | D008661 |
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Overview
Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). 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.
Etymology
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, 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 diseases. 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-10 codes are provided where available.
- Disorders of carbohydrate metabolism
- E.g., glycogen storage disease (E74.0)
- Disorders of amino acid metabolism
- E.g., phenylketonuria (E70.0), maple syrup urine disease (E71.0), glutaric acidemia type 1
- Disorders of organic acid metabolism (organic acidurias)
- E.g., alcaptonuria (E70.2)
- Disorders of 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 disorders
- 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
- Ambiguous genitalia, delayed puberty, precocious puberty
- Developmental delay, seizures, dementia, encephalopathy, stroke
- Deafness, blindness, pain agnosia
- Skin rash, abnormal pigmentation, lack of pigmentation, excessive hair growth, lumps and bumps
- Dental abnormalities
- Immunodeficiency, thrombocytopenia, anemia, enlarged spleen, enlarged lymph nodes
- 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 malformations
- Excessive breathing (hyperventilation), respiratory failure
- Abnormal behavior, depression, psychosis
- Joint pain, muscle weakness, cramps
- Hypothyroidism, adrenal insufficiency, hypogonadism, diabetes mellitus
Diagnostic techniques
Because of the multiplicity of conditions, many different diagnostic tests 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 bacterial inhibition assay (detected a few amino acids in excessive amounts in blood)
- Quantitative plasma amino acids, quantitative urine amino acids
- Urine organic acids 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
In the middle of the 20th century the principal treatment for some of the amino acid disorders 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 disorders.
- Dietary supplementation or replacement
- E.g., cornstarch several times a day helps prevent people with glycogen storage disease from becoming 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 [1]. Fernandes [2], Clarke [3], Blau (diagnosis) [4], Blau (treatment) [5], Lyon [6], Nyhan [7], Hoffmann [8] and Zschocke [9]. Other ressources include genetests, orphanet, OMIM, Metab-L,societies such as the SSIEM, the SIMD and links therein. For medical students and clinicians looking for overviews of the field, such reviews can be found on pubmed and in good pediatric textbooks (e.g. articles by Saudubray[10], Ellaway[11], Raghuveer[12] or Burton[13] and textbooks by Hay[14] or Behrman[15]).
For patients, their families or other individuals seeking good information and support groups, the National Institutes of Health offers the office of rare diseases, genetics home reference, medlineplus and health information. The National Human Genome Research Institute hosts an information center, a section for patients and the public and additional educational resources. Support groups can be found at NORD, Genetic Alliance and Orphanet. The genetic education center at the KUMC has many more useful links.
References
- ↑ Charles Scriver, Beaudet, A.L., Valle, D., Sly, W.S., Vogelstein, B., Childs, B., Kinzler, K.W. (accessed 2007). 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 OMMBID blog.
- ↑ Fernandes, J.; Saudubray, J.M.; van den Berghe, G.; Walter, J.H. (2006). Inborn Metabolic Diseases : Diagnosis and Treatment, 4th, Springer, 561 p.
- ↑ Clarke, J.T.R. (2005). A Clinical Guide to Inherited Metabolic Diseases, 3rd, Cambridge: Cambridge University Press, 358 p. DOI:10.2277/0521614996. ISBN 978-0521614993.
- ↑ Blau, N.; Duran, M.; Blaskovics, M.E.; Gibson, K.M. (2002). Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases, 2nd, Springer, 716 p. ISBN 978-3-540-42542-7.
- ↑ Blau, N; Hoffmann, G.F.; Leonard, J.; Clarke, J.T.R. (2006). Physician's Guide to the Treatment And Follow-up of Metabolic Diseases, 1st, Springer, 416 p. ISBN 3-540-22954-X.
- ↑ Lyon, G.; Kolodny, E.H.; Pastores, G. (2006). Neurology of Hereditary Molecular & Metabolic Disease of Children, 3rd, McGraw-Hill Professional, 500p.
- ↑ Nyhan, W.L.; Barshop, B.; Ozand, P.T. (2005). Atlas of Metabolic Diseases, 2nd, Oxford University Press, 800 p.
- ↑ Hoffmann, G.F; Nyhan, W.L.; Zschocke, J.; Kahler, S.G; Mayatepek, E. (2001). Inherited Metabolic diseases. Lippincott Williams & Wilkins, 448 p.
- ↑ Zschocke, J; Hoffmann, G.F. (2004). Vademecum Metabolicum, 2nd, Schattauer GmbH, 176 p.
- ↑ Saudubray J, Sedel F, Walter J. "Clinical approach to treatable inborn metabolic diseases: an introduction". J Inherit Metab Dis 29 (2-3): 261-74. PMID 16763886.
- ↑ Ellaway C, Wilcken B, Christodoulou J (2002). "Clinical approach to inborn errors of metabolism presenting in the newborn period". J Paediatr Child Health 38 (5): 511-7. PMID 12354271.
- ↑ Raghuveer T, Garg U, Graf W (2006). "Inborn errors of metabolism in infancy and early childhood: an update". Am Fam Physician 73 (11): 1981-90. PMID 16770930.
- ↑ Burton B (1998). "Inborn errors of metabolism in infancy: a guide to diagnosis". Pediatrics 102 (6): E69. PMID 9832597.
- ↑ Hay, W.H., Jr.; Levin, M.J.; Sondheimer, J.M.; Deterding, R.R. (2006). Current Pediatric Diagnosis and Treatment, 18th ed., McGraw-Hill, 1306 p.
- ↑ Behrman, R.E.; Kliegman, R.M.; Jenson, H.B. (2004). Nelson Textbook of Pediatrics, 17th ed., Elsevier, 2672 p.
Inborn errors of carbohydrate metabolism (including glycogen storage diseases) (E73-74, 271) | |
|---|---|
| Disaccharide catabolism | Lactose intolerance - Sucrose intolerance |
| Monosaccharide catabolism | fructose: Essential fructosuria - Fructose intolerance galactose/galactosemia : Galactokinase deficiency - Galactose-1-phosphate uridylyltransferase galactosemia - Galactose epimerase deficiency |
| Monosaccharide transport | Glucose-galactose malabsorption - Renal glycosuria |
| Glycolysis | GSD type VII, Tarui's, phosphofructokinase - Triosephosphate isomerase deficiency - Pyruvate kinase deficiency |
| Pyruvate catabolism | PDHA - Fumarase deficiency |
| Gluconeogenesis | PCD - Fructose bisphosphatase deficiency - GSD type I, von Gierke, glucose 6-phosphatase |
| Glycogenesis | GSD type 0, glycogen synthase - GSD type IV, Andersen's, branching |
| Glycogenolysis | GSD type II, Pompe's, glucosidase - GSD type III, Cori's, debranching - GSD type V, McArdle, glycogen phosphorylase/GSD type VI, Hers', glycogen phosphorylase - GSD type I, von Gierke, glucose 6-phosphatas |
| Pentose phosphate pathway | Glucose-6-phosphate dehydrogenase deficiency - Pentosuria |
Inborn errors of amino acid metabolism (E70-72, 270) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| K |
| ||||||||
| G→pyruvate |
| ||||||||
| G→alpha-ketoglutarate |
| ||||||||
| G→succinyl-CoA |
| ||||||||
| G→fumarate |
| ||||||||
| G→oxaloacetate |
| ||||||||
| Transport | Cystinuria - Hartnup disease - Oculocerebrorenal syndrome - Lysinuric protein intolerance - Inborn errors of renal tubular transport (Cystinosis, Fanconi syndrome) | ||||||||
| Tyrosine→Melanin | Albinism: Ocular albinism - Oculocutaneous albinism (Hermansky-Pudlak syndrome) - Waardenburg syndrome | ||||||||
| Glycine→Creatine | GAMT deficiency | ||||||||
| Other | Trimethylaminuria - 2-Hydroxyglutaric aciduria - Fumarase deficiency | ||||||||
| see also Amino acid metabolism enzymes, Urea cycle enzymes, intermediates | |||||||||
Inborn error of lipid metabolism - dyslipidemia (E78 and E71.3, 272) | |
|---|---|
| Hyperlipidemia | Hypercholesterolemia/Hypertriglyceridemia (Familial hypercholesterolemia, Combined hyperlipidemia) - Xanthoma |
| Hypolipoproteinemia | Hypoalphalipoproteinemia/HDL (Lecithin cholesterol acyltransferase deficiency, Tangier disease) Hypobetalipoproteinemia/LDL (Abetalipoproteinemia, Apolipoprotein B deficiency) |
| Lipodystrophy | Barraquer-Simons syndrome |
| Fatty acid metabolism deficiency | transport: Carnitine (Primary, I, II, -acylcarnitine) - Adrenoleukodystrophy
beta oxidation: Acyl CoA dehydrogenase (Short-chain, Medium-chain, Long-chain 3-hydroxy, Very long-chain) - Mitochondrial trifunctional protein deficiency to acetyl-CoA: Malonic aciduria |
| Cholesterol synthesis | Smith-Lemli-Opitz syndrome |
| Other | Sjögren-Larsson syndrome - Lipomatosis - Adiposis dolorosa |
| see also lipid metabolism enzymes, lipoprotein metabolism | |
Heme metabolism disorders (E80, 277.1, 277.4) | |
|---|---|
| Porphyrin | Hepatic porphyria: Acute intermittent - Cutanea tarda/Hepatoerythropoietic - Hereditary copro- - Variegate Erythropoietic: Gunther's |
| Hereditary hyperbilirubinemia | Unconjugated: Lucey-Driscoll syndrome - Gilbert's syndrome - Crigler-Najjar syndrome Conjugated: Dubin-Johnson syndrome - Rotor syndrome |
| see also porphyrin metabolism enzymes, intermediates | |
Inborn errors of purine-pyrimidine metabolism (E79, 277.2) | |||||||
|---|---|---|---|---|---|---|---|
| Purine metabolism |
| ||||||
| Pyrimidine metabolism |
| ||||||
| see also nucleotide metabolism, intermediates | |||||||
Other Metabolic pathology / Inborn error of metabolism (E70-90, 270-279) | |
|---|---|
| Other | Alpha 1-antitrypsin deficiency - Cystic fibrosis - Amyloidosis (Familial Mediterranean fever) - Acatalasia |
WikiDoc Research Resources for Inborn error of metabolism | |
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| Articles on Inborn error of metabolism | Most recent articles on Inborn error of metabolism • Most cited articles on Inborn error of metabolism • Review articles on Inborn error of metabolism • Articles on Inborn error of metabolism in N Eng J Med, Lancet, BMJ |
| Media (Slides, Video, Images, MP3) on Inborn error of metabolism | Powerpoint slides on Inborn error of metabolism • Images of Inborn error of metabolism • Photos of Inborn error of metabolism • Podcasts & MP3s on Inborn error of metabolism • Videos on Inborn error of metabolism |
| Evidence Based Medicine Regarding Inborn error of metabolism | Cochrane Collaboration on Inborn error of metabolism • Bandolier on Inborn error of metabolism • TRIP on Inborn error of metabolism |
| Cost Effectiveness of Inborn error of metabolism | Cost Effectiveness of Inborn error of metabolism |
| Clinical Trials Involving Inborn error of metabolism | Ongoing Trials on Inborn error of metabolism at Clinical Trials.gov • Trial results on Inborn error of metabolism • Clinical Trials on Inborn error of metabolism at Google |
| Guidelines / Policies / Government Resources (FDA/CDC) Regarding Inborn error of metabolism | US National Guidelines Clearinghouse on Inborn error of metabolism • NICE Guidance on Inborn error of metabolism • NHS PRODIGY Guidance • FDA on Inborn error of metabolism • CDC on Inborn error of metabolism |
| Textbook Information on Inborn error of metabolism | Books and Textbook Information on Inborn error of metabolism |
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| Genetics, Pharmacogenomics, and Proteinomics of Inborn error of metabolism | Genetics of Inborn error of metabolism • Pharmacogenomics of Inborn error of metabolism • Proteomics of Inborn error of metabolism |
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| Healthcare Provider Resources on Inborn error of metabolism | Symptoms of Inborn error of metabolism • Causes & Risk Factors for Inborn error of metabolism • Diagnostic studies for Inborn error of metabolism • Treatment of Inborn error of metabolism |
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Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
